WO2014146044A1 - Administration of nicotinamide mononucleotide in the treatment of disease - Google Patents
Administration of nicotinamide mononucleotide in the treatment of disease Download PDFInfo
- Publication number
- WO2014146044A1 WO2014146044A1 PCT/US2014/030920 US2014030920W WO2014146044A1 WO 2014146044 A1 WO2014146044 A1 WO 2014146044A1 US 2014030920 W US2014030920 W US 2014030920W WO 2014146044 A1 WO2014146044 A1 WO 2014146044A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- nmn
- accordance
- per day
- body weight
- administered
- Prior art date
Links
- DAYLJWODMCOQEW-TURQNECASA-O NMN(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(O)=O)O2)O)=C1 DAYLJWODMCOQEW-TURQNECASA-O 0.000 title claims abstract 436
- 238000011282 treatment Methods 0.000 title claims description 144
- 201000010099 disease Diseases 0.000 title abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 665
- 239000000203 mixture Substances 0.000 claims abstract description 249
- 210000004369 blood Anatomy 0.000 claims abstract description 35
- 239000008280 blood Substances 0.000 claims abstract description 35
- 230000007423 decrease Effects 0.000 claims abstract description 32
- 208000002780 macular degeneration Diseases 0.000 claims abstract description 25
- 230000006870 function Effects 0.000 claims abstract description 22
- 150000002632 lipids Chemical class 0.000 claims abstract description 18
- 206010022489 Insulin Resistance Diseases 0.000 claims abstract description 17
- 230000006386 memory function Effects 0.000 claims abstract description 15
- 208000008589 Obesity Diseases 0.000 claims abstract description 11
- 235000020824 obesity Nutrition 0.000 claims abstract description 11
- 230000037396 body weight Effects 0.000 claims description 266
- 238000009472 formulation Methods 0.000 claims description 164
- 239000007788 liquid Substances 0.000 claims description 124
- 239000007864 aqueous solution Substances 0.000 claims description 122
- 239000007900 aqueous suspension Substances 0.000 claims description 122
- 239000003826 tablet Substances 0.000 claims description 67
- 239000000243 solution Substances 0.000 claims description 66
- 239000000839 emulsion Substances 0.000 claims description 64
- 239000007903 gelatin capsule Substances 0.000 claims description 64
- 239000000725 suspension Substances 0.000 claims description 63
- 239000006188 syrup Substances 0.000 claims description 63
- 235000020357 syrup Nutrition 0.000 claims description 63
- 239000012931 lyophilized formulation Substances 0.000 claims description 61
- 230000002207 retinal effect Effects 0.000 claims description 55
- 230000001594 aberrant effect Effects 0.000 claims description 42
- 241000124008 Mammalia Species 0.000 claims description 40
- 108091008695 photoreceptors Proteins 0.000 claims description 40
- 239000003814 drug Substances 0.000 claims description 38
- 239000002775 capsule Substances 0.000 claims description 37
- 201000007737 Retinal degeneration Diseases 0.000 claims description 35
- 229940023488 pill Drugs 0.000 claims description 35
- 239000006187 pill Substances 0.000 claims description 35
- 239000000843 powder Substances 0.000 claims description 35
- 230000004258 retinal degeneration Effects 0.000 claims description 35
- 239000008187 granular material Substances 0.000 claims description 34
- 230000001965 increasing effect Effects 0.000 claims description 34
- 239000007894 caplet Substances 0.000 claims description 32
- 239000007910 chewable tablet Substances 0.000 claims description 32
- 229940068682 chewable tablet Drugs 0.000 claims description 32
- 239000007938 effervescent tablet Substances 0.000 claims description 32
- 230000035755 proliferation Effects 0.000 claims description 32
- 238000001990 intravenous administration Methods 0.000 claims description 31
- 230000007850 degeneration Effects 0.000 claims description 24
- 201000004569 Blindness Diseases 0.000 claims description 23
- 230000004393 visual impairment Effects 0.000 claims description 22
- 230000004243 retinal function Effects 0.000 claims description 20
- 230000006378 damage Effects 0.000 claims description 16
- 210000001178 neural stem cell Anatomy 0.000 claims description 15
- 201000003533 Leber congenital amaurosis Diseases 0.000 claims description 14
- 210000000130 stem cell Anatomy 0.000 claims description 14
- 208000007014 Retinitis pigmentosa Diseases 0.000 claims description 13
- 230000037182 bone density Effects 0.000 claims description 12
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 11
- 206010013774 Dry eye Diseases 0.000 claims description 9
- 230000007547 defect Effects 0.000 claims description 9
- 230000006735 deficit Effects 0.000 claims description 9
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 7
- 201000006754 cone-rod dystrophy Diseases 0.000 claims description 7
- 230000007812 deficiency Effects 0.000 claims description 7
- 208000001132 Osteoporosis Diseases 0.000 claims description 6
- 208000034461 Progressive cone dystrophy Diseases 0.000 claims description 6
- 206010038848 Retinal detachment Diseases 0.000 claims description 6
- 201000008615 cone dystrophy Diseases 0.000 claims description 6
- 230000004264 retinal detachment Effects 0.000 claims description 6
- 208000036443 AIPL1-related retinopathy Diseases 0.000 claims description 5
- 208000029725 Metabolic bone disease Diseases 0.000 claims description 3
- 230000001737 promoting effect Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 34
- 230000000116 mitigating effect Effects 0.000 abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- DAYLJWODMCOQEW-TURQNECASA-N NMN zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)([O-])=O)O2)O)=C1 DAYLJWODMCOQEW-TURQNECASA-N 0.000 description 446
- 241000699670 Mus sp. Species 0.000 description 152
- 108010064862 Nicotinamide phosphoribosyltransferase Proteins 0.000 description 140
- 102100033223 Nicotinamide phosphoribosyltransferase Human genes 0.000 description 122
- 210000004027 cell Anatomy 0.000 description 115
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 66
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 44
- 229950006238 nadide Drugs 0.000 description 43
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 43
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 41
- 230000000694 effects Effects 0.000 description 40
- -1 copper amino acid Chemical class 0.000 description 37
- 239000007924 injection Substances 0.000 description 35
- 238000002347 injection Methods 0.000 description 35
- 229960001603 tamoxifen Drugs 0.000 description 33
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 28
- 239000003795 chemical substances by application Substances 0.000 description 27
- 238000011002 quantification Methods 0.000 description 27
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 26
- 238000012360 testing method Methods 0.000 description 26
- 230000004069 differentiation Effects 0.000 description 25
- 210000002569 neuron Anatomy 0.000 description 25
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 23
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 23
- 239000008103 glucose Substances 0.000 description 23
- 229940002612 prodrug Drugs 0.000 description 23
- 239000000651 prodrug Substances 0.000 description 23
- 150000001875 compounds Chemical class 0.000 description 22
- 230000002708 enhancing effect Effects 0.000 description 22
- 210000004248 oligodendroglia Anatomy 0.000 description 21
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 20
- 108010088225 Nestin Proteins 0.000 description 20
- 102000008730 Nestin Human genes 0.000 description 20
- 210000005055 nestin Anatomy 0.000 description 20
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 19
- 238000004458 analytical method Methods 0.000 description 19
- 210000001947 dentate gyrus Anatomy 0.000 description 19
- 235000009200 high fat diet Nutrition 0.000 description 19
- 150000003839 salts Chemical class 0.000 description 19
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 18
- 102000015532 Nicotinamide phosphoribosyltransferase Human genes 0.000 description 18
- 230000014509 gene expression Effects 0.000 description 18
- 239000000546 pharmaceutical excipient Substances 0.000 description 18
- 101150057182 GFAP gene Proteins 0.000 description 16
- 238000004090 dissolution Methods 0.000 description 16
- 239000003651 drinking water Substances 0.000 description 16
- 235000020188 drinking water Nutrition 0.000 description 16
- 239000005090 green fluorescent protein Substances 0.000 description 16
- 238000001727 in vivo Methods 0.000 description 16
- 101100247004 Rattus norvegicus Qsox1 gene Proteins 0.000 description 15
- 238000000338 in vitro Methods 0.000 description 15
- 229960003966 nicotinamide Drugs 0.000 description 15
- 235000005152 nicotinamide Nutrition 0.000 description 15
- 239000011570 nicotinamide Substances 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 239000011324 bead Substances 0.000 description 14
- 230000008045 co-localization Effects 0.000 description 14
- 239000011248 coating agent Substances 0.000 description 14
- 238000000576 coating method Methods 0.000 description 14
- 230000000971 hippocampal effect Effects 0.000 description 14
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 14
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 14
- 230000003247 decreasing effect Effects 0.000 description 13
- 235000021588 free fatty acids Nutrition 0.000 description 13
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 12
- 210000000877 corpus callosum Anatomy 0.000 description 12
- 238000012217 deletion Methods 0.000 description 12
- 230000037430 deletion Effects 0.000 description 12
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 12
- 210000001320 hippocampus Anatomy 0.000 description 12
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 12
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 12
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 12
- 101001092197 Homo sapiens RNA binding protein fox-1 homolog 3 Proteins 0.000 description 11
- 102100035530 RNA binding protein fox-1 homolog 3 Human genes 0.000 description 11
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 11
- 229920001223 polyethylene glycol Polymers 0.000 description 11
- 230000004044 response Effects 0.000 description 11
- 241000701161 unidentified adenovirus Species 0.000 description 11
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 10
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 10
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 10
- 230000030833 cell death Effects 0.000 description 10
- 235000014113 dietary fatty acids Nutrition 0.000 description 10
- 239000003623 enhancer Substances 0.000 description 10
- 229930195729 fatty acid Natural products 0.000 description 10
- 239000000194 fatty acid Substances 0.000 description 10
- 235000001055 magnesium Nutrition 0.000 description 10
- 229910052749 magnesium Inorganic materials 0.000 description 10
- 239000011777 magnesium Substances 0.000 description 10
- 229940091250 magnesium supplement Drugs 0.000 description 10
- 230000001404 mediated effect Effects 0.000 description 10
- 102000003952 Caspase 3 Human genes 0.000 description 9
- 108090000397 Caspase 3 Proteins 0.000 description 9
- DSRJIHMZAQEUJV-UHFFFAOYSA-N Cuprizon Chemical compound C1CCCCC1=NNC(=O)C(=O)NN=C1CCCCC1 DSRJIHMZAQEUJV-UHFFFAOYSA-N 0.000 description 9
- 102000000477 Sirtuin 2 Human genes 0.000 description 9
- 108010041216 Sirtuin 2 Proteins 0.000 description 9
- 230000032683 aging Effects 0.000 description 9
- 230000003750 conditioning effect Effects 0.000 description 9
- 230000001276 controlling effect Effects 0.000 description 9
- 238000002571 electroretinography Methods 0.000 description 9
- 238000013265 extended release Methods 0.000 description 9
- 210000001508 eye Anatomy 0.000 description 9
- 230000036541 health Effects 0.000 description 9
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 9
- 238000003119 immunoblot Methods 0.000 description 9
- 239000003550 marker Substances 0.000 description 9
- 210000001525 retina Anatomy 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 231100000419 toxicity Toxicity 0.000 description 9
- 230000001988 toxicity Effects 0.000 description 9
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 8
- 229920002785 Croscarmellose sodium Polymers 0.000 description 8
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 8
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 8
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 8
- 229930006000 Sucrose Natural products 0.000 description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 8
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 230000036765 blood level Effects 0.000 description 8
- 210000004556 brain Anatomy 0.000 description 8
- 239000013522 chelant Substances 0.000 description 8
- 229960001681 croscarmellose sodium Drugs 0.000 description 8
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000010166 immunofluorescence Methods 0.000 description 8
- 230000003993 interaction Effects 0.000 description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 8
- 239000008108 microcrystalline cellulose Substances 0.000 description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 description 8
- 210000000535 oligodendrocyte precursor cell Anatomy 0.000 description 8
- 239000000600 sorbitol Substances 0.000 description 8
- 239000005720 sucrose Substances 0.000 description 8
- 150000003626 triacylglycerols Chemical class 0.000 description 8
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 235000021355 Stearic acid Nutrition 0.000 description 7
- 239000008139 complexing agent Substances 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 7
- 235000013305 food Nutrition 0.000 description 7
- 230000008014 freezing Effects 0.000 description 7
- 238000007710 freezing Methods 0.000 description 7
- 238000002493 microarray Methods 0.000 description 7
- 235000001968 nicotinic acid Nutrition 0.000 description 7
- 229960003512 nicotinic acid Drugs 0.000 description 7
- 239000011664 nicotinic acid Substances 0.000 description 7
- 235000015097 nutrients Nutrition 0.000 description 7
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 7
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 7
- 230000002062 proliferating effect Effects 0.000 description 7
- 239000008117 stearic acid Substances 0.000 description 7
- 230000004489 tear production Effects 0.000 description 7
- 229940088594 vitamin Drugs 0.000 description 7
- 229930003231 vitamin Natural products 0.000 description 7
- 235000013343 vitamin Nutrition 0.000 description 7
- 239000011782 vitamin Substances 0.000 description 7
- 150000003722 vitamin derivatives Chemical class 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 108010051219 Cre recombinase Proteins 0.000 description 6
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 6
- JEVVKJMRZMXFBT-XWDZUXABSA-N Lycophyll Natural products OC/C(=C/CC/C(=C\C=C\C(=C/C=C/C(=C\C=C\C=C(/C=C/C=C(\C=C\C=C(/CC/C=C(/CO)\C)\C)/C)\C)/C)\C)/C)/C JEVVKJMRZMXFBT-XWDZUXABSA-N 0.000 description 6
- 229930195725 Mannitol Natural products 0.000 description 6
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 239000001506 calcium phosphate Substances 0.000 description 6
- 239000011651 chromium Substances 0.000 description 6
- 229940107218 chromium Drugs 0.000 description 6
- 229910052804 chromium Inorganic materials 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 6
- 239000010949 copper Substances 0.000 description 6
- 229940108928 copper Drugs 0.000 description 6
- 229910052802 copper Inorganic materials 0.000 description 6
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 6
- 229940038472 dicalcium phosphate Drugs 0.000 description 6
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 229960000304 folic acid Drugs 0.000 description 6
- 235000019152 folic acid Nutrition 0.000 description 6
- 239000011724 folic acid Substances 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 229940125396 insulin Drugs 0.000 description 6
- 235000019136 lipoic acid Nutrition 0.000 description 6
- 235000012680 lutein Nutrition 0.000 description 6
- 229960005375 lutein Drugs 0.000 description 6
- 239000001656 lutein Substances 0.000 description 6
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 description 6
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 description 6
- 235000012661 lycopene Nutrition 0.000 description 6
- 229960004999 lycopene Drugs 0.000 description 6
- 239000001751 lycopene Substances 0.000 description 6
- OAIJSZIZWZSQBC-GYZMGTAESA-N lycopene Chemical compound CC(C)=CCC\C(C)=C\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C=C(/C)CCC=C(C)C OAIJSZIZWZSQBC-GYZMGTAESA-N 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000000594 mannitol Substances 0.000 description 6
- 235000010355 mannitol Nutrition 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 238000001543 one-way ANOVA Methods 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 229960002477 riboflavin Drugs 0.000 description 6
- 239000011669 selenium Substances 0.000 description 6
- 229910052711 selenium Inorganic materials 0.000 description 6
- 229940091258 selenium supplement Drugs 0.000 description 6
- 230000009469 supplementation Effects 0.000 description 6
- 238000013268 sustained release Methods 0.000 description 6
- 239000012730 sustained-release form Substances 0.000 description 6
- 229960002663 thioctic acid Drugs 0.000 description 6
- ZCIHMQAPACOQHT-ZGMPDRQDSA-N trans-isorenieratene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/c1c(C)ccc(C)c1C)C=CC=C(/C)C=Cc2c(C)ccc(C)c2C ZCIHMQAPACOQHT-ZGMPDRQDSA-N 0.000 description 6
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 6
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 6
- 235000005282 vitamin D3 Nutrition 0.000 description 6
- 239000011647 vitamin D3 Substances 0.000 description 6
- 229940011671 vitamin b6 Drugs 0.000 description 6
- 229940021056 vitamin d3 Drugs 0.000 description 6
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 6
- 229920000858 Cyclodextrin Polymers 0.000 description 5
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 102000011990 Sirtuin Human genes 0.000 description 5
- 108050002485 Sirtuin Proteins 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 230000002068 genetic effect Effects 0.000 description 5
- 238000003364 immunohistochemistry Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000007928 intraperitoneal injection Substances 0.000 description 5
- 238000011813 knockout mouse model Methods 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 230000001537 neural effect Effects 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 230000006798 recombination Effects 0.000 description 5
- 238000005215 recombination Methods 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 241000251468 Actinopterygii Species 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 4
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- 108050006400 Cyclin Proteins 0.000 description 4
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 4
- 101100447432 Danio rerio gapdh-2 gene Proteins 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 101150112014 Gapdh gene Proteins 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 102000014842 Multidrug resistance proteins Human genes 0.000 description 4
- 108050005144 Multidrug resistance proteins Proteins 0.000 description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 4
- 101150038994 PDGFRA gene Proteins 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- 229940049937 Pgp inhibitor Drugs 0.000 description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 description 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 229930003779 Vitamin B12 Natural products 0.000 description 4
- 229930003471 Vitamin B2 Natural products 0.000 description 4
- 229930003268 Vitamin C Natural products 0.000 description 4
- 229930003427 Vitamin E Natural products 0.000 description 4
- 208000021017 Weight Gain Diseases 0.000 description 4
- 238000002679 ablation Methods 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 210000001130 astrocyte Anatomy 0.000 description 4
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 229960002685 biotin Drugs 0.000 description 4
- 235000020958 biotin Nutrition 0.000 description 4
- 239000011616 biotin Substances 0.000 description 4
- 239000004067 bulking agent Substances 0.000 description 4
- 230000003915 cell function Effects 0.000 description 4
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 4
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- ZQPPMHVWECSIRJ-MDZDMXLPSA-N elaidic acid Chemical compound CCCCCCCC\C=C\CCCCCCCC(O)=O ZQPPMHVWECSIRJ-MDZDMXLPSA-N 0.000 description 4
- 239000002532 enzyme inhibitor Substances 0.000 description 4
- 239000003889 eye drop Substances 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 4
- 239000002748 glycoprotein P inhibitor Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 238000010348 incorporation Methods 0.000 description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 208000015122 neurodegenerative disease Diseases 0.000 description 4
- 230000000324 neuroprotective effect Effects 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 230000036284 oxygen consumption Effects 0.000 description 4
- 235000019161 pantothenic acid Nutrition 0.000 description 4
- 239000011713 pantothenic acid Substances 0.000 description 4
- 229940055726 pantothenic acid Drugs 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 description 4
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- 238000010149 post-hoc-test Methods 0.000 description 4
- 239000012268 protein inhibitor Substances 0.000 description 4
- 229940121649 protein inhibitor Drugs 0.000 description 4
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 4
- 230000000241 respiratory effect Effects 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 235000019163 vitamin B12 Nutrition 0.000 description 4
- 239000011715 vitamin B12 Substances 0.000 description 4
- 235000019164 vitamin B2 Nutrition 0.000 description 4
- 239000011716 vitamin B2 Substances 0.000 description 4
- 235000019158 vitamin B6 Nutrition 0.000 description 4
- 239000011726 vitamin B6 Substances 0.000 description 4
- 235000019154 vitamin C Nutrition 0.000 description 4
- 239000011718 vitamin C Substances 0.000 description 4
- 229940046009 vitamin E Drugs 0.000 description 4
- 235000019165 vitamin E Nutrition 0.000 description 4
- 239000011709 vitamin E Substances 0.000 description 4
- 235000019786 weight gain Nutrition 0.000 description 4
- 235000016804 zinc Nutrition 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 3
- ULQISTXYYBZJSJ-UHFFFAOYSA-N 12-hydroxyoctadecanoic acid Chemical compound CCCCCCC(O)CCCCCCCCCCC(O)=O ULQISTXYYBZJSJ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- 102000016736 Cyclin Human genes 0.000 description 3
- 208000016192 Demyelinating disease Diseases 0.000 description 3
- 206010012305 Demyelination Diseases 0.000 description 3
- 229930091371 Fructose Natural products 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241000270322 Lepidosauria Species 0.000 description 3
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- 101150008755 PCNA gene Proteins 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 3
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 3
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 3
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000004900 autophagic degradation Effects 0.000 description 3
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 3
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000005754 cellular signaling Effects 0.000 description 3
- 229960000541 cetyl alcohol Drugs 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 235000011180 diphosphates Nutrition 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000009547 dual-energy X-ray absorptiometry Methods 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 230000004438 eyesight Effects 0.000 description 3
- 229930182830 galactose Natural products 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000007927 intramuscular injection Substances 0.000 description 3
- 238000010255 intramuscular injection Methods 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 230000001272 neurogenic effect Effects 0.000 description 3
- 229920002113 octoxynol Polymers 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 3
- 229920001515 polyalkylene glycol Polymers 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 229920001451 polypropylene glycol Polymers 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000003757 reverse transcription PCR Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007929 subcutaneous injection Substances 0.000 description 3
- 238000010254 subcutaneous injection Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 238000007492 two-way ANOVA Methods 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- SVENPFFEMUOOGK-SDNWHVSQSA-N (e)-2-cyano-3-[5-(2,5-dichlorophenyl)furan-2-yl]-n-quinolin-5-ylprop-2-enamide Chemical compound ClC1=CC=C(Cl)C(C=2OC(\C=C(/C#N)C(=O)NC=3C4=CC=CN=C4C=CC=3)=CC=2)=C1 SVENPFFEMUOOGK-SDNWHVSQSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 2
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 2
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 2
- 229920000178 Acrylic resin Polymers 0.000 description 2
- 239000004925 Acrylic resin Substances 0.000 description 2
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 2
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229920000856 Amylose Polymers 0.000 description 2
- 101100069026 Arabidopsis thaliana GK-2 gene Proteins 0.000 description 2
- 208000020084 Bone disease Diseases 0.000 description 2
- ONAIRGOTKJCYEY-XXDXYRHBSA-N CCCCCCCCCCCCCCCCCC(O)=O.O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 ONAIRGOTKJCYEY-XXDXYRHBSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 2
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 108700024394 Exon Proteins 0.000 description 2
- 239000001116 FEMA 4028 Substances 0.000 description 2
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 101000904152 Homo sapiens Transcription factor E2F1 Proteins 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 208000002720 Malnutrition Diseases 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- JLEBZPBDRKPWTD-TURQNECASA-O N-ribosylnicotinamide Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 JLEBZPBDRKPWTD-TURQNECASA-O 0.000 description 2
- 101150086808 NAMPT gene Proteins 0.000 description 2
- 206010067482 No adverse event Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920002562 Polyethylene Glycol 3350 Polymers 0.000 description 2
- 229920003080 Povidone K 25 Polymers 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 230000018199 S phase Effects 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 2
- 102100024026 Transcription factor E2F1 Human genes 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229960001456 adenosine triphosphate Drugs 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 2
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 230000003712 anti-aging effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 230000003376 axonal effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 2
- 229960002903 benzyl benzoate Drugs 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000008236 biological pathway Effects 0.000 description 2
- 238000004820 blood count Methods 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 2
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 2
- 239000001354 calcium citrate Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 210000003986 cell retinal photoreceptor Anatomy 0.000 description 2
- 210000003570 cell-matrix junction Anatomy 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 229920003086 cellulose ether Polymers 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 229960000913 crospovidone Drugs 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 235000000639 cyanocobalamin Nutrition 0.000 description 2
- 239000011666 cyanocobalamin Substances 0.000 description 2
- 229960002104 cyanocobalamin Drugs 0.000 description 2
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 description 2
- 229940068840 d-biotin Drugs 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 210000001650 focal adhesion Anatomy 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 229910021485 fumed silica Inorganic materials 0.000 description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 2
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 229940074076 glycerol formal Drugs 0.000 description 2
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 2
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 229920001477 hydrophilic polymer Polymers 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000012744 immunostaining Methods 0.000 description 2
- 150000002484 inorganic compounds Chemical class 0.000 description 2
- 229910010272 inorganic material Inorganic materials 0.000 description 2
- 210000003963 intermediate filament Anatomy 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000006193 liquid solution Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 230000001071 malnutrition Effects 0.000 description 2
- 235000000824 malnutrition Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 210000005060 membrane bound organelle Anatomy 0.000 description 2
- 229940041616 menthol Drugs 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 2
- 235000020956 nicotinamide riboside Nutrition 0.000 description 2
- 239000011618 nicotinamide riboside Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 208000015380 nutritional deficiency disease Diseases 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- YYZUSRORWSJGET-UHFFFAOYSA-N octanoic acid ethyl ester Natural products CCCCCCCC(=O)OCC YYZUSRORWSJGET-UHFFFAOYSA-N 0.000 description 2
- 201000005111 ocular hyperemia Diseases 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 150000002482 oligosaccharides Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical compound CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 description 2
- 239000003961 penetration enhancing agent Substances 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 230000037081 physical activity Effects 0.000 description 2
- 238000007747 plating Methods 0.000 description 2
- 229940044476 poloxamer 407 Drugs 0.000 description 2
- 229920001992 poloxamer 407 Polymers 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 description 2
- 229920000151 polyglycol Polymers 0.000 description 2
- 239000010695 polyglycol Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920000193 polymethacrylate Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 239000001508 potassium citrate Substances 0.000 description 2
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 2
- 235000008160 pyridoxine Nutrition 0.000 description 2
- 239000011677 pyridoxine Substances 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 210000003994 retinal ganglion cell Anatomy 0.000 description 2
- 235000019192 riboflavin Nutrition 0.000 description 2
- 239000002151 riboflavin Substances 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 231100000161 signs of toxicity Toxicity 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- 239000008137 solubility enhancer Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229940035044 sorbitan monolaurate Drugs 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 229960004274 stearic acid Drugs 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- 230000008093 supporting effect Effects 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 230000033772 system development Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 239000006068 taste-masking agent Substances 0.000 description 2
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 2
- ISXOBTBCNRIIQO-UHFFFAOYSA-N tetrahydrothiophene 1-oxide Chemical compound O=S1CCCC1 ISXOBTBCNRIIQO-UHFFFAOYSA-N 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- 229960004860 thiamine mononitrate Drugs 0.000 description 2
- 235000019191 thiamine mononitrate Nutrition 0.000 description 2
- 239000011748 thiamine mononitrate Substances 0.000 description 2
- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 description 2
- 210000000211 third ventricle Anatomy 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- 235000010215 titanium dioxide Nutrition 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 235000013337 tricalcium citrate Nutrition 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- 235000015870 tripotassium citrate Nutrition 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 230000004304 visual acuity Effects 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- UOXSXMSTSYWNMH-UHFFFAOYSA-L zinc;2-aminoacetate Chemical compound [Zn+2].NCC([O-])=O.NCC([O-])=O UOXSXMSTSYWNMH-UHFFFAOYSA-L 0.000 description 2
- WJTCHBVEUFDSIK-NWDGAFQWSA-N (2r,5s)-1-benzyl-2,5-dimethylpiperazine Chemical compound C[C@@H]1CN[C@@H](C)CN1CC1=CC=CC=C1 WJTCHBVEUFDSIK-NWDGAFQWSA-N 0.000 description 1
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- YUFFSWGQGVEMMI-JLNKQSITSA-N (7Z,10Z,13Z,16Z,19Z)-docosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCCC(O)=O YUFFSWGQGVEMMI-JLNKQSITSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- NDJNDUULNXNRQD-XKBRQERYSA-N 1-[(2r,4s,5s)-5-[bromo(hydroxy)methyl]-4-hydroxyoxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](C(Br)O)O[C@H]1N1C(=O)NC(=O)C=C1 NDJNDUULNXNRQD-XKBRQERYSA-N 0.000 description 1
- 229940114072 12-hydroxystearic acid Drugs 0.000 description 1
- KMZHZAAOEWVPSE-UHFFFAOYSA-N 2,3-dihydroxypropyl acetate Chemical compound CC(=O)OCC(O)CO KMZHZAAOEWVPSE-UHFFFAOYSA-N 0.000 description 1
- CTPDSKVQLSDPLC-UHFFFAOYSA-N 2-(oxolan-2-ylmethoxy)ethanol Chemical compound OCCOCC1CCCO1 CTPDSKVQLSDPLC-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- AUYYCJSJGJYCDS-UHFFFAOYSA-N 2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propanoic acid Chemical compound IC1=CC(CC(N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-UHFFFAOYSA-N 0.000 description 1
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 1
- BUOYTFVLNZIELF-UHFFFAOYSA-N 2-phenyl-1h-indole-4,6-dicarboximidamide Chemical compound N1C2=CC(C(=N)N)=CC(C(N)=N)=C2C=C1C1=CC=CC=C1 BUOYTFVLNZIELF-UHFFFAOYSA-N 0.000 description 1
- LAMQVIQMVKWXOC-UHFFFAOYSA-N 4-methyl-n-[2-[3-(morpholin-4-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]-2-pyridin-3-yl-1,3-thiazole-5-carboxamide Chemical compound CC=1N=C(C=2C=NC=CC=2)SC=1C(=O)NC1=CC=CC=C1C(N=C1SC=2)=CN1C=2CN1CCOCC1 LAMQVIQMVKWXOC-UHFFFAOYSA-N 0.000 description 1
- PWJFNRJRHXWEPT-UHFFFAOYSA-N ADP ribose Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OCC(O)C(O)C(O)C=O)C(O)C1O PWJFNRJRHXWEPT-UHFFFAOYSA-N 0.000 description 1
- SRNWOUGRCWSEMX-KEOHHSTQSA-N ADP-beta-D-ribose Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=2N=CN=C(C=2N=C1)N)OP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O SRNWOUGRCWSEMX-KEOHHSTQSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241001133760 Acoelorraphe Species 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 239000012114 Alexa Fluor 647 Substances 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 1
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 1
- 240000002791 Brassica napus Species 0.000 description 1
- 235000004977 Brassica sinapistrum Nutrition 0.000 description 1
- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- 244000020518 Carthamus tinctorius Species 0.000 description 1
- 235000003255 Carthamus tinctorius Nutrition 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 108010060273 Cyclin A2 Proteins 0.000 description 1
- 102100025191 Cyclin-A2 Human genes 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- ZAQJHHRNXZUBTE-NQXXGFSBSA-N D-ribulose Chemical compound OC[C@@H](O)[C@@H](O)C(=O)CO ZAQJHHRNXZUBTE-NQXXGFSBSA-N 0.000 description 1
- ZAQJHHRNXZUBTE-UHFFFAOYSA-N D-threo-2-Pentulose Natural products OCC(O)C(O)C(=O)CO ZAQJHHRNXZUBTE-UHFFFAOYSA-N 0.000 description 1
- ZAQJHHRNXZUBTE-WUJLRWPWSA-N D-xylulose Chemical compound OC[C@@H](O)[C@H](O)C(=O)CO ZAQJHHRNXZUBTE-WUJLRWPWSA-N 0.000 description 1
- 230000032515 DNA integrity checkpoint Effects 0.000 description 1
- 102000052510 DNA-Binding Proteins Human genes 0.000 description 1
- 108700020911 DNA-Binding Proteins Proteins 0.000 description 1
- 101150061941 Dcx gene Proteins 0.000 description 1
- 235000021294 Docosapentaenoic acid Nutrition 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000010156 Dunnett's T3 test Methods 0.000 description 1
- 102100021238 Dynamin-2 Human genes 0.000 description 1
- 102000057846 EC 2.1.-.- Human genes 0.000 description 1
- 108700033392 EC 2.1.-.- Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- URXZXNYJPAJJOQ-UHFFFAOYSA-N Erucic acid Natural products CCCCCCC=CCCCCCCCCCCCC(O)=O URXZXNYJPAJJOQ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 102100037854 G1/S-specific cyclin-E2 Human genes 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 239000004348 Glyceryl diacetate Substances 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- 108700014808 Homeobox Protein Nkx-2.2 Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000924577 Homo sapiens Adenomatous polyposis coli protein Proteins 0.000 description 1
- 101000817607 Homo sapiens Dynamin-2 Proteins 0.000 description 1
- 101000738575 Homo sapiens G1/S-specific cyclin-E2 Proteins 0.000 description 1
- 101000720704 Homo sapiens Neuronal migration protein doublecortin Proteins 0.000 description 1
- 101000891649 Homo sapiens Transcription elongation factor A protein-like 1 Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 240000006240 Linum usitatissimum Species 0.000 description 1
- 235000004431 Linum usitatissimum Nutrition 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 102000016397 Methyltransferase Human genes 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101100149887 Mus musculus Sox10 gene Proteins 0.000 description 1
- 102100031455 NAD-dependent protein deacetylase sirtuin-1 Human genes 0.000 description 1
- 102100030710 NAD-dependent protein deacetylase sirtuin-3, mitochondrial Human genes 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100025929 Neuronal migration protein doublecortin Human genes 0.000 description 1
- 101710112302 Nicotinamide/nicotinic acid mononucleotide adenylyltransferase Proteins 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010033546 Pallor Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 235000021319 Palmitoleic acid Nutrition 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 235000010678 Paulownia tomentosa Nutrition 0.000 description 1
- 240000002834 Paulownia tomentosa Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102100036691 Proliferating cell nuclear antigen Human genes 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 108010081734 Ribonucleoproteins Proteins 0.000 description 1
- 102000004389 Ribonucleoproteins Human genes 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 108091005770 SIRT3 Proteins 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 102000003838 Sialyltransferases Human genes 0.000 description 1
- 108090000141 Sialyltransferases Proteins 0.000 description 1
- 108010041191 Sirtuin 1 Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000016569 actin filament-based process Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000005529 alkyleneoxy group Chemical group 0.000 description 1
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-STGXQOJASA-N alpha-D-lyxopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-STGXQOJASA-N 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000009050 anatomical structure development Effects 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000003579 anti-obesity Effects 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000003140 astrocytic effect Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000003416 augmentation Effects 0.000 description 1
- 230000004009 axon guidance Effects 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229940007550 benzyl acetate Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000035289 cell-matrix adhesion Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- SECPZKHBENQXJG-UHFFFAOYSA-N cis-palmitoleic acid Natural products CCCCCCC=CCCCCCCCC(O)=O SECPZKHBENQXJG-UHFFFAOYSA-N 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002577 cryoprotective agent Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 230000005786 degenerative changes Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 150000004862 dioxolanes Chemical class 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 1
- 229940090949 docosahexaenoic acid Drugs 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000081 effect on glucose Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 1
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 1
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 108091008592 enzyme-linked receptors Proteins 0.000 description 1
- 102000027412 enzyme-linked receptors Human genes 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- DPUOLQHDNGRHBS-KTKRTIGZSA-N erucic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-KTKRTIGZSA-N 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 235000004426 flaxseed Nutrition 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 235000019443 glyceryl diacetate Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 150000002340 glycosyl compounds Chemical class 0.000 description 1
- 210000004565 granule cell Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000009643 growth defect Effects 0.000 description 1
- 108091005708 gustatory receptors Proteins 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 150000002386 heptoses Chemical class 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 229940051250 hexylene glycol Drugs 0.000 description 1
- 238000010842 high-capacity cDNA reverse transcription kit Methods 0.000 description 1
- 210000004295 hippocampal neuron Anatomy 0.000 description 1
- 230000003118 histopathologic effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 210000004692 intercellular junction Anatomy 0.000 description 1
- 230000016507 interphase Effects 0.000 description 1
- 230000016506 interphase of mitotic cell cycle Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 210000004561 lacrimal apparatus Anatomy 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- 230000004322 lipid homeostasis Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 230000006993 memory improvement Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 230000003847 mesoderm development Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 230000027291 mitotic cell cycle Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000017028 multicellular organismal development Effects 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- 229940094933 n-dodecane Drugs 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 230000032405 negative regulation of neuron apoptotic process Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000006764 neuronal dysfunction Effects 0.000 description 1
- 230000003955 neuronal function Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 229940101270 nicotinamide adenine dinucleotide (nad) Drugs 0.000 description 1
- 108010068475 nicotinic acid mononucleotide adenylyltransferase Proteins 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 210000003733 optic disk Anatomy 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 230000005305 organ development Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003906 phosphoinositides Chemical class 0.000 description 1
- 210000000608 photoreceptor cell Anatomy 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001522 polyglycol ester Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 230000024715 positive regulation of secretion Effects 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000007425 progressive decline Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 230000021014 regulation of cell growth Effects 0.000 description 1
- 230000016515 regulation of signal transduction Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- WBHHMMIMDMUBKC-QJWNTBNXSA-M ricinoleate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC([O-])=O WBHHMMIMDMUBKC-QJWNTBNXSA-M 0.000 description 1
- 229940066675 ricinoleate Drugs 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical group O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000021317 sensory perception Effects 0.000 description 1
- 239000010686 shark liver oil Substances 0.000 description 1
- 229940069764 shark liver oil Drugs 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 230000026676 system process Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003538 tetroses Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical class CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 150000003641 trioses Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- SCEZSEOTDXHAOD-UHFFFAOYSA-N tris(2,3-dihydroxypropyl) 2-hydroxypropane-1,2,3-tricarboxylate Chemical class OCC(O)COC(=O)CC(O)(C(=O)OCC(O)CO)CC(=O)OCC(O)CO SCEZSEOTDXHAOD-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000011870 unpaired t-test Methods 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- 239000011653 vitamin D2 Substances 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000011816 wild-type C57Bl6 mouse Methods 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/20—Animal model comprising regulated expression system
- A01K2217/206—Animal model comprising tissue-specific expression system, e.g. tissue specific expression of transgene, of Cre recombinase
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
Definitions
- Age-related obesity is a health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed.
- U.S. Patent 8,268,575 to Imai, S., et al. asserts that "Chemical effectors for mammalian NAD biosynthesis can mediate a variety of anti-aging effects including anti-obesity, neuroprotective, and pancreatic ⁇ cell-protective effects as well as be effective to treat cancers.”
- U.S. Patent 8,017,634 to Sinclair, D.A., et al. teaches treating a cell with "an agent that increases Nrk enzyme.”
- U.S. Patent Application Publication 2006/0229265 of Milburn, M., et al. discusses nicotinamide riboside and analogs thereof, including their use in methods of treating diseases or conditions, such as
- Example 7 of Milburn, M., et al. purports to describe testing of neuroprotective effects of nicotinamide riboside and nicotinamide mononucleotide on ganglion cell survival. None of these references teach or suggest oral administration of NMN.
- PCT Patent Application Publication WO2009062910 of Inufusa, H. states that an objective is to provide compositions effective in reducing blood triglyceride levels and/or cholesterol levels for the treatment and/or prophylaxis of hypertriglyceridemia, hypercholesterolemia and disease states induced thereby such as arteriosclerosis and obesity.
- this application does not disclose administering NMN for controlling age-related blood lipid increases.
- Age-related loss or decreases in memory function constitute another health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed. While U.S. Patent Application Publication 2006/0229265 of Milburn, M., et al. alleges, in Example 7, of "neuroprotective effects" of NMN, no data are presented. This application does not discuss using NMN to treat or prevent memory loss. U.S. Patent Application Publication 2006/0002914 of Milbrandt, J., et al. discloses administering an agent that acts by increasing NAD activity in diseased and/or injured neurons in the treatment of diseases such as Alzheimer's. There is no explicit teaching of administering NMN to improve memory function under normal aging conditions.
- Age-related dry eye constitutes another health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed. Dry eye is one of the most prevalent eye disorders, particularly among the elderly, and no fundamental treatments are yet available (Tsubota, K., et al. Cornea. 31 Suppl 1 : S l-8, 2012). Decrease in lacrimal gland secretory function might be a possible cause of age-associated dry eye diseases (Kawashima, M., et al. Biochem Biophys. Res. Commun. 397: 724-8, 2010).
- Age-related cognitive impairment constitutes another health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed.
- Aging is a negative regulator of adult neural stem and progenitor cell (NSPC) proliferation (Artegiani, B., et al.) While NSPC proliferation declines exponentially throughout life (Artegiani & Calegari, 2012), quiescent NSPCs can be reactivated in the aged murine hippocampus by multiple environmental stimuli (Decker et al, 2002; Jin et al, 2003; Lugert et al, 2010). Aging can reduce levels of the essential cofactor nicotinamide adenine dinucleotide (NAD+) in multiple peripheral tissues (Yoshino et al, 2011).
- NAD+ essential cofactor nicotinamide adenine dinucleotide
- Photoreceptor neuron dysfunction and cell death is the leading cause of blindness over the lifespan in humans.
- Photoreceptor neuron dysfunction constitutes another health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed.
- U.S. Patent 7,776,326 of Milbrandt, J., et al. discusses methods of treating or preventing axonal degradation in neuropathic diseases in mammals by administering an agent that can increase sirtuin activity in diseased/injured neuronal cells.
- the patent does not specify protection or treatment of rods and cones with NMN.
- This patent does not disclose administration of NMN to maintain NSPCs or promote oligodendrocyte proliferation.
- PCT Application PCT/IB2012/001146 of Alvarez, C.C., et al. discloses treating a mitochondrial dysfunction with a compound that increases intracellular nicotinamide adenine dinucleotide (NAD+) in an amount sufficient to activate SIRT1 or SIRT3.
- NAD+ nicotinamide adenine dinucleotide
- the application does not disclose administration of NMN to neuronal cells. This reference does not mention NSPCs.
- U.S. Patent 7,737, 158 of Imai, S., et al. discloses processes for regulating blood glucose concentration by administration of NMN.
- the patent does not teach administration of NMN to rod/cone-type photoreceptor neurons.
- This reference does not discuss administration of NMN to treat NSPCs or for age-related diseases or neurodegenerative diseases unrelated to glucose levels.
- NMN nicotinamide mononucleotide
- compositions comprising NMN.
- these compositions can further comprise one or more excipients.
- These compositions can be used for administration of NMN for the treatment, amelioration, mitigation, slowing, arrest, prevention and/ or reversal of age-associated degenerative changes.
- any of the dosages of the present teachings of nicotinamide mononucleotide (NMN), a salt thereof and/or a prodrug therof can be used to treat any of the diseases of the present teachings.
- the present teachings include a pharmaceutically acceptable composition comprising, consisting essentially of, or consisting of nicotinamide
- NTN mononucleotide
- salt thereof and/or a prodrug therof and at least one
- a pharmaceutically acceptable composition can, comprise, consist essentially of, or consist of a single dosage formulation.
- a single dosage formulations can be a sustained-release formulation.
- a pharmaceutically acceptable composition of the present teachings can be a formulation including a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a granule, a capsule, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension or solution, a non-aqueous suspension or solution, a lyophilized formulation, or a suppository.
- a pharmaceutically acceptable composition of the present teachings can be a single dosage formulation.
- a single dosage formulation can comprise an enteric coating.
- a pharmaceutically acceptable composition of the present teachings can comprise, consist essentially of, or consist of NMN, a salt thereof and/or a prodrug thereof in an amount of about lOOmg, from 100 mg to 2000 mg, about 2000 mg, or greater.
- a pharmaceutically acceptable composition of the present teachings can comprise, consist essentially of, or consist of NMN, a salt thereof and/or a prodrug thereof in an amount of about lOOmg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about lOOOmg, about HOOmg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, or greater.
- a pharmaceutically acceptable composition of the present teachings can comprise, consist essentially of, or consist of NMN, a salt thereof and/or a prodrug thereof in an amount of 50-150mg, 151-250mg, 251-350mg, 351-450mg, 451- 550mg, 561-650mg, 651-750mg, 751-860mg, 861-950mg, 951-1050mg, 1051-1150mg, 1151-1250mg, 1251-1350mg, 1351-1450mg, 1451-1550mg, 1551-1650mg, 1651-1750mg, 1751-1850mg, 1851-1950mg, 1951-2000mg, or greater.
- a pharmaceutically acceptable composition of the present teachings can comprise, consist essentially of, or consist of NMN, a salt thereof and/or a prodrug thereof in an amount of 50-150mg, 151-250mg, 251-350mg, 351-450mg, 451-
- composition of the present teachings can comprise, consist essentially of, or consist of NMN, a salt thereof and/or a prodrug thereof in an amount of at least 0.5 mg up to about 6800 mg, such as, without limitation, 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 680 mg, about 680 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, about
- a pharmaceutically acceptable composition of the present teachings can comprise a food product. In some embodiments, a pharmaceutically acceptable composition of the present teachings can comprise a composition suitable for oral
- administration sublingual administration, parenteral administration, administration by injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intraocular injection, direct ocular application (eye drop) or a combination thereof.
- a pharmaceutically acceptable composition of the present teachings can further comprise least one excipient.
- the at least one excipient can comprise a bulking agent, a tableting agent, a dissolution agent, a wetting agent, a lubricant, a coloring, a flavoring, a disintegrant, a coating, a binder, an antioxidant, a taste masking agent, a sweetener, or a combination thereof.
- a bulking agent can comprise mannitol, sorbitol, sucrose, trehalose, or a combination thereof.
- a pharmaceutically acceptable composition of the present teachings can be formulated as an orally disintegrating capsule, tablet, pill or wafer. In some embodiment, a pharmaceutically acceptable composition of the present teachings can be formulated as a liquid, syrup, or spray.
- a pharmaceutically acceptable composition of the present teachings can further comprise at least one vitamin or nutrient.
- a vitamin or nutrient can be vitamin C, vitamin D3, vitamin E, vitamin Bl, vitamin B2, niacin, vitamin B6, folic acid, vitamin B12, pantothenic acid, biotin, magnesium, zinc, copper, selenium, chromium, alpha lipoic acid, b co-enzyme Q-10, lutein, lycopene, or a combination thereof.
- a vitamin or nutrient can be an amount comprising 150 mg to about 750 mg of vitamin C, from about 315 IUs to about 1800 IUs of vitamin D3, from about 75 IUs to about 150 IUs of vitamin E, from about 15 mg to about 35 mg of vitamin Bl, from about 1.7 mg to about 5.1 mg of vitamin B2, from about 20 mg to about 50 mg of niacin, from about 20 mg to about 50 mg of vitamin B6, from about 0.5 mg to about 2.5 mg of folic acid, from about 35 meg to about 105 meg of vitamin B12, from about 2.5 mg to about 7.5 mg of pantothenic acid, from about 50 meg to about 450 meg of biotin, from about 15 mg to about 55 mg of magnesium, from about 15 mg to about 55 mg of zinc, from about 0.5 to about 1.5 mg of copper, from about 75 meg to about 175 meg of selenium, from about 75 meg to about 225 meg of chromium, from about 10 mg to about 40 mg of al
- a vitamin or nutrient can be about 500 mg of ascorbic acid, about 400 IUs of cholecalciferol, about 125 IUs of d-alpha tocopherol succinate, about 35 mg of thiamine mononitrate, about 5.1 mg of riboflavin, about 50 mg of niacinamide, about 50 mg of pyridoxine HC1, about 2.5 mg of folic acid, about 105 meg of cyanocobalamin, about 7.5 mg of d-calcium pantothenate, about 75 meg of d-biotin, about 55 mg of dimagnesium malate, about 55 mg of zinc bisglycinate chelate, about 1.5 mg of copper amino acid chelate, about 175 meg of selenium amino acid chelate, about 225 meg of chromium amino acid chelate, about 10 mg of alpha lipoic acid, about 50 mg of co-enzyme Q-10, about 400 meg of lutein, about 125 me
- an excipient of the present teachings can be dicalcium phosphate, microcrystalline cellulose, stearic acid, croscarmellose sodium, magnesium trisillicate, magnesium stearate, hydro xypropyl methylcellulose, hypromellose, titanium dioxide, tripotassium citrate, polyvinyl alcohol, fumed silica, citric acid, polyethylene glycol, talc, or a combination thereof.
- an excipient of the present teachings can be about 100 mg to about 300 mg of dicalcium phosphate, from about 25 mg to about 75 mg of microcrystalline cellulose, from about 10 mg to about 30 mg of stearic acid, from about 10 mg to about 30 mg of croscarmellose sodium, from about 5 mg to about 15 mg of magnesium trisillicate, from about 5 mg to about 15 mg of magnesium stearate, from about 5 mg to about 15 mg of hydro xypropyl methylcellulose, or a combination thereof.
- an excipient of the present teachings can be about 200 mg of dicalcium phosphate, about 50 mg of microcrystalline cellulose, about 20 mg of stearic acid, about 20 mg of croscarmellose sodium, about 10 mg of magnesium trisillicate, about 10 mg of magnesium stearate, about 10 mg of hydroxypropyl methylcellulose, or a combination thereof.
- a pharmaceutically acceptable composition of the present teachings can be a sustained release formulation of nicotinamide mononucleotide for oral administration.
- a sustained release formulation of nicotinamide mononucleotide for oral administration can comprise nicotinamide mononucleotide as an active ingredient that is released from the formulation along a pre-determined release profile, wherein the formulation comprises an extended release component and an immediate release component, wherein the extended release component is contained in at least one population of beads and releases nicotinamide mononucleotide in a continuous manner and each bead population is coated with its own release controlling coating and characterized by its own rate of release.
- an extended release component can release the nicotinamide mononucleotide in vivo in a continuous manner. In some embodiments, an extended release component can release the nicotinamide mononucleotide in vivo in a continuous manner and 80% of the nicotinamide mononucleotide can be released in vivo in a period of time selected from not more than 24 hours, not more than 16 hours, not more than 12 hours, not more than 8 hours or not more than 4 hours.
- an immediate release component of the present teachings can be an enhanced immediate release (EI ) composition comprising a complexing agent, an enhancing agent, or a combination.
- EI enhanced immediate release
- an EIR composition can exhibit an in vitro release profile such that 80% of the active ingredient is dissolved in not more than 30 min.
- an EIR composition can exhibit an in vitro release profile selected from a group consisting of: a) a dissolution of at least 50% of the active compound in not more than 10 minutes, b) a dissolution of at least 70% of the active compound in not more than 10 minutes, c) a dissolution of at least 25% of the active compound in not more than 5 minutes, d) a dissolution of at least 40% of the active compound in not more than 5 minutes, or e) a dissolution of at least 55% of the active compound in not more than 5 minutes.
- a pharmaceutically acceptable composition of the present teachings can include a complexing agent.
- a complexing agent can be hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, alpha- cyclodextrin, derivatives thereof, or a combination thereof.
- a pharmaceutically acceptable composition of the present teachings can include an enhancing agent.
- an enhancing agent can be a solubility enhancing agent, a dissolution enhancing agent, an absorption enhancing agent, a penetration enhancing agent, a surface active agent, a stabilizer, an enzyme inhibitor, a p- glycoprotein inhibitor, a multidrug resistance protein inhibitor, or a combination thereof.
- an enhancing agent can be Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins, glycerolpolyethylene glycol oxystearate, PEG-32 glyceryl palmitostearate, sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitan monolaurate, Poloxamer 407, PEG3350, PVP K25, oleic acid, glyceryl monooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, HPMC, substituted
- hydroxypropylcellulose microcrystalline cellulose sodium bicarbonate, calcium citrate, sodium docusate, menthol, or any combination thereof.
- a pharmaceutically acceptable composition of the present teachings can include at least a part of the active ingredient in a form of micronized particles.
- a micronized particle can have an average size of from about 2 ⁇ to about 100 ⁇ .
- a pharmaceutically acceptable composition of the present teachings can include a specific amount of each component determined according to the purpose of administration and the pre-determined release profile, and the total amount of NMN in the formulation is from 0.5 to 3000 mg.
- a population of beads of the present teachings can comprise an inert carrier, NMN, an optional enhancer, a release controlling coating that comprises a coating material, a pore former, an excipient, or a combination thereof.
- an inert carrier of the present teachings can be a cellulose sphere, silicon dioxide, starch, a sugar sphere, or a combination thereof.
- an enhancer can be a solubility enhancer, a dissolution enhancer, a permeability enhancer, a stabilizer, a complexing agent, an enzyme inhibitor, a p- glycoprotein inhibitor, a multidrug resistance protein inhibitor, or a combination thereof.
- a coating material of the present teachings can be any suitable material of the present teachings.
- ethylcellulose methylcellulose, hydro xypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylates,
- a pore former is selected from a group consisting of glucose, fructose, mannitol, mannose, galactose, sorbitol, puUulan, dextran, water-soluble hydrophilic polymers, hydro xyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross- linked polyvinylpyrrolidone, polyethylene oxide, Carbowaxes, Carbopol, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly(a-w)alkylenediols; inorganic compounds selected from a group consisting of alkali metal salts and alkaline earth metal salts, or combinations thereof.
- an amount of an individual bead population is determined according to a pre-determined release profile.
- a pre-determined release profile can comprise a sustained rate of release after an initial immediate release.
- a pharmaceutically acceptable composition of the present teachings can be suitable for once a day oral administration.
- a population of beads can comprise, consist essentially of, or consist of extended release NMN beads additionally comprising an immediate release component coated on top of the release controlling coating.
- a formulation of a pharmaceutically acceptable composition of the present teachings can comprise an enhancer contained in a layer separate from the release controlling coating.
- a formulation of a pharmaceutically acceptable composition of the present teachings can comprise at least one enhancing agent wherein the enhancing agent is incorporated into the formulation in the form of a powder or of a population of beads that are optionally characterized by a controlled rate of release, and wherein the enhancing agent is separated from the active ingredient.
- a composition of the present teachings can comprise nicotinamide mononucleotide (NMN), a pharmaceutical salt of NMN, or a prodrug of NMN.
- a salt can be a pharmaceutically acceptable salt; that is, a salt prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
- suitable non-toxic acids include inorganic and organic acids of basic residues such as amines, for example, acetic, benzenesulfonic, benzoic, amphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic,
- hydroxide magnesium hydroxide, zinc hydroxide, ammonia, trimethylammonia,
- Pharmaceutically acceptable salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
- NMN can be delivered in prodrug form.
- the present teachings are intended to cover prodrugs of NMN, methods of delivering the same and compositions containing them.
- a "prodrug” can include any covalently bonded carriers which release an active drug in vivo when such prodrug is administered to a mammalian subject.
- a prodrug can be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
- prodrugs include, without limitation, compounds of the present teachings wherein a hydroxyl or amino group can be bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino group, respectively.
- prodrugs include acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds and conjugates of the present teachings.
- Prodrugs of NMN can be, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present teachings.
- prodrugs can refer to compounds that can be transformed in vivo to yield NMN, for example by hydrolysis in blood.
- NMN can be dispersed in a pharmaceutically acceptable carrier prior to administration to a subject.
- a carrier also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, can be a substance that is pharmaceutically inert, can confer a suitable consistency or form to the composition, and does not diminish the efficacy of the NMN.
- a carrier can be considered to be
- pharmaceutically or pharmacologically acceptable if it does not lead to pharmaceutically unacceptable adverse, allergic or other untoward reactions when administered to a subject, including a mammalian subject.
- a pharmaceutically acceptable carrier can also, in part, be a function of the route of administration.
- suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (nasal, transdermal, ocular such as eyedrops, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional,
- Nonaqueous, pharmaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., a-glycerol formal, ⁇ -glycerol formal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such
- alcohols e.g., a-glycerol formal, ⁇ -glycerol formal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30 carbon atoms such as methanol
- polyoxyethylene-sorbitan monolaurate polyoxyethylene-sorbitan monostearate
- polyoxyethylated castor oil alkyl or aryl halides having 1-30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (Solutol® HS-15, from BASF,
- the present teachings include methods of treating,
- the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated obesity in a subject.
- the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated increases in blood lipid levels in a subject.
- the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age- associated loss of insulin sensitivity in a subject.
- the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age- associated impairment of memory function in a subject.
- the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated decline in eye function in a subject. In some embodiments, the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated retinal degeneration in a subject. In some embodiments, the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing dry eye. In some embodiments, the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age- associated dry eye.
- these methods can each independently comprise, consist essentially of, or consist of administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- NMN can be administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day.
- NMN can be administered at a dosage rate of of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, about 100 mg per day, 100 mg per day, 150 mg, about 150 mg, about 200 mg per day, 200 mg per day, about 300 mg per day, 300 mg per day, about 400 mg per day, 400 mg per day, about 500 mg per day, 500 mg per day, about 600 mg per day, 600 mg per day, about 700 mg per day, 700 mg per day, about 800 mg per day, 800 mg per day, about 900 mg per day, 900 mg per day, about 1000 mg per day, 1000 mg per day, 1000 mg per day, 1000 mg per day, about 1100 mg per day, 1100 mg per day, about 1200 mg per day
- NMN can be administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg/kg body weight/day to 500 mg/kg body weight/day, or about 500 mg/kg body weight/day. In some embodiments, NMN can be administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg/kg body weight/day to 300 mg/kg body weight/day, or about 300 mg/kg body weight/day. In some embodiments, these methods can comprise administering to a subject any of the pharmaceutically acceptable compositions of the present teachings. In some embodiments, these methods can comprise, consist essentially of or consist of administering a formulation once per day. In some embodiments, these methods can comprise, consist essentially of or consist of administering a formulation twice per day.
- the present teachings include methods of increasing NAD+ levels in a subject through administration of NMN. In some embodiments, the present teachings include methods of treating age-associated defects in neural stem/progenitor cell (NSPC) functionality in a subject through administration of NMN. In some embodiments, the present teachings include methods of reducing age-associated decrease in a NSPC population in a subject through administration of NMN. In some embodiments, the present teachings include methods of maintaining at least one NSPC in a subject through administration of NMN. In some embodiments, the present teachings include methods of enhancing NAD biosynthesis in a subject through administration of NMN.
- NSPC neural stem/progenitor cell
- the present teachings include methods of promoting NSPC proliferation in a subject, in which the methods comprise administration of NMN to the subject.
- the methods of each of these embodiments can comprise, consist essentially of, or consist of administration of a therapeutically effective amount of NMN.
- the present teachings include methods of increasing bone density levels in a subject. In some embodiments, the present teachings include methods of treating aberrantly low bone density levels in a subject. In some embodiments, the present teachings include methods of treating an age-associated bone density decrease in a subject. In some embodiments, the present teachings include methods of treating osteoporosis in a subject. In some embodiments, the present teachings include methods of preventing an age- associated bone density decrease in a subject. The methods of each of these embodiments can comprise, consist essentially of, or consist of administration of a therapeutically effective amount of NMN. In various embodiments, the inventors disclose that photoreceptor neuronal cell death and vision can be rescued by NMN administration.
- the present inventors demonstrate that nicotinamide phosphoribosyl transferase (NAMPT)-mediated NAD biosynthesis can play a role in for rod and/or cone PR neuron survival.
- NAMPT nicotinamide phosphoribosyl transferase
- the present inventors demonstrate that decreased NAD levels can cause impaired mitochondrial function in PR neurons, alterations in TCA cycle metabolites, and can lead to cell death and blindness.
- the inventors have demonstrated that deleting NAMPT can lead to photoreceptor death, loss of normal retinal structure and function, and vision loss. In some embodiments, the inventors have demonstrated that such damage to photoreceptor neurons and their function can be reversed with supplementation of nicotinamide
- NMN mononucleotide
- NAMPT NAMPT enzymatic reaction product
- the present teachings include NMN administration to restore NAD levels in the retina.
- NMN supplementation can be an effective therapeutic intervention for many retinal degenerative diseases. Without being limited by theory, NMN supplementation can restore retinal NAD levels.
- the present inventors have demonstrated in vivo using mouse models and in vitro using cell lines that photoreceptor death can be prevented by NMN supplementation.
- methods of NMN supplementation for the prevention/treatment of many retinal degenerative diseases are disclosed.
- the inventors disclose methods of preventing, methods of reducing risk of, and methods of treating various diseases associated with photoreceptor dysfunction, including, without limitation, age-related macular degeneration (AMD), inherited and acquired retinal diseases such as, without limitation, retinitis pigmentosa (RP), rod and cone dystrophism, and Leber's congenital amaurosis (LCA) by administration of NMN.
- AMD age-related macular degeneration
- RP retinitis pigmentosa
- LCA Leber's congenital amaurosis
- NMN administration can be an effective intervention for the prevention and/or treatment of orphan retinal degenerative diseases including but not limited to rod dystrophy, cone dystrophy, retinitis pigmentosa, other inherited retinal degenerations, Leber's congenital amaurosis (LCA) and acquired retinal degenerations such as, but not limited to, age-related macular dengeration photoreceptor degeneration following retinal detachment.
- NMN can be administered by any administration route known to skilled artisans, such as, without limitation, oral, parenteral, intraocular,
- NMN intraperitoneal, intravenous or intramuscular routes.
- NMN can be administered with or without an excipient.
- the present teachings include methods of treating macular degeneration in a subject. In some embodiments, the present teachings include methods of treating aberrant retinal NAD levels in a subject, including aberrantly low retinal NAD levels. In some embodiments, the present teachings include methods of treating retinal degeneration in a subject. In some embodiments, the present teachings include methods of treating photoreceptor damage in a subject. In some embodiments, the present teachings include methods of treating photoreceptor degeneration in a subject. In some embodiments, the present teachings include methods of treating vision loss associated with retinal degeneration in a subject. In some embodiments, the present teachings include methods of treating vision loss in a subject.
- the present teachings include methods of treating aberrant retinal structure in a subject. In some embodiments, the present teachings include methods of treating aberrant retinal function in a subject. In some embodiments, the present teachings include methods of treating aberrant retinal function in a subject. In some embodiments, the present teachings include methods of treating aberrant retinal function in a subject. In some embodiments, the present teachings include methods of increasing retinal NAD levels in a subject. In some embodiments, the present teachings include methods of reducing risk of developing macular degeneration in a subject. In some embodiments, the present teachings include methods of reducing risk of developing macular degeneration in a subject.
- the present teachings include methods of reducing risk of developing aberrant retinal NAD levels in a subject. In some embodiments, the present teachings include methods of reducing risk of developing retinal degeneration in a subject. In some embodiments, the present teachings include methods of reducing risk of developing photoreceptor damage/degeneration in a subject. In some embodiments, the present teachings include methods of reducing risk of developing vision loss associated with retinal
- the present teachings include methods of reducing risk of developing vision loss in a subject. In some embodiments, the present teachings include methods of reducing risk of developing aberrant retinal structure in a subject. In some embodiments, the present teachings include methods of reducing risk of developing aberrant retinal structure in a subject. In some embodiments, the present teachings include methods of reducing risk of developing aberrant retinal structure in a subject. In some embodiments, the present teachings include methods of reducing risk of developing aberrant retinal function in a subject. In some embodiments, the present teachings include methods of reducing risk of developing aberrant retinal function in a subject. In some embodiments, the present teachings include methods of treating a photoreceptor dysfunction in a subject. In some embodiments, the present teachings include methods of treating a retina disease in a subject.
- these methods can comprise, consist essentially of, or consist of administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- a pharmaceutically effective amount of nicotinamide mononucleotide (NMN) can be an amount effective for increasing retinal NAD levels.
- a retina disease that can be treated by administration of NMN can be retinitis pigmentosa (RP), Leber's congenital amaurosis (LCA), rod dystrophy, cone dystrophy, rod-cone dystrophy, cone-rod dystrophy, age-related macular degeneration, photoreceptor degeneration following retinal detachments, or a combination thereof.
- these methods can each independently comprise, consist essentially of, or consist of administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- NMN can be administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day.
- NMN can be administered at a dosage rate of of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, about 100 mg per day, 100 mg per day, 150 mg, about 150 mg, about 200 mg per day, 200 mg per day, about 300 mg per day, 300 mg per day, about 400 mg per day, 400 mg per day, about 500 mg per day, 500 mg per day, about 600 mg per day, 600 mg per day, about 700 mg per day, 700 mg per day, about 800 mg per day, 800 mg per day, about 900 mg per day, 900 mg per day, about 1000 mg per day, 1000 mg per day, 1000 mg per day, 1000 mg per day, about 1100 mg per day, 1100 mg per day, about 1200 mg per day
- NMN can be administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg/kg body weight/day to 500 mg/kg body weight/day, or about 500 mg/kg body weight/day. In some embodiments, NMN can be administered at a dosage rate of about 100 mg kg body weight/day, from 100 mg/kg body weight/day to 300 mg/kg body weight/day, or about 300 mg/kg body weight/day. In some embodiments, these methods can comprise administering to a subject any of the pharmaceutically acceptable compositions of the present teachings. In some embodiments, these methods can comprise, consist essentially of or consist of administering a formulation once per day.
- these methods can comprise, consist essentially of or consist of administering a formulation twice per day, three times per day, or four times per day. In some embodiments, these methods can comprise, consist essentially of or consist of administering a sustained-release formulation once, or at long intervals such as, without limitation, once per week, semi-weekly, or once per month.
- these methods can each independently comprise, consist essentially of, or consist of administering to a subject a pharmaceutically effective amount of a formulation comprising nicotinamide mononucleotide (NMN) such as, without limitation, a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a granule, a capsule, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension or solution, a non-aqueous suspension or solution, a lyophilized formulation, a suppository or a food product.
- these methods can each independently comprise, consist essentially of, or consist of administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide by oral administration,
- subcutaneous injection intramuscular injection, intraperitoneal injection, intra-ocular injection, direct ocular contact (eye drops) or a combination thereof.
- a subject can be a mammal.
- a subject can be a vertebrate, such as a mammal, a fish, a bird or a reptile.
- a mammal can be, without limitation, a human, a rodent, a canine, a feline, a bovine, an ovine, an equine or a porcine.
- a subject can be a bird such as a chicken, a reptile, a fish, or other aquatic organism.
- the present teachings include methods of augmentation of NAD+ levels during aging with NMN administration to maintain an NSPC pool, through administration of NMN.
- the present teachings include methods of enhancing NAD+ levels in NSPCs in a subject through administration of NMN, to preserve an endogenous NSPC population for the repair of aged, diseased, or damaged brain.
- the present teachings include the following non-limiting aspects.
- a pharmaceutically acceptable composition comprising, consisting essentially of, or consisting of: nicotinamide mononucleotide (NMN), a salt thereof and/or a prodrug therof; and
- At least one pharmaceutically acceptable excipient at least one pharmaceutically acceptable excipient.
- a pharmaceutically acceptable composition in accordance with aspect 1, comprising, consisting essentially of, or consisting of a single dosage formulation.
- composition in accordance with aspect 2, wherein the single dosage formulation comprises an enteric coating.
- a pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation comprises, consists essentially of, or consists of NMN, a salt thereof and/or a prodrug thereof in an amount of about lOOmg, from 100 mg to 2000 mg, or about 2000 mg.
- nicotinamide mononucleotide NPN
- a salt thereof NPN
- a prodrug therof in an amount selected from the group consisting of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 680 mg, about 680 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg,
- a pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation comprises a food product.
- a pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation is a food product.
- composition in accordance with aspect 1, wherein the composition is suitable for oral administration.
- composition in accordance with aspect 1, wherein the composition is suitable for sublingual administration.
- composition in accordance with aspect 1, wherein the composition is suitable for parenteral administration.
- composition in accordance with aspect 1, wherein the composition is suitable for administration by injection.
- composition in accordance with aspect 1, wherein the composition is suitable for administration by subcutaneous injection.
- composition in accordance with aspect 1, wherein the composition is suitable for administration by intramuscular injection.
- composition in accordance with aspect 1, wherein the composition is suitable for administration by intraperitoneal injection.
- composition in accordance with aspect 1, wherein the composition is suitable for administration by intra-ocular injection or topically to the eye (eye drops).
- compositions in accordance with aspect 1 wherein the composition is selected from the group consisting of a tablet, a pill, powder, granules, a capsule, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension or solution, a non-aqueous suspension or solution, a lyophilized formulation, and a suppository.
- the bulking agent is selected from the group consisting of mannitol, sorbitol, sucrose and trehalose.
- at least one vitamin or nutrient selected from the group consisting of vitamin C, vitamin D3, vitamin E, vitamin Bl, vitamin B2, niacin, vitamin B6, folic acid, vitamin B12, pantothenic acid, biotin, magnesium, zinc, copper, selenium, chromium, alpha lipoic acid, b co-enzyme Q-10, lutein and lycopene.
- microcrystalline cellulose stearic acid, croscarmellose sodium, magnesium trisillicate, magnesium stearate, hydro xypropyl methylcellulose, hypromellose, titanium dioxide, tripotassium citrate, polyvinyl alcohol, fumed silica, citric acid, polyethylene glycol, talc, and any combination thereof.
- a sustained release formulation of nicotinamide mononucleotide for oral administration to a subject comprising nicotinamide mononucleotide as an active ingredient that is released from the formulation along a pre-determined release profile, wherein the formulation comprises an extended release component and an immediate release component, wherein the extended release component is contained in at least one population of beads and releases nicotinamide mononucleotide in a continuous manner and each bead population is coated with its own release controlling coating and characterized by its own rate of release.
- the immediate release component is an enhanced immediate release (EI ) composition comprising a complexing agent, an enhancing agent, or both.
- EI enhanced immediate release
- the complexing agent is a cyclodextrin selected from a group consisting of hydro xypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma- cyclodextrin, alpha-cyclodextrin, and derivatives thereof.
- enhancing agent is selected from a group comprising solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizers, enzyme inhibitors, p- glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.
- the enhancing agent is selected from a group consisting of Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins, glycerolpolyethylene glycol oxystearate, PEG-32 glyceryl palmitostearate, sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitan monolaurate, Poloxamer 407, PEG3350, PVP K25, oleic acid, glyceryl monooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, HPMC, substituted hydro xypropylcellulose, micro
- the coating material is selected from a group consisting of ethylcellulose, methylcellulose, hydro xypropyl cellulose, hydro xypropylm ethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylates, polymethacrylates and copolymers thereof; and/or the pore former is selected from a group consisting of glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran, water-soluble hydrophilic polymers, hydro xyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross- linked polyvinylpyrrolidone, polyethylene oxide, Carbowaxes, Carbopol, diols, polyols, polyhydric alcohols, polyalkylene glycols, poly
- composition of aspect 32 additionally comprising at least one enhancing agent, wherein the enhancing agent is incorporated into the formulation in the form of a powder or of a population of beads that are optionally characterized by a controlled rate of release, and wherein the enhancing agent is separated from the active ingredient.
- a method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated obesity in a subject comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- NNN nicotinamide mononucleotide
- a method in accordance with aspect 53 comprising administering to a subject a formulation of any one of aspects 1-52.
- a method in accordance with aspect 76, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
- a method in accordance with aspect 76, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
- a method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated increases in blood lipid levels in a subject comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- NNN nicotinamide mononucleotide
- a method in accordance with aspect 79 comprising administering to a subject a formulation of any one of aspects 1-51.
- a method in accordance with aspect 102, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
- a method in accordance with aspect 102, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
- a method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age- associated loss of insulin sensitivity in a subject comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- NNN nicotinamide mononucleotide
- a method in accordance with aspect 105 comprising administering to a subject a formulation of any one of aspects 1- 1.
- a method in accordance with aspect 128, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
- a method in accordance with aspect 128, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
- a method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age- associated impairment of memory function in a subject comprising:
- NPN mononucleotide
- a method in accordance with aspect 131 comprising administering to a subject a formulation of any one of aspects 1-51.
- a method in accordance with aspect 154, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
- a method in accordance with aspect 154, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
- a method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age- associated decline in eye function in a subject comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- NNN nicotinamide mononucleotide
- a method in accordance with aspect 157 comprising administering to a subject a formulation of any one of aspects 1-51.
- a method in accordance with aspect 180, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
- a method in accordance with aspect 180, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
- a method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated retinal degeneration in a subject comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- NMN nicotinamide mononucleotide
- a method in accordance with aspect 206, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
- a method in accordance with aspect 206, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
- a method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing dry eye comprising administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- NMN nicotinamide mononucleotide
- a method in accordance with aspect 209 comprising administering to a subject a formulation of any one of aspects 1-52.
- a method in accordance with aspect 232, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
- a method in accordance with aspect 232, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
- a method of increasing NAD+ levels in a subject comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- a method of treating age-associated defects in NSPC functionality in a subject comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- a method of maintaining at least one NSPC in a subject comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- NNN nicotinamide mononucleotide
- a method of enhancing NAD biosynthesis in a subject comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- NNN nicotinamide mononucleotide
- a method of promoting NSPC proliferation in a subject comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- NPN nicotinamide mononucleotide
- a method in accordance with aspect 243, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
- a method in accordance with aspect 243, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
- a method of increasing bone density levels in a subject comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
- NNN nicotinamide mononucleotide
- a method of treating aberrantly low bone density levels in a subject comprising:
- NPN mononucleotide
- a method of treating an age-associated bone disorder in a subject comprising:
- NPN mononucleotide
- a method in accordance with aspect 253, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
- a method in accordance with aspect 253, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
- a method of treating macular degeneration in a subject comprising administering to a subject a therapeutically effective amount of NMN.
- a method of treating macular degeneration in a subject comprising administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of treating aberrant retinal NAD levels in a subject comprising administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of treating retinal degeneration in a subject comprising administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of treating retinal degeneration in a subject comprising administering to a subject a therapeutically effective amount of NMN.
- a method of treating photoreceptor damage/degeneration in a subject comprising administering to a subject a therapeutically effective amount of NMN.
- a method of treating photoreceptor damage/degeneration in a subject comprising administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of treating vision loss associated with retinal degeneration in a subject comprising: administering to a subject a therapeutically effective amount of NMN.
- a method of treating vision loss in a subject comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of treating aberrant retinal structure in a subject comprising: administering to a subject a therapeutically effective amount of NMN.
- a method of treating aberrant retinal structure in a subject comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of treating aberrant retinal function in a subject comprising: administering to a subject a therapeutically effective amount of NMN.
- a method of treating aberrant retinal function in a subject comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of increasing retinal NAD levels in a subject comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of reducing risk of developing macular degeneration in a subject comprising: administering to a subject NMN in an amount effective for preventing macular degeneration.
- a method of reducing risk of developing macular degeneration in a subject comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of reducing risk of developing aberrant retinal NAD levels in a subject comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of reducing risk of developing retinal degeneration in a subject comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of reducing risk of developing photoreceptor damage/degeneration in a subject comprising: administering to a subject NMN in an amount effective for preventing photoreceptor damage/degeneration.
- a method of reducing risk of developing photoreceptor damage/degeneration in a subject comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of reducing risk of developing vision loss associated with retinal degeneration in a subject comprising: administering to a subject NMN in an amount effective for reducing risk of developing vision loss associated with retinal degeneration.
- a method of reducing risk of developing vision loss in a subject comprising:
- administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of reducing risk of developing aberrant retinal structure in a subject comprising: administering to a subject NMN in an amount effective for preventing development of aberrant retinal structure.
- a method of reducing risk of developing aberrant retinal structure in a subject comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of reducing risk of developing aberrant retinal function in a subject comprising: administering to a subject NMN in an amount effective for preventing development of aberrant retinal function.
- a method of reducing risk of developing aberrant retinal function in a subject comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
- a method of treating a retina disease in a subject comprising: administering to a subject a therapeutically effective amount of NMN.
- RP retinitis pigmentosa
- LCA Leber's congenital amaurosis
- rod dystrophy cone dystrophy
- rod-cone dystrophy rod-cone dystrophy
- cone-rod dystrophy age-related macular degeneration
- age-related macular degeneration and photoreceptor degeneration following retinal detachment.
- a method in accordance with aspect 283, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
- a method in accordance with aspect 283, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
- FIG. 1 illustrates structure of nicotinamide mononucleotide (NMN).
- FIG. 2 illustrates age-associated body weight increase.
- FIG. 3 illustrates age-associated body weight gain
- FIG. 4 illustrates oxygen consumption in control, 100 and 300 mg/kg NMN-administered mice.
- FIG. 5 illustrates energy expenditure in control, 100 and 300 mg/kg NMN-administered mice.
- FIG. 6 illustrates respiratory quotient in control, 100 and 300 mg kg NMN-administered mice.
- FIG. 7 illustrates blood levels of (A) cholesterol, (B) triglycerides and (C) free fatty acids shown over 12 months in the control and the 100 and 300 mg/kg NMN-administered cohorts.
- FIG. 8 illustrates body weight-matched blood levels of (A) cholesterol, (B) triglycerides and (C) free fatty acids shown over 12 months in the control and the 100 and 300 mg/kg NMN- administered cohorts.
- FIG. 9 illustrates insulin tolerance shown in (A) blood glucose levels and (B) percent glucose changes in control and the 100 mg/kg and 300 mg/kg NMN-administered groups at the 12- month time point.
- FIG. 10 illustrates freezing responses of regular chow-fed control, HFD-fed, and HFD-fed, NMN-treated mice in contextual and cued fear conditioning tests on Day 1, Day 2 and Day3.
- FIG. 11 illustrates fundus biomicroscopy images from control and NMN-administered mice.
- FIG. 12 illustrates electroretino grams from control and NMN-administered mice.
- FIG. 13 illustrates tear production in 18 month-old control and NMN-administered mice. All values are presented as mean ⁇ SEM. **p ⁇ 0.01.
- FIG. 14 illustrates hippocampal NAD+ levels and Nampt expression declining with age.
- C-D Quantification of immunofluoresence for Nampt in the subgranular zone (SGZ). Measurement of thresholded levels of Nampt immunore activity (C) and the number of highly immunoreactive Nampt+ cells (D) along the SGZ. E)
- FIG. 15 illustrates that Nampt is expressed in a subpopulation of SGZ NSPCs.
- DG dentate gyrus
- G Representative images of immunofluorescence for Gfap (original blue), Dcx (original green), and BrdU (original red) in the subgranular zone (SGZ). Scale bar denotes 200 ⁇ .
- H To assess differentiation, control littermates and iNSPC-Nampt-KO mice were subjected to 4 total TAM injections (2 injections on the first day coupled with BrdU at 100 mg/kg body weight as well as 2 total injections on the subsequent 2 days).
- FIG. 17 illustrates that inhibition of Nampt in NSPCs in vitro impairs NAD+ biosynthesis and proliferation.
- Neurospheres were cultured with the Nampt-specific inhibitor FK866 (10 nM) with or without NMN (100 ⁇ ) for 48 hours.
- FK866 10 nM
- NMN 100 ⁇
- A) HPLC analysis of NAD+ levels (n 6).
- B) Quantification of the fold increase of cell number in neurospheres (n 6-30).
- FIG. 18 illustrates that genetic ablation of Nampt in NSPCs in vitro impairs NAD+ biosynthesis, proliferation, and differentiation.
- Neurospheres were isolated from Nampt ⁇ TM mice and infected with a Cre-recombinase expressing adenovirus (Nampt AD-Cre) or a control adenovirus expressing LacZ (Nampt AD-LacZ).
- A) HPLC analysis of NAD+ levels with and without NMN (100 ⁇ , 48 hours) (n 10-22).
- *, ⁇ , and # indicate statistical significance between Nampt AD-LacZ and Nampt AD-Cre, Nampt AD- LacZ and Nampt AD-LacZ +NMN, and Nampt AD-Cre and Nampt AD-Cre+NMN, respectively. Data are presented as mean ⁇ s.e.m. *P ⁇ 0.05. **P ⁇ 0.01. ***p ⁇ 0.001.
- FIG. 19 illustrates that genetic ablation of Nampt in vitro impairs OPC formation.
- A A scheme for oligodendrocyte differentiation with stage-specific markers.
- B-C Neurospheres were infected with a Cre recombinase-expressing adenovirus (Nampt AD-Cre) or a control adenovirus expressing LacZ (Nampt AD-LacZ). To assess oligodendrocyte formation, dissociated neurospheres were harvested after 6-7 days of differentiation (B). To assess OPC formation, dissociated neurospheres were examined after 2 days of differentiation (C).
- NSPCs Gfap, Nestin
- OPCs Pdgfra+
- oligodendrocyte lineage cells 01ig2+, 04+
- D Treatment of dissociated neurospheres with the selective inhibitor of Sirtl, EX527 (80 ⁇ ) or the selective inhibitor of Sirt2, AGK2 (10 ⁇ ).
- E-G Knockout and control neurospheres were formed by infecting with a Cre- recombinase expressing adenovirus or a control adenovirus expressing LacZ, respectively.
- E) Neurospheres were isolated from Sirtl ⁇ mice and Sirtl - /?OJc/ ⁇ ;Sirt2-/- mice. The formation of oligodendrocytes was evaluated after 6-7 days of differentiation (n 3-l 1 independent samples, 12-28 fields of view).
- F-G Neurospheres were isolated from
- FIG. 20 illustrates adult NSPC-specific deletion of Nampt impairs NSPC self-renewal and differentiation in response to insult-induced demyelination in vivo.
- Nampt in the adult Nestin+ population was induced by 5 tamoxifen (TAM) injections at 180 mg kg body weight per day the week before starting the cuprizone diet.
- FIG. 21 illustrates a model for the role of Nampt-mediated NAD biosynthesis in NSPCs.
- Nampt-mediated NAD+ biosynthesis promotes NSPC self-renewal, proliferation and differentiation into oligodendrocytes. While the mechanism by which Nampt promotes self- renewal and proliferation remains unidentified, Nampt-mediated NAD+ biosynthesis activates Sirtl and Sirt2 to promote NSPC oligodendrocyte lineage fate decisions by a mechanism involving transcriptional downregulation of Pdgfra, SoxlO, and Nkx2.2 and transcriptional upregulation of p21 icdknld). Sirtl and Sirt2 may act via an effect on 01ig2 activity. See text for a detailed discussion.
- FIG. 22 illustrates Nampt expressed in a subpopulation of SGZ NSPCs.
- FIG. 23 illustrates that adult NSPC-specific deletion of Nampt impairs NSPC proliferation and self-renewal in vivo.
- A-F iNSPC-Nampt-KO and littermate control (iNSPC-GFP) mice were injected with tamoxifen (TAM) or vehicle (5 total injections, 1 injection per day).
- A-B Representative images of immunofluorescence for Dapi (blue), activated caspase 3 (red), and NestinGFP (green) in the indicated brain regions at 28 (A) or 3 (B) days post TAM injection. Arrows highlight the rare activated caspase 3+ cells observed. Scale bars denote 50 ⁇ .
- C) Recombination-confirmatory PCR performed on hippocampal DNA from TAM treated iNSPC-Nampt-KO (KO) and control mice (n 7-8).
- E) Quantification of the percentages of NestinGFP-positive cells that also express Nampt in iNSPC-Nampt-KO and iNSPC-GFP mice in the DG at the indicated days post initial TAM injection (n more than 350 cells from 7 mice).
- H-I Mice were administered NMN (100 or 300 mg/kg body weight) in their drinking water from 6 to 18 months of age.
- FIG. 24 illustrates that inhibition of Nampt in NSPCs impairs NAD+ biosynthesis and proliferation in vitro.
- Neurospheres were cultured with the Nampt-specific inhibitor FK866 (10 iiM) with or without NMN (100 ⁇ ) for 24 (A-B) or 48 hours (C-G).
- FK866 10 iiM
- A-B HPLC analysis of NAD+ levels
- C A representative immunoblot of FK866-treated neurospheres.
- F-G Top 50 biological pathways downregulated (F) or upregulated (G) by FK866.
- FIG. 25 illustrates genetic ablation of Nampt in NSPCs in vitro impairs NAD+ biosynthesis, proliferation, and differentiation.
- A-G Neurospheres were isolated from Namptflox/flox mice and infected with a Cre-recombinase expressing adenovirus (Nampt AD-Cre) or a control adenovirus expressing LacZ (Nampt ADLacZ).
- A) Quantitative RT-PCR results for mRNA expression of Nampt in AD-LacZ and Nampt Ad-Cre infected neurospheres (n 3-33).
- FIG. 26 illustrates A) A scheme for the oligodendrocytic lineage differentiation protocol used.
- Dotted lines denote the SGZ. Single arrowheads indicate examples of colocalization of cell immunore activity. Scale bar denotes 10 ⁇ .
- E-F Immunoflorescence for Dapi (blue), Sirt2 (red), and NestinGFP (original green, 3 days post TAM) along the SGZ. Dotted lines denote the SGZ. E) Scale bar denotes 50 ⁇ . F) Scale bar denotes 20 ⁇ .
- G-H Neurospheres were isolated from Sirtl flox/flox mice and infected with a Cre recombinase-expressing adenovirus (Sirtl AD-Cre) or a control adenovirus expressing LacZ (Sirtl AD-LacZ).
- Neurospheres were derived from full body Sirtl KO mice (I), Sirt2 KO (J) mice, and their respective littermate controls.
- FIG. 27 illustrates adult NSPC specific deletion of Nampt impairs NSPC self-renewal in response to insult-induced demyelination in vivo.
- H Representative images of immunoflorescence for Dapi (blue), Nampt (red), and Sox2 (green) in the CC. Arrows indicate examples of colocalization of immunore activity. Scale bars denote 20 ⁇ .
- FIG. 28 illustrates the NAD biosynthetic pathway from nicotinamide.
- A The rate-limiting step catalyzed by nicotinamide phosphoribosyltransferase (NAMPT).
- NAMPT nicotinamide phosphoribosyltransferase
- Nic nicotinamide
- PRPP 5'-phosphoribosyl-l -pyrophosphate
- NMN nicotinamide mononucleotide
- PPi pyrophosphate.
- B The NAD biosynthetic pathway from nicotinamide.
- FIG. 29 illustrates bone mineral density (BMD) in control and NMN -treated mice at the 12- month time point measured by dual-energy X-ray absorptiometry (DXA).
- BMD bone mineral density
- DXA dual-energy X-ray absorptiometry
- FIG. 30 illustrates (A-B) retinas from NAMPT rod-CKO mice showed a significant reduction of NAMPT within rods by PCR, immunohistochemistry and immunoblotting. (C)
- Neurosensory retinal degeneration was associated with secondary atrophy and pallor of the optic nerve.
- D-F Electroretinography (ERG) was performed to measure PR neuron and retinal function.
- G Photopic visual acuity measurements confirmed vision loss in rod-CKO mice.
- H Histopathologic examination of eyes from NAMPT rod-CKO mice.
- I Normalized NAD measurements obtained from NAMPT rod-cko whole retinas.
- J-L CKO mice treated with NMN showed significant rescue of photopic and scotopic function
- FIG. 31 illustrates (A) NAMPT cone-CKO mice (B-D) ERG demonstrated progressive decline in cone function. (E) Significant decrease in visual acuity in cone-CKO mice. (F-H)
- FIG. 32 illustrates (A- J) Retinal and PR neuron structure and function. (K-L) Examination of mice that had normal retinal structure and function.
- FIG. 33 illustrates (A-B) Electron microscopic examination. (C) Role of NAD in NAMPT- mediated effects on PR neurons.
- FIG. 34 illustrates NMN treatment effect on littermate controls.
- FIG. 35 illustrates retinal and PR neuron structure and function.
- FIG. 36 illustrates changes in inner segments could be identified in rod-CKO mice.
- BMD Bone mineral density
- FFA Free fatty acid
- NMN Nicotinamide mononucleotide
- OPC Oligodendrocyte precursor cells
- NMN neuropeptide
- body weight body temperature
- food and water intake were periodically monitored, including body weight, body temperature, food and water intake, fed and fasted blood glucose levels, fed and fasted plasma lipid panels, and glucose and insulin tolerance, in NMN-administered and control mice.
- Blood chemistry, blood cell counts, urine strip test, and other physiological tests including physical activity test were also checked. Based on all these assessments, no adverse effects, such as malnutrition, or signs of toxicity were observed in either of the 100 mg kg or 300 mg/kg groups.
- HFD high fat diet
- NMN a sensitive test to examine the memory function that involves the hippocampus
- mice were maintained on a regular chow ad libitum on a 12 hr light/dark cycle (lights on from 6 am to 6 pm).
- Namptflox/flox mice (Rongvaux et al, 2008), in which exons 5 and 6 of the Nampt gene are flanked by loxP sites, were crossed to Nestin-CreERT2 mice (Lagace et al, 2007) to generate Nampt flox/+; Cre double heterozygous mice. Double heterozygous mice were bred to Namptflox/flox mice to obtain Namptflox/flox; Cre mutant mice (iNSPC-Nampt-KO mice) in the expected Mendelian ratio.
- iNSPC-Nampt-KO and Nestin-CreERT2 mice were crossed to a reporter mouse strain that expresses a loxP-flanked STOP cassette that prevents transcription of the downstream enhanced green fluorescent protein [ZsGreenl; Jackson laboratories #7906 (Madisen et al, 2010)].
- Recombination PCR on hippocampal extracts of tamoxifen or vehicle treated mice showed successful deletion upon treatment with tamoxifen (FIG. 23C)
- Tamoxifen injections were performed as described previously (Lagace et al, 2007). Briefly, iNSPC-Nampt-KO mice (5-7 weeks old) were administered tamoxifen (TAM, Sigma T5648) at 180 mg/kg/d for 5 days (d, intraperitoneally; dissolved in 10% EtOH/ 90% sunflower oil), a protocol that produces maximal recombination with minimal lethality (5%) (Lagace et al, 2007).
- TAM tamoxifen
- Demyelination was induced by feeding 6 to 8- week-old mice a diet containing 0.2% cuprizone (bis-cyclohexanone oxaldihydrazone; Sigma C9012) mixed into a ground standard rodent chow for 4 to 5 weeks (Harlan Laboratories, TD.01453). To allow recovery from cuprizone treatment, food was replaced with standard chow for an additional 1 week. This protocol has been shown to successfully demyelinate and remyelinate the
- NAD+ levels were determined using an HPLC system (Shimadzu) with a Supelco LC-18-T column (15cm x 4.6cm; Sigma), as described previously (Yoshino et al, 2011).
- Protein extracts (15-50 ⁇ g) from mouse hippocampi or neurospheres were prepared as previously described (Yoshino et al, 2011).
- GeneAmp 7500 fast sequence detection system (Applied Biosystems). Relative expression levels were calculated for each gene by normalizing to Gapdh levels and then to a control.
- Neurosphere cultures and culture media were prepared as described by Dasgupta & Gutmann, 2005 and Lu & Ramanan, 2012 with the following minor modifications. Briefly, postnatal hippocampi were dissected in Hibernate A (Invitrogen, A12475-01) and trypsinized at 37°C for 7 m. Cells were mechanically dissociated by pipetting and pelleted by centrifugation (1700 rpm, 7 min). Dissociation medium (0.1% sodium bicarbonate, 15 mM HEPES, 0.5% glucose in HBSS) was used to wash the cells before they were resuspended in growth medium.
- Hibernate A Invitrogen, A12475-01
- Dissociation medium 0.1% sodium bicarbonate, 15 mM HEPES, 0.5% glucose in HBSS
- Growth medium consisted of DMEM:F12 (1 : 1, Invitrogen 11966-025 and 21700-075, respectively), B27 (Invitrogen, 17504-044), N2 (Invitrogen, 17502-048), Pen/Strep (Invitrogen), epidermal growth factor (EGF, 20 ng/ml, Sigma, E4127), fibroblast growth factor (FGF, 10 ng mL, R&D Systems, 233-fb), and heparin (Sigma). Cultures were maintained at 37°C with 5% C02, and passaged twice before use in experiments. Three to nine independent samples, each in 1 to 3 replicates, from at least two different litters, were used in all experiments.
- Neurospheres were cultured in the physiological glucose level of 5 mM (Dienel & Cruz, 2006), which has been previously shown to have no negative consequences on NSPC proliferation, differentiation, or death (Fu et al, 2006; Gao & Gao, 2007).
- Neurospheres derived from Nampt ⁇ mice were infected with Ad5 Cre recombinase- or b-galactosidase -expressing (LacZ, control) adenoviruses at an MOI of 100. All assessments were performed at least 6 days post infection.
- Neurospheres derived from Nampt ⁇ mice were dissociated by trypsin digestion and seeded at similar cell densities in 24-well plates with fresh growth medium. Every 24 hours, neurospheres from triplicate wells were collected, dissociated, and counted on a hemocytometer using 0.2% trypan blue exclusion to distinguish viable cells. For analysis of neurosphere diameter, the largest neurosphere in each well was imaged (20x objective) and the diameter was calculated using Image J. For secondary neurosphere analysis, the total number of neurospheres in each well was counted at 7 days post-plating.
- neurospheres were trypsinized, washed with dissociation medium, and plated at 150,000 cells per well in 24-well plates in differentiation medium [growth medium without FGF and EGF and with BDNF (5 ng mL, Peprotech, 450-02) on glass coverslips coated with poly-D-lysine (50 ug/mL; Sigma) and laminin (20 ug/mL; BD Biosciences)]. 6-well plates were coated with poly-D-lysine (20 ug/mL) and laminin (10 ug/mL).
- PDGFIl ⁇ (10 ng/ml, Peprotech 100-13A) was added to neurospheres at passage 2 and PDGF I (2.5 ng/ml) and 3,3-,5-triiodo-L-thyronine (T3, 40 ng ml, Sigma T4397) were added to differentiation medium.
- OPCs oligodendrocyte precursor cells
- NMN neuropeptide
- body weight body temperature
- food and water intake were periodically monitored, including body weight, body temperature, food and water intake, fed and fasted blood glucose levels, fed and fasted plasma lipid panels, and glucose and insulin tolerance, in NMN-administered and control mice.
- Blood chemistry, blood cell counts, urine strip test, and other physiological tests including physical activity test were also checked. Based on all these assessments, no adverse effects, such as malnutrition, or signs of toxicity were observed in either of the 100 mg/kg or 300 mg/kg groups.
- This example illustrates a suppressive effect of NMN on age-associated body weight increase.
- NMN was administered to mice at a dosage rate of 100 mg/kg per day or 300 mg/kg per day.
- NMN demonstrated a suppressive effect on age-associated body weight increase in a 12 month-long NMN administration study.
- NMN demonstrated a suppressive effect on age-associated body weight increase (FIG. 2).
- This example illustrates an enhancement of energy metabolism over age with NMN administration.
- mice administered 100 mg/kg NMN per day and mice administered 300 mg/kg NMN per day at the 12 month time point were used to measure oxygen consumption, energy expenditure, and respiratory quotient for control, mice administered 100 mg/kg NMN per day and mice administered 300 mg/kg NMN per day at the 12 month time point.
- Example 3 This example illustrates a suppressive effect of NMN on age-associated increases in blood lipid levels.
- NMN at the dose of 300 mg/kg suppressed age-associated increases in blood levels of FFAs, particularly at the 6-month time point (P ⁇ 0.05 from the one-way ANOVA with the Dunnett T3 post-hoc test). Therefore, NMN is capable of suppressing age-associated increases in blood lipid levels, particularly blood FFA levels.
- NMN has an effect of suppressing age- associated body weight increase
- NMN's effect on blood lipid levels could be due to the reduction in body weight.
- NMN has a capability of suppressing the age-associated increase in blood FFA levels, which distinguishes NMN from nicotinic acid. NMN is also able to reduce cholesterol levels through the suppression of age-associated body weight increase.
- chronic administration of nicotinic acid can cause skeletal muscle insulin resistance (Fraterrigo, G., et al. Cardiorenal. Med. 2: 211-7, 2012)
- NMN does not show any adverse effect on glucose metabolism. Therefore, NMN administration can be an effective intervention to suppress age-associated increases in blood lipid levels.
- This example illustrates that administration of NMN enhances insulin sensitivity in old individuals.
- insulin tolerance assessed by the insulin tolerance test, showed significant differences among the control and the 100 mg/kg and 300 mg/kg NMN- administered groups after the 12-month time point.
- This example illustrates improvement of memory function under a high-fat diet (HFD) by administration of NMN. (See Methods; Memory Function Study)
- FIG. 10 illustrates freezing responses of regular chow-fed control, HFD-fed, and HFD-fed, NMN-treated mice in contextual and cued fear conditioning tests on Day 1, Day 2 and Day3.
- NMN was administered at the dose of 300mg/kg/day for 4 months.
- mice were given an auditory cue and then a mild electric foot shock, and a time of freezing was analyzed individually.
- the trained mice were placed into a training chamber with no tone cues, and their freezing responses were evaluated.
- cued fear conditioning which does not involve the hippocampus, was tested by giving the same tone cue used in the conditioning session (Day 1) and analyzing their freezing responses.
- HFD-fed mice showed an impairment of contextual fear conditioning on Day 2 compared to regular chow-fed control mice but did not show any defect in the conditioning session on Day 1 and the cued fear conditioning test on Day 3 (FIG. 10), demonstrating that HFD specifically impairs the hippocampus-dependent memory function.
- NMN-treated, HFD-fed mice demonstrated freezing responses indistinguishable from those of regular chow-fed control mice in the contextual fear conditioning test on Day 2. Their freezing responses did not differ from those of control mice on both Day 1 and Day 3.
- This example illustrates the improvement of retinal photoreceptor cell function over age.
- FIG. 11 illustrates fundus biomicroscopy images from control and NMN-administered mice. For each group, five mice were examined, and two representative images are shown.
- Intraretinal whitish deposits were reduced dramatically in NMN-administered mice. On fundus biomicroscopy, all five control mice at 18 months of age showed many intraretinal whitish deposits, whereas two and four each out of five mice at 100 mg/kg and 300 mg/kg doses, respectively, showed dramatic reductions in these deposits, suggesting that age- associated pathological changes in the retina are suppressed by NMN (FIG. 11).
- the present inventors assessed the physiological importance of NAMPT-mediated NAD biosynthesis in the retina by generating rod cell- and cone cell-specific NAMPT knockout mice.
- cone cell-specific NAMPT knockout mice had an atrophic appearance at the optic nerve head, intraretinal whitish deposits, and perivascular sheathing, while littermate control animals were normal.
- ERG demonstrated a significant and dramatic decrease in the scotopic b and photopic b wave amplitudes as compared to the littermate control mice.
- the scotopic a wave amplitudes in the cone cell-specific NAMPT knockout mice were significantly decreased but to a lesser extent than the photopic b wave responses.
- rod cell-specific NAMPT knockout mice exhibited total retinal degeneration. Both a and b wave ERG responses were completely depressed as characterized by a total lack of response to all stimuli. Additionally, the treatment of the mouse photoreceptor-derived 661W cone cell line with FK866, a potent NAMPT inhibitor, led them to apoptotic cell death. Adding NMN to the culture media successfully rescued 661W cells from FK866-mediated cell death, suggesting that NAD deficiency causes the observed cell death. These results indicate that inhibition of NAMPT-mediated NAD biosynthesis by genetic and pharmacologic means leads to photoreceptor cell death and eventually retinal degeneration. NMN administration is an effective intervention to treat/prevent retinal degeneration.
- the inventors first measured NAD+ levels in hippocampi isolated from 1, 3-4, 6, and 10-12 month-old C57B16 mice.
- FIG. 14 illustrates hippocampal NAD+ levels and Nampt expression declining with age.
- Nampt converts nicotinamide and 5'-phosphoribosyl-l- pyrophosphate (P PP) to nicotinamide mononucleotide (NMN).
- Nicotinamide/nicotinic acid mononucleotide adenylyltransferase (NMNAT) converts NMN and adenosine-5'-triphosphate (ATP) to NAD+. While NAD+ is commonly used in redox reactions, cells primarily require NAD+ as a co-substrate for several families of enzymes, one of which is the sirtuin family of protein deacetylases.
- the sirtuin family includes Sirtl and Sirt2, which cleave NAD+ at its glycosidic bond, releasing ADP-ribose (Stein & Imai, 2012). Inhibitors used in subsequent experiments is indicated.
- C-D) Quantification of immunofluoresence for Nampt in the subgranular zone (SGZ). Measurement of thresholded levels of Nampt immunoreactivity (C) and the number of highly immunoreactive Nampt+ cells (D) along the SGZ (n 5).
- Nampt has been reported as predominantly expressed in hippocampal neurons but not in stellate astrocytes (Wang et al, 201 la; Zhang et al, 2010). Consistent with this finding, immunohistochemistry for Nampt and cell type specific markers revealed almost all NeuN+ neurons in the granule layer of the DG expressed Nampt, while almost no S100p+ glial cells did (FIG. 22A-E).
- FIG. 22 illustrates that Nampt is expressed in a subpopulation of SGZ NSPCs.
- mice expressing Cre recombinase under the Nestin promoter (Nestin-CreERT2) to a GFP reporter mouse strain that expresses a loxP-flanked STOP cassette that prevents transcription of the downstream enhanced GFP (see Methods), generating iNSPC-GFP mice.
- Nampt also colocalized with GFP driven by the Nestin promoter (NestinGFP, FIG. 15C).
- Nampt is highly expressed in NSPCs
- the inventors cultured NSPCs from the hippocampi of postnatal pups as neurospheres.
- Neurospheres showed 22 or 32% higher expression levels of Nampt than did whole hippocampal extracts taken from postnatal (P12) or adult mice (2.5-4.5 months), respectively (FIG. 15E), indicating that NSPCs have higher expression levels of Nampt compared to other hippocampal cell types.
- P12 postnatal
- adult mice 2.5-4.5 months
- the inventors thresholded Nampt immunoreactivity, and assessed the thresholded Nampt+ cells for colocalization with the neuronal marker NeuN and the NSPC marker Sox2 to determine which cell populations lose Nampt expression with age. With age, the
- This example illustrates that adult NSPC-specific deletion of Nampt impairs NSPC self-renewal in vivo.
- the inventors investigated whether inactivating Nampt specifically in adult NSPCs could recapitulate age-associated phenotypic changes in NSPC functionality in vivo.
- the inventors generated adult NSPC-specific inducible Nampt knockout mice by crossing Nampf 0 * 0* mice (Rongvaux et al, 2008) with Nestin-CreERT2 mice (iNSPC-Nampt-KO mice).
- mice To trace the progeny of adult NSPCs in which Nampt was inactivated and to confirm the specificity and magnitude of the deletion induced by tamoxifen, the inventors also crossed iNSPC-Nampt-KO mice to the aforementioned iNSPC-GFP mice. After tamoxifen injection, these mice expressed NestinGFP in the SGZ and SVZ but not in non-neurogenic regions of the brain such as the corpus callosum or cortex FIG. 23 A-B).
- NestinGFP+ population consisted of NSPCs, the inventors co-stained for the NSPC markers Sox2 and Gfap. 61% of Sox2+ cells and 34% of radial Gfap+ cells co-expressed NestinGFP 7 days post tamoxifen (FIG. 23D). The inventors also verified Nampt deletion efficiency by quantifying the percentage of NestinGFP+ cells that expressed Nampt 3 and 7 days post tamoxifen injection.
- Mature cells had vertical projections spanning the granule cell layer.
- NSPC/daughter cell survival was accessed by immunostaining for activated caspase 3. Only rare activated caspase 3+ cells were observed in both neurogenic and non-neurogenic regions of the brain (FIG. 23A-23B), and these activated caspase 3+ cells were never observed in GFP+ cells in iNSPC-Nampt-KO DG, without being limited by theory, providing evidence against a potential contribution of cell death to the observed effects.
- mice were labeled by injecting the mice with BrdU concurrently with the first day of tamoxifen treatment. 4 total TAM injections (2 injections on the first day coupled with BrdU at 100 mg kg body weight as well as 2 total injections on the subsequent 2 days).
- iNSPC-Nampt-KO mice displayed significantly reduced levels of colocalization of BrdU with radial Nestin+ cells (FIG. 161), without being limited by theory, suggesting decreased self-renewal decisions.
- iNSPC-Nampt-KO mice exhibited normal levels of BrdU colocalization with neuronal (Dcx+), astrocytic (Gfap+) and oligodendrocytic (01ig2+) markers, indicating that alterations in differentiated cell lineage decisions were undetectable under basal conditions.
- Dcx+ neuronal
- Gfap+ astrocytic
- oligodendrocytic 01ig2+
- NMN neuropeptide
- Intraperitoneal injection of NMN 500 mg/kg body weight
- hippocampal NAD+ levels 34 to 39% within 15 minutes suggesting that NMN can cross the blood-brain barrier (FIG. 23G).
- NMN supplementation can maintain NSPC proliferation and self-renewal with age
- the inventors treated 6 month-old mice with NMN at the daily dose of 100 or 300 mg kg body weight in their drinking water until 18 months of age.
- the number of Nestin+ cells along the SGZ was significantly lower in the 18 month-old control mice relative to 6 month-old mice, as previously reported (Encinas et al, 2011) (FIG. 16J). Data are presented as mean ⁇ s.e.m. *P ⁇ 0.05. **P ⁇ 0.01. ***P ⁇ 0.001. Mice treated with 300 mg/kg body weight NMN showed improved maintenance of the Type 1 (radial Nestin+) population with age. However, the population of proliferating cells ( ⁇ 67+) remained similar to controls (FIG. 23H). The population of newborn neurons (Dcx+) trended to increase (FIG. 231).
- Neurospheres were treated with a highly specific Nampt inhibitor, FK866, at a dosage and duration (10 nM, 48 hours) that has little to no effect on cellular viability (Hasmann & Schemainda, 2003).
- FK866 reduced NAD+ levels in neurospheres to 4% of controls, a decrease completely rescued by concurrent NMN treatment (FIG. 17A and 24A), suggesting that, without being limited by theory, Nampt activity is the predominant source of NAD+ biosynthesis in NSPCs.
- This example illustrates that genetic ablation of Nampt in NSPCs in vitro impairs NAD biosynthesis, proliferation, and differentiation.
- Nampt Ad-Cre Cre recombinase
- Neurospheres were isolated from Namptfiox/flox mice and infected with a Cre-recombinase expressing adenovirus (Nampt AD-Cre) or a control adenovirus expressing LacZ (Nampt AD-LacZ).
- Nampt Ad-Cre infected NSPCs Like FK866-treated cultures, proliferating Nampt Ad-Cre infected NSPCs displayed reduced cell number (FIG. 18B). Nampt Ad-Cre NSPCs were unable to increase their cell number between 24 and 144 hours of culture. In contrast, Nampt AD- LacZ infected cells were able to exponentially increase their cell number over 13-fold in this time frame.
- Nampt Ad-Cre infected NSPCs also showed a 49% reduction in diameter relative to Nampt AD-LacZ infected NSPCs, indicative of reduced proliferation (FIGS. 18C-D). Since NSPC self-renewal decisions can also contribute to cell number, the inventors assessed secondary neurosphere formation, an assay that quantifies the ability of neurosphere inhabitant cells to reformulate neurospheres upon dissociation. Nampt Ad-Cre infected cells generated 63% fewer secondary neurospheres than did Nampt AD-LacZ infected cells (FIG. 18E).
- Nampt AD-LacZ and Nampt Ad-Cre NSPCs exhibited no difference in the percentages of TUNEL- or activated caspase 3- positive cells as well as no difference in activated caspase3 immunoreactivity as detected by immunoblotting, without being limited by theory, indicating that the observed phenotypes upon loss of Nampt are not primarily due to cell death (FIG. 25E-F).
- Nampt Ad-Cre infected neurospheres could be reactivated to proliferate
- the inventors plated equal numbers of Nampt AD-LacZ and Nampt Ad-Cre cells after the second passage and cultured them in the presence or the absence of NMN.
- NMN treatment was able to fully reactivate the proliferative potential of Nampt Ad-Cre cells (FIG. 18F-G).
- the inventors did not observe a difference in NSPC fate decisions in the neurogenic environment of the SGZ in vivo, the inventors detected a decrease in self-renewal decisions. To see if this would occur in the absence of the influences of the SGZ niche, the inventors differentiated dissociated neurospheres and assessed the proportion of resulting cell types by immunofluorescence after 6 to 7 days of differentiation induced by removal of growth factors (FIG. 18H, FIG. 25G). Differentiated Nampt Ad-Cre NSPCs exhibited a 90% reduction in oligodendrocytes (FIG. 181). In contrast, Nampt Ad-Cre infected NSPCs exhibited no change in the generation of Gfap+ cells (FIG. 18J).
- FIG. 26C The inventors acutely treated NSPCs with the selective inhibitor of Sirt2, AGK2, or the Sirtl inhibitor, EX527. Whereas both inhibitors acutely suppressed oligodendrocyte formation (04+, FIG.
- This example illustrates adult NSPC-specific deletion of Nampt impairs NSPC differentiation in response to insult in vivo.
- the inventors observed Nampt ablation on NSPC differentiation into OPCs in vitro, but not oligodendrogenesis in the SGZ of iNSPC-Nampt-KO mice in vivo (FIG. 161).
- the inventors assessed the percentage of NestinGFP+ cells that expressed OHg2 in the SVZs of iNSPC-GFP and iNSPC-Nampt-KO mice (FIG. 20A).
- iNSPC-Nampt-KO mice showed a lower percentage of oligodendrocytes generated from adult NSPCs.
- the inventors employed the cuprizone model of demyelination and remyelination. Specifically, the inventors fed 6- to 9-week-old iNSPC-Nampt-KO and littermate control mice (iNSPC-GFP) a diet containing 0.2% cuprizone for 4-5 weeks, inducing deletion of Nampt in the adult Nestin+ population the week before starting the cuprizone diet (FIG. 20B) (Skripuletz et al, 2011).
- iNSPC-GFP littermate control mice
- mice in our cohort expressed Cre recombinase under the inducible Nestin promoter (Nestin- CreE T2) (Lagace et al, 2007) and the aforementioned Cre recombinase responsive GFP reporter transgene.
- the analysis focus was on lineage tracer marked (NestinGFP+) cells.
- the iNSPC- GFP CC virtually no NestinGFP+ or Nestin+ cells were seen in regular chow fed mice (FIG. 20C-D, FIG. 27 A).
- FIG. 20C-D FIG. 27 A
- cuprizone feeding significantly increased the percentage of
- NestinGFP+Nestin+ cells from 3 to 41%) but decreased the NestinGFP+Gfap+ (from 60 to 24%) double positive cells, suggesting, without being limited by theory, increased self- renewal fate decisions at the expense of astrocytic fate decisions (FIG. 20E-G).
- cuprizone feeding also increased the number of NestinGFP+SoxlO+ (from 2 to 16%) and NestinGFP+Apc+ (from 0 to 4%) double positive cells, suggesting increased
- oligodendrocytes (Ohg2, FIG. 20J). These results suggest, without being limited by theory, that Nampt is specifically expressed in SGZ/SVZ derived remyelinating NSPCs and plays a role in oligodendrogenesis in response to insult.
- This example illustrates a model for the role of Nampt-mediated NAD biosynthesis in NSPCs without being limited by theory.
- Nampt-mediated NAD+ biosynthesis promotes NSPC self-renewal, proliferation and differentiation into oligodendrocytes. While the mechanism by which Nampt promotes self- renewal and proliferation remains unidentified, Nampt-mediated NAD+ biosynthesis activates Sirtl and Sirt2 to promote NSPC oligodendrocyte lineage fate decisions by a mechanism involving transcriptional downregulation of Pdgfra, SoxlO, and Nkx2.2 and transcriptional upregulation of p21 (cdknla). Sirtl and Sirt2 may act via an effect on 01ig2 activity. (FIG. 21)
- NMN neuropeptide
- the upregulation of p21 that we see upon loss of Nampt may also contribute to the downregulation of E2F/Cyclin E activity.
- Cyclin A expression is induced after E2F and Cyclin E (Wong et al, 2011)
- the changes in Cyclin A levels are likely downstream of both the aforementioned changes.
- connecting mediator(s) remain unclear.
- the inventors found neither Sirtl nor Sirt2 to be downstream of the effect of Nampt-mediated NAD+ biosynthesis on proliferation. While it is possible that Sirtl/2 function redundantly to mediate NSPC proliferation, the relatively low expression of Sirt2 in NSPCs (FIG. 26G) makes this possibility unlikely, without being limited by theory.
- the present inventors revealed that ablation of Nampt specifically reduced the proportion of NSPC-generated Pdgfra+ OPCs as well as the transcription of Pdgfra, SoxlO, and Nkx2.2 but upregulated the expression of p21.
- the results showed that in neurospheres, treatment with NMN rescued defects in oligodendrogenesis caused by a reduction in NAD+ levels.
- systemic NMN administration was able to substantially augment hippocampal NAD+ levels and increase the NSPC pool.
- NMN administration could be an efficient intervention to enhance the NSPC pool and promote remyelination by activating endogenous NSPCs during the aging process and/or in neurodegenerative diseases that cause demyelination.
- the results provide evidence of the therapeutic potential of Nampt-mediated NSPC self-renewal, proliferation, and differentiation into oligodendrocytes.
- This example illustrates an increase in bone density in aged individuals by NMN administration.
- This example illustrates characterization of loss of NAMPT-mediated NAD biosynthesis on PR neuron survival.
- the inventors examined the effect of selectively disrupting NAD biosynthesis within PR.
- the inventors utilized the cre-lox strategy to generate mice that had NAMPT
- NAMPT rod-CKO NAMPT rod-CKO
- cone-CKO NAMPT cone-CKO
- the NAMPT fl/fl mice as well as the rhodopsin-cre and cone opsin-cre mice have been previously characterized. Both rod and cone cko mice are generated with normal Mendelian frequencies and are born normal with no observable systemic abnormalities (data not shown). All structural and functional analyses performed in CKO mice are analyzed in comparison to littermate controls. Rods constitute a majority of the PR neurons (97% of all photoreceptors). Retinas from NAMPT rod-CKO mice showed a significant reduction of NAMPT within rods by PCR, immunohistochemistry and immunob lotting (FIG. 30A-B).
- This example illustrates electroretinography (ERG) performed to measure PR neuron and retinal function.
- NAMPT rod-CKO mice demonstrated a dramatic reduction in scotopic (rod- associated) and photopic (cone-associated) responses compared to littermate control animals (FIG. 30D-H)
- Photopic visual acuity measurements confirmed vision loss in rod-CKO mice (FIG. 30G).
- Histopathologic examination of eyes from NAMPT rod-CKO mice was characterized by retinal degeneration with progressive loss of the outer nuclear layer over time with significant reduction of retinal thickness and subsequent extension of the neurodegeneration to multiple retinal layers (FIG. 30H).
- Normalized NAD measurements obtained from NAMPT rod-cko whole retinas showed a significant reduction in NAD which is especially important given that NAMPT function is selectively eliminated only from rod PR neurons with other retinal cells being normal (FIG. 301).
- the present inventors determined that exogenous supplementation with NMN is able to rescue PR neurons from cell death in CKO mice.
- Intraperitoneal (i.p.) delivery was chosen to obtain early and sustained levels of NMN.
- NAMPT rod-CKO mice were given NMN (150 mg/kg) or PBS i.p. daily starting at day P5.
- ERG at 4 weeks in CKO mice treated with NMN showed significant rescue of photopic and scotopic function compared to PBS treatment (FIG. 30 J- L). There was no effect of NMN on littermate control animals.
- NAMPT cone-CKO mice (without NMN treatment) demonstrated similar but milder changes on biomicroscopy consistent with neuroretinal degeneration as seen in the rod-CKO mice (FIG. 31 A).
- ERG demonstrated significant and progressive decline in cone function as evidenced by reduced photopic responses over time with secondary reduction in scotopic responses (FIG. 31B-D).
- FIG. 31B-D These quantifiable structural and functional changes were associated with decrease in visual acuity in cone-CKO mice (FIG. 3 IE).
- Histopathologic analyses confirmed outer nuclear layer degeneration with subsequent multilayer retinal degeneration and cell death in cone-CKO mice similar to the changes seen above for rod-CKO mice.
- delivery of NMN i.p.
- NAMPT cone-CKO mice was also able to improve ERG function compared to PBS treated cone-CKO mice (FIG. 31 F-H).
- NMN treatment had no effect on littermate controls (FIG. 34).
- the inventors used a 661 W cone PR cell line and treated the cells with the specific pharmacological NAMPT inhibitor FK866 (200 nM).
- FK866 treatment of cone cells in vitro causes decrease in intracellular NAD levels and significant cell death after the 4 hours of treatment (FIGS. 311, 31 J). Cell death progresses dramatically over the next 20 hours.
- NMN 100 ⁇ was able to completely rescue cells from death associated with FK866 treatment and restore NAD to normal levels (FIGS. 3 II, 3 IK).
- sirt6 rod and cone conditional knockout mice that also had normal retinal structure and function (FIG. 32, 32L and FIG. 35). Without being limityed by theory, these findings demonstrate that individual sirtuins are not causative of N AMPT-mediated PR degeneration.
- Electron microscopic examination demonstrated dysmorphic changes in the retinal inner segments along with disruption of the outer segments in rod CKO mice but showed normal cellular organization and sub-cellular structures in littermate controls at 4 weeks of age (FIG. 33 A, 33B).
- the mitochondrial numbers in CKO retinas were significantly reduced, the mitochondria were rounded and constricted with loss of cristae as opposed to the normally elongated mitochondria with healthy cristae seen in age-matched littermate control mice (FIG. 33A, 33B).
- GC-MS and LC- MS A non-biased metabolomic analysis using mass spectrophotometry (GC-MS and LC- MS) was performed on retinas isolated from NAMPT rod CKO mice and compared to littermate control retinas. Significant differences were identified in mitochondrial metabolites involved in the TCA cycle.
- NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. (2012) Cell-Metab. 15, 838- 847
- SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase- 3beta/beta-catenin signaling.
- Hepatology (Baltimore, Md 57: 2287-2298
- Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation. Proceedings of the National Academy of Sciences of the United States of America 105: 15599-15604
- SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer cell 20: 487-499
- Sirtuin 2 a mammalian homolog of yeast silent information regulator-2 longevity regulator, is an oligodendro glial protein that decelerates cell differentiation through deacetylating alpha-tubulin. J Neurosci 27: 2606-2616
- SIRT1 regulates the neurogenic potential of neural precursors in the adult subventricular zone and hippocampus. Journal of neuroscience research 91: 642-659
- Oligodendrocytes use lactate as a source of energy and as a precursor of lipids. Glia 36: 321-329
- Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1- dependent adenosine monophosphate-activated kinase pathway.
- Nicotinamide mononucleotide a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell metabolism 14: 528-536
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Ophthalmology & Optometry (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Disclosed are methods and compositions related to methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing various diseases and conditions, including age-related obesity, age-related increases in blood lipid levels, age-related decreases in insulin sensitivity, age-related decreases in memory function, and age-related changes in eye function such as macular degeneration. The methods comprise administering nicotinamide mononucleotide (NMN) to a subject. In some embodiments, the administration can be oral administration. Also disclosed are pharmaceutical compositions comprising NMN.
Description
Administration of Nicotinamide Mononucleotide in the Treatment of Disease
Cross-Reference to Related Applications
This application claims the benefit of priority to U.S. Provisional Patent Application 61/801,188 filed March 15, 2013 and U.S. Provisional Patent Application 61/947,387 filed March 3, 2014, each of which is incorporated herein by reference in its entirety.
Government Support
This work received government support from National Institutes of Health National Institute on Aging under Grant No. AG024150 and Grant No. AG037457. The government may have certain rights in the invention.
Introduction
Age-related obesity is a health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed. U.S. Patent 8,268,575 to Imai, S., et al. asserts that "Chemical effectors for mammalian NAD biosynthesis can mediate a variety of anti-aging effects including anti-obesity, neuroprotective, and pancreatic β cell-protective effects as well as be effective to treat cancers." U.S. Patent 8,017,634 to Sinclair, D.A., et al. teaches treating a cell with "an agent that increases Nrk enzyme." U.S. Patent Application Publication 2006/0229265 of Milburn, M., et al. discusses nicotinamide riboside and analogs thereof, including their use in methods of treating diseases or conditions, such as
diabetes/insulin resistance, hyperlipidemia and obesity. Example 7 of Milburn, M., et al. purports to describe testing of neuroprotective effects of nicotinamide riboside and nicotinamide mononucleotide on ganglion cell survival. None of these references teach or suggest oral administration of NMN.
Age-related increases in blood lipid levels constitute another health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed. US Patent 7,737,158 of knai, S., et al. discloses "a process for regulating the concentration of blood glucose in a mammal, the process comprising administering to the mammal a blood glucose concentration-regulating amount of nicotinamide mononucleotide (NMN) or a salt or prodrug thereof." This patent is not related to administering NMN for preventing age- associated increases in blood lipids, in particular there is no disclosure of oral administration of NMN for preventing age-associated increases in blood lipids. PCT Patent Application
Publication WO2009062910 of Inufusa, H. states that an objective is to provide compositions effective in reducing blood triglyceride levels and/or cholesterol levels for the treatment and/or prophylaxis of hypertriglyceridemia, hypercholesterolemia and disease states induced thereby such as arteriosclerosis and obesity. However, this application does not disclose administering NMN for controlling age-related blood lipid increases.
Age-related decreases in insulin sensitivity constitute another health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed. U.S. Patent 7,737, 158 to Imai, S., et al. discusses "processes for regulating the concentration of blood glucose in a mammal. The processes include administering to a mammal a blood glucose concentration-regulating amount of a compound ...useful in nicotinamide adenine dinucleotide (NAD) biosynthesis. This disclosure does not teach administering NMN, including oral administration of NMN, for improvement of insulin sensitivity in aging.
Age-related loss or decreases in memory function constitute another health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed. While U.S. Patent Application Publication 2006/0229265 of Milburn, M., et al. alleges, in Example 7, of "neuroprotective effects" of NMN, no data are presented. This application does not discuss using NMN to treat or prevent memory loss. U.S. Patent Application Publication 2006/0002914 of Milbrandt, J., et al. discloses administering an agent that acts by increasing NAD activity in diseased and/or injured neurons in the treatment of diseases such as Alzheimer's. There is no explicit teaching of administering NMN to improve memory function under normal aging conditions.
Age-related loss or decreases in eye function constitute another health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed. U.S. Patent Application Publication 2007/0014833 of Milburn, M., et al. discloses use of "sirtuin modulators" to treat vision impairment. U.S. Patent Application Publication 2006/0229265 of Milburn, M., et al. states "Conditions of the eye can be treated or prevented by, e.g., systemic, topical, intraocular injection of a sirtuin modulating compound, or by insertion of a sustained release device that releases a sirtuin-modulating compound. Neither of these publications disclose administration of NMN for the prevention of decline of eye function during aging.
Age-related dry eye constitutes another health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed. Dry eye is one
of the most prevalent eye disorders, particularly among the elderly, and no fundamental treatments are yet available (Tsubota, K., et al. Cornea. 31 Suppl 1 : S l-8, 2012). Decrease in lacrimal gland secretory function might be a possible cause of age-associated dry eye diseases (Kawashima, M., et al. Biochem Biophys. Res. Commun. 397: 724-8, 2010).
Age-related cognitive impairment constitutes another health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed. Aging is a negative regulator of adult neural stem and progenitor cell (NSPC) proliferation (Artegiani, B., et al.) While NSPC proliferation declines exponentially throughout life (Artegiani & Calegari, 2012), quiescent NSPCs can be reactivated in the aged murine hippocampus by multiple environmental stimuli (Decker et al, 2002; Jin et al, 2003; Lugert et al, 2010). Aging can reduce levels of the essential cofactor nicotinamide adenine dinucleotide (NAD+) in multiple peripheral tissues (Yoshino et al, 2011).
US Patent Application 12/524,718 Milbrandt, J., et al. discloses experimental applications of NMN. This reference does not mention administering NMN to affect NSPCs or for oligodendrocyte proliferation.
Sasaki, Y., et al. J Neurosci. 2006 Aug 16;26(33): 8484-91 discloses applications of NMN. This article does not disclose administration of NMN to affect NSPCs or promote proliferation of oligodendrocytes. U.S. Application US20130059384 Al of Tilly, J.L., et al. discloses the use of NMN for enhancing female fertility.
Photoreceptor neuron dysfunction and cell death is the leading cause of blindness over the lifespan in humans. Photoreceptor neuron dysfunction constitutes another health-related problem for which new treatments and methods of ameliorating, mitigating, or reversing are needed.
PCT Application PCT US2006/011930 (Pub No. WO2006105403) of Dipp, M., et al. disclosed methods of treating vision impairment by administration of a sirtuin modulator. In example 10 of this reference, the investigators tested neuroprotective effects of nicotinamide mononucleotide (NMN) in a retinal ganglion cell injury model. However, the retinal ganglion cells disclosed in this application not classical photoreceptors (rods and cones).
U.S. Patent Application Publication US20100047177 of Milbrandt, J., et al. discusses administering to a mammal an agent that increases NAD activity in diseased and/or injured neurons or supporting cells. The application does not specify protection or treatment of rods and cones with NMN.
U.S. Patent 7,776,326 of Milbrandt, J., et al. discusses methods of treating or preventing axonal degradation in neuropathic diseases in mammals by administering an agent
that can increase sirtuin activity in diseased/injured neuronal cells. The patent does not specify protection or treatment of rods and cones with NMN. This patent does not disclose administration of NMN to maintain NSPCs or promote oligodendrocyte proliferation.
"Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy" J Neurosci. 2006 Aug 16;26(33):8484-8491 of Sasaki, Y., et al. discusses adding NMN to cultured neurons. This article does not disclose administration of NMN to retinal cells in vivo.
Chinese Patent CN 101601679 B "Application of nicotinamide mononucleotide" discloses applications of NMN for prevention of stroke.
PCT Application PCT/IB2012/001146 of Alvarez, C.C., et al. discloses treating a mitochondrial dysfunction with a compound that increases intracellular nicotinamide adenine dinucleotide (NAD+) in an amount sufficient to activate SIRT1 or SIRT3. The application does not disclose administration of NMN to neuronal cells. This reference does not mention NSPCs.
U.S. Patent 7,737, 158 of Imai, S., et al. discloses processes for regulating blood glucose concentration by administration of NMN. The patent does not teach administration of NMN to rod/cone-type photoreceptor neurons. This reference does not discuss administration of NMN to treat NSPCs or for age-related diseases or neurodegenerative diseases unrelated to glucose levels.
Revollo, J.R., et al. Cell metabolism 6, 363-375 (2007), Ramsey, K.M., et al. Aging Cell. 2008 Jan;7(l):78-88, and Yoshino, J., et al. Cell Metab. 2011 Oct 5;14(4):528-36 do not disclose administration of NMN for treating photoreceptor degeneration, retinal degeneration, or macular degeneration. Exp Eye Res. 2013 Mar; 108:76-83 of Bai, S., et al. does not disclose targeting rod/cone-type photoreceptor neurons with NMN. These articles do not discuss NSPCs.
Summary
The present inventors describe administration of nicotinamide mononucleotide (NMN), as illustrated in (FIG. 1), to a subject such as a vertebrate, including a human or other mammal, a bird, a reptile, a fish or other aquatic organism.
In addition, also disclosed in various embodiments are compositions comprising NMN. In various configurations, these compositions can further comprise one or more excipients. These compositions can be used for administration of NMN for the treatment,
amelioration, mitigation, slowing, arrest, prevention and/ or reversal of age-associated degenerative changes.
In some embodiments, any of the dosages of the present teachings of nicotinamide mononucleotide (NMN), a salt thereof and/or a prodrug therof can be used to treat any of the diseases of the present teachings.
In various embodiments, the present teachings include a pharmaceutically acceptable composition comprising, consisting essentially of, or consisting of nicotinamide
mononucleotide (NMN), a salt thereof and/or a prodrug therof and at least one
pharmaceutically acceptable excipient. In various configurations, a pharmaceutically acceptable composition can, comprise, consist essentially of, or consist of a single dosage formulation. In some configurations, a single dosage formulations can be a sustained-release formulation.
In various configurations, a pharmaceutically acceptable composition of the present teachings can be a formulation including a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a granule, a capsule, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension or solution, a non-aqueous suspension or solution, a lyophilized formulation, or a suppository.
In some embodiments, a pharmaceutically acceptable composition of the present teachings can be a single dosage formulation. In various embodiments, a single dosage formulation can comprise an enteric coating. In some embodiments, a pharmaceutically acceptable composition of the present teachings can comprise, consist essentially of, or consist of NMN, a salt thereof and/or a prodrug thereof in an amount of about lOOmg, from 100 mg to 2000 mg, about 2000 mg, or greater. In some embodiments, a pharmaceutically acceptable composition of the present teachings can comprise, consist essentially of, or consist of NMN, a salt thereof and/or a prodrug thereof in an amount of about lOOmg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about lOOOmg, about HOOmg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, or greater. In some embodiments, a pharmaceutically acceptable composition of the present teachings can comprise, consist essentially of, or consist of NMN, a salt thereof and/or a prodrug thereof in an amount of 50-150mg, 151-250mg, 251-350mg, 351-450mg, 451- 550mg, 561-650mg, 651-750mg, 751-860mg, 861-950mg, 951-1050mg, 1051-1150mg,
1151-1250mg, 1251-1350mg, 1351-1450mg, 1451-1550mg, 1551-1650mg, 1651-1750mg, 1751-1850mg, 1851-1950mg, 1951-2000mg, or greater. In some embodiments, a
pharmaceutically acceptable composition of the present teachings can comprise, consist essentially of, or consist of NMN, a salt thereof and/or a prodrug thereof in an amount of at least 0.5 mg up to about 6800 mg, such as, without limitation, 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 680 mg, about 680 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1130 mg, about 1130 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1350 mg, about 1350 mg, 1360 mg, about 1360 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2040 mg, about 2040 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2250 mg, about 2250 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg, about 3000 mg, 3100 mg, about 3100 mg, 3200 mg, about 3200 mg, 3300 mg, about 3300 mg, 3400 mg, about 3400 mg, 3500 mg, about 3500 mg, 3600 mg, about 3600 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, or about 6800 mg.
In some embodiments, a pharmaceutically acceptable composition of the present teachings can comprise a food product. In some embodiments, a pharmaceutically acceptable composition of the present teachings can comprise a composition suitable for oral
administration, sublingual administration, parenteral administration, administration by injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intraocular injection, direct ocular application (eye drop) or a combination thereof.
In some embodiments, a pharmaceutically acceptable composition of the present teachings can further comprise least one excipient. In some embodiments, the at least one excipient can comprise a bulking agent, a tableting agent, a dissolution agent, a wetting agent, a lubricant, a coloring, a flavoring, a disintegrant, a coating, a binder, an antioxidant, a taste
masking agent, a sweetener, or a combination thereof. In some embodiments, a bulking agent can comprise mannitol, sorbitol, sucrose, trehalose, or a combination thereof.
In some embodiment, a pharmaceutically acceptable composition of the present teachings can be formulated as an orally disintegrating capsule, tablet, pill or wafer. In some embodiment, a pharmaceutically acceptable composition of the present teachings can be formulated as a liquid, syrup, or spray.
In some embodiment, a pharmaceutically acceptable composition of the present teachings can further comprise at least one vitamin or nutrient. In some embodiments, a vitamin or nutrient can be vitamin C, vitamin D3, vitamin E, vitamin Bl, vitamin B2, niacin, vitamin B6, folic acid, vitamin B12, pantothenic acid, biotin, magnesium, zinc, copper, selenium, chromium, alpha lipoic acid, b co-enzyme Q-10, lutein, lycopene, or a combination thereof. In some embodiments, a vitamin or nutrient can be an amount comprising 150 mg to about 750 mg of vitamin C, from about 315 IUs to about 1800 IUs of vitamin D3, from about 75 IUs to about 150 IUs of vitamin E, from about 15 mg to about 35 mg of vitamin Bl, from about 1.7 mg to about 5.1 mg of vitamin B2, from about 20 mg to about 50 mg of niacin, from about 20 mg to about 50 mg of vitamin B6, from about 0.5 mg to about 2.5 mg of folic acid, from about 35 meg to about 105 meg of vitamin B12, from about 2.5 mg to about 7.5 mg of pantothenic acid, from about 50 meg to about 450 meg of biotin, from about 15 mg to about 55 mg of magnesium, from about 15 mg to about 55 mg of zinc, from about 0.5 to about 1.5 mg of copper, from about 75 meg to about 175 meg of selenium, from about 75 meg to about 225 meg of chromium, from about 10 mg to about 40 mg of alpha lipoic acid, from about 20 mg to about 50 mg of co-enzyme Q-10, from about 350 meg to about 3 mg of lutein, from about 100 meg to about 750 meg of lycopene, or a combination thereof.
In some embodiments, a vitamin or nutrient can be about 500 mg of ascorbic acid, about 400 IUs of cholecalciferol, about 125 IUs of d-alpha tocopherol succinate, about 35 mg of thiamine mononitrate, about 5.1 mg of riboflavin, about 50 mg of niacinamide, about 50 mg of pyridoxine HC1, about 2.5 mg of folic acid, about 105 meg of cyanocobalamin, about 7.5 mg of d-calcium pantothenate, about 75 meg of d-biotin, about 55 mg of dimagnesium malate, about 55 mg of zinc bisglycinate chelate, about 1.5 mg of copper amino acid chelate, about 175 meg of selenium amino acid chelate, about 225 meg of chromium amino acid chelate, about 10 mg of alpha lipoic acid, about 50 mg of co-enzyme Q-10, about 400 meg of lutein, about 125 meg of lycopene, or a combination thereof.
In some embodiments, an excipient of the present teachings can be dicalcium phosphate, microcrystalline cellulose, stearic acid, croscarmellose sodium, magnesium trisillicate, magnesium stearate, hydro xypropyl methylcellulose, hypromellose, titanium dioxide, tripotassium citrate, polyvinyl alcohol, fumed silica, citric acid, polyethylene glycol, talc, or a combination thereof. In some embodiments, an excipient of the present teachings can be about 100 mg to about 300 mg of dicalcium phosphate, from about 25 mg to about 75 mg of microcrystalline cellulose, from about 10 mg to about 30 mg of stearic acid, from about 10 mg to about 30 mg of croscarmellose sodium, from about 5 mg to about 15 mg of magnesium trisillicate, from about 5 mg to about 15 mg of magnesium stearate, from about 5 mg to about 15 mg of hydro xypropyl methylcellulose, or a combination thereof.
In some embodiments, an excipient of the present teachings can be about 200 mg of dicalcium phosphate, about 50 mg of microcrystalline cellulose, about 20 mg of stearic acid, about 20 mg of croscarmellose sodium, about 10 mg of magnesium trisillicate, about 10 mg of magnesium stearate, about 10 mg of hydroxypropyl methylcellulose, or a combination thereof.
In some embodiments, a pharmaceutically acceptable composition of the present teachings can be a sustained release formulation of nicotinamide mononucleotide for oral administration. In some embodiments, a sustained release formulation of nicotinamide mononucleotide for oral administration can comprise nicotinamide mononucleotide as an active ingredient that is released from the formulation along a pre-determined release profile, wherein the formulation comprises an extended release component and an immediate release component, wherein the extended release component is contained in at least one population of beads and releases nicotinamide mononucleotide in a continuous manner and each bead population is coated with its own release controlling coating and characterized by its own rate of release.
In some embodiments, an extended release component can release the nicotinamide mononucleotide in vivo in a continuous manner. In some embodiments, an extended release component can release the nicotinamide mononucleotide in vivo in a continuous manner and 80% of the nicotinamide mononucleotide can be released in vivo in a period of time selected from not more than 24 hours, not more than 16 hours, not more than 12 hours, not more than 8 hours or not more than 4 hours. In some embodiments, an immediate release component of the present teachings can be an enhanced immediate release (EI ) composition comprising a
complexing agent, an enhancing agent, or a combination. In some embodiments, an EIR composition can exhibit an in vitro release profile such that 80% of the active ingredient is dissolved in not more than 30 min. In some embodiments, an EIR composition can exhibit an in vitro release profile selected from a group consisting of: a) a dissolution of at least 50% of the active compound in not more than 10 minutes, b) a dissolution of at least 70% of the active compound in not more than 10 minutes, c) a dissolution of at least 25% of the active compound in not more than 5 minutes, d) a dissolution of at least 40% of the active compound in not more than 5 minutes, or e) a dissolution of at least 55% of the active compound in not more than 5 minutes.
In some embodiments, a pharmaceutically acceptable composition of the present teachings can include a complexing agent. In some embodiments, a complexing agent can be hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, alpha- cyclodextrin, derivatives thereof, or a combination thereof.
In some embodiments, a pharmaceutically acceptable composition of the present teachings can include an enhancing agent. In some embodiments, an enhancing agent can be a solubility enhancing agent, a dissolution enhancing agent, an absorption enhancing agent, a penetration enhancing agent, a surface active agent, a stabilizer, an enzyme inhibitor, a p- glycoprotein inhibitor, a multidrug resistance protein inhibitor, or a combination thereof.
In some embodiments, an enhancing agent can be Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins, glycerolpolyethylene glycol oxystearate, PEG-32 glyceryl palmitostearate, sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitan monolaurate, Poloxamer 407, PEG3350, PVP K25, oleic acid, glyceryl monooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, HPMC, substituted
hydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate, calcium citrate, sodium docusate, menthol, or any combination thereof.
In some embodiments, a pharmaceutically acceptable composition of the present teachings can include at least a part of the active ingredient in a form of micronized particles. In some embodiments, a micronized particle can have an average size of from about 2 μιη to about 100 μιη.
In some embodiments, a pharmaceutically acceptable composition of the present teachings can include a specific amount of each component determined according to the purpose of administration and the pre-determined release profile, and the total amount of NMN in the formulation is from 0.5 to 3000 mg.
In some embodiments, a population of beads of the present teachings can comprise an inert carrier, NMN, an optional enhancer, a release controlling coating that comprises a coating material, a pore former, an excipient, or a combination thereof. In some
embodiments, an inert carrier of the present teachings can be a cellulose sphere, silicon dioxide, starch, a sugar sphere, or a combination thereof.
In some embodiments, an enhancer can be a solubility enhancer, a dissolution enhancer, a permeability enhancer, a stabilizer, a complexing agent, an enzyme inhibitor, a p- glycoprotein inhibitor, a multidrug resistance protein inhibitor, or a combination thereof.
In some embodiments, a coating material of the present teachings can be
ethylcellulose, methylcellulose, hydro xypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylates,
polymethacrylates and copolymers thereof; and/or a pore former is selected from a group consisting of glucose, fructose, mannitol, mannose, galactose, sorbitol, puUulan, dextran, water-soluble hydrophilic polymers, hydro xyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross- linked polyvinylpyrrolidone, polyethylene oxide, Carbowaxes, Carbopol, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly(a-w)alkylenediols; inorganic compounds selected from a group consisting of alkali metal salts and alkaline earth metal salts, or combinations thereof.
In some embodiments, an amount of an individual bead population is determined according to a pre-determined release profile. In some embodiments, a pre-determined release profile can comprise a sustained rate of release after an initial immediate release. IN some embodiments, a pharmaceutically acceptable composition of the present teachings can be suitable for once a day oral administration. In some embodiments, a population of beads can comprise, consist essentially of, or consist of extended release NMN beads additionally comprising an immediate release component coated on top of the release controlling coating. In some embodiments, a formulation of a pharmaceutically acceptable composition of the
present teachings can comprise an enhancer contained in a layer separate from the release controlling coating. In some embodiments, a formulation of a pharmaceutically acceptable composition of the present teachings can comprise at least one enhancing agent wherein the enhancing agent is incorporated into the formulation in the form of a powder or of a population of beads that are optionally characterized by a controlled rate of release, and wherein the enhancing agent is separated from the active ingredient.
In various configurations, a composition of the present teachings can comprise nicotinamide mononucleotide (NMN), a pharmaceutical salt of NMN, or a prodrug of NMN. In various configurations, a salt can be a pharmaceutically acceptable salt; that is, a salt prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Non-limiting examples of suitable non-toxic acids include inorganic and organic acids of basic residues such as amines, for example, acetic, benzenesulfonic, benzoic, amphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic,
hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, barbaric acid, p-toluenesulfonic and the like; and alkali or organic salts of acidic residues such as carboxylic acids, for example, alkali and alkaline earth metal salts derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium
hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylammonia,
triethylammonia, ethylenediamine, lysine, arginine, ornithine, choline, N,N"- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, n- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
NMN can be delivered in prodrug form. Thus, the present teachings are intended to cover prodrugs of NMN, methods of delivering the same and compositions containing them. A "prodrug" can include any covalently bonded carriers which release an active drug in vivo when such prodrug is administered to a mammalian subject. In various configurations, a
prodrug can be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. In various configurations, prodrugs include, without limitation, compounds of the present teachings wherein a hydroxyl or amino group can be bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino group, respectively. Non-limiting examples of prodrugs include acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds and conjugates of the present teachings. Prodrugs of NMN can be, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present teachings. In some configurations, prodrugs can refer to compounds that can be transformed in vivo to yield NMN, for example by hydrolysis in blood.
In some embodiments, NMN can be dispersed in a pharmaceutically acceptable carrier prior to administration to a subject. In various embodiments, a carrier, also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, can be a substance that is pharmaceutically inert, can confer a suitable consistency or form to the composition, and does not diminish the efficacy of the NMN. A carrier can be considered to be
"pharmaceutically or pharmacologically acceptable" if it does not lead to pharmaceutically unacceptable adverse, allergic or other untoward reactions when administered to a subject, including a mammalian subject.
The selection of a pharmaceutically acceptable carrier can also, in part, be a function of the route of administration. For example, suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (nasal, transdermal, ocular such as eyedrops, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional,
percutaneous, endoscopical, transmucosal, sublingual and intestinal administration.
Pharmaceutically acceptable carriers for use in the present teachings can be selected based upon a number of factors: the particular compound used, and its concentration, stability and intended bioavailability; the subject, its age, size and general condition; and the route of administration. Suitable nonaqueous, pharmaceutically-acceptable polar solvents include, but
are not limited to, alcohols (e.g., a-glycerol formal, β-glycerol formal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N-(p-hydroxyethyl)- lactamide, N,N-dimethylacetamide amides, 2-pyrrolidinone, l-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g., l-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esters such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzyl acetate, dimethyl sulfoxide (DMSO), esters of glycerin such as mono, di, or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, fatty acid derived PEG esters, glyceryl monostearate, glyceride esters such as mono, di, or tri-glycerides, fatty acid esters such as isopropyl myristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate and PEG-hydroxystearate, N-methyl pyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic polyesters such as poly(ethoxylated) 30-60 sorbitol poly(oleate)2-4,
poly(oxyethylene) 15-20 monooleate, poly(oxyethylene)15-20 mono 12-hydroxystearate, and poly(oxyethylene) 15-20 mono ricinoleate, polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate,
polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate, and
Polysorbate® 20, 40, 60 or 80 from ICI Americas, Wilmington, Del., polyvinylpyrrolidone, alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® H 40 solution), saccharide fatty acid esters (i.e., the condensation product of a monosaccharide (e.g., pentoses such as ribose, ribulose, arabinose, xylose, lyxose and xylulose, hexoses such as glucose, fructose, galactose, mannose and sorbose, trioses, tetroses, heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactose and trehalose) or oligosaccharide or mixture thereof with a C4-C22 fatty acid(s) (e.g., saturated fatty acids such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, and unsaturated fatty acids such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)), or steroidal esters); alkyl, aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having 3-30 carbon atoms (e.g., acetone, methyl
ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene, dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral, vegetable, animal, essential or synthetic origin (e.g., mineral oils such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil, vegetable oils such as linseed, tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, persic and peanut oil and glycerides such as mono-, di- or triglycerides, animal oils such as fish, marine, sperm, cod-liver, haliver, squalene, squalane, and shark liver oil, oleic oils, and
polyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (Solutol® HS-15, from BASF,
Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitan monooleate.
Other pharmaceutically acceptable solvents for use in the present teachings are well known to those of ordinary skill in the art, and are identified in The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, D.C., and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics, (G. Banker et al., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y., 1995), The Pharmacological Basis of
Therapeutics, (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.)(Marcel Dekker, Inc., New York, N.Y., 1980), Remington's Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, Pa., 1995), The United States Pharmacopeia 24, The National Formulary 19, (National Publishing, Philadelphia, Pa., 2000), A. J. Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products, Journal Of Pharmaceutical Sciences, Vol. 52, No. 10, pp. 917-927 (1963).
In some embodiments, the present teachings include methods of treating,
ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated obesity in a subject. In some embodiments, the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated increases in blood lipid levels in a subject. In some embodiments, the present teachings include
methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age- associated loss of insulin sensitivity in a subject. In some embodiments, the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age- associated impairment of memory function in a subject. In some embodiments, the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated decline in eye function in a subject. In some embodiments, the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated retinal degeneration in a subject. In some embodiments, the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing dry eye. In some embodiments, the present teachings include methods of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age- associated dry eye.
In various embodiments, these methods can each independently comprise, consist essentially of, or consist of administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN). In some embodiments, NMN can be administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day. In some embodiments, NMN can be administered at a dosage rate of of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, about 100 mg per day, 100 mg per day, 150 mg, about 150 mg, about 200 mg per day, 200 mg per day, about 300 mg per day, 300 mg per day, about 400 mg per day, 400 mg per day, about 500 mg per day, 500 mg per day, about 600 mg per day, 600 mg per day, about 700 mg per day, 700 mg per day, about 800 mg per day, 800 mg per day, about 900 mg per day, 900 mg per day, about 1000 mg per day, 1000 mg per day, about 1100 mg per day, 1100 mg per day, about 1200 mg per day, 1200 mg per day, about 1300 mg per day, 1300 mg per day, 1350 mg, about 1350 mg, about 1400 mg per day, 1400 mg per day, about 1500 mg per day, 1500 mg per day, about 1600 mg per day, 1600 mg per day, about 1700 mg per day, 1700 mg per day, about 1800 mg per day, 1800 mg per day, about 1900 mg per day, 1900 mg per day, about 2000 mg per day, 2000 mg per day, 2040 mg, about 2040 mg, 2250 mg, about 2250 mg, 2260 mg, about 2260 mg, 2700 mg, about 2700 mg, 2720 mg, about 2720 mg, 3400 mg, about 3400 mg, 3390 mg, about 3390 mg, 3400 mg, about 3400 mg, 3600 mg, about 3600 mg, 4080 mg, about 4080 mg, 4500 mg, about 4500 mg, 4520 mg, about 4520 mg, 5440 mg, about 5440 mg, 5650 mg, about
5650 mg, 6800 mg, about 6800 mg. or an alternation or combination thereof. In some embodiments, NMN can be administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg/kg body weight/day to 500 mg/kg body weight/day, or about 500 mg/kg body weight/day. In some embodiments, NMN can be administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg/kg body weight/day to 300 mg/kg body weight/day, or about 300 mg/kg body weight/day. In some embodiments, these methods can comprise administering to a subject any of the pharmaceutically acceptable compositions of the present teachings. In some embodiments, these methods can comprise, consist essentially of or consist of administering a formulation once per day. In some embodiments, these methods can comprise, consist essentially of or consist of administering a formulation twice per day.
In some embodiments, the present teachings include methods of increasing NAD+ levels in a subject through administration of NMN. In some embodiments, the present teachings include methods of treating age-associated defects in neural stem/progenitor cell (NSPC) functionality in a subject through administration of NMN. In some embodiments, the present teachings include methods of reducing age-associated decrease in a NSPC population in a subject through administration of NMN. In some embodiments, the present teachings include methods of maintaining at least one NSPC in a subject through administration of NMN. In some embodiments, the present teachings include methods of enhancing NAD biosynthesis in a subject through administration of NMN. In some embodiments, the present teachings include methods of promoting NSPC proliferation in a subject, in which the methods comprise administration of NMN to the subject. The methods of each of these embodiments can comprise, consist essentially of, or consist of administration of a therapeutically effective amount of NMN.
In some embodiments, the present teachings include methods of increasing bone density levels in a subject. In some embodiments, the present teachings include methods of treating aberrantly low bone density levels in a subject. In some embodiments, the present teachings include methods of treating an age-associated bone density decrease in a subject. In some embodiments, the present teachings include methods of treating osteoporosis in a subject. In some embodiments, the present teachings include methods of preventing an age- associated bone density decrease in a subject. The methods of each of these embodiments can comprise, consist essentially of, or consist of administration of a therapeutically effective amount of NMN.
In various embodiments, the inventors disclose that photoreceptor neuronal cell death and vision can be rescued by NMN administration. In various embodiments, the present inventors demonstrate that nicotinamide phosphoribosyl transferase (NAMPT)-mediated NAD biosynthesis can play a role in for rod and/or cone PR neuron survival. In various embodiments, the present inventors demonstrate that decreased NAD levels can cause impaired mitochondrial function in PR neurons, alterations in TCA cycle metabolites, and can lead to cell death and blindness.
In some embodiments, the inventors have demonstrated that deleting NAMPT can lead to photoreceptor death, loss of normal retinal structure and function, and vision loss. In some embodiments,the inventors have demonstrated that such damage to photoreceptor neurons and their function can be reversed with supplementation of nicotinamide
mononucleotide (NMN), an NAMPT enzymatic reaction product. In some embodiments, the present teachings include NMN administration to restore NAD levels in the retina. In some embodiments, NMN supplementation can be an effective therapeutic intervention for many retinal degenerative diseases. Without being limited by theory, NMN supplementation can restore retinal NAD levels.
In some embodiments, the present inventors have demonstrated in vivo using mouse models and in vitro using cell lines that photoreceptor death can be prevented by NMN supplementation. In some embodiments, methods of NMN supplementation for the prevention/treatment of many retinal degenerative diseases are disclosed.
Accordingly, in various embodiments, the inventors disclose methods of preventing, methods of reducing risk of, and methods of treating various diseases associated with photoreceptor dysfunction, including, without limitation, age-related macular degeneration (AMD), inherited and acquired retinal diseases such as, without limitation, retinitis pigmentosa (RP), rod and cone dystrophism, and Leber's congenital amaurosis (LCA) by administration of NMN. In various embodiments, NMN administration can be an effective intervention for the prevention and/or treatment of orphan retinal degenerative diseases including but not limited to rod dystrophy, cone dystrophy, retinitis pigmentosa, other inherited retinal degenerations, Leber's congenital amaurosis (LCA) and acquired retinal degenerations such as, but not limited to, age-related macular dengeration photoreceptor degeneration following retinal detachment.
In various embodiments, NMN can be administered by any administration route known to skilled artisans, such as, without limitation, oral, parenteral, intraocular,
intraperitoneal, intravenous or intramuscular routes. In various embodiments, NMN can be administered with or without an excipient.
In some embodiments, the present teachings include methods of treating macular degeneration in a subject. In some embodiments, the present teachings include methods of treating aberrant retinal NAD levels in a subject, including aberrantly low retinal NAD levels. In some embodiments, the present teachings include methods of treating retinal degeneration in a subject. In some embodiments, the present teachings include methods of treating photoreceptor damage in a subject. In some embodiments, the present teachings include methods of treating photoreceptor degeneration in a subject. In some embodiments, the present teachings include methods of treating vision loss associated with retinal degeneration in a subject. In some embodiments, the present teachings include methods of treating vision loss in a subject. In some embodiments, the present teachings include methods of treating aberrant retinal structure in a subject. In some embodiments, the present teachings include methods of treating aberrant retinal function in a subject. In some embodiments, the present teachings include methods of treating aberrant retinal function in a subject. In some embodiments, the present teachings include methods of treating aberrant retinal function in a subject. In some embodiments, the present teachings include methods of increasing retinal NAD levels in a subject. In some embodiments, the present teachings include methods of reducing risk of developing macular degeneration in a subject. In some embodiments, the present teachings include methods of reducing risk of developing macular degeneration in a subject. In some embodiments, the present teachings include methods of reducing risk of developing aberrant retinal NAD levels in a subject. In some embodiments, the present teachings include methods of reducing risk of developing retinal degeneration in a subject. In some embodiments, the present teachings include methods of reducing risk of developing photoreceptor damage/degeneration in a subject. In some embodiments, the present teachings include methods of reducing risk of developing vision loss associated with retinal
degeneration in a subject. In some embodiments, the present teachings include methods of reducing risk of developing vision loss in a subject. In some embodiments, the present teachings include methods of reducing risk of developing aberrant retinal structure in a subject. In some embodiments, the present teachings include methods of reducing risk of developing aberrant retinal structure in a subject. In some embodiments, the present teachings
include methods of reducing risk of developing aberrant retinal function in a subject. In some embodiments, the present teachings include methods of reducing risk of developing aberrant retinal function in a subject. In some embodiments, the present teachings include methods of treating a photoreceptor dysfunction in a subject. In some embodiments, the present teachings include methods of treating a retina disease in a subject. In various embodiments, these methods can comprise, consist essentially of, or consist of administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN). In some embodiments, a pharmaceutically effective amount of nicotinamide mononucleotide (NMN) can be an amount effective for increasing retinal NAD levels. In some embodiments a retina disease that can be treated by administration of NMN can be retinitis pigmentosa (RP), Leber's congenital amaurosis (LCA), rod dystrophy, cone dystrophy, rod-cone dystrophy, cone-rod dystrophy, age-related macular degeneration, photoreceptor degeneration following retinal detachments, or a combination thereof.
In various embodiments, these methods can each independently comprise, consist essentially of, or consist of administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN). In some embodiments, NMN can be administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day. In some embodiments, NMN can be administered at a dosage rate of of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, about 100 mg per day, 100 mg per day, 150 mg, about 150 mg, about 200 mg per day, 200 mg per day, about 300 mg per day, 300 mg per day, about 400 mg per day, 400 mg per day, about 500 mg per day, 500 mg per day, about 600 mg per day, 600 mg per day, about 700 mg per day, 700 mg per day, about 800 mg per day, 800 mg per day, about 900 mg per day, 900 mg per day, about 1000 mg per day, 1000 mg per day, about 1100 mg per day, 1100 mg per day, about 1200 mg per day, 1200 mg per day, about 1300 mg per day, 1300 mg per day, 1350 mg, about 1350 mg, about 1400 mg per day, 1400 mg per day, about 1500 mg per day, 1500 mg per day, about 1600 mg per day, 1600 mg per day, about 1700 mg per day, 1700 mg per day, about 1800 mg per day, 1800 mg per day, about 1900 mg per day, 1900 mg per day, about 2000 mg per day, 2000 mg per day, 2040 mg, about 2040 mg, 2250 mg, about 2250 mg, 2260 mg, about 2260 mg, 2700 mg, about 2700 mg, 2720 mg, about 2720 mg, 3400 mg, about 3400 mg, 3390 mg, about 3390 mg, 3400 mg, about 3400 mg, 3600 mg, about 3600 mg, 4080 mg, about 4080 mg, 4500
mg, about 4500 mg, 4520 mg, about 4520 mg, 5440 mg, about 5440 mg, 5650 mg, about 5650 mg, 6800 mg, about 6800 mg. or an alternation or combination thereof. In some embodiments, NMN can be administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg/kg body weight/day to 500 mg/kg body weight/day, or about 500 mg/kg body weight/day. In some embodiments, NMN can be administered at a dosage rate of about 100 mg kg body weight/day, from 100 mg/kg body weight/day to 300 mg/kg body weight/day, or about 300 mg/kg body weight/day. In some embodiments, these methods can comprise administering to a subject any of the pharmaceutically acceptable compositions of the present teachings. In some embodiments, these methods can comprise, consist essentially of or consist of administering a formulation once per day. In some embodiments, these methods can comprise, consist essentially of or consist of administering a formulation twice per day, three times per day, or four times per day. In some embodiments, these methods can comprise, consist essentially of or consist of administering a sustained-release formulation once, or at long intervals such as, without limitation, once per week, semi-weekly, or once per month.
In various embodiments, these methods can each independently comprise, consist essentially of, or consist of administering to a subject a pharmaceutically effective amount of a formulation comprising nicotinamide mononucleotide (NMN) such as, without limitation, a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a granule, a capsule, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension or solution, a non-aqueous suspension or solution, a lyophilized formulation, a suppository or a food product. In various embodiments, these methods can each independently comprise, consist essentially of, or consist of administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide by oral administration, sublingual administration, parenteral administration, administration by injection,
subcutaneous injection, intramuscular injection, intraperitoneal injection, intra-ocular injection, direct ocular contact (eye drops) or a combination thereof.
In various embodiments, a subject can be a mammal. In various embodiments, a subject can be a vertebrate, such as a mammal, a fish, a bird or a reptile. A mammal can be, without limitation, a human, a rodent, a canine, a feline, a bovine, an ovine, an equine or a porcine. In some embodiments, a subject can be a bird such as a chicken, a reptile, a fish, or other aquatic organism.
In some embodiments, the present teachings include methods of augmentation of NAD+ levels during aging with NMN administration to maintain an NSPC pool, through administration of NMN. In some embodiments, the present teachings include methods of enhancing NAD+ levels in NSPCs in a subject through administration of NMN, to preserve an endogenous NSPC population for the repair of aged, diseased, or damaged brain.
The present teachings include the following non-limiting aspects.
1. A pharmaceutically acceptable composition comprising, consisting essentially of, or consisting of: nicotinamide mononucleotide (NMN), a salt thereof and/or a prodrug therof; and
at least one pharmaceutically acceptable excipient.
2. A pharmaceutically acceptable composition in accordance with aspect 1, comprising, consisting essentially of, or consisting of a single dosage formulation.
3. A pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation is selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid and an emulsion.
4. A pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation comprises an enteric coating.
5. A pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation comprises, consists essentially of, or consists of NMN, a salt thereof and/or a prodrug thereof in an amount of about lOOmg, from 100 mg to 2000 mg, or about 2000 mg.
6. A pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation comprises, consists essentially of, or consists of NMN, a salt thereof and/or a prodrug thereof in an amount selected from the group consisting of about lOOmg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about lOOOmg, about 1 lOOmg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg and about 2000mg.
7. A pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation comprises, consists essentially of, or consists of NMN, a salt thereof and/or the prodrug thereof in an amount selected from the group consisting of 50- 150mg, 151-250mg, 251-350mg, 351-450mg, 451-550mg, 561-650mg, 651-750mg, 751- 860mg, 861-950mg, 951-1050mg, 1051-1150mg, 1151-1250mg, 1251-1350mg, 1351- 1450mg, 1451-1550mg, 1551-1650mg, 1651-1750mg, 1751-1850mg, 1851-1950mg and 1951-2000mg.
8. A pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation comprises nicotinamide mononucleotide (NMN), a salt thereof and/or a prodrug therof in an amount selected from the group consisting of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 680 mg, about 680 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1130 mg, about 1130 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1350 mg, about 1350 mg, 1360 mg, about 1360 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 2040 mg, about 2040 mg, 2250 mg, about 2250 mg, 2260 mg, about 2260 mg, 2700 mg, about 2700 mg, 2720 mg, about 2720 mg, 3400 mg, about 3400 mg, 3390 mg, about 3390 mg, 3400 mg, about 3400 mg, 3600 mg, about 3600 mg, 4080 mg, about 4080 mg, 4500 mg, about 4500 mg, 4520 mg, about 4520 mg, 5440 mg, about 5440 mg, 5650 mg, about 5650 mg, 6800 mg, and about 6800 mg.
9. A pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation comprises a liquid solution, an emulsion or a suspension.
10. A pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation is a liquid solution, an emulsion or a suspension.
11. A pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation comprises a food product.
12. A pharmaceutically acceptable composition in accordance with aspect 2, wherein the single dosage formulation is a food product.
13. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the composition is suitable for oral administration.
14. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the composition is suitable for sublingual administration.
15. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the composition is suitable for parenteral administration.
16. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the composition is suitable for administration by injection.
17. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the composition is suitable for administration by subcutaneous injection.
18. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the composition is suitable for administration by intramuscular injection.
19. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the composition is suitable for administration by intraperitoneal injection.
20. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the composition is suitable for administration by intra-ocular injection or topically to the eye (eye drops).
21. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the composition is selected from the group consisting of a tablet, a pill, powder, granules, a capsule, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension or solution, a non-aqueous suspension or solution, a lyophilized formulation, and a suppository.
22. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the at least one excipient is selected from the group consisting of a bulking agent, a tableting agent, a dissolution agent, a wetting agent, a lubricant, a coloring, a flavoring, a disintegrant, a coating, a binder, an antioxidant, a taste masking agent and a sweetener.
23. A pharmaceutically acceptable composition in accordance with aspect 22, wherein the bulking agent is selected from the group consisting of mannitol, sorbitol, sucrose and trehalose.
24. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the composition is formulated as an orally disintegrating capsule, tablet, pill or wafer.
25. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the composition is formulated as a liquid, syrup, or spray.
26. A pharmaceutically acceptable composition in accordance with aspect 1, further comprising at least one vitamin or nutrient selected from the group consisting of vitamin C, vitamin D3, vitamin E, vitamin Bl, vitamin B2, niacin, vitamin B6, folic acid, vitamin B12, pantothenic acid, biotin, magnesium, zinc, copper, selenium, chromium, alpha lipoic acid, b co-enzyme Q-10, lutein and lycopene.
27. A pharmaceutically acceptable composition in accordance with aspect 1, further comprising at least one vitamin or nutrient selected from the group consisting of from about 150 mg to about 750 mg of vitamin C, from about 315 IUs to about 1800 IUs of vitamin D3, from about 75 IUs to about 150 IUs of vitamin E, from about 15 mg to about 35 mg of vitamin Bl, from about 1.7 mg to about 5.1 mg of vitamin B2, from about 20 mg to about 50 mg of niacin, from about 20 mg to about 50 mg of vitamin B6, from about 0.5 mg to about 2.5 mg of folic acid, from about 35 meg to about 105 meg of vitamin B12, from about 2.5 mg to about 7.5 mg of pantothenic acid, from about 50 meg to about 450 meg of biotin, from about 15 mg to about 55 mg of magnesium, from about 15 mg to about 55 mg of zinc, from about 0.5 to about 1.5 mg of copper, from about 75 meg to about 175 meg of selenium, from about 75 meg to about 225 meg of chromium, from about 10 mg to about 40 mg of alpha lipoic acid, from about 20 mg to about 50 mg of co-enzyme Q-10, from about 350 meg to about 3 mg of lutein and from about 100 meg to about 750 meg of lycopene.
28. A pharmaceutically acceptable composition in accordance with aspect 1, further comprising at least one vitamin or nutrient selected from the group consisting of about 500 mg of ascorbic acid; about 400 IUs of cholecalciferol; about 125 IUs of d-alpha tocopherol succinate; about 35 mg of thiamine mononitrate; about 5.1 mg of riboflavin; about 50 mg of niacinamide; about 50 mg of pyridoxine HC1; about 2.5 mg of folic acid; about 105 meg of cyanocobalamin; about 7.5 mg of d-calcium pantothenate; about 75 meg of d-biotin; about 55
mg of dimagnesium malate; about 55 mg of zinc bisglycinate chelate; about 1.5 mg of copper amino acid chelate; about 175 meg of selenium amino acid chelate; about 225 meg of chromium amino acid chelate; about 10 mg of alpha lipoic acid; about 50 mg of co-enzyme Q-10; about 400 meg of lutein; about 125 meg of lycopene.
29. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the at least one excipient is selected from the group consisting of dicalcium phosphate,
microcrystalline cellulose, stearic acid, croscarmellose sodium, magnesium trisillicate, magnesium stearate, hydro xypropyl methylcellulose, hypromellose, titanium dioxide, tripotassium citrate, polyvinyl alcohol, fumed silica, citric acid, polyethylene glycol, talc, and any combination thereof.
30. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the at least one excipient is selected from the group consisting of from about 100 mg to about 300 mg of dicalcium phosphate; from about 25 mg to about 75 mg of microcrystalline cellulose; from about 10 mg to about 30 mg of stearic acid; from about 10 mg to about 30 mg of croscarmellose sodium; from about 5 mg to about 15 mg of magnesium trisillicate; from about 5 mg to about 15 mg of magnesium stearate; and from about 5 mg to about 15 mg of hydroxypropyl methylcellulose.
31. A pharmaceutically acceptable composition in accordance with aspect 1, wherein the at least one excipient is selected from the group consisting of about 200 mg of dicalcium phosphate; about 50 mg of microcrystalline cellulose; about 20 mg of stearic acid; about 20 mg of croscarmellose sodium; about 10 mg of magnesium trisillicate; about 10 mg of magnesium stearate; and about 10 mg of hydroxypropyl methylcellulose.
32. A sustained release formulation of nicotinamide mononucleotide for oral administration to a subject, comprising nicotinamide mononucleotide as an active ingredient that is released from the formulation along a pre-determined release profile, wherein the formulation comprises an extended release component and an immediate release component, wherein the extended release component is contained in at least one population of beads and releases nicotinamide mononucleotide in a continuous manner and each bead population is coated with its own release controlling coating and characterized by its own rate of release.
33. The formulation of aspect 32, wherein the extended release component releases the nicotinamide mononucleotide in vivo in a continuous manner, and 80% of the nicotinamide
mononucleotide is released in vitro in a period of time selected from not more than 24 hours, not more than 16 hours, not more than 12 hours, not more than 8 hours and not more than 4 hours.
34. The formulation of aspect 32, wherein the immediate release component is an enhanced immediate release (EI ) composition comprising a complexing agent, an enhancing agent, or both.
35. The formulation of aspect 34, wherein the EIR composition exhibits an in vitro release profile such that 80% of the active ingredient is dissolved in not more than 30 min.
36. The formulation of aspect 35, wherein the EIR composition exhibits an in vitro release profile selected from a group consisting of: a) a dissolution of at least 50% of the active compound in not more than 10 minutes; b) a dissolution of at least 70% of the active compound in not more than 10 minutes; c) a dissolution of at least 25% of the active compound in not more than 5 minutes; d) a dissolution of at least 40% of the active compound in not more than 5 minutes; and e) a dissolution of at least 55% of the active compound in not more than 5 minutes.
37. The formulation of aspect 34, wherein the complexing agent is a cyclodextrin selected from a group consisting of hydro xypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma- cyclodextrin, alpha-cyclodextrin, and derivatives thereof.
38. The formulation of aspect 34, wherein the enhancing agent is selected from a group comprising solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizers, enzyme inhibitors, p- glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.
39. The formulation of aspect 38, wherein the enhancing agent is selected from a group consisting of Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins, glycerolpolyethylene glycol oxystearate, PEG-32 glyceryl palmitostearate, sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitan monolaurate, Poloxamer 407, PEG3350, PVP K25, oleic acid, glyceryl monooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, HPMC, substituted hydro xypropylcellulose, micro crystalline
cellulose sodium bicarbonate, calcium citrate, sodium docusate, menthol and any combination thereof.
40. The formulation of aspect 32, wherein at least a part of the active ingredient is in a form of micronized particles.
41. The formulation of aspect 40, wherein the particles have an average size of from about 2 μηι to about 100 μιη.
42. The formulation of aspect 32, wherein a specific amount of each component is determined according to the purpose of administration and the pre-determined release profile, and the total amount of NMN in the formulation is from 0.5 to 3000 mg.
43. The formulation of aspect 32, wherein the beads comprise an inert carrier, NMN, an optional enhancer, and a release controlling coating that comprises a coating material and optionally a pore former and other excipients.
44. The formulation of aspect 43, wherein the inert carrier is selected from a group consisting of cellulose spheres, silicon dioxide, starch and sugar spheres.
45. The formulation of aspect 43, wherein the enhancer is selected from a group consisting of solubility enhancers, dissolution enhancers, permeability enhancers, stabilizers, complexing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.
46. The formulation of aspect 43, wherein the coating material is selected from a group consisting of ethylcellulose, methylcellulose, hydro xypropyl cellulose, hydro xypropylm ethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylates, polymethacrylates and copolymers thereof; and/or the pore former is selected from a group consisting of glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran, water-soluble hydrophilic polymers, hydro xyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross- linked polyvinylpyrrolidone, polyethylene oxide, Carbowaxes, Carbopol, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly(a-w)alkylenediols; inorganic compounds selected from a group consisting of alkali metal salts and alkaline earth metal salts, and combinations thereof.
47. The formulation of aspect 32, wherein an amount of each bead population is determined according to a pre-determined release profile.
48. The formulation of aspect 32, wherein the pre-determined release profile comprises a sustained rate of release after an initial immediate release.
49. The formulation of aspect 32, suitable for once a day oral administration.
50. The formulation of aspect 32, wherein at least one population of beads consists of extended release NMN beads additionally comprising an immediate release component coated on top of the release controlling coating.
51. The formulation of aspect 43, wherein the enhancer is contained in a layer separate from the release controlling coating.
52. The formulation of aspect 32, additionally comprising at least one enhancing agent, wherein the enhancing agent is incorporated into the formulation in the form of a powder or of a population of beads that are optionally characterized by a controlled rate of release, and wherein the enhancing agent is separated from the active ingredient.
53. A method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated obesity in a subject, comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
54. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day.
55. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 100 mg per day, or 100 mg per day.
56. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 200 mg per day, or 200 mg per day.
57. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 300 mg per day, or 300 mg per day.
58. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 400 mg per day, or 400 mg per day.
59. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 500 mg per day, or 500 mg per day.
60. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 600 mg per day, or 600 mg per day.
61. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 700 mg per day, or 700 mg per day.
62. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 800 mg per day, or 800 mg per day.
63. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 900 mg per day, or 900 mg per day.
64. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 1,000 mg per day, or 1,000 mg per day.
65. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 1, 100 mg per day, or 1,100 mg per day.
66. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 1,200 mg per day, or 1,200 mg per day.
67. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 1,300 mg per day, or 1,300 mg per day.
68. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 1,400 mg per day, or 1,400 mg per day.
69. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 1,500 mg per day, or 1,500 mg per day.
70. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 1,600 mg per day, or 1,600 mg per day.
71. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 1,700 mg per day, or 1,700 mg per day.
72. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 1,800 mg per day, or 1,800 mg per day.
73. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 1,900 mg per day, or 1,900 mg per day.
74. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 2,000 mg per day, or 2,000 mg per day.
75. A method in accordance with aspect 53, wherein the NMN is administered at a dosage rate of about 100 mg kg body weight/day, from 100 mg kg body weight/day to 300 mg/kg body weight/day, or about 300 mg kg body weight/day.
76. A method in accordance with aspect 53, comprising administering to a subject a formulation of any one of aspects 1-52.
77. A method in accordance with aspect 76, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
78. A method in accordance with aspect 76, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
79. A method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated increases in blood lipid levels in a subject, comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
80. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day.
81. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 100 mg per day, or 100 mg per day.
82. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 200 mg per day, or 200 mg per day.
83. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 300 mg per day, or 300 mg per day.
84. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 400 mg per day, or 400 mg per day.
85. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 500 mg per day, or 500 mg per day.
86. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 600 mg per day, or 600 mg per day.
87. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 700 mg per day, or 700 mg per day.
88. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 800 mg per day, or 800 mg per day.
89. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 900 mg per day, or 900 mg per day.
90. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 1,000 mg per day, or 1,000 mg per day.
91. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 1, 100 mg per day, or 1,100 mg per day.
92. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 1,200 mg per day, or 1,200 mg per day.
93. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 1,300 mg per day, or 1,300 mg per day.
94. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 1,400 mg per day, or 1,400 mg per day.
95. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 1,500 mg per day, or 1,500 mg per day.
96. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 1,600 mg per day, or 1,600 mg per day.
97. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 1,700 mg per day, or 1,700 mg per day.
98. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 1,800 mg per day, or 1,800 mg per day.
99. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 1,900 mg per day, or 1,900 mg per day.
100. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 2,000 mg per day, or 2,000 mg per day.
101. A method in accordance with aspect 79, wherein the NMN is administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg/kg body weight/day to 300 mg/kg body weight/day, or about 300 mg/kg body weight/day.
102. A method in accordance with aspect 79, comprising administering to a subject a formulation of any one of aspects 1-51.
103. A method in accordance with aspect 102, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
104. A method in accordance with aspect 102, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
105. A method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age- associated loss of insulin sensitivity in a subject, comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
106. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day.
107. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 100 mg per day, or 100 mg per day.
108. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 200 mg per day, or 200 mg per day.
109. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 300 mg per day, or 300 mg per day.
110. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 400 mg per day, or 400 mg per day.
111. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 500 mg per day, or 500 mg per day.
112. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 600 mg per day, or 600 mg per day.
113. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 700 mg per day, or 700 mg per day.
114. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 800 mg per day, or 800 mg per day.
115. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 900 mg per day, or 900 mg per day.
116. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 1,000 mg per day, or 1,000 mg per day.
117. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 1, 100 mg per day, or 1,100 mg per day.
118. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 1,200 mg per day, or 1,200 mg per day.
119. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 1,300 mg per day, or 1,300 mg per day.
120. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 1,400 mg per day, or 1,400 mg per day.
121. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 1,500 mg per day, or 1,500 mg per day.
122. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 1,600 mg per day, or 1,600 mg per day.
123. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 1,700 mg per day, or 1,700 mg per day.
124. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 1,800 mg per day, or 1,800 mg per day.
125. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 1,900 mg per day, or 1,900 mg per day.
125. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 2,000 mg per day, or 2,000 mg per day.
127. A method in accordance with aspect 105, wherein the NMN is administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg/kg body weight/day to 300 mg/kg body weight/day, or about 300 mg/kg body weight/day.
128. A method in accordance with aspect 105, comprising administering to a subject a formulation of any one of aspects 1- 1.
129. A method in accordance with aspect 128, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
130. A method in accordance with aspect 128, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
131. A method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age- associated impairment of memory function in a subject, comprising:
administering to a subject a pharmaceutically effective amount of nicotinamide
mononucleotide (NMN).
131. A method in accordance with aspect 130, wherein the NMN is administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day.
133. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 100 mg per day, or 100 mg per day.
134. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 200 mg per day, or 200 mg per day.
135. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 300 mg per day, or 300 mg per day.
136. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 400 mg per day, or 400 mg per day.
137. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 500 mg per day, or 500 mg per day.
138. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 600 mg per day, or 600 mg per day.
139. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 700 mg per day, or 700 mg per day.
140. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 800 mg per day, or 800 mg per day.
141. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 900 mg per day, or 900 mg per day.
142. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 1,000 mg per day, or 1,000 mg per day.
143. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 1, 100 mg per day, or 1,100 mg per day.
144. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 1,200 mg per day, or 1,200 mg per day.
145. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 1,300 mg per day, or 1,300 mg per day.
146. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 1,400 mg per day, or 1,400 mg per day.
147. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 1,500 mg per day, or 1,500 mg per day.
148. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 1,600 mg per day, or 1,600 mg per day.
149. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 1,700 mg per day, or 1,700 mg per day.
150. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 1,800 mg per day, or 1,800 mg per day.
151. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 1,900 mg per day, or 1,900 mg per day.
152. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 2,000 mg per day, or 2,000 mg per day.
153. A method in accordance with aspect 131, wherein the NMN is administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg/kg body weight/day to 300 mg/kg body weight/day, or about 300 mg kg body weight/day.
154. A method in accordance with aspect 131, comprising administering to a subject a formulation of any one of aspects 1-51.
155. A method in accordance with aspect 154, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
156. A method in accordance with aspect 154, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
157. A method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age- associated decline in eye function in a subject, comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
158. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day.
159. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 100 mg per day, or 100 mg per day.
160. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 200 mg per day, or 200 mg per day.
161. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 300 mg per day, or 300 mg per day.
162. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 400 mg per day, or 400 mg per day.
163. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 500 mg per day, or 500 mg per day.
164. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 600 mg per day, or 600 mg per day.
165. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 700 mg per day, or 700 mg per day.
166. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 800 mg per day, or 800 mg per day.
167. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 900 mg per day, or 900 mg per day.
168. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 1,000 mg per day, or 1,000 mg per day.
169. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 1, 100 mg per day, or 1,100 mg per day.
170. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 1,200 mg per day, or 1,200 mg per day.
171. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 1,300 mg per day, or 1,300 mg per day.
172. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 1,400 mg per day, or 1,400 mg per day.
173. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 1,500 mg per day, or 1,500 mg per day.
174. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 1,600 mg per day, or 1,600 mg per day.
175. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 1,700 mg per day, or 1,700 mg per day.
176. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 1,800 mg per day, or 1,800 mg per day.
177. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 1,900 mg per day, or 1,900 mg per day.
178. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 2,000 mg per day, or 2,000 mg per day.
179. A method in accordance with aspect 157, wherein the NMN is administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg/kg body weight/day to 300 mg/kg body weight/day, or about 300 mg/kg body weight/day.
180. A method in accordance with aspect 157, comprising administering to a subject a formulation of any one of aspects 1-51.
181. A method in accordance with aspect 180, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
182. A method in accordance with aspect 180, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
183. A method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing age-associated retinal degeneration in a subject, comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
184. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day.
185. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 100 mg per day, or 100 mg per day.
186. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 200 mg per day, or 200 mg per day.
187. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 300 mg per day, or 300 mg per day.
188. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 400 mg per day, or 400 mg per day.
189. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 500 mg per day, or 500 mg per day.
190. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 600 mg per day, or 600 mg per day.
191. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 700 mg per day, or 700 mg per day.
192. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 800 mg per day, or 800 mg per day.
193. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 900 mg per day, or 900 mg per day.
194. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 1,000 mg per day, or 1,000 mg per day.
195. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 1, 100 mg per day, or 1,100 mg per day.
196. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 1,200 mg per day, or 1,200 mg per day.
197. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 1,300 mg per day, or 1,300 mg per day.
198. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 1,400 mg per day, or 1,400 mg per day.
199. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 1,500 mg per day, or 1,500 mg per day.
200. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 1,600 mg per day, or 1,600 mg per day.
201. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 1,700 mg per day, or 1,700 mg per day.
202. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 1,800 mg per day, or 1,800 mg per day.
203. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 1,900 mg per day, or 1,900 mg per day.
204. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 2,000 mg per day, or 2,000 mg per day.
205. A method in accordance with aspect 183, wherein the NMN is administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg/kg body weight/day to 300 mg/kg body weight/day, or about 300 mg kg body weight/day.
206. A method in accordance with aspect 183, comprising administering to a subject a formulation of any one of aspects 1-52.
207. A method in accordance with aspect 206, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
208. A method in accordance with aspect 206, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
209. A method of treating, ameliorating, mitigating, slowing, arresting, preventing or reversing dry eye, comprising administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
210. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day.
211. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 100 mg per day, or 100 mg per day.
212. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 200 mg per day, or 200 mg per day.
213. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 300 mg per day, or 300 mg per day.
214. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 400 mg per day, or 400 mg per day.
215. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 500 mg per day, or 500 mg per day.
216. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 600 mg per day, or 600 mg per day.
217. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 700 mg per day, or 700 mg per day.
216. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 800 mg per day, or 800 mg per day.
219. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 900 mg per day, or 900 mg per day.
220. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 1,000 mg per day, or 1,000 mg per day.
221. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 1, 100 mg per day, or 1,100 mg per day.
222. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 1,200 mg per day, or 1,200 mg per day.
223. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 1,300 mg per day, or 1,300 mg per day.
224. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 1,400 mg per day, or 1,400 mg per day.
225. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 1,500 mg per day, or 1,500 mg per day.
226. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 1,600 mg per day, or 1,600 mg per day.
227. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 1,700 mg per day, or 1,700 mg per day.
228. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 1,800 mg per day, or 1,800 mg per day.
229. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 1,900 mg per day, or 1,900 mg per day.
230. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 2,000 mg per day, or 2,000 mg per day.
231. A method in accordance with aspect 209, wherein the NMN is administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg/kg body weight/day to 300 mg/kg body weight/day, or about 300 mg kg body weight/day.
232. A method in accordance with aspect 209, comprising administering to a subject a formulation of any one of aspects 1-52.
233. A method in accordance with aspect 232, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
234. A method in accordance with aspect 232, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
235. A method of increasing NAD+ levels in a subject, comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
236. A method of treating age-associated defects in NSPC functionality in a subject, comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
237. A method of maintaining at least one NSPC in a subject, comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
238. A method of enhancing NAD biosynthesis in a subject, comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
239. A method of promoting NSPC proliferation in a subject, comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
240. A method in accordance with any of aspects 235 - 239, wherein the NMN is
administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day.
241. A method in accordance with any of aspects 235 - 239, wherein the NMN is
administered at a dosage rate of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 680 mg, about 680 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1130 mg, about 1130 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1350 mg, about 1350 mg, 1360 mg, about 1360 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 2040 mg, about 2040 mg, 2250 mg, about 2250 mg, 2260 mg, about 2260 mg, 2700 mg, about 2700 mg, 2720 mg, about 2720 mg, 3400 mg, about 3400 mg, 3390 mg, about 3390 mg, 3400 mg, about 3400 mg, 3600 mg, about 3600 mg, 4080 mg, about 4080 mg, 4500 mg, about 4500 mg, 4520 mg, about 4520 mg, 5440 mg, about 5440 mg, 5650 mg, about 5650 mg, 6800 mg, and about 6800 mg.
242. A method in accordance with any of aspects 235 - 239, wherein the NMN is
administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg kg body weight/day to 300 mg kg body weight/day, or about 300 mg/kg body weight/day.
243. A method in accordance with any of aspects 235 - 239, comprising administering to a subject a formulation of any one of aspects 1-52.
244. A method in accordance with aspect 243, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
245. A method in accordance with aspect 243, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
246. A method of increasing bone density levels in a subject, comprising: administering to a subject a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
247. A method of treating aberrantly low bone density levels in a subject, comprising:
administering to a subject a pharmaceutically effective amount of nicotinamide
mononucleotide (NMN).
248. A method of treating an age-associated bone disorder in a subject, comprising:
administering to a subject a pharmaceutically effective amount of nicotinamide
mononucleotide (NMN).
249. A method in accordance with claim 284, wherein the age-associated bone disorder is osteoporosis.
250. A method in accordance with any of aspects 246 - 249, wherein the NMN is
administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day.
251. A method in accordance with any of aspects 246 - 249, wherein the NMN is
administered at a dosage rate of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 680 mg, about 680 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1130 mg, about 1130 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1350 mg, about 1350 mg, 1360 mg, about 1360 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 2040 mg, about 2040 mg, 2250 mg, about 2250 mg, 2260 mg, about 2260 mg, 2700 mg, about 2700 mg, 2720 mg, about 2720 mg, 3400 mg, about 3400 mg, 3390 mg, about 3390 mg, 3400 mg, about 3400 mg, 3600 mg, about 3600 mg, 4080 mg, about 4080 mg, 4500 mg, about 4500 mg, 4520 mg, about 4520 mg, 5440 mg, about 5440 mg, 5650 mg, about 5650 mg, 6800 mg, and about 6800 mg.
252. A method in accordance with any of aspects 246 - 249, wherein the NMN is administered at a dosage rate of about 100 mg kg body weight/day, from 100 mg kg body weight/day to 300 mg kg body weight/day, or about 300 mg/kg body weight/day.
253. A method in accordance with any of aspects 246 - 249, comprising administering to a subject a formulation of any one of aspects 1-52.
254. A method in accordance with aspect 253, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
255. A method in accordance with aspect 253, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
256. A method of treating macular degeneration in a subject, comprising administering to a subject a therapeutically effective amount of NMN.
257. A method of treating macular degeneration in a subject, comprising administering to a subject NMN in an amount effective for increasing retinal NAD levels.
258. A method of treating aberrant retinal NAD levels in a subject, comprising administering to a subject NMN in an amount effective for increasing retinal NAD levels.
259. A method of treating retinal degeneration in a subject, comprising administering to a subject NMN in an amount effective for increasing retinal NAD levels.
260. A method of treating retinal degeneration in a subject, comprising administering to a subject a therapeutically effective amount of NMN.
261. A method of treating photoreceptor damage/degeneration in a subject, comprising administering to a subject a therapeutically effective amount of NMN.
262. A method of treating photoreceptor damage/degeneration in a subject, comprising administering to a subject NMN in an amount effective for increasing retinal NAD levels.
263. A method of treating vision loss associated with retinal degeneration in a subject, comprising: administering to a subject a therapeutically effective amount of NMN.
264. A method of treating vision loss in a subject, comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
265. A method of treating aberrant retinal structure in a subject, comprising: administering to a subject a therapeutically effective amount of NMN.
266. A method of treating aberrant retinal structure in a subject, comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
267. A method of treating aberrant retinal function in a subject, comprising: administering to a subject a therapeutically effective amount of NMN.
268. A method of treating aberrant retinal function in a subject, comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
269. A method of increasing retinal NAD levels in a subject, comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
270. A method of reducing risk of developing macular degeneration in a subject, comprising: administering to a subject NMN in an amount effective for preventing macular degeneration.
271. A method of reducing risk of developing macular degeneration in a subject, comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
272. A method of reducing risk of developing aberrant retinal NAD levels in a subject, comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
273. A method of reducing risk of developing retinal degeneration in a subject, comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
274. A method of reducing risk of developing photoreceptor damage/degeneration in a subject, comprising: administering to a subject NMN in an amount effective for preventing photoreceptor damage/degeneration.
275. A method of reducing risk of developing photoreceptor damage/degeneration in a subject, comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
276. A method of reducing risk of developing vision loss associated with retinal degeneration in a subject, comprising: administering to a subject NMN in an amount effective for reducing risk of developing vision loss associated with retinal degeneration.
277. A method of reducing risk of developing vision loss in a subject, comprising:
administering to a subject NMN in an amount effective for increasing retinal NAD levels.
278. A method of reducing risk of developing aberrant retinal structure in a subject, comprising: administering to a subject NMN in an amount effective for preventing development of aberrant retinal structure.
279. A method of reducing risk of developing aberrant retinal structure in a subject, comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
280. A method of reducing risk of developing aberrant retinal function in a subject, comprising: administering to a subject NMN in an amount effective for preventing development of aberrant retinal function.
281. A method of reducing risk of developing aberrant retinal function in a subject, comprising: administering to a subject NMN in an amount effective for increasing retinal NAD levels.
282. A method of treating a retina disease in a subject, comprising: administering to a subject a therapeutically effective amount of NMN.
283. A method in accordance with aspect 282, wherein the retina disease is selected from the group consisting of retinitis pigmentosa (RP), Leber's congenital amaurosis (LCA), rod dystrophy, cone dystrophy, rod-cone dystrophy, cone-rod dystrophy, age-related macular degeneration and photoreceptor degeneration following retinal detachment.
284. A method in accordance with any of aspects 256 - 283, wherein the NMN is
administered at a dosage rate of about 100 mg per day, from 100 mg per day to 2000 mg per day, or about 2000 mg per day.
285. A method in accordance with any of aspects 256 - 283, wherein the NMN is
administered at a dosage rate of 0.5 mg, about 0.5 mg, Img, about Img, 5 mg, about 5 mg,
lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 680 mg, about 680 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1130 mg, about 1130 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1350 mg, about 1350 mg, 1360 mg, about 1360 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 2040 mg, about 2040 mg, 2250 mg, about 2250 mg, 2260 mg, about 2260 mg, 2700 mg, about 2700 mg, 2720 mg, about 2720 mg, 3400 mg, about 3400 mg, 3390 mg, about 3390 mg, 3400 mg, about 3400 mg, 3600 mg, about 3600 mg, 4080 mg, about 4080 mg, 4500 mg, about 4500 mg, 4520 mg, about 4520 mg, 5440 mg, about 5440 mg, 5650 mg, about 5650 mg, 6800 mg, and about 6800 mg.
286. A method in accordance with any of aspects 256 - 283, wherein the NMN is
administered at a dosage rate of about 100 mg/kg body weight/day, from 100 mg kg body weight/day to 300 mg kg body weight/day, or about 300 mg/kg body weight/day.
287. A method in accordance with any of aspects 256 - 283, comprising administering to a subject a formulation of any one of aspects 1-52.
288. A method in accordance with aspect 283, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation once per day.
289. A method in accordance with aspect 283, wherein the administering a formulation comprises, consists essentially of or consists of administering the formulation twice per day.
290. A method in accordance with any of aspects 32 or 53-289, wherein the subject is a mammal.
291. A method in accordance with any of aspects 32 or 53-289, wherein the subject is a human.
292. A method in accordance with any of aspects 32 or 53-289, wherein the subject is a vertebrate.
Brief Description of the Drawings
FIG. 1 illustrates structure of nicotinamide mononucleotide (NMN).
FIG. 2 illustrates age-associated body weight increase.
FIG. 3 illustrates age-associated body weight gain.
FIG. 4 illustrates oxygen consumption in control, 100 and 300 mg/kg NMN-administered mice.
FIG. 5 illustrates energy expenditure in control, 100 and 300 mg/kg NMN-administered mice. FIG. 6 illustrates respiratory quotient in control, 100 and 300 mg kg NMN-administered mice.
FIG. 7 illustrates blood levels of (A) cholesterol, (B) triglycerides and (C) free fatty acids shown over 12 months in the control and the 100 and 300 mg/kg NMN-administered cohorts. FIG. 8 illustrates body weight-matched blood levels of (A) cholesterol, (B) triglycerides and (C) free fatty acids shown over 12 months in the control and the 100 and 300 mg/kg NMN- administered cohorts.
FIG. 9 illustrates insulin tolerance shown in (A) blood glucose levels and (B) percent glucose changes in control and the 100 mg/kg and 300 mg/kg NMN-administered groups at the 12- month time point.
FIG. 10 illustrates freezing responses of regular chow-fed control, HFD-fed, and HFD-fed, NMN-treated mice in contextual and cued fear conditioning tests on Day 1, Day 2 and Day3. FIG. 11 illustrates fundus biomicroscopy images from control and NMN-administered mice. FIG. 12 illustrates electroretino grams from control and NMN-administered mice.
FIG. 13 illustrates tear production in 18 month-old control and NMN-administered mice. All values are presented as mean ± SEM. **p<0.01.
FIG. 14 illustrates hippocampal NAD+ levels and Nampt expression declining with age. A) NAD+ biosynthesis from nicotinamide. B) HPLC analysis of NAD+ levels in
hippocampal extracts. C-D) Quantification of immunofluoresence for Nampt in the subgranular zone (SGZ). Measurement of thresholded levels of Nampt immunore activity (C) and the number of highly immunoreactive Nampt+ cells (D) along the SGZ. E)
Representative images of immunofluorescence for Dapi and Nampt in the SGZ in young (6 months old) and old (18 months old) mice.
FIG. 15 illustrates that Nampt is expressed in a subpopulation of SGZ NSPCs. A-C)
Representative fluorescence images for Dapi (original blue), Nampt (original red), and NSPC markers (Sox2, Gfap, and NestinGFP 3 days post tamoxifen injection; original green) in the SGZ. Dotted lines denote the SGZ. D) Quantification of the percentages of NSPC marker- positive cells in the SGZ that also express Nampt in 3 to 6 month old mice.
FIG. 16 illustrates that adult NSPC-specific deletion of Nampt impairs NSPC proliferation and self-renewal in vivo. A) To assess proliferation, iNSPC-Nampt-KO mice and littermate controls were subjected to three rounds of 5 tamoxifen (TAM) injections (1 injection per day, 6 weeks apart). Sacrifice was performed at 6 months of age. B) A scheme for the specificity of the markers assessed. C-F) Quantification of radial Nestin+ NSPCs (n=15-16 mice) (C), BrdU+ proliferating cells (n=14-16 mice) (D), Ki67+ proliferating cells (n=7 mice) (E), and newborn neurons (Dcx+, n=15-20 mice) (F), per unit area of the dentate gyrus (DG) in control and iNSPC-Nampt-KO mice. For BrdU labeling, 4 injections of BrdU at 100 mg kg body weight were given intraperitoneally over 48 hours. G) Representative images of immunofluorescence for Gfap (original blue), Dcx (original green), and BrdU (original red) in the subgranular zone (SGZ). Scale bar denotes 200 μηι. H) To assess differentiation, control littermates and iNSPC-Nampt-KO mice were subjected to 4 total TAM injections (2 injections on the first day coupled with BrdU at 100 mg/kg body weight as well as 2 total injections on the subsequent 2 days). I) Quantification of the percentage of BrdU+ cells in the DG that also express markers of NSPCs (Gfap+, Nestin+), newborn neurons (Dcx+), and OPCs/oligodendrocytes (OHg2+) (n=6-13 mice). J) Quantification of radial Nestin+ NSPCs in 6 and 18 month-old C57B16 mice and 18 month-old C57B16 mice treated with 100 or 300 mg/kg body weight NMN in their drinking water for 12 months (n=5 mice). Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***p < 0.001.
FIG. 17 illustrates that inhibition of Nampt in NSPCs in vitro impairs NAD+ biosynthesis and proliferation. Neurospheres were cultured with the Nampt-specific inhibitor FK866 (10 nM) with or without NMN (100 μΜ) for 48 hours. A) HPLC analysis of NAD+ levels (n=6). B) Quantification of the fold increase of cell number in neurospheres (n=6-30). C)
Representative bright-field image of neurospheres. Scale bar denote 10 μηι. D) Cell cycle- related pathways among the top 50 biological pathways downregulated by FK866. Parametric analysis of gene enrichment (PAGE) was conducted based on microarray analyses. See the Methods section. E) Quantitative RT-PCR results for mRNA expression of cyclin E2
(Ccne2), cyclin El (Ccnel), cyclin A2 (Ccna2), and E2F1 (n=3). F) FACS analysis of FK866-treated NSPCs (n=8). Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***P < 0.001.
FIG. 18 illustrates that genetic ablation of Nampt in NSPCs in vitro impairs NAD+ biosynthesis, proliferation, and differentiation. Neurospheres were isolated from Nampt^™ mice and infected with a Cre-recombinase expressing adenovirus (Nampt AD-Cre) or a control adenovirus expressing LacZ (Nampt AD-LacZ). A) HPLC analysis of NAD+ levels
with and without NMN (100 μΜ, 48 hours) (n=10-22). B-C) Quantification of the fold increase in cell number (n=13-50) and neurosphere diameter (n=9 independent samples, 57- 96 neurospheres). D) Representative images of neurospheres 7 days after dissociation. Scale bars denote 10 μιη. E) The number of neurospheres formed 7 days after plating dissociated cells at 100 cells/ml, 0.5 ml/well in 24-well plates (n=8 independent samples, 48-84 wells). F- G) Nampt Ad-Cre and Nampt AD-LacZ infected neurospheres were cultured without NMN until Nampt Ad-Cre infected neurospheres exhibited a growth defect. Cultures were then passaged and plated at equal density with or without NMN (200 μΜ). Fold increases in cell number (F) (n=6), and the percentages of total Dapi+ cells that express Ki67+ cells were quantified (G) (n=3 independent samples, 9 fields of view). H-L) The percentages of total Dapi+ cells that express the indicated cell type-specific markers (H) by immunoflorescence after 6-7 days of differentiation: 04 (I), Gfap (J), and B-III-tubulin (K) (n=3-6 independent samples, 23-43 fields of view). The effect of NMN was also examined for 04, S 100p, TUNEL, and Nestin (L) (n=3-6 independent samples, 10-26 fields of view). *, Λ, and # indicate statistical significance between Nampt AD-LacZ and Nampt AD-Cre, Nampt AD- LacZ and Nampt AD-LacZ +NMN, and Nampt AD-Cre and Nampt AD-Cre+NMN, respectively. Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***p < 0.001.
FIG. 19 illustrates that genetic ablation of Nampt in vitro impairs OPC formation. A) A scheme for oligodendrocyte differentiation with stage-specific markers. B-C) Neurospheres were infected with a Cre recombinase-expressing adenovirus (Nampt AD-Cre) or a control adenovirus expressing LacZ (Nampt AD-LacZ). To assess oligodendrocyte formation, dissociated neurospheres were harvested after 6-7 days of differentiation (B). To assess OPC formation, dissociated neurospheres were examined after 2 days of differentiation (C).
Markers of NSPCs (Gfap, Nestin), OPCs (Pdgfra+), and oligodendrocyte lineage cells (01ig2+, 04+) were assessed (n=3-9 independent samples, 6-51 fields of view). D) Treatment of dissociated neurospheres with the selective inhibitor of Sirtl, EX527 (80 μΜ) or the selective inhibitor of Sirt2, AGK2 (10 μΜ). The formation of oligodendrocytes was evaluated after 6-7 days of differentiation (n=6-l 1 independent samples, 21-32 fields of view). E-G) Knockout and control neurospheres were formed by infecting with a Cre- recombinase expressing adenovirus or a control adenovirus expressing LacZ, respectively. E) Neurospheres were isolated from Sirtl^^mice and Sirtl -/?OJc/^;Sirt2-/- mice. The formation of oligodendrocytes was evaluated after 6-7 days of differentiation (n=3-l 1 independent samples, 12-28 fields of view). F-G) Neurospheres were isolated from
Nampt^^mice (F, n=8-9) or Sirtl■/¾n¾3fo*;Sirt2-/- mice (G, n=3-7) and differentiated for 2
days. Quantitative T-PC results for mRNA expression of oligodendrocyte lineage genes. Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***P < 0.001.
FIG. 20 illustrates adult NSPC-specific deletion of Nampt impairs NSPC self-renewal and differentiation in response to insult-induced demyelination in vivo. A) Quantification of the percentage of NestinGFP-positive cells in the SVZ that also express Ohg2 in iNSPC-GFP (n=7) and iNSPC-Nampt-KO (n=8) mice 7 days post initial TAM injection. B) 6- to 9-week- old iNSPC-GFP control and iNSPC-Nampt-KO mice were fed a diet containing 0.2% cuprizone for 4-5 weeks. Deletion of Nampt in the adult Nestin+ population was induced by 5 tamoxifen (TAM) injections at 180 mg kg body weight per day the week before starting the cuprizone diet. C) A scheme of a coronal mouse brain section. Original red boxed areas indicate regions used for quantification. Original red dotted line indicates the SGZ. CC, corpus callosum; DHC, dorsal hippocampal commissure; DG, dentate gyrus; HPF, hippocampal formation; SCZ, subcallosal zone; SGZ, subgranular zone; V3, third ventricle. D) Quantification of the number of NestinGFP+ cells per unit area in the CC. E) A scheme for the specificity of the markers assessed. F-I) Quantification of the percentages of
NestinGFP+ cells that express NSPC markers (Nestin, Gfap) or oligodendrocyte markers (SoxlO, Ape) in the CC (n=2-l l mice). * and Λ indicate statistical significance between iNSPC-GFP control littermates and iNSPC-Nampt-KO mice and between regular chow- and cuprizone-fed iNSPC-GFP mice, respectively. J) Representative images of
immunoflorescence for Dapi (blue), Nampt (red), and Ohg2 (green) in the CC. Arrows indicate examples of colocalization. Scale bars denote 20 μιη. Data are presented as mean ± s.e.m. *P < 0.05. **, ΛΛΡ < 0.01. ***, ΛΛΛΡ < 0.001.
FIG. 21 illustrates a model for the role of Nampt-mediated NAD biosynthesis in NSPCs. Nampt-mediated NAD+ biosynthesis promotes NSPC self-renewal, proliferation and differentiation into oligodendrocytes. While the mechanism by which Nampt promotes self- renewal and proliferation remains unidentified, Nampt-mediated NAD+ biosynthesis activates Sirtl and Sirt2 to promote NSPC oligodendrocyte lineage fate decisions by a mechanism involving transcriptional downregulation of Pdgfra, SoxlO, and Nkx2.2 and transcriptional upregulation of p21 icdknld). Sirtl and Sirt2 may act via an effect on 01ig2 activity. See text for a detailed discussion.
FIG. 22 illustrates Nampt expressed in a subpopulation of SGZ NSPCs. A-C, H-I)
Representative images of immunofluorescence for Dapi (blue), Nampt (red), and cell type specific markers (NeuN: mature neurons, SlOOp: mature astrocytes, Ki67: proliferating
cells, 01ig2: oligodendrocyte lineage cells; green) in the subgranular zone (SGZ). Dotted lines denote the SGZ. Single arrowheads indicate examples of colocalization. Double arrowheads indicate examples of non-colocalization. Scale bars denote 10 μιη. B) Zoom of boxed region shown in A). D) A scheme for the specificity of the markers assessed. E) Percentage of Dapi+ cells that express the neuronal marker NeuN in the SGZ (n=5). F) Percentage of Dapi+ cells that express the NSPC marker Sox2 in the SGZ (n=5). G)
Quantification of the percentages of marker-positive cells that also express Nampt in the SGZ (Ki67: n=304 cells from 13 mice; 01ig2: n=122 cells from 10 mice).
FIG. 23 illustrates that adult NSPC-specific deletion of Nampt impairs NSPC proliferation and self-renewal in vivo. A-F) iNSPC-Nampt-KO and littermate control (iNSPC-GFP) mice were injected with tamoxifen (TAM) or vehicle (5 total injections, 1 injection per day). A-B) Representative images of immunofluorescence for Dapi (blue), activated caspase 3 (red), and NestinGFP (green) in the indicated brain regions at 28 (A) or 3 (B) days post TAM injection. Arrows highlight the rare activated caspase 3+ cells observed. Scale bars denote 50 μιη. A) Control iNSPC-GFP mice were treated with oil or TAM to ensure that there was no leaky NestinGFP reporter expression. B) iNSPC-Nampt-KO or iNSPC-GFP mice were treated with TAM. C) Recombination-confirmatory PCR performed on hippocampal DNA from TAM treated iNSPC-Nampt-KO (KO) and control mice (n=7-8). D) Quantification of the percentages of NestinGFP-positive cells in the SGZ that also express NSPC (Sox2: n=190 cells from 7 mice; Gfap: n=208 cells from 7 mice) or neuronal (Dcx, NeuN, n=473 cells from 7 mice) markers in 3 to 6 month old iNSPC-GFP mice 7 days post initial TAM injection. E) Quantification of the percentages of NestinGFP-positive cells that also express Nampt in iNSPC-Nampt-KO and iNSPC-GFP mice in the DG at the indicated days post initial TAM injection (n= more than 350 cells from 7 mice). F) Newborn neurons (Dcx+, n=12-16) were categorized by the length of their projection per unit area of the dentate gyrus (DG). G) Mice were injected with NMN (500 mg kg body weight, IP), and hippocampal NAD+ levels were measured by HPLC at the indicated time points post injection (n=3-9). H-I) Mice were administered NMN (100 or 300 mg/kg body weight) in their drinking water from 6 to 18 months of age.
FIG. 24 illustrates that inhibition of Nampt in NSPCs impairs NAD+ biosynthesis and proliferation in vitro. Neurospheres were cultured with the Nampt-specific inhibitor FK866 (10 iiM) with or without NMN (100 μΜ) for 24 (A-B) or 48 hours (C-G). A) HPLC analysis
of NAD+ levels (n=6). B) Quantification of the fold increase of cell number in neurospheres under each condition indicated (n=5-l l). C) A representative immunoblot of FK866-treated neurospheres. D-E) Quantification of immunoblots for Ki67 (D) and Pcna (E) normalized by actin in neurospheres (n=6). F-G) Top 50 biological pathways downregulated (F) or upregulated (G) by FK866.
FIG. 25 illustrates genetic ablation of Nampt in NSPCs in vitro impairs NAD+ biosynthesis, proliferation, and differentiation. A-G) Neurospheres were isolated from Namptflox/flox mice and infected with a Cre-recombinase expressing adenovirus (Nampt AD-Cre) or a control adenovirus expressing LacZ (Nampt ADLacZ). A) Quantitative RT-PCR results for mRNA expression of Nampt in AD-LacZ and Nampt Ad-Cre infected neurospheres (n=3-33). B) Representative immunoblots for Nampt and Gapdh. C) Quantification of immunoblots for Nampt in neurospheres normalized by Gapdh (n=4-13). D) HPLC analysis of NAD+ levels. NAD+ levels in Nampt Ad-Cre infected neurospheres were normalized by NAD+ levels in Nampt Ad-LacZ infected neurospheres (n=4-9). E) Representative immunoblots of Nampt Ad-Cre or Nampt AD- LacZ infected neurospheres 8 days post infection for markers of cell death (activated caspase 3) and proliferation (Ki67, Pcna). Neurospheres were grown under proliferation conditions (left blot) or differentiated for 2 days (right blot). F)
Immunoflorescence analysis of dissociated neurospheres cultured in proliferation media. Histogram shows the percentages of activated caspase 3+ (n=3 independent samples, 6 fields of view) or TUNEL+ cells (n=9 independent samples, 14-21 fields of view) relative to the total number of Dapi+ cells. G) A scheme for the non-directed lineage differentiation protocol used.
FIG. 26 illustrates A) A scheme for the oligodendrocytic lineage differentiation protocol used. B) Histogram shows the percentages of Dapi+ cells that express markers of NSPCs (Gfap, Nestin), OPCs (Pdgfra+, 01ig2+), and astrocytes (S lOOp) (n=3-12 independent samples, 6-30 fields of view). C) A representative immunoblot for Sirt2 in neurospheres cultured as NSPCs (with EGF, FGF) or OPCs (with EGF, FGF, PDGFaa) before and after differentiation. D) Immunoflorescence for Dapi (original blue), Nampt (original red), and Sirt2 (original green) along the SGZ. Dotted lines denote the SGZ. Single arrowheads indicate examples of colocalization of cell immunore activity. Scale bar denotes 10 μηι. E-F) Immunoflorescence for Dapi (blue), Sirt2 (red), and NestinGFP (original green, 3 days post TAM) along the SGZ. Dotted lines denote the SGZ. E) Scale bar denotes 50 μηι. F) Scale bar
denotes 20 μιη. G-H) Neurospheres were isolated from Sirtl flox/flox mice and infected with a Cre recombinase-expressing adenovirus (Sirtl AD-Cre) or a control adenovirus expressing LacZ (Sirtl AD-LacZ). G) Quantitative RT-PCR results for mRNA expression of Sirtl (n=17-24). H-J) Quantification of the fold increase in cell number (n=5-20). Neurospheres were derived from full body Sirtl KO mice (I), Sirt2 KO (J) mice, and their respective littermate controls.
FIG. 27 illustrates adult NSPC specific deletion of Nampt impairs NSPC self-renewal in response to insult-induced demyelination in vivo. A) Representative images of
immunofluorescence for Dapi (blue), Nestin (red), and NestinGFP (green), and in regular chow (RC) and cuprizone fed (CUPR) mice in the indicated regions of the brain: SGZ, subgranular zone; SVZ, subventricular zone; CC, corpus callosum. Scale bars denote 20 μιη. B) Representative images of immunofluorescence for Dapi (blue), MBP (red), and
NestinGFP (green) in regular chow- and cuprizone-fed mice before and after 1 week of recovery in the SGZ. Scale bars denote 20 μηι. C-G) Quantification of the number of NestinGFP+ cells per unit area of the dentate gyrus (C) and percentages of NestinGFP+ cells that express NSPC markers (Nestin, Gfap) or oligodendrocyte markers (Sox 10, Ape) in the SGZ (D-G) (n=5-12 mice). * and Λ indicate statistical significance between iNSPC-GFP control littermates and iNSPC-Nampt-KO mice and between regular chow- and cuprizone- fed iNSPCGFP mice, respectively. H) Representative images of immunoflorescence for Dapi (blue), Nampt (red), and Sox2 (green) in the CC. Arrows indicate examples of colocalization of immunore activity. Scale bars denote 20 μηι.
FIG. 28 illustrates the NAD biosynthetic pathway from nicotinamide. (A) The rate-limiting step catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). Nic, nicotinamide; PRPP, 5'-phosphoribosyl-l -pyrophosphate; NMN, nicotinamide mononucleotide; PPi, pyrophosphate. (B) The NAD biosynthetic pathway from nicotinamide.
FIG. 29 illustrates bone mineral density (BMD) in control and NMN -treated mice at the 12- month time point measured by dual-energy X-ray absorptiometry (DXA).
FIG. 30 illustrates (A-B) retinas from NAMPT rod-CKO mice showed a significant reduction of NAMPT within rods by PCR, immunohistochemistry and immunoblotting. (C)
Neurosensory retinal degeneration was associated with secondary atrophy and pallor of the optic nerve. (D-F) Electroretinography (ERG) was performed to measure PR neuron and retinal function. (G) Photopic visual acuity measurements confirmed vision loss in rod-CKO mice. (H) Histopathologic examination of eyes from NAMPT rod-CKO mice. (I) Normalized
NAD measurements obtained from NAMPT rod-cko whole retinas. (J-L) CKO mice treated with NMN showed significant rescue of photopic and scotopic function
FIG. 31 illustrates (A) NAMPT cone-CKO mice (B-D) ERG demonstrated progressive decline in cone function. (E) Significant decrease in visual acuity in cone-CKO mice. (F-H)
ERG function compared to PBS treated cone-CKO mice. (I- J) FK866 treatment of cone cells in vitro causes decrease in intracellular NAD levels and significant cell death after the 4 hours of treatment. (TK) NMN (100 μΜ) was able to completely rescue cells.
FIG. 32 illustrates (A- J) Retinal and PR neuron structure and function. (K-L) Examination of mice that had normal retinal structure and function.
FIG. 33 illustrates (A-B) Electron microscopic examination. (C) Role of NAD in NAMPT- mediated effects on PR neurons.
FIG. 34 illustrates NMN treatment effect on littermate controls.
FIG. 35 illustrates retinal and PR neuron structure and function.
FIG. 36 illustrates changes in inner segments could be identified in rod-CKO mice.
Detailed Description
Abbreviations
BMD: Bone mineral density
CC: Corpus callosum
DG: Dentate gyrus
DXA: Dual-energy X-ray absorptiometry
EIR: Enhanced immediate release
ERG: Electroretinography
FFA: Free fatty acid
HFD: High fat diet
NMN: Nicotinamide mononucleotide
OPC: Oligodendrocyte precursor cells
PR: Photoreceptor
SGZ: Subgranular zone
SVZ: Subventricular zone
Methods
The methods and compositions described herein utilize laboratory techniques well known to skilled artisans, and can be found in laboratory manuals such as Sambrook, J., et
al, Molecular Cloning: A Laboratory Manual, 3rd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2001; Spector, D. L. et al, Cells: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1998; Nagy, A., Manipulating the Mouse Embryo: A Laboratory Manual (Third Edition), Cold Spring Harbor, NY, 2003 and Harlow, E., Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999. Methods of administration of pharmaceuticals and dosage regimes, can be determined according to standard principles of pharmacology well known skilled artisans, using methods provided by standard reference texts such as Remington: the Science and Practice of Pharmacy (Alfonso R. Gennaro ed. 19th ed. 1995); Hardman, J.G., et al, Goodman & Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, 1996; and Rowe, R.C., et al, Handbook of Pharmaceutical Excipients, Fourth Edition, Pharmaceutical Press, 2003. As used in the present description and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context indicates otherwise.
The following Methods are applicable to Examples 1-7
Administration of NMN through Drinking Water and Determination of NMN Stability and Toxicity
A 12 month-long NMN administration study using wild-type mice under a regular chow-fed condition was conducted. NMN was administered through drinking water, and two doses of NMN, 100 and 300 mg/kg body weight/day, were tested. The stability of NMN was examined in drinking water and found that NMN was stable in solution. No significant degradation was observed at room temperature. Water intake was also monitored very carefully, and the water intake did not change significantly through the experimental period. To assess beneficial and possible adverse effects of NMN, a variety of physiological parameters were periodically monitored, including body weight, body temperature, food and water intake, fed and fasted blood glucose levels, fed and fasted plasma lipid panels, and glucose and insulin tolerance, in NMN-administered and control mice. Blood chemistry, blood cell counts, urine strip test, and other physiological tests including physical activity test were also checked. Based on all these assessments, no adverse effects, such as malnutrition, or signs of toxicity were observed in either of the 100 mg kg or 300 mg/kg groups.
Memory Function Study
Two groups of wild-type C57BL/6 mice at ~2 months of age were fed a high fat diet (HFD) containing 42% of the total calories from fat (TD88137; Harlan Taklad). NMN at a
dose of 300 mg kg/day began to be administered through drinking water to one of the HFD- fed groups after 4 months of HFD feeding. The control group was fed a regular chow. After 8 months of HFD feeding with or without 4 months of NMN treatment, the contextual fear conditioning test, a sensitive test to examine the memory function that involves the hippocampus, was conducted for mice in these three groups.
The following Methods are applicable to Examples 8-15
Mice
Mice were maintained on a regular chow ad libitum on a 12 hr light/dark cycle (lights on from 6 am to 6 pm). Namptflox/flox mice (Rongvaux et al, 2008), in which exons 5 and 6 of the Nampt gene are flanked by loxP sites, were crossed to Nestin-CreERT2 mice (Lagace et al, 2007) to generate Nampt flox/+; Cre double heterozygous mice. Double heterozygous mice were bred to Namptflox/flox mice to obtain Namptflox/flox; Cre mutant mice (iNSPC-Nampt-KO mice) in the expected Mendelian ratio. To trace the progeny of adult NSPCs and to confirm the specificity and magnitude of the recombination induced by tamoxifen injection, iNSPC-Nampt-KO and Nestin-CreERT2 mice were crossed to a reporter mouse strain that expresses a loxP-flanked STOP cassette that prevents transcription of the downstream enhanced green fluorescent protein [ZsGreenl; Jackson laboratories #7906 (Madisen et al, 2010)]. Recombination PCR on hippocampal extracts of tamoxifen or vehicle treated mice showed successful deletion upon treatment with tamoxifen (FIG. 23C)
Induction of Nampt Deletion
Tamoxifen injections were performed as described previously (Lagace et al, 2007). Briefly, iNSPC-Nampt-KO mice (5-7 weeks old) were administered tamoxifen (TAM, Sigma T5648) at 180 mg/kg/d for 5 days (d, intraperitoneally; dissolved in 10% EtOH/ 90% sunflower oil), a protocol that produces maximal recombination with minimal lethality (5%) (Lagace et al, 2007).
BrdU Incorporation
5'-bromodeoxyuridine (BrdU, Sigma, B9285) was diluted in sterile saline and administered by intraperitoneal injections (100 mg/kg body weight). For analysis of the cumulative effects of loss of Nampt, mice were given BrdU twice a day for 2 days and sacrificed the following day or 28 days later. For analysis of the effect of loss of Nampt on
adult NSC differentiation and postnatal oligodendrocyte differentiation, mice were given BrdU twice a day for 1 day and sacrificed 2 days later.
Cuprizone
Demyelination was induced by feeding 6 to 8- week-old mice a diet containing 0.2% cuprizone (bis-cyclohexanone oxaldihydrazone; Sigma C9012) mixed into a ground standard rodent chow for 4 to 5 weeks (Harlan Laboratories, TD.01453). To allow recovery from cuprizone treatment, food was replaced with standard chow for an additional 1 week. This protocol has been shown to successfully demyelinate and remyelinate the
hippocampus (Skripuletz et al, 2011).
Immunoflorescence
All tissue sections were and cells incubated in blocking/permeabilization solution containing 10% normal goat serum, 1% BSA, and 0.3% Triton-X in PBS for 45 to 60 min prior to 24 or 48 h of incubation with primary antibodies in 5% normal goat serum and 0.1% Triton-X in PBS at 4°C at the concentrations listed below. Alexa627, Alexa488, or Cy3 conjugated-secondary antibodies diluted in 2% normal goat serum, 1% BSA, and 0.1% Triton-X in PBS were added for 2 h at room temperature. Nuclei were stained with 4,6- diamidino-2-phenylindole (Sigma) for 10 min at room temperature.
Cells were harvested by fixation with 4% paraformaldehyde in PBS (15 min). Mice were anesthetized by i.p. injection of ketamine and xylazine, and perfused trans cardially through left ventricle with cold 0.1 M phosphate buffer at pH 7.4 followed by a phosphate- buffered solution of 4% paraformaldehyde (PFA). Brains were postfixed with 4% PFA overnight and placed into 15% sucrose followed by 30% sucrose, frozen, and stored at -80°C until use. Coronal sections (30 μηι) were made by cryostat in a 1 in 8 series and stored at - 30°C in cryoprotectant until use. To remove any endogenous peroxidase activity, all sections were incubated with 3% H202 for 10 min. Tissue sections used to assess BrdU incorporation were treated before the immunostaining procedure with 50% formamide in 2x saline/sodium citrate (SSC) at 65°C for 2 h, 2N HC1 for 30 min at 37°C, 0.1 M borate pH 8.5, and then washed twice with PBS before proceeding with the staining protocol. Tissue sections not used to assess BrdU incorporation were either incubated in 50% formamide in 2x saline/sodium citrate (SSC) at 65°C for 2 h or 10 mM citrate buffer at 65°C for 1 h before proceeding with the staining protocol. Detection of Dcx, Nestin, Nampt, and APC was performed using the TSA-Plus fluorescein kit (PerkinElmer).
Quantification
For tissue sections, high-magnification (20x, 0.8DICII or 40x oil 1.3DICII) microscopic imaging was performed using a Zeiss Axioimage.Zl. Images were taken in z- stacks of 1 μιη steps through the range of tissue section immunoreactivity. For the
dorsolateral corner of the SVZ, images were taken from bregma l. lO to -0.10 mm. For the corpus callosum, images were taken from bregma -1.06 to -2.54 mm. For the dentate gyrus, images were taken from bregma -1.34 to -3.64 mm. Quantification was performed blinded to genotype on 3-8 tissue sections per animal. Cell densities were estimated by the number of immunore active cells divided by the area of the structure, measured with ImageJ. Verification of colocalization was achieved by importing stacks of Z images into ImageJ and performing 3D rendering. For cells, 10 or 20x microscopic imaging was performed using a Zeiss
Axioimage.Zl. Quantification was performed blinded to genotype on 2 to 3 fields of view per sample and treatment, from 3 to 9 independent samples.
NAD+ Measurement
NAD+ levels were determined using an HPLC system (Shimadzu) with a Supelco LC-18-T column (15cm x 4.6cm; Sigma), as described previously (Yoshino et al, 2011).
Microarrays and Bioinformatic Analyses
For individual genes, raw microarray data were subjected to Z score transformation, and Z ratios were calculated as described previously (Cheadle et al, 2003). Subsequent analysis and Parametric Analysis of Gene Set Enrichment (PAGE) analysis was performed as previously described (Yoshino et al, 2011). The microarray data used in this study has been deposited into the NCBI GEO database (GEO accession number GSE49784).
Western Blotting
Protein extracts (15-50 μg) from mouse hippocampi or neurospheres were prepared as previously described (Yoshino et al, 2011).
Quantitative Real-Time RT-PCR
Total RNA was extracted from the hippocampus using an RNeasy kit (Qiagen) and reverse-transcribed into cDNA with a High Capacity cDNA Reverse Transcription kit (Applied Biosystems). Quantitative real-time RT-PCR was conducted with the TaqMan Fast
Universal PC Master mix and appropriate TaqMan primers for each gene with the
GeneAmp 7500 fast sequence detection system (Applied Biosystems). Relative expression levels were calculated for each gene by normalizing to Gapdh levels and then to a control.
Reagents
The following primary and secondary antibodies were used:
Primary antibodies and their uses or cell type specificities (See von Bohlen und Halbach, 2011): Actin: normalization, WB 1:4000 CPOl, Sigma; Gapdh: normalization, WB 1 :4000 6C5 Millipore CBIOOI; Nampt: IHC 1 : 1000; WB 1:3000 Alexis Biochemicals ALX- 804-717-C100; Pdgfra: oligodendrocyte precursor cells, IF 1:500 APA5 BD Biosciences; Ohg2: all oligodendrocyte lineage cells, IHC 1 :500, IF 1 : 1000; Millipore; 04: immature oligodendrocytes, IF 1 : 1000 Millipore, MAB345; APC: oligodendrocytes, IHC 1 : 1000 Millipore CC-1 OP80; MBP: mature oligodendrocytes, IHC 1: 1000 Millipore MAB386; Ki67: proliferating cells, IHC, IF 1:500; WB 1 :3000 Abeam ab66155; Pcna: proliferating cells, WB 1:2000; PC10 Cell signaling #2586; 5-bromo-2'-deoxyuridine (BrdU): a thymine analog that incorporates into the DNA of cells in S phase, IHC 1 :500; OBT0030 Accurate; Activated caspase 3: apoptosis, IHC, IF 1:500; Cell Signaling #9661; LC3B: autophagy, WB 1 : 1000; Novus NB600-1384; TUNEL: cell death, Roche In Situ Cell Death Detection Kit 11 684 795 910; Dcx: newly born neurons, IHC 1 : 1000; Cell Signaling #4604; NeuN: mature neurons, IHC, 1:500, Millipore, MAB377; Nestin: NSPCs, IHC, IF 1 : 1000, Millipore MAB353; Sox2: NSPCs, IHC, IF 1 :500; WB 1 :2000; Millipore AB5603; Gfap: NSPCs and astrocytes, IHC, IF 1: 1000; Millipore MAB360;
Secondary antibodies: Jackson ImmunoResearch anti-rat, anti-rabbit, anti-mouse Cy3 (1 :400), Alexa Fluor488 (1:200), and Alexa Fluor647 (1 :200). Anti-rabbit, anti-mouse horseradish peroxidase (Invitrogen).
FK866 (Hasmann & Schemainda, 2003) (Sigma F8557), EX527 (Peck et al, 2010) (Cayman Chemical 10009798), and AGK2 (Outeiro et al, 2007) (Sigma A8231) were dissolved in DMSO and used to inhibit Nampt, Sirtl, and Sirt2 respectively.
Neuro sphere Culture
Neurosphere cultures and culture media were prepared as described by Dasgupta & Gutmann, 2005 and Lu & Ramanan, 2012 with the following minor modifications. Briefly, postnatal hippocampi were dissected in Hibernate A (Invitrogen, A12475-01) and trypsinized at 37°C for 7 m. Cells were mechanically dissociated by pipetting and pelleted by
centrifugation (1700 rpm, 7 min). Dissociation medium (0.1% sodium bicarbonate, 15 mM HEPES, 0.5% glucose in HBSS) was used to wash the cells before they were resuspended in growth medium. Growth medium consisted of DMEM:F12 (1 : 1, Invitrogen 11966-025 and 21700-075, respectively), B27 (Invitrogen, 17504-044), N2 (Invitrogen, 17502-048), Pen/Strep (Invitrogen), epidermal growth factor (EGF, 20 ng/ml, Sigma, E4127), fibroblast growth factor (FGF, 10 ng mL, R&D Systems, 233-fb), and heparin (Sigma). Cultures were maintained at 37°C with 5% C02, and passaged twice before use in experiments. Three to nine independent samples, each in 1 to 3 replicates, from at least two different litters, were used in all experiments. Neurospheres were cultured in the physiological glucose level of 5 mM (Dienel & Cruz, 2006), which has been previously shown to have no negative consequences on NSPC proliferation, differentiation, or death (Fu et al, 2006; Gao & Gao, 2007).
Neurosphere Infection
Neurospheres derived from Nampt^^mice were infected with Ad5 Cre recombinase- or b-galactosidase -expressing (LacZ, control) adenoviruses at an MOI of 100. All assessments were performed at least 6 days post infection.
Neurosphere Proliferation Analysis
Neurospheres derived from Nampt^^mice were dissociated by trypsin digestion and seeded at similar cell densities in 24-well plates with fresh growth medium. Every 24 hours, neurospheres from triplicate wells were collected, dissociated, and counted on a hemocytometer using 0.2% trypan blue exclusion to distinguish viable cells. For analysis of neurosphere diameter, the largest neurosphere in each well was imaged (20x objective) and the diameter was calculated using Image J. For secondary neurosphere analysis, the total number of neurospheres in each well was counted at 7 days post-plating.
Neurosphere Differentiation
Three to five days after their first passage, neurospheres were trypsinized, washed with dissociation medium, and plated at 150,000 cells per well in 24-well plates in differentiation medium [growth medium without FGF and EGF and with BDNF (5 ng mL, Peprotech, 450-02) on glass coverslips coated with poly-D-lysine (50 ug/mL; Sigma) and laminin (20 ug/mL; BD Biosciences)]. 6-well plates were coated with poly-D-lysine (20 ug/mL) and laminin (10 ug/mL). To enrich for oligodendrocytes, PDGFIl Π (10 ng/ml,
Peprotech 100-13A) was added to neurospheres at passage 2 and PDGF I (2.5 ng/ml) and 3,3-,5-triiodo-L-thyronine (T3, 40 ng ml, Sigma T4397) were added to differentiation medium. The percentage of oligodendrocyte precursor cells (OPCs) generated was analyzed after 2 d of differentiation, and the percentage of differentiated oligodendrocytes was analyzed after 6-7 d of differentiation.
Statistical analyses
Differences between two groups were assessed using the Student's unpaired t-test. Comparisons among several groups were performed using one-way ANOVA with the Tukey- Kramer post hoc test except for FIG. 16J and FIG. 24D-E, in which the Games-Howell post- hoc test and the Fisher LSD posthoc test were used, respectively. P values < 0.050 were considered statistically significant.
The following Methods are applicable to Example 15
Administration of NMN through Drinking Water and Determination of NMN Stability and Toxicity
A 12 month-long NMN administration study using wild-type mice under a regular chow-fed condition was conducted. NMN was administered through drinking water, and two doses of NMN, 100 and 300 mg/kg body weight/day, were tested. The stability of NMN was examined in drinking water and found that NMN was stable in solution. No significant degradation was observed at room temperature. Water intake was also monitored very carefully, and the water intake did not change significantly through the experimental period. To assess beneficial and possible adverse effects of NMN, a variety of physiological parameters were periodically monitored, including body weight, body temperature, food and water intake, fed and fasted blood glucose levels, fed and fasted plasma lipid panels, and glucose and insulin tolerance, in NMN-administered and control mice. Blood chemistry, blood cell counts, urine strip test, and other physiological tests including physical activity test were also checked. Based on all these assessments, no adverse effects, such as malnutrition, or signs of toxicity were observed in either of the 100 mg/kg or 300 mg/kg groups.
Examples
The present teachings including descriptions provided in the Examples that are not intended to limit the scope of any claim or aspect. Unless specifically presented in the past tense, an example can be a prophetic or an actual example. The following non-limiting examples are provided to further illustrate the present teachings. Those of skill in the art, in
light of the present disclosure, will appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present teachings.
Example 1
This example illustrates a suppressive effect of NMN on age-associated body weight increase.
In these experiments, NMN was administered to mice at a dosage rate of 100 mg/kg per day or 300 mg/kg per day. NMN demonstrated a suppressive effect on age-associated body weight increase in a 12 month-long NMN administration study. (See Methods;
Administration of NMN through Drinking Water and Determination of NMN Stability and Toxicity) In these experiments, NMN demonstrated a suppressive effect on age-associated body weight increase (FIG. 2). The results were analyzed with two-way RANOVA and oneway RANOVA with the unweighted linear term. All values are presented as mean ± SEM (n=15, 14, and 14 for control, 100, and 300 mg/kg NMN-administered groups).
Average body weights in each group are shown through 0-12 months. There was a statistically highly significant interaction between time and group (P<0.001 from the two-way RANOVA), and linear dose-dependent effects were statistically significant at all time points through 4-12 months (P<0.05 from one-way RANOVA with the unweighted linear term). The average percent body weight reduction normalized to control mice were 4% and 9% in 100 and 300 mg/kg groups, respectively.
This suppressive effect of NMN on age-associated body weight increase was further recognized by calculating body weight gains in each group (FIG. 3 0569) In FIG. 3, average body weight gains in each group are shown through 0-12 months. The results were analyzed with two-way RANOVA and one-way RANOVA with the unweighted linear term. All values are presented as mean ± SEM (n=15, 14, and 14 for control, 100, and 300 mg/kg NMN- administered groups). The interaction between time and group was statistically highly significant (P<0.001 from the two-way RANOVA), and the linear dose-dependent effects were significant at all points through 2-12 months (P<0.01 from the one-way RANOVA with the unweighted linear term). The average numbers of percent body weight gain suppression normalized to control mice were 12% and 30% in 100 and 300 mg/kg groups, respectively.
Taken together, these results from this 12 month-long NMN administration study demonstrate that NMN can suppress age-associated body weight increase in a dose- dependent manner, without showing any serious side effects during the entire experimental
period. These results demonstrate that NMN can be used for the treatment, reduction or prevention of age-associated obesity.
Example 2
This example illustrates an enhancement of energy metabolism over age with NMN administration.
In this long-term NMN administration study (See Methods; Administration of NMN through Drinking Water and Determination of NMN Stability and Toxicity), the inventors measured oxygen consumption, energy expenditure, and respiratory quotient for control, mice administered 100 mg/kg NMN per day and mice administered 300 mg/kg NMN per day at the 12 month time point by using the Oxymax Lab Animal Monitoring System (Columbus Instruments, Columbus, OH).
FIG. 4 shows oxygen consumption in control, 100 and 300 mg/kg NMN-administered mice. The data were analyzed by Wilcoxon signed ranks test. All values are presented as mean ± SEM (n=5 in each group). ***P<0.001.As illustrated in FIG. 4, oxygen consumption significantly increased in both 100 mg/kg and 300 mg/kg groups when examined at times 0 through 27 (P<0.001, Wilcoxon signed ranks test).
Energy expenditure measurements also showed significant increases in both 100 mg/kg and 300 mg/kg groups through 24 hours (P<0.001, Wilcoxon signed ranks test) (FIG. 5). Energy expenditure in control, 100 and 300 mg/kg NMN-administered mice is presented in FIG. 5. The data were analyzed by Wilcoxon signed ranks test. All values are presented as mean ± SEM (n=5 in each group). ***P<0.001.
Respiratory quotient in control, 100 and 300 mg/kg NMN-administered mice are presented in FIG. 6. The data were analyzed by Wilcoxon signed ranks test. All values are presented as mean ± SEM (n=5 in each group). ***P<0.001. Respiratory quotient significantly decreased in both groups (P<0.001, Wilcoxon signed ranks test) (FIG. 6 0569). Without being limited by theory, these results suggest that NMN increases energy expenditure by switching their main energy source from glucose to fatty acids, thereby increasing fatty acid oxidation. Without being limited by theory, this phenomenon could provide an explanation for the suppressive effect of NMN on age-associated body weight increase.
Example 3
This example illustrates a suppressive effect of NMN on age-associated increases in blood lipid levels.
Blood levels of cholesterol, triglycerides, and free fatty acids are shown over 12 months in the control and the 100 and 300 mg/kg NMN-administered cohorts in FIG. 7. The results were analyzed with two-way ANOVA and one-way RANOVA. All values are presented as mean ± SEM (n=25 for each group).
Blood levels of cholesterol, triglycerides, and free fatty acids are shown over 12 months in the control and the 100 and 300 mg/kg NMN-administered cohorts. The results were analyzed with two-way RANOVA and one-way RANOVA. All values are presented as mean ± SEM (n=25 for each group).
In the control cohort of a long-term NMN study (See Methods; Administration of NMN through Drinking Water and Determination of NMN Stability and Toxicity), blood levels of cholesterol showed steady increases over time, whereas blood levels of triglycerides and free fatty acids (FFAs) peaked at the 6-month time point and then decreased. However, in both 100 and 300 mg kg groups, these age-associated increases in cholesterol and free fatty acids tended to be suppressed (FIG. 7A-C). In particular, the interaction between time and group was statistically highly significant for FFAs (P=0.003 from the two-way RANOVA), and the 300 mg/kg group did not show any statistically significant increase over time, whereas the control and the 100 mg/kg groups did show statistically significant increases over 12 months and the first 6 months, respectively (P<0.05 from tests of within-subjects effects in the oneway RANOVA). All values are presented as mean ± SEM (n=25 for each group). Although the average level of free fatty acids at the 0-month time point in the 300 mg/kg group was significantly higher than those in the other two groups, NMN at the dose of 300 mg/kg suppressed age-associated increases in blood levels of FFAs, particularly at the 6-month time point (P<0.05 from the one-way ANOVA with the Dunnett T3 post-hoc test). Therefore, NMN is capable of suppressing age-associated increases in blood lipid levels, particularly blood FFA levels.
Without being limited by theory, since NMN has an effect of suppressing age- associated body weight increase, it was hypothesized that NMN's effect on blood lipid levels could be due to the reduction in body weight. To address this possibility, lipid levels were compared among individual mice whose average body weights were matched through control and experimental cohorts. Body weight-matched blood levels of cholesterol, triglycerides, and free fatty acids are shown over 12 months in the control and the 100 and 300 mg/kg
NMN- administered cohorts in FIG. 8. The results were analyzed with two-way ANOVA and one-way RANOVA. All values are presented as mean ± SEM (n=10-15 for each group). After matching body weight, blood cholesterol levels became very similar through control and experimental groups, whereas FFA levels were still lower in 100 and 300 mg/kg groups compared to those in the control group (FIG. 8A-C). Even after body weight match, the interaction between time and group was still statistically highly significant for FFAs (P=0.007 from the two-way RANOVA), and again, the 300 mg/kg group did not show any statistically significant increases over time, whereas the control and the 100 mg/kg groups showed significant increases over time (P<0.01 from tests of within-subjects effects in the one-way RANOVA). Blood FFA levels tended to be lower in the 100 mg/kg and 300 mg/kg groups compared to those in the control group after the 6-month time point, although the differences did not reach statistical significance (FIG. 8C). All values are presented as mean ± SEM (n=10-15 for each group). These findings indicate that NMN has the effect of suppressing the age-associated increase in blood FFA levels, independent of the reduction in body weight. Without being limited by theory, the effect of NMN on blood cholesterol levels may be secondary to the effect of suppressing age-associated body weight increase.
It has been reported that chronic treatment with nicotinic acid tends to increase blood FFA levels, whereas it lowers total cholesterol and triglyceride levels (Wang, W., et al. Am. J. Phyisol. Endocrinol. Metab. 279: E50-E59, 2000). As shown herein, NMN has a capability of suppressing the age-associated increase in blood FFA levels, which distinguishes NMN from nicotinic acid. NMN is also able to reduce cholesterol levels through the suppression of age-associated body weight increase. Whereas chronic administration of nicotinic acid can cause skeletal muscle insulin resistance (Fraterrigo, G., et al. Cardiorenal. Med. 2: 211-7, 2012), NMN does not show any adverse effect on glucose metabolism. Therefore, NMN administration can be an effective intervention to suppress age-associated increases in blood lipid levels.
Example 4
This example illustrates that administration of NMN enhances insulin sensitivity in old individuals.
In these investigations, insulin sensitivity, assessed by the insulin tolerance test, showed significant differences among the control and the 100 mg/kg and 300 mg/kg NMN- administered groups after the 12-month time point. (See Methods; Administration of NMN
through Drinking Water and Determination of NMN Stability and Toxicity). As illustrated in FIG. 9, insulin tolerance results from body weight-matched mice in the control and the 100 and 300 mg/kg NMN- administered groups at the 12-month time point are presented. Blood glucose levels (A) and percent glucose changes (B) after insulin injection are shown. The results were analyzed with two-way ANOVA and one-way ANOVA. All values are presented as mean ± SEM (n=10-15 for each group).
In these experiments, the last measured time point when mice reached 17 month-old, the NMN-administered, body weight-matched mice showed significantly enhanced insulin sensitivity compared to the body weight-matched control group (FIG. 9A). There was a statistically significant interaction between time and group (P=0.023 from the Greenhouse- Geisser test in two-way RANOVA), and the linear dose-dependent effects were statistically significant or close to significance at the 30-min and 45-min time points, respectively (P=0.026 and P=0.061 in the one-way ANOVA with unweighted linear term). The results were analyzed with two-way RANOVA and one-way ANOVA. All values are presented as mean ± SEM (n=10-15 for each group). This enhanced insulin sensitivity in the 100 mg/kg and 300 mg/kg groups was recognized further when plotting percent glucose changes (FIG. 9B), although the interaction between time and group did not reach statistical significance in this assessment (P=0.091 from the Greenhouse-Geisser test in two-way RANOVA). Long- term NMN administration can enhance insulin sensitivity in old mice, indicating that NMN administration is an effective anti-aging intervention to maintain better insulin sensitivity in the elderly.
Example 5
This example illustrates improvement of memory function under a high-fat diet (HFD) by administration of NMN. (See Methods; Memory Function Study)
FIG. 10 illustrates freezing responses of regular chow-fed control, HFD-fed, and HFD-fed, NMN-treated mice in contextual and cued fear conditioning tests on Day 1, Day 2 and Day3. NMN was administered at the dose of 300mg/kg/day for 4 months. On Day 1 of the study, mice were given an auditory cue and then a mild electric foot shock, and a time of freezing was analyzed individually. On Day 2, the trained mice were placed into a training chamber with no tone cues, and their freezing responses were evaluated. On Day 3, cued fear conditioning, which does not involve the hippocampus, was tested by giving the same tone cue used in the conditioning session (Day 1) and analyzing their freezing responses. HFD-fed mice showed an impairment of contextual fear conditioning on Day 2 compared to regular
chow-fed control mice but did not show any defect in the conditioning session on Day 1 and the cued fear conditioning test on Day 3 (FIG. 10), demonstrating that HFD specifically impairs the hippocampus-dependent memory function. NMN-treated, HFD-fed mice demonstrated freezing responses indistinguishable from those of regular chow-fed control mice in the contextual fear conditioning test on Day 2. Their freezing responses did not differ from those of control mice on both Day 1 and Day 3. These results demonstrate that the 4- month administration of NMN in mice can restore the normal hippocampus-dependent memory function even under a HFD-fed condition. NMN was administered at the dose of 300mg/kg day for 4 months. The results were analyzed by one-way ANOVA with
unweighted quadratic term. All values are presented as mean ± SEM (n=17, 15, and 12 for regular chow-fed control, HFD-fed, and HFD-fed, NMN-treated mice, respectively). ** P<0.01; * P<0.05. These results demonstrate that the 4-month administration of NMN in mice can restore the normal hippocampus-dependent memory function even under a HFD-fed condition.
Example 6
This example illustrates the improvement of retinal photoreceptor cell function over age.
In the long-term NMN administration study (See Methods; Administration of NMN through Drinking Water and Determination of NMN Stability and Toxicity), retinal function was evaluated by fundus biomicroscopy and electroretinography (ERG). FIG. 11 illustrates fundus biomicroscopy images from control and NMN-administered mice. For each group, five mice were examined, and two representative images are shown.
Intraretinal whitish deposits were reduced dramatically in NMN-administered mice. On fundus biomicroscopy, all five control mice at 18 months of age showed many intraretinal whitish deposits, whereas two and four each out of five mice at 100 mg/kg and 300 mg/kg doses, respectively, showed dramatic reductions in these deposits, suggesting that age- associated pathological changes in the retina are suppressed by NMN (FIG. 11).
FIG. 12 illustrates electroretino grams from control and NMN-administered mice. Amplitudes of scotopic a and b (A, B) and photopic b (C) waves over each stimulus range are shown. Consistently, in the ERG analysis, there was a significant interaction between stimulus and group (P=0.009 from the two-way RANOVA) for the scotopic a wave, and NMN-administered mice showed significantly higher amplitudes at 0 and 5 db (P=0.035 and 0.022 for the 300 mg kg group at 0 and 5 db, respectively; P=0.009 for the 100 mg/kg group
at 5 db from the Dunnett T3 test in the one-way RANOVA within groups), demonstrating that NMN is able to improve rod cell function in aged mice (FIG. 12 A). The data were analyzed with the two-way repeated ANOVA. All values are presented as mean ± SEM. *p<0.05; p<0.01.
Although there were no significant interactions between stimulus and group for the scotopic b and photopic b waves, there appeared to be a trend of improvement for the photopic b wave, which represents cone cell function, through an entire range of stimulus in both 100 and 300 mg/kg groups (FIG. 12B and 12C). The data were analyzed with the two- way repeated ANOVA. All values are presented as mean ± SEM. *p<0.05; p<0.01. Taken together, these findings indicate that NMN is able to improve the retinal photoreceptor cell function in aged mice.
The present inventors assessed the physiological importance of NAMPT-mediated NAD biosynthesis in the retina by generating rod cell- and cone cell-specific NAMPT knockout mice. On fundus biomicroscopy, cone cell-specific NAMPT knockout mice had an atrophic appearance at the optic nerve head, intraretinal whitish deposits, and perivascular sheathing, while littermate control animals were normal. ERG demonstrated a significant and dramatic decrease in the scotopic b and photopic b wave amplitudes as compared to the littermate control mice. The scotopic a wave amplitudes in the cone cell-specific NAMPT knockout mice were significantly decreased but to a lesser extent than the photopic b wave responses. Furthermore, rod cell-specific NAMPT knockout mice exhibited total retinal degeneration. Both a and b wave ERG responses were completely depressed as characterized by a total lack of response to all stimuli. Additionally, the treatment of the mouse photoreceptor-derived 661W cone cell line with FK866, a potent NAMPT inhibitor, led them to apoptotic cell death. Adding NMN to the culture media successfully rescued 661W cells from FK866-mediated cell death, suggesting that NAD deficiency causes the observed cell death. These results indicate that inhibition of NAMPT-mediated NAD biosynthesis by genetic and pharmacologic means leads to photoreceptor cell death and eventually retinal degeneration. NMN administration is an effective intervention to treat/prevent retinal degeneration.
Example 7
This example illustrates the improvement of tear production over age using modified Schirmer testing.
In this long-term NMN administration study (See Methods; Administration of NMN through Drinking Water and Determination of NMN Stability and Toxicity), tear production was assessed in control and NMN-administered mice with modified Schirmer's test. All values are presented as mean ± SEM. **p<0.01. NMN increased tear production in a dose- dependent manner in 18 month-old mice (FIG. 13). The tear production observed in the 300 mg kg group was comparable to the maximal tear production through the mouse lifespan. These findings indicate that NMN administration is able to increase tear production significantly in aged mice, providing an effective intervention to protect eye function from dry eye diseases.
Example 8
This example illustrates that hippocampal NAD+ levels and Nampt expression decline with age.
The inventors hypothesized that aging may reduce Nampt-mediated NAD+ biosynthesis in the brain, particularly in the hippocampus, affecting the function of NSPCs. The inventors first measured NAD+ levels in hippocampi isolated from 1, 3-4, 6, and 10-12 month-old C57B16 mice. FIG. 14 illustrates hippocampal NAD+ levels and Nampt expression declining with age. A) NAD+ biosynthesis from nicotinamide. Nicotinamide
phosphoribosyltransferase (Nampt) converts nicotinamide and 5'-phosphoribosyl-l- pyrophosphate (P PP) to nicotinamide mononucleotide (NMN). Nicotinamide/nicotinic acid mononucleotide adenylyltransferase (NMNAT) converts NMN and adenosine-5'-triphosphate (ATP) to NAD+. While NAD+ is commonly used in redox reactions, cells primarily require NAD+ as a co-substrate for several families of enzymes, one of which is the sirtuin family of protein deacetylases. The sirtuin family includes Sirtl and Sirt2, which cleave NAD+ at its glycosidic bond, releasing ADP-ribose (Stein & Imai, 2012). Inhibitors used in subsequent experiments is indicated. B) HPLC analysis of NAD+ levels in hippocampal extracts (1 month, n=5; 3-4 months, n=16; 6 months, n=10; 10-12 months, n=28). C-D) Quantification of immunofluoresence for Nampt in the subgranular zone (SGZ). Measurement of thresholded levels of Nampt immunoreactivity (C) and the number of highly immunoreactive Nampt+ cells (D) along the SGZ (n=5). E) Representative images of immunofluorescence for Dapi (original blue) and Nampt (original red) in the SGZ in young (6 months old) and old (18 months old) mice. Scale bars denote 20 μιη. Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***P < 0.001.
NAD+ levels gradually decreased with age, reaching 63% in 10-12 month-old mice compared to that of 1 month-old mice (FIG. 14B). Consistent with this finding, quantifying Nampt immunoreactivity in the SGZ of the DG by both a thresholded level of Nampt intensity as well as a count of the number of thresholded Nampt+ cells demonstrated that 18 month-old mice exhibit 52-66% of the Nampt immunoreactivity present in 6 month-old mice (FIG. 14C-E). Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***P < 0.001. Without being limited by theory, these results suggest that Nampt-mediated NAD+ biosynthesis in the hippocampus declines with age at a time course similar to that of NSPC proliferation.
Example 9
This example illustrates that Nampt is expressed in a subpopulation of SGZ NSPCs.
Nampt has been reported as predominantly expressed in hippocampal neurons but not in stellate astrocytes (Wang et al, 201 la; Zhang et al, 2010). Consistent with this finding, immunohistochemistry for Nampt and cell type specific markers revealed almost all NeuN+ neurons in the granule layer of the DG expressed Nampt, while almost no S100p+ glial cells did (FIG. 22A-E).
However, the inventors also noticed that many Nampt immunoreactive cells along the SGZ of the DG did not express NeuN (FIG. 22B-22E). The inventors performed co- immunohistochemistry for NSPC markers (Sox2+, radial Gfap+), and found that a significant population of NSPCs expressed Nampt (Figure 2A-B 0596). FIG. 22 illustrates that Nampt is expressed in a subpopulation of SGZ NSPCs. A-C) Representative images of
immunofluorescence for Dapi (original blue), Nampt (original red), and NSPC markers (Sox2, Gfap, and NestinGFP 3 days post tamoxifen injection; original green) in the SGZ. Dotted lines denote the SGZ. Single arrows indicate examples of colocalization. Double arrows indicate examples of non-colocalization. Scale bars denote 10 μιη. D) Quantification of the percentages of NSPC marker-positive cells in the SGZ that also express Nampt in 3 to 6 month old mice. At least 350 cells from 7-14 mice were assessed per group. E) A representative immunoblot and quantification of immunoblots for Nampt normalized by actin in neurospheres cultured from postnatal mice (n=6 independent samples, 16 replicates), as well as hippocampal tissue extracts (HC) isolated from either postnatal (n=12) or adult mice (n=12). F) Nampt immunoreactivity was thresholded and the number of highly
immunoreactive Nampt+ cells along the SGZ was assessed for colocalization with the
neuronal marker NeuN or the NSPC marker Sox2 in the subgranular zone (SGZ, n=5). Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***P < 0.001 (FIG. 15A-B).
To assess in vivo colocalization between Nampt and Nestin, the inventors crossed mice expressing Cre recombinase under the Nestin promoter (Nestin-CreERT2) to a GFP reporter mouse strain that expresses a loxP-flanked STOP cassette that prevents transcription of the downstream enhanced GFP (see Methods), generating iNSPC-GFP mice. Nampt also colocalized with GFP driven by the Nestin promoter (NestinGFP, FIG. 15C).
Quantification of these observations revealed that along the SGZ, 32% of Sox2+ cells, 55% of radial Gfap+ cells, and 78% of NestinGFP+ cells expressed Nampt (FIG. 15D, and Table 2). Additionally, ΚΪ67+ and Ohg2+ cells along the SGZ also expressed Nampt (Table 3, FIG. 22H-22I). Separate from SGZ-localized cell populations, 3 ± 1% of NestinGFP+ cells had extremely strong GFP expression, were localized to the granule layer, and expressed NeuN, likely due to residual CreERT2 protein left in the progeny of previously differentiated NSPCs. Data are presented as mean ± s.e.m. *P < 0.05. ***P < 0.001.
Table 2
HYDROLASE ACTIVITY HYDROLYZING N GLYCOSYL COMPOU NDS 10 10 -3.63 0.000
NUCLEOPLASM 279 230 -3.62 0.000
REPLICATION FORK 18 16 -3.60 0.000
CON DENSED CHROMOSOME 34 27 -3.57 0.000
TRNA PROCESSING 10 9 -3.51 0.000
RIBONUCLEOPROTEIN COMPLEX 143 116 -3.49 0.000
MITOTIC CELL CYCLE 153 133 -3.48 0.001
CHROMOSOMAL PART 96 83 -3.48 0.001
NUCLEOLUS 126 97 -3.47 0.001
NON MEMBRANE BOUND ORGANELLE 632 513 -3.46 0.001
INTRACELLULAR NON MEMBRANE BOUND ORGANELLE 632 513 -3.46 0.001
RNA BINDING 259 211 -3.44 0.001
TRANSFERASE ACTIVITY TRANSFERRING ONE CARBON GROUPS 37 34 -3.37 0.001
CON DENSED NUCLEAR CHROMOSOME 18 15 -3.36 0.001
NUCLEOBASE NUCLEOSIDE_AND_NUCLEOTIDE_METABOLIC_PROCE 52 45 -3.35 0.001
ΞΞ
METHYLTRANSFERASE ACTIVITY 36 33 -3.30 0.001
INTERPHASE 68 57 -3.28 0.001
NUCLEOTIDE METABOLIC PROCESS 42 36 -3.21 0.001
DNA INTEGRITY CHECKPOINT 24 16 -3.20 0.001
SINGLE STRANDED DNA BIN DING 35 27 -3.17 0.002
PROTEIN COMPLEX 816 689 -3.08 0.002
INTERPHASE OF MITOTIC CELL CYCLE 62 52 -3.07 0.002
Table 3
Top 50 Upregulated Pathways
Pathway Members Changed Z P
Ratio Value
SYSTEM DEVELOPMENT 863 759 4.69 0.000
MULTICELLULAR ORGANISMAL DEVELOPMENT 1051 910 4.64 0.000
SIALYLTRANSFERASE ACTIVITY 10 10 1.61 0.000
PHOSPHOINOSITIDE BINDING 20 13 4.49 0.000
ANATOMICAL STRUCTURE DEVELOPMENT 1017 891 4.47 0.000
ORGAN DEVELOPMENT 572 499 4.28 0.000
RECEPTOR BINDING 378 321 4.25 0.000
EXTRACELLULAR REGION 448 374 4.10 0.000
ENZYME LINKED RECEPTOR PROTEIN SIGNALING PATHWAY 140 126 4.05 0.000
Growth 77 63 3.85 0.000
NEGATIVE REGULATION OF GROWTH 40 34 3.84 0.000
FOCAL ADHESION FORMATION 10 9 3.83 0.000
OLIGOSACCHARIDE METABOLIC PROCESS 1 1 1 1 3.82 0.000
EXTRACELLULAR REGION PART 339 283 3.82 0.000
REGULATION OF SIGNAL TRANSDUCTION 223 189 3.77 0.000
SYSTEM PROCESS 563 489 3.74 0.000
EXTRACELLULAR SPACE 246 204 3.66 0.000
NEURON PROJECTION 21 18 3.62 0.000
INTERMEDIATE FILAMENT CYTOSKELETON 24 22 3.61 0.000
INTERMEDIATE FILAMENT 24 22 3.61 0.000
SENSORY PERCEPTION 190 159 3.57 0.000
MEMBRANE 1998 1678 3.55 0.000
POSITIVE REGULATION OF SECRETION 20 15 3.51 0.000
REGULATION OF CELL GROWTH 46 38 3.49 0.000
REGULATION OF G ROWTH 58 49 3.48 0.000
SIGNAL TRANSDUCTION 1637 1394 3.47 0.001
PLASMA MEMBRANE 1429 1 199 3.46 0.001
MESODERM DEVELOPMENT 22 17 3.45 0.001
CELL DEVELOPMENT 579 512 3.44 0.001
FOCAL ADHESION 13 10 3.44 0.001
ANATOMICAL STRUCTURE MORPHOGENESIS 379 335 3.39 0.001
N ERVOUS SYSTEM DEVELOPMENT 386 342 3.39 0.001
EARLY EN DOSOME 18 1 5 3.37 0.001
CYTOSKELETAL PROTEIN BINDING 1 59 1 37 3.36 0.001
TASTE RECEPTOR ACTIVITY 1 5 3 3.36 0.001
AXON GUIDANCE 22 19 3.34 0.001
GEN ERATION OF NEURONS 83 76 3.34 0.001
CELL JUNCTION 83 67 3.29 0.001
LIPID HOMEOSTASIS 16 1 2 3.28 0.001
PDZ DOMAIN BIN DING 14 1 3 3.26 0.001
LIGAN D DEPENDENT N UCLEAR RECEPTOR ACTIVITY 25 23 3.26 0.001
N EUROGEN ESIS 93 84 3.21 0.001
CELL MATRIX JUNCTION 18 14 3.20 0.001
VACUOLE 69 56 3.19 0.001
IDENTICAL PROTEIN BIN DING 305 253 3.19 0.001
CELL MATRIX ADHESION 38 34 3.18 0.001
TRANSMEMBRAN E_RECEPTOR_PROTEIN_TYROSINE_KINASE_ 83 75 3.18 0.001 SIGNALING PATH
ACTIN FILAMENT BASED PROCESS 1 16 96 3.18 0.001
CELL_SURFACE_RECEPTOR_LIN KED_SIGNAL_TRANSDUCTION_GO_ 642 547 3.17 0.002 000 166
CELL SUBSTRATE ADHERENS JU NCTION 16 1 3 3.17 0.002
To confirm that Nampt is highly expressed in NSPCs, the inventors cultured NSPCs from the hippocampi of postnatal pups as neurospheres. Neurospheres showed 22 or 32% higher expression levels of Nampt than did whole hippocampal extracts taken from postnatal (P12) or adult mice (2.5-4.5 months), respectively (FIG. 15E), indicating that NSPCs have higher expression levels of Nampt compared to other hippocampal cell types. Without being limited by theory, these results suggest that Nampt is expressed in a large subpopulation of NSPCs.
The inventors thresholded Nampt immunoreactivity, and assessed the thresholded Nampt+ cells for colocalization with the neuronal marker NeuN and the NSPC marker Sox2 to determine which cell populations lose Nampt expression with age. With age, the
percentage of intensely Nampt immunoreactive cells that colocalized with NeuN increased slightly, whereas the percentage of intensely Nampt immunoreactive cells that colocalized with Sox2 decreased from 21% to 4% (FIG 15F). Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***P < 0.001. Similarly, in the SGZ, the percentage of NeuN+ that expressed Nampt increased with age, while the percentage of Sox2+ cells that expressed Nampt decreased (FIG. 22E, table 2). Thus, at least part of the decrease in Nampt expression in the SGZ with age is due to loss of Sox2+ NSPCs.
Example 10
This example illustrates that adult NSPC-specific deletion of Nampt impairs NSPC self-renewal in vivo.
The inventors investigated whether inactivating Nampt specifically in adult NSPCs could recapitulate age-associated phenotypic changes in NSPC functionality in vivo. The inventors generated adult NSPC-specific inducible Nampt knockout mice by crossing Nampf0 *0* mice (Rongvaux et al, 2008) with Nestin-CreERT2 mice (iNSPC-Nampt-KO mice). To trace the progeny of adult NSPCs in which Nampt was inactivated and to confirm the specificity and magnitude of the deletion induced by tamoxifen, the inventors also crossed iNSPC-Nampt-KO mice to the aforementioned iNSPC-GFP mice. After tamoxifen injection, these mice expressed NestinGFP in the SGZ and SVZ but not in non-neurogenic regions of the brain such as the corpus callosum or cortex FIG. 23 A-B).
Immunohistochemistry and recombination PCR for NestinGFP confirmed that there was undetectable recombination present in vehicle injected mice. The—350 base pair band confirms the deletion of exons 5 and 6. The 1,800 base pair band corresponds to a Nampt gene with a full-length exon 5 to 6 sequence. (FIGS. 23 A, 23C) To verify that the
NestinGFP+ population consisted of NSPCs, the inventors co-stained for the NSPC markers Sox2 and Gfap. 61% of Sox2+ cells and 34% of radial Gfap+ cells co-expressed NestinGFP 7 days post tamoxifen (FIG. 23D). The inventors also verified Nampt deletion efficiency by quantifying the percentage of NestinGFP+ cells that expressed Nampt 3 and 7 days post tamoxifen injection. At 3 days post tamoxifen injection, the percentage of NestinGFP+ cells that expressed Nampt in iNSPC-Nampt-KO mice was 40% less than littermate controls, and at 7 days post tamoxifen injection, the percentage of NestinGFP+ cells that expressed Nampt was reduced by 62% (FIG. 23E).
To assess the cumulative effect of loss of Nampt on NSPC proliferation, the inventors deleted Nampt in iNSPC-Nampt-KO mice at 6 weeks of age with 3 rounds of 5 consecutive days of tamoxifen injections, separated by 6 weeks (Fig. 16 A). Parametric analysis of gene enrichment (PAGE) was conducted based on microarray analyses. See the Methods section. Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***P < 0.001. The inventors then assessed control and iNSPC-Nampt-KO mice for the expression of lineage specific markers by immunohistochemistry (FIG. 16C). In iNSPC-Nampt-KO mice, the inventors found that the Nestin+ NSPC pool was decreased by 49% in the DG (FIG. 16C). Incorporation of BrdU and the population of proliferating cells [ΚΪ67+ (von Bohlen und Halbach, 2011)] were also decreased by 22% and 35%, respectively (FIG. 16D-16E. Consistent with this defect in the NSPC pool and proliferation, the pool of newborn neurons [doublecortin, Dcx+, (von Bohlen und Halbach, 2011)] was also significantly decreased by 26% (FIG. 16 F-16G). In contrast, the inventors did not observe any significant difference in the maturation of newborn neurons
(FIG. 23F). Immature cells had no or horizontal projections. Mature cells had vertical projections spanning the granule cell layer. NSPC/daughter cell survival was accessed by immunostaining for activated caspase 3. Only rare activated caspase 3+ cells were observed in both neurogenic and non-neurogenic regions of the brain (FIG. 23A-23B), and these activated caspase 3+ cells were never observed in GFP+ cells in iNSPC-Nampt-KO DG, without being limited by theory, providing evidence against a potential contribution of cell death to the observed effects.
To assess the acute effect of loss of Nampt on NSPC fate decisions, the inventors induced deletion of Nampt at 6 weeks of age with 4 total tamoxifen injections followed by sacrifice 72 hours after the first injection (FIG. 16H). To facilitate assessment of
differentiation, dividing cells were labeled by injecting the mice with BrdU concurrently with the first day of tamoxifen treatment. 4 total TAM injections (2 injections on the first day coupled with BrdU at 100 mg kg body weight as well as 2 total injections on the subsequent 2 days). iNSPC-Nampt-KO mice displayed significantly reduced levels of colocalization of BrdU with radial Nestin+ cells (FIG. 161), without being limited by theory, suggesting decreased self-renewal decisions. However, iNSPC-Nampt-KO mice exhibited normal levels of BrdU colocalization with neuronal (Dcx+), astrocytic (Gfap+) and oligodendrocytic (01ig2+) markers, indicating that alterations in differentiated cell lineage decisions were undetectable under basal conditions. Without being limited by theory, the lack of increase in colocalization of BrdU with cell type specific markers may imply that a larger percentage of BrdU+ cells have failed to differentiate in iNSPC-Nampt-KO mice. iNSPC-Nampt-KO NSPCs could have stalled during differentiation after losing Nestin expression.
The inventors hypothesized that systemic administration of NMN may be able to correct age-associated defects in NSPC functionality. Intraperitoneal injection of NMN (500 mg/kg body weight) increased hippocampal NAD+ levels 34 to 39% within 15 minutes, suggesting that NMN can cross the blood-brain barrier (FIG. 23G). To see if NMN supplementation can maintain NSPC proliferation and self-renewal with age, the inventors treated 6 month-old mice with NMN at the daily dose of 100 or 300 mg kg body weight in their drinking water until 18 months of age. The number of Nestin+ cells along the SGZ was significantly lower in the 18 month-old control mice relative to 6 month-old mice, as previously reported (Encinas et al, 2011) (FIG. 16J). Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***P < 0.001. Mice treated with 300 mg/kg body weight NMN showed improved maintenance of the Type 1 (radial Nestin+) population with age. However, the population of proliferating cells (ΚΪ67+) remained similar to controls (FIG. 23H). The
population of newborn neurons (Dcx+) trended to increase (FIG. 231). Quantification of ΚΪ67+ (H) and Dcx+ (I) cells in the DG per unit area of the DG (n=5). Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***p < 0.001. Without being limited by theory, it is possible that NMN administration maintains the NSPC pool by preventing the age-associated increase in terminal fate decisions.
Example 11
This example illustrates that inhibition of Nampt in NSPCs in vitro impairs NAD+ biosynthesis and proliferation.
The inventors hypothesized whether Nampt mediates NSPC-specific NAD+ biosynthesis by using hippocampal neurospheres as the in vitro NSPC culture model.
Neurospheres were treated with a highly specific Nampt inhibitor, FK866, at a dosage and duration (10 nM, 48 hours) that has little to no effect on cellular viability (Hasmann & Schemainda, 2003). FK866 reduced NAD+ levels in neurospheres to 4% of controls, a decrease completely rescued by concurrent NMN treatment (FIG. 17A and 24A), suggesting that, without being limited by theory, Nampt activity is the predominant source of NAD+ biosynthesis in NSPCs.
The inventors investigated how inhibition of Nampt affects neurosphere proliferation. Consistent with the decreases in the NSPC pool and in NSPC proliferation in iNSPC-Nampt- KO mice, FK866 reduced NSPC number by 61% after 48 hours, but not 24 hours, of treatment (FIG. 17B-C and FIG. 24B). To distinguish whether this decrease in cell number was due to an inhibition of proliferation or enhancement of death, the inventors analyzed the protein levels of markers of proliferation, apoptosis, and autophagy. Expression of the proliferation markers Ki67 and PCNA decreased 87% and 43% respectively (FIG. 24C-24E), whereas levels of activated caspase 3 were only slightly increased and levels of the autophagy marker, glycosylated LC3B, were unchanged. Consistent with these observations, parametric analysis of gene set enrichment (PAGE) of a microarray performed on neurospheres treated with FK866 showed that out of the top 50 downregulated pathways, 13 of them were related to the cell cycle, while none of the top 50 upregulated pathways were involved in cell death Table 1, FIGS. 24F-G). Parametric analysis of gene enrichment (PAGE) was conducted based on microarray analyses. See the Methods section. Analysis of specific gene changes by qRT-PCR revealed that cyclins E and A, the two cyclins required for cellular progression from Gl to S, as well as their upstream transcriptional regulator E2F1 (Wong et al, 2011), were the primary cell cycle factors affected by this treatment (FIG. 17E). These alterations in
gene expression indicated that reducing Nampt activity stalls NSPCs at G0/G1. Supporting this notion, FACS analysis of neurospheres demonstrated that FK866 treatment increased the proportion of NSPCs in G0/G1 and decreased the proportion in S phase (FIG. 17F). Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.0.1. ***P < 0.001.
Table 1
Example 12
This example illustrates that genetic ablation of Nampt in NSPCs in vitro impairs NAD biosynthesis, proliferation, and differentiation.
To assess the effect of chronic Nampt ablation on NSPC functionality, the inventors genetically ablated Nampt by infecting neurospheres from Nampfox'^ox mice with Cre recombinase- or LacZ- expressing (control) adenoviruses. Neurospheres infected with Cre recombinase (Nampt Ad-Cre) at passage 1 exhibited a 94% reduction in Nampt mRNA expression 3 days post deletion, and the corresponding decreases in Nampt protein expression and NAD+ levels appeared 6 days post deletion (FIGS. 25A-25E). Analyses were conducted after passage 2, at 6 or more days post infection. Data are presented as mean ± s.e.m. *P <0.05. **P < 0.01. ***P < 0.001. Eight days post deletion, NSPCs exhibited a 73% reduction in NAD+ levels that was rescued by concurrent NMN administration, and without being limited by theory, further supporting the notion that Nampt activity is the predominant source of NSPCs NAD+ levels (FIG. 18A). Neurospheres were isolated from Namptfiox/flox mice
and infected with a Cre-recombinase expressing adenovirus (Nampt AD-Cre) or a control adenovirus expressing LacZ (Nampt AD-LacZ).
Like FK866-treated cultures, proliferating Nampt Ad-Cre infected NSPCs displayed reduced cell number (FIG. 18B). Nampt Ad-Cre NSPCs were unable to increase their cell number between 24 and 144 hours of culture. In contrast, Nampt AD- LacZ infected cells were able to exponentially increase their cell number over 13-fold in this time frame.
Consistent with this finding, Nampt Ad-Cre infected NSPCs also showed a 49% reduction in diameter relative to Nampt AD-LacZ infected NSPCs, indicative of reduced proliferation (FIGS. 18C-D). Since NSPC self-renewal decisions can also contribute to cell number, the inventors assessed secondary neurosphere formation, an assay that quantifies the ability of neurosphere inhabitant cells to reformulate neurospheres upon dissociation. Nampt Ad-Cre infected cells generated 63% fewer secondary neurospheres than did Nampt AD-LacZ infected cells (FIG. 18E). Nampt AD-LacZ and Nampt Ad-Cre NSPCs exhibited no difference in the percentages of TUNEL- or activated caspase 3- positive cells as well as no difference in activated caspase3 immunoreactivity as detected by immunoblotting, without being limited by theory, indicating that the observed phenotypes upon loss of Nampt are not primarily due to cell death (FIG. 25E-F). As a positive control for activated caspase 3 immunoreactivity, indicated samples were treated with stauroporine (1 mM) (n=6). To see if Nampt Ad-Cre infected neurospheres could be reactivated to proliferate, the inventors plated equal numbers of Nampt AD-LacZ and Nampt Ad-Cre cells after the second passage and cultured them in the presence or the absence of NMN. NMN treatment was able to fully reactivate the proliferative potential of Nampt Ad-Cre cells (FIG. 18F-G). Collectively, without being limited by theory, these results suggest that Nampt-mediated NAD+ biosynthesis plays a role for NSPCs to successfully progress through the cell cycle.
Whereas the inventors did not observe a difference in NSPC fate decisions in the neurogenic environment of the SGZ in vivo, the inventors detected a decrease in self-renewal decisions. To see if this would occur in the absence of the influences of the SGZ niche, the inventors differentiated dissociated neurospheres and assessed the proportion of resulting cell types by immunofluorescence after 6 to 7 days of differentiation induced by removal of growth factors (FIG. 18H, FIG. 25G). Differentiated Nampt Ad-Cre NSPCs exhibited a 90% reduction in oligodendrocytes (FIG. 181). In contrast, Nampt Ad-Cre infected NSPCs exhibited no change in the generation of Gfap+ cells (FIG. 18J). Genetic knockdown of Nampt also significantly but more mildly decreased the generation of neurons (by 43% β-ΙΙΙ- tubulin+, FIG. 18K). Thus, the decrease in oligodendrocytes was not due to an increase in
neuronal fate. As Gfap can recognize both NSPCs and mature astrocytes, the inventors employed Nestin and S ΙΟΟβ to distinguish whether the decrease in oligodendrocytes we observed upon Nampt knockdown was due to a cell fate choice in these directions. While there was no detectable change in the generation of S 100β+ mature astrocytes in Nampt Ad- Cre cultures, there was a 4-fold increase in the percentage of Nestin+ cells (6% in Nampt Ad- LacZ cells; 23% in Nampt Ad-Cre cells), without being limited by theory, suggesting quiescence rather than precocious astrocytic differentiation (FIG. 18L). All of these effects were rescued by treatment with NMN. The inventors also observed a mild increase in TUNEL+ cell death under these conditions (33% increase relative to Nampt Ad-LacZ cells). *, Λ, and # indicate statistical significance between Nampt AD-LacZ and Nampt AD-Cre, Nampt AD-LacZ and Nampt AD-LacZ+NMN, and Nampt AD-Cre and Nampt AD- Cre+NMN, respectively. Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***P < 0.001. (FIGS. 18A-L) Together, without being limited by theory, these data suggest that genetic knockdown of Nampt prevents the successful differentiation of oligodendrocytes from NSPCs, potentially due to quiescence as indicated by a retention of NSPC
characteristics.
Example 13
This example illustrates that genetic knockdown of Nampt impairs OPC formation in vitro.
Since differentiation using a nonspecific lineage differentiation protocol (by removal of growth factors) revealed a specific requirement for Nampt in the successful generation of 04+ immature oligodendrocytes, the inventors next asked which stage(s) of NSPC differentiation into oligodendrocytes depends on Nampt by employing a differentiation protocol that promotes the oligodendrocyte lineage (FIG. 19 A, FIG. 26 A). Neurospheres were isolated from Namptflox/flox mice and infected with a Cre-recombinase expressing adenovirus (Nampt AD-Cre) or a control adenovirus expressing LacZ (Nampt AD-LacZ). As previously observed using a nonspecific lineage differentiation protocol, the proportion of 04+ intermediate oligodendrocytes was dramatically decreased in Nampt Ad-Cre cultures at 6-7 days post differentiation (FIG. 19B). The inventors observed that ablation of Nampt resulted in a decreased pool of OPCs (Pdgfra+), but an increased pool of Nestin+ NSPCs. The proportion of Gfap+ astrocytes/NSPCs also mildly increased. To investigate whether the depletion of the OPC population was preexisting to or induced upon differentiation, the inventors assessed the OPC population present during proliferation. Dissociated neurospheres
were cultured in proliferation media containing PDGFaa. (FIG. 26B) and after 2 days of differentiation (FIG. 19C), a time point that enriches for OPCs as assessed by
immunoflorescence. Both of these time points also showed loss of OPCs (Pdgfra+, 01ig2+). These results support that, without being limited by theory, Nampt is plays a role for NSPCs to differentiate into OPCs.
The inventors observed that Sirt2 was upregulated during oligodendrocyte
differentiation in vitro and expressed in the SGZ in Nampt+ cells and NestinGFP+ NSPCs (FIG. 26C). The inventors acutely treated NSPCs with the selective inhibitor of Sirt2, AGK2, or the Sirtl inhibitor, EX527. Whereas both inhibitors acutely suppressed oligodendrocyte formation (04+, FIG. 19D), neither chronic ablation of Sirt2 in the NSPCs isolated from Sirt2~ ' mice nor Cre adenovirus mediated knockdown of Sirtl in Sirtlfi→0> derived neurospheres affected oligodendrogenesis (Pdgfra+, 01ig2+, 04+), except that Sirtl deficiency affected the production of 04+ intermediate oligodendrocytes (FIG. 19E). The inventors generated S/rf /S/rf 2- double knockout (Sirtl/2 DKO) neurospheres. Consistent with the inhibitor studies (FIG. 19D), dissociated Sirtl/2 DKO neurospheres were unable to form oligodendrocyte lineage cells upon differentiation (FIG. 19E). To assess the role of Sirtl and Sirt2 downstream of Nampt activity, the inventors examined the expression of genes associated with OPC formation in Nampt Ad-Cre neurospheres, Sirtl/2 DKO neurospheres, and their respective controls. Dissociated Nampt Ad-Cre and Sirtl/2 DKO neurospheres showed similar decreases in the mRNA expression of Pdgfra, SoxlO, Nkx2.2 after 2 days of differentiation (FIG. 19F-G). Dissociated Nampt Ad-Cre and Sirtl/2 DKO neurospheres respectively exhibited similar increases in the expression of p21 (cdknld). Oligl expression showed no change or slight reduction by these genetic ablations, potentially due to its lesser expression in NSPCs relative to 01ig2 (Ligon et al, 2007) and predominant roles in oligodendrocyte maturation and remyelination rather than specification. Neither Cre mediated knockdown of Sirtl in neurospheres nor neurospheres cultured from whole-body Sirtl-*' or Sirtl1- mice exhibited defects in proliferation (FIG. 26G-J). Data are presented as mean ± s.e.m. *P < 0.05. **P < 0.01. ***p < 0.001. The inventors conclude that Sirtl and Sirt2 can redundantly mediate NSPC differentiation into OPCs.
Example 14
This example illustrates adult NSPC-specific deletion of Nampt impairs NSPC differentiation in response to insult in vivo.
The inventors observed Nampt ablation on NSPC differentiation into OPCs in vitro, but not oligodendrogenesis in the SGZ of iNSPC-Nampt-KO mice in vivo (FIG. 161). The inventors assessed the percentage of NestinGFP+ cells that expressed OHg2 in the SVZs of iNSPC-GFP and iNSPC-Nampt-KO mice (FIG. 20A). iNSPC-Nampt-KO mice showed a lower percentage of oligodendrocytes generated from adult NSPCs.
The inventors employed the cuprizone model of demyelination and remyelination. Specifically, the inventors fed 6- to 9-week-old iNSPC-Nampt-KO and littermate control mice (iNSPC-GFP) a diet containing 0.2% cuprizone for 4-5 weeks, inducing deletion of Nampt in the adult Nestin+ population the week before starting the cuprizone diet (FIG. 20B) (Skripuletz et al, 2011). To ensure that analysis of progeny of adult Nestin+ cells, all mice in our cohort expressed Cre recombinase under the inducible Nestin promoter (Nestin- CreE T2) (Lagace et al, 2007) and the aforementioned Cre recombinase responsive GFP reporter transgene. The analysis focus was on lineage tracer marked (NestinGFP+) cells.
Cuprizone feeding did not alter the total number of NestinGFP+ cells present in the iNSPC-GFP DG (FIG. 27A-C), suggesting, without being limited by theory, that NSPC proliferation was unaltered. Data are presented as mean ± s.e.m. *, ΛΡ < 0.05. **, ΛΛΡ < 0.01. ***, ΛΛΛΡ < 0.001. Cuprizone fed mice exhibited an increased percentage of NestinGFP+ cells that co-localized with the NSPC markers Nestin+ (from 13 to 35%) and Gfap+ (from 19 to 41%), suggesting that, without being limited by theory, cuprizone treatment prevented SGZ NSPCs from terminally differentiating and instead resulted in their retention of NSPC characteristics, which could occur through increased self-renewal decisions and/or quiescence (FIG. 27D-E). The inventors next assessed colocalization between NestinGFP and oligodendrocyte specific markers, SoxlO and APC. However, the SGZ did not substantially produce oligodendrocytes even in response to demyelination (FIG. 27F-G Therefore, without being limited by theory, SGZ NSPCs do not appear to be the main mediators of short-term remyelination in the hippocampus.
The inventors assessed the fate decisions of migratory cells derived from the adult Nestin+ population in the subcallosal zone of the corpus callosum (FIG. 27 A). In the iNSPC- GFP CC, virtually no NestinGFP+ or Nestin+ cells were seen in regular chow fed mice (FIG. 20C-D, FIG. 27 A). There were no differences in the number of NestinGFP+ cells in the CC between control and iNSPC-Nampt-KO mice, suggesting, without being limited by theory, that loss of Nampt neither affected insult-induced NSPC proliferation or migration. In the iNSPC-GFP CC, cuprizone feeding significantly increased the percentage of
NestinGFP+Nestin+ cells (from 3 to 41%) but decreased the NestinGFP+Gfap+ (from 60 to
24%) double positive cells, suggesting, without being limited by theory, increased self- renewal fate decisions at the expense of astrocytic fate decisions (FIG. 20E-G). In control mice, cuprizone feeding also increased the number of NestinGFP+SoxlO+ (from 2 to 16%) and NestinGFP+Apc+ (from 0 to 4%) double positive cells, suggesting increased
oligodendrocyte lineage fate decisions (FIG. 20H-I).
In contrast, the NestinGFP+ cells in the iNSPC-Nampt-KO CC showed significantly less colocalization with Nestin, SoxlO, and Ape and more colocalization with Gfap (FIG. 20F-I). Interestingly, Nampt was only expressed in the CC upon insult (.FIG. 20J, FIG. 27H). Moreover, Nampt colocalized with markers of NSPCs (Sox2, FIG. 27H) and
oligodendrocytes (Ohg2, FIG. 20J). These results suggest, without being limited by theory, that Nampt is specifically expressed in SGZ/SVZ derived remyelinating NSPCs and plays a role in oligodendrogenesis in response to insult.
Example 15
This example illustrates a model for the role of Nampt-mediated NAD biosynthesis in NSPCs without being limited by theory.
Nampt-mediated NAD+ biosynthesis promotes NSPC self-renewal, proliferation and differentiation into oligodendrocytes. While the mechanism by which Nampt promotes self- renewal and proliferation remains unidentified, Nampt-mediated NAD+ biosynthesis activates Sirtl and Sirt2 to promote NSPC oligodendrocyte lineage fate decisions by a mechanism involving transcriptional downregulation of Pdgfra, SoxlO, and Nkx2.2 and transcriptional upregulation of p21 (cdknla). Sirtl and Sirt2 may act via an effect on 01ig2 activity. (FIG. 21)
The inventors showed that the NSPC pool decreased with age and that long-term NMN administration was able to maintain the NSPC pool. The inventors assert that a higher dosage of NMN can be used to promote NSPC proliferation. Intraperitoneal injection of NMN substantially increases hippocampal NAD+ levels within 15 minutes (FIG. 23G), without being limited by theory, suggests that NMN can cross the blood-brain barrier.
As E2Fl-deficient mice have significantly reduced hippocampal NSPC death
(Cooper- Kuhn et al, 2002), without being limited by theory, the observed decrease in E2F1 upon inhibition of Nampt may explain this phenomenon (FIG. 17E). The inventors also observed that loss of Nampt activity specifically downregulated Cyclin E and A expression. E-type cyclins regulate Gl progression. The inventors observed downregulation of E2F1 expression, which transcriptionally regulates Cyclin E, therefore, without being limited by
theory, it is likely that the downregulation of E2F1 contributes to the downregulation of Cyclin E. The inventors also observed upregulation of p21 upon loss of Nampt. Thus, the upregulation of p21 that we see upon loss of Nampt, without being limited by theory, may also contribute to the downregulation of E2F/Cyclin E activity. As Cyclin A expression is induced after E2F and Cyclin E (Wong et al, 2011), the changes in Cyclin A levels are likely downstream of both the aforementioned changes. While we have linked Nampt to the E2F/Cyclin E pathway, connecting mediator(s) remain unclear. The inventors found neither Sirtl nor Sirt2 to be downstream of the effect of Nampt-mediated NAD+ biosynthesis on proliferation. While it is possible that Sirtl/2 function redundantly to mediate NSPC proliferation, the relatively low expression of Sirt2 in NSPCs (FIG. 26G) makes this possibility unlikely, without being limited by theory.
The present inventors revealed that ablation of Nampt specifically reduced the proportion of NSPC-generated Pdgfra+ OPCs as well as the transcription of Pdgfra, SoxlO, and Nkx2.2 but upregulated the expression of p21. The results showed that in neurospheres, treatment with NMN rescued defects in oligodendrogenesis caused by a reduction in NAD+ levels. Furthermore, systemic NMN administration was able to substantially augment hippocampal NAD+ levels and increase the NSPC pool. Thus, NMN administration could be an efficient intervention to enhance the NSPC pool and promote remyelination by activating endogenous NSPCs during the aging process and/or in neurodegenerative diseases that cause demyelination. The results provide evidence of the therapeutic potential of Nampt-mediated NSPC self-renewal, proliferation, and differentiation into oligodendrocytes.
Example 16
This example illustrates an increase in bone density in aged individuals by NMN administration.
The inventors measured the bone mineral density (BMD) of control and NMN-treated mice at the 12-month time point of a 12 month long NMN administration experiment (FIG. 28A-B) by dual-energy X-ray absorptiometry (DXA) (Figure 2 of Disclosure 7). At this time point, mice were 17-18 month old. The inventors found that NMN-treated mice showed increases in the BMD in a dose-dependent manner, and the difference between control and 300 mg/kg groups is statistically significant (P=0.037, ANOVA, Tukey HSD post hoc test). Mice from 100 and 300 mg kg groups showed 2.8% and 5.9% increases in the BMD, respectively. (FIG. 29) Although age-associated BMD loss is extensively varied among mouse strains (http://phenome.jax.org), the extent of these observed BMD increases is
significant, indicating that NMN is able to enhance the BMD in aged individuals. These data indicate that NMN administration can be used to treat age-associated osteoporosis in humans.
Example 17
This example illustrates characterization of loss of NAMPT-mediated NAD biosynthesis on PR neuron survival.
The inventors examined the effect of selectively disrupting NAD biosynthesis within PR. The inventors utilized the cre-lox strategy to generate mice that had NAMPT
conditionally deleted from either rods (NAMPT rod-CKO) or cones (NAMPT cone-CKO). The NAMPT fl/fl mice as well as the rhodopsin-cre and cone opsin-cre mice have been previously characterized. Both rod and cone cko mice are generated with normal Mendelian frequencies and are born normal with no observable systemic abnormalities (data not shown). All structural and functional analyses performed in CKO mice are analyzed in comparison to littermate controls. Rods constitute a majority of the PR neurons (97% of all photoreceptors). Retinas from NAMPT rod-CKO mice showed a significant reduction of NAMPT within rods by PCR, immunohistochemistry and immunob lotting (FIG. 30A-B). Biomicroscopic examination of NAMPT rod-cko mice demonstrated a degenerative phenotype characterized by massive atrophy of the neurosensory retina, vascular attenuation with pigment mottling and atrophy of the underlying retinal pigment epithelium. Neurosensory retinal degeneration was associated with secondary atrophy and pallor of the optic nerve (FIG. 30C).
Example 18
This example illustrates electroretinography (ERG) performed to measure PR neuron and retinal function.
NAMPT rod-CKO mice demonstrated a dramatic reduction in scotopic (rod- associated) and photopic (cone-associated) responses compared to littermate control animals (FIG. 30D-H) Photopic visual acuity measurements confirmed vision loss in rod-CKO mice (FIG. 30G). Histopathologic examination of eyes from NAMPT rod-CKO mice was characterized by retinal degeneration with progressive loss of the outer nuclear layer over time with significant reduction of retinal thickness and subsequent extension of the neurodegeneration to multiple retinal layers (FIG. 30H). Normalized NAD measurements obtained from NAMPT rod-cko whole retinas showed a significant reduction in NAD which is especially important given that NAMPT function is selectively eliminated only from rod PR neurons with other retinal cells being normal (FIG. 301). These results suggest that,
without being limited to theory, if enzymatic activity of NAMPT in NAD biosynthesis in rod PR neurons is necessary for cell survival, intracellular conversion of NAM to NMN by NAMPT can play a role.
The present inventors determined that exogenous supplementation with NMN is able to rescue PR neurons from cell death in CKO mice. Intraperitoneal (i.p.) delivery was chosen to obtain early and sustained levels of NMN. In these experiments, NAMPT rod-CKO mice were given NMN (150 mg/kg) or PBS i.p. daily starting at day P5. ERG at 4 weeks in CKO mice treated with NMN showed significant rescue of photopic and scotopic function compared to PBS treatment (FIG. 30 J- L). There was no effect of NMN on littermate control animals.
Example 19
This example illustrates NMN rescue in NAMPT cone-CKO mice.
In these experiments, NAMPT cone-CKO mice (without NMN treatment) demonstrated similar but milder changes on biomicroscopy consistent with neuroretinal degeneration as seen in the rod-CKO mice (FIG. 31 A). ERG demonstrated significant and progressive decline in cone function as evidenced by reduced photopic responses over time with secondary reduction in scotopic responses (FIG. 31B-D). These quantifiable structural and functional changes were associated with decrease in visual acuity in cone-CKO mice (FIG. 3 IE). Histopathologic analyses confirmed outer nuclear layer degeneration with subsequent multilayer retinal degeneration and cell death in cone-CKO mice similar to the changes seen above for rod-CKO mice. As with NAMPT rod-CKO mice, delivery of NMN i.p. to NAMPT cone-CKO mice was also able to improve ERG function compared to PBS treated cone-CKO mice (FIG. 31 F-H). NMN treatment had no effect on littermate controls (FIG. 34). These data suggest that, without being limited by theory, NAMPT-mediated NAD biosynthesis is necessary for the survival and function of both rod and cone PR neurons. Furthermore, providing NMN treatment is able to rescue PR neurons and vision.
The inventors used a 661 W cone PR cell line and treated the cells with the specific pharmacological NAMPT inhibitor FK866 (200 nM). FK866 treatment of cone cells in vitro causes decrease in intracellular NAD levels and significant cell death after the 4 hours of treatment (FIGS. 311, 31 J). Cell death progresses dramatically over the next 20 hours. NMN (100 μΜ) was able to completely rescue cells from death associated with FK866 treatment and restore NAD to normal levels (FIGS. 3 II, 3 IK). These in vitro results confirm that NMN administration can promote PR neuron survival.
Example 20
This example illustrates that NAD-regulated PR survival is independent of individual sirtuins.
The inventors examined the effect of deletion of several sirtuins on PR survival. Sirt 1 PR CKO mice and Sirt 2-5 -/- mice had normal retinal and PR neuron structure and function when examined by fundus biomicroscopy and ERG (FIG. 3a-j and FIG. S2). Sirt6 -/- mice have a profound neurodegenerative phenotype and die around 3-4 weeks of age. As such, we examined sirt6 rod and cone conditional knockout mice that also had normal retinal structure and function (FIG. 32, 32L and FIG. 35). Without being limityed by theory, these findings demonstrate that individual sirtuins are not causative of N AMPT-mediated PR degeneration.
Example 21
This example illustrates that photoreceptor loss and blindness is associated with mitochondrial dysfunction.
Electron microscopic examination demonstrated dysmorphic changes in the retinal inner segments along with disruption of the outer segments in rod CKO mice but showed normal cellular organization and sub-cellular structures in littermate controls at 4 weeks of age (FIG. 33 A, 33B). By 4 weeks of age, the mitochondrial numbers in CKO retinas were significantly reduced, the mitochondria were rounded and constricted with loss of cristae as opposed to the normally elongated mitochondria with healthy cristae seen in age-matched littermate control mice (FIG. 33A, 33B). There was an abundance of degenerative vacuoles with ingested organelles including mitochondria in rod-CKO mice with no such structures identified in littermate wild type controls. At 3 weeks of age, subtle changes in inner segments could be identified in rod-CKO mice although they were not as dramatic as those seen by 4 weeks (FIG. 36). These results suggest that, without being limited by theory, NAD deficiency might impair mitochondrial structure and function. The inventors treated 661W cone cells with NAMPT inhibitor FK866 (200 nM). In the oxygen consumption rate measurement assay, multiple aspects of mitochondrial function were analyzed. As shown in FIG. 33C, maximal respiration was significantly reduced in 661W cone cells after inhibition of NAMPT function (FIG. 33C). NMN treatment was able to completely reverse the effects of FK866 on cone cell photoreceptor mitochondrial function confirming the role of NAD in NAMPT-mediated effects on PR neurons (FIG. 33C).
A non-biased metabolomic analysis using mass spectrophotometry (GC-MS and LC- MS) was performed on retinas isolated from NAMPT rod CKO mice and compared to littermate control retinas. Significant differences were identified in mitochondrial metabolites involved in the TCA cycle.
References
Arnett HA, Fancy SP, Alberta JA, Zhao C, Plant SR, Kaing S, Raine CS, Rowitch DH, Franklin RJ, Stiles CD (2004) bHLH transcription factor Oligl is required to repair demyelinated lesions in the CNS. Science (New York, NY 306: 2111-2115
Artegiani, B., et al. (2012) Age-related cognitive decline: can neural stem cells help us? Aging 4: 176-186
Ben Abdallah, N.M., et al. (2010) Early age-related changes in adult hippocampal neurogenesis in C57 mice. Neurobiology of aging 31: 151-161
Bieganowski, P., et al. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. (2004) Cell 117, 495-502.
Bouab, M., et al. (2011) Aging of the subventricular zone neural stem cell niche: evidence for quiescence-associated changes between early and mid-adulthood. Neuroscience 173: 135-149
Canto, C, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. (2012) Cell-Metab. 15, 838- 847
Carlson, L.A. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. (2005) J. Intern. Med. 258, 94-114.
Cheadle, C, et al. (2003) Analysis of microarray data using Z score transformation. J Mol Diagn 5: 73-81
Chen, J., et al. (2013) SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase- 3beta/beta-catenin signaling. Hepatology (Baltimore, Md 57: 2287-2298
Colak, D., et al. (2008) Adult neurogenesis requires Smad4-mediated bone morphogenic protein signaling in stem cells. J Neurosci 28: 434-446
Collins, P.B., et al. Comparative metabolism of nicotinamide and nicotinic acid in mice. (1971) Biochem. J. 125, 117P
Collins, P.B., et al. The management of nicotinamide and nicotinic acid in the mouse. (1972) J. Biol. Chem. 247, 778-783
Cooper- Kuhn, CM., et al. (2002) Impaired adult neurogenesis in mice lacking the transcription factor E2F1. Molecular and cellular neurosciences 21 : 312-323
Dasgupta, B., et al. (2005) Neurofibromin regulates neural stem cell proliferation, survival, and astroglial differentiation in vitro and in vivo. J Neurosci 25: 5584-5594
Decker, L., et al. (2002) Growth factor treatment promotes mobilization of young but not aged adult subventricular zone precursors in response to demyelination. Journal of neuroscience research 69: 763-771
Deng, W., et al. (2010) New neurons and new memories: how does adult
hippocampal neurogenesis affect learning and memory? Nature reviews 11 : 339-350
Dienel, G. A., et al. (2006) Astrocyte activation in working brain: energy supplied by minor substrates. Neuro chemistry international 48: 586-595
Di Girolamo, M., et al. Physiological relevance of the endogenous mono(ADP- ribosyl)ation of cellular proteins. (2005) FEBS J. 272, 4565-4575.
Doucette, J. ., et al. (2010) Age-related and cuprizone-induced changes in myelin and transcription factor gene expression and in oligodendrocyte cell densities in the rostral corpus callosum of mice. Cellular and molecular neurobiology 30: 607-629
Encinas, J.M., et al. (2011) Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell stem cell 8: 566-579
Folmes, CD., et al. (2012) Metabolic plasticity in stem cell homeostasis and differentiation. Cell stem cell 11: 596-606
Franklin, R.J., et al. (2008) Remyelination in the CNS: from biology to therapy. Nature reviews 9: 839-855
Friebe, D., et al. (2011) Impact of metabolic regulators on the expression of the obesity associated genes FTO and NAMPT in human preadipocytes and adipocytes. PloS one 6: el9526
Fu, J., et al. (2006) High glucose alters the expression of genes involved in proliferation and cell-fate specification of embryonic neural stem cells. Diabetologia 49: 1027-1038
Gao, Q., et al. (2007) Hyperglycemic condition disturbs the proliferation and cell death of neural progenitors in mouse embryonic spinal cord. Int J Dev Neurosci 25: 349-357
Garten, A., et al. Nampt: linking NAD biology, metabolism and cancer. (2009) Trends Endocrinol. Metab. 20, 130-138.
Gudi, V., et al. (2009) Regional differences between grey and white matter in cuprizone induced demyelination. Brain research 1283: 127-138
Guillemin, G. J., et al. (2007) Characterization of the kynurenine pathway in human neurons. J Neurosci 27: 12884-12892
Hack, M. A., et al. (2005) Neuronal fate determinants of adult olfactory bulb neurogenesis. Nature neuroscience 8: 865-872
Hack, M. A., et al. (2004) Regionalization and fate specification in neurospheres: the role of Ohg2 and Pax6. Molecular and cellular neurosciences 25: 664-678
Hara, N., et al. Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphonbosyltransferase in human cells. (2007) J Biol Chem 282, 24574-82.
Hasmann, M., et al. (2003) FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphonbosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer research 63: 7436-7442
Hisahara, S., et al. (2008) Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation. Proceedings of the National Academy of Sciences of the United States of America 105: 15599-15604
Houtkooper, R.H., et al. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. (2010) Endocr. Rev. 31, 194-223.
Husain, J., et al. (1995) Oligodendroglial precursor cell susceptibility to hypoxia is related to poor ability to cope with reactive oxygen species. Brain research 698: 86-94
Imai, S. Dissecting systemic control of metabolism and aging in the NAD World: the importance of SIRT1 and NAMPT-mediated NAD biosynthesis. (2011) FEBS Lett. 585, 1657-1662.
Imai, S. et al. Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. (2010) Trends Pharmacol. Sci. 31, 212-220.
Imai, S. Nicotinamide phosphonbosyltransferase (Nampt): a link between NAD biology, metabolism, and diseases. (2009) Curr. Pharm. Des. 15, 20-28.
Imai, S. A possibility of nutriceuticals as an anti-aging intervention: Activation of sirtuins by promoting mammalian NAD biosynthesis. (2010) Pharmacol. Res. 62, 42-47.
Ito, K., et al. (2012) A PML-PPAR-delta pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nature medicine 18: 1350-1358
Jablonska, B., et al. (2010) Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination. Nature neuroscience 13: 541-550
Jackson, E.L., et al. (2006) PDGF alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron 51: 187-199
Jadasz, J.J., et al. (2012) The remyelination Philosopher's Stone: stem and progenitor cell therapies for multiple sclerosis. Cell and tissue research 349: 331-347
Ji, S., et al. (2011) Sirt2 is a novel in vivo downstream target of Nkx2.2 and enhances oligodendro glial cell differentiation. Journal of molecular cell biology 3: 351-359
Jin, K., et al. (2003) Neurogenesis and aging: FGF-2 and HB-EGF restore
neurogenesis in hippocampus and subventricular zone of aged mice. Aging cell 2: 175-183
Jin, Y.H., et al. (2008) Sirt2 interacts with 14-3-3 beta/gamma and down-regulates the activity of p53. Biochemical and biophysical research communications 368: 690-695
Kim, H.S., et al. (2011) SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer cell 20: 487-499
Knobloch, M., et al. (2013) Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493: 226-230
Lagace, DC, et al. (2007) Dynamic contribution of nestin-expressing stem cells to adult neurogenesis. J Neurosci 27: 12623-12629
Lau, C, et al. Isoform-specific targeting and interaction domains in human nicotinamide mononucleotide adenylyltransferases. (2010) J. Biol. Chem. 285, 18868-18876.
Lee, H.C. Cyclic ADP-ribose and NAADP: fraternal twin messengers for calcium signaling. (2011) Sci. China Life Sci. 54, 699-711.
Li, W., et al. (2007) Sirtuin 2, a mammalian homolog of yeast silent information regulator-2 longevity regulator, is an oligodendro glial protein that decelerates cell differentiation through deacetylating alpha-tubulin. J Neurosci 27: 2606-2616
Ligon, K.L., et al. (2007) 01ig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 53: 503-517
Liu, A., et al. (2006) A molecular insight of Hes5-dependent inhibition of myelin gene expression: old partners and new players. The EMBO journal 25: 4833-4842
Lu, P.P., et al. (2012) A critical cell-intrinsic role for serum response factor in glial specification in the CNS. J Neurosci 32: 8012-8023
Lu, Q.R., et al. (2002) Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109: 75-86
Lugert, S., et al. (2010) Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell stem cell 6: 445-456
Luo, J., et al. (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107: 137-148
Madisen, L., et al. (2010) A robust and high-throughput Cre reporting and
characterization system for the whole mouse brain. Nature neuroscience 13: 133-140
Mehta, S., et al. (2011) The central nervous system-restricted transcription factor Ohg2 opposes p53 responses to genotoxic damage in neural progenitors and malignant glioma. Cancer cell 19: 359-371
Menn, B., et al. (2006) Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci 26: 7907-7918
Nait-Oumesmar, B., et al. (1999) Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. The European journal of neuroscience 11 : 4357-4366
Norkute, A., et al. (2009) Cuprizone treatment induces demyelination and astrocytosis in the mouse hippocampus. Journal of neuroscience research 87: 1343-1355
Outeiro, T.F., et al. (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science (New York, NY 317: 516-519
Peck, B., et al. (2010) SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Molecular cancer therapeutics 9: 844-855
Picard-Riera, N., et al. (2002) Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proceedings of the National Academy of Sciences of the United States of America 99: 13211- 13216
Plassman, B.L., et al. (2008) Prevalence of cognitive impairment without dementia in the United States. Annals of internal medicine 148: 427-434
Polager, S., et al. (2009) p53 and E2f: partners in life and death. Nat Rev Cancer 9: 738-748
Prozorovski, T., et al. (2008) Sirtl contributes critically to the redox-dependent fate of neural progenitors. Nature cell biology 10: 385-394
Rafalski, V.A., et al. (2013) Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nature cell biology 15: 614-624
Revollo, J.R., et al. (2004) The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. The Journal of biological chemistry 279: 50754-50763
Revollo, J.R., et al. (2007) Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell metabolism 6: 363-375
Rongvaux, A, et al. (2008) Nicotinamide phosphoribosyl transferase/pre-B cell colony-enhancing factor/visfatin is required for lymphocyte development and cellular resistance to genotoxic stress. J Immunol 181: 4685-4695
Rothgiesser, K.M., et al. (2010) SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. Journal of cell science 123: 4251-4258
Saharan, S., et al. (2013) SIRT1 regulates the neurogenic potential of neural precursors in the adult subventricular zone and hippocampus. Journal of neuroscience research 91: 642-659
Saito, K., et al. (2009) Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis. Proceedings of the National Academy of Sciences of the United States of America 106: 8350-8355
Sanchez-Abarca, L.I., et al. (2001) Oligodendrocytes use lactate as a source of energy and as a precursor of lipids. Glia 36: 321-329
Sassone-Corsi, P. Minireview: NAD+, a circadian metabolite with an epigenetic twist. (2012) Endocrinology 153, 1-5.
Schreiber, V., et al. Poly(ADP-ribose): novel functions for an old molecule. (2006) Nat. Rev. Mol. Cell. Biol. 7, 517-528.
Sim, F. J., et al. (2002) The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and
differentiation. J Neurosci 22: 2451-2459
Skripuletz, T., et al. (2011) De- and remyelination in the CNS white and grey matter induced by cuprizone: the old, the new, and the unexpected. Histology and histopathology 26: 1585-1597
Soundarapandian, M.M., et al. (2011) Zfp488 promotes oligodendrocyte
differentiation of neural progenitor cells in adult mice after demyelination. Scientific reports 1 : 2
Stein, L.R., et al. (2012) The dynamic regulation of NAD metabolism in
mitochondria. Trends in endocrinology and metabolism: TEM 23: 420-428
Steiner, B., et al. (2004) Differential regulation of gliogenesis in the context of adult hippocampal neurogenesis in mice. Glia 46: 41-52
Stoll, E. A., et al. (2011) Aging neural progenitor cells have decreased mitochondrial content and lower oxidative metabolism. The Journal of biological chemistry 286: 38592- 38601
Sun, Y., et al. (2011) Phosphorylation state of 01ig2 regulates proliferation of neural progenitors. Neuron 69: 906-917
Takebayashi, H., et al.(2002) The basic helix-loop-helix factor olig2 is essential for the development of motoneuron and oligodendrocyte lineages. Curr Biol 12: 1157-1163
Tyler, W. A., et al. (2011) Proteomic identification of novel targets regulated by the mammalian target of rapamycin pathway during oligodendrocyte differentiation. Glia 59: 1754-1769
Van Leeuwen, I.M., et al. (2013) Modulation of p53 C-terminal acetylation by mdn 2, pl4A F, and cytoplasmic SirT2. Molecular cancer therapeutics 12: 471-480
Verderio, C, et al. (2001) Evidence of a role for cyclic ADP-ribose in calcium signalling and neurotransmitter release in cultured astrocytes. Journal of neurochemistry 78: 646-657
Voloboueva, L.A., et al. (2010) Mitochondrial protection attenuates inflammation- induced impairment of neurogenesis in vitro and in vivo. J Neurosci 30: 12242-122 1
von Bohlen und Halbach O (2011) Immunohistological markers for proliferative events, gliogenesis, and neurogenesis within the adult hippocampus. Cell and tissue research 345: 1-19
Wang, C, et al. (2006) Interactions between E2F1 and SirTl regulate apoptotic response to DNA damage. Nature cell biology 8: 1025-1031
Wang, P., et al. (201 la) Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1- dependent adenosine monophosphate-activated kinase pathway. Annals of neurology 69: 360-374
Wang, W., et al. (201 lb) Mitochondrial DNA damage level determines neural stem cell differentiation fate. J Neurosci 31 : 9746-9751
Wegner, M., et al. (2008) A matter of identity: transcriptional control in
oligodendrocytes. J Mol Neurosci 35: 3-12
Wilhelm, F., et al. The NAD+ NADH redox state in astrocytes: independent control of the NAD+ and NADH content. (2011) J Neurosci Res 89, 1956-1964.
Wong, J. V., et al. (2011) Network calisthenics: control of E2F dynamics in cell cycle entry. Cell cycle (Georgetown, Tex 10: 3086-3094
Yang, H., et al. Nutrientsensitive mitochondrial NAD(+) levels dictate cell survival. (2007) Cell 130, 1095- 1107.
Yoshino, J., et al. (2011) Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell metabolism 14: 528-536
Zhang, J., et al. (2012) Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal. Cell stem cell 11 : 589-595
Zhang, W., et al. (2010) Neuronal protective role of PBEF in a mouse model of cerebral ischemia. J Cereb Blood Flow Metab 30: 1962-1971
Zhang, Y., et al. (2011) Inhibition of Sirtl promotes neural progenitors toward motoneuron differentiation from human embryonic stem cells. Biochemical and biophysical research communications 404: 610-614
Zhou, Q., et al. (2002) The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109: 61-73
Design of Prodrugs, H. Bundgaard, ea., Elsevier, 1985; Methods in Enzymology, K. Widder et ai, Ed., Academic Press, 42, p.309-396, 25 1985; A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ea., Chapter 5; "Design and
Applications of Prodrugs" p.113-191, 1991; Advanced Drug Delivery Reviews, H. Bundgard, 8, p.1-38, 1992; Journal of Pharmaceutical Sciences, 77, p. 285, 30 1988; Chem. Pharm. Bull., N. Nakeya et ai, 32, p. 692, 1984; Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ea., American Pharmaceutical Association and Pergamon Press, 1987
All publications cited in this application are herein incorporated by reference in their entirety as if each individual publication, patent, patent application or other reference were specifically and individually indicated to be incorporated by reference.
Claims
Claims
What is claimed is :
1. A method of treating age-associated obesity in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide
mononucleotide (NMN).
2. A method in accordance with claim 1, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
3. A method in accordance with claim 1, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
4. A method in accordance with claim 1, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg kg body weight, from 100 mg/kg body weight to 300 mg kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
5. A method in accordance with claim 1, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous
suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
6. A method in accordance with claim 1, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
7. A method in accordance with claim 1, wherein the NMN is administered by intravenous.
8. A method in accordance with claim 1, wherein the administrating is enterically
administrating.
9. A method in accordance with claim 1, wherein the administrating is parenterally administrating.
10. A method in accordance with claim 1, wherein the subject is a mammal.
11. A method in accordance with claim 1, wherein the subject is a human.
12. A method of treating age-associated increases in blood lipid levels in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
13. A method in accordance with claim 12, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about
3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
14. A method in accordance with claim 12, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
15. A method in accordance with claim 12, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg kg body weight.
16. A method in accordance with claim 12, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
17. A method in accordance with claim 12, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
18. A method in accordance with claim 12, wherein the NMN is administered by intravenous.
19. A method in accordance with claim 12, wherein the administrating is enterically administrating.
20. A method in accordance with claim 12, wherein the administrating is parenterally administrating.
21. A method in accordance with claim 12, wherein the subject is a mammal.
22. A method in accordance with claim 12, wherein the subject is a human.
23. A method of treating age-associated loss of insulin sensitivity in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
24. A method in accordance with claim 23, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
25. A method in accordance with claim 23, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
26. A method in accordance with claim 23, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
27. A method in accordance with claim 23, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
28. A method in accordance with claim 23, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
29. A method in accordance with claim 23, wherein the NMN is administered by intravenous.
30. A method in accordance with claim 23, wherein the administrating is enterically administrating.
31. A method in accordance with claim 23, wherein the administrating is parenterally administrating.
32. A method in accordance with claim 23, wherein the subject is a mammal.
33. A method in accordance with claim 23, wherein the subject is a human.
34. A method of treating age-associated impairment of memory function in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
35. A method in accordance with claim 34, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500
mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
36. A method in accordance with claim 34, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
37. A method in accordance with claim 34, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg kg body weight.
38. A method in accordance with claim 34, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
39. A method in accordance with claim 34, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
40. A method in accordance with claim 34, wherein the NMN is administered by intravenous.
41. A method in accordance with claim 34, wherein the administrating is enterically administrating.
42. A method in accordance with claim 34, wherein the administrating is parenterally administrating.
43. A method in accordance with claim 34, wherein the subject is a mammal.
44. A method in accordance with claim 34, wherein the subject is a human.
45. A method of treating age-associated decline in eye function in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
46. A method in accordance with claim 45, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
47. A method in accordance with claim 45, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
48. A method in accordance with claim 45, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg kg body weight, from 100 mg/kg body weight to 300 mg kg body weight, 500 mg/kg body weight, or about 500 mg kg body weight.
49. A method in accordance with claim 45, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
50. A method in accordance with claim 45, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized
aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
51. A method in accordance with claim 45, wherein the NMN is administered by intravenous.
52. A method in accordance with claim 45, wherein the administrating is enterically administrating.
53. A method in accordance with claim 45, wherein the administrating is parenterally administrating.
54. A method in accordance with claim 45, wherein the subject is a mammal.
55. A method in accordance with claim 45, wherein the subject is a human.
56. A method of treating age-associated retinal degeneration in a subject, comprising:
administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
57. A method in accordance with claim 56, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
58. A method in accordance with claim 56, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
59. A method in accordance with claim 56, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
60. A method in accordance with claim 56, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
61. A method in accordance with claim 56, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
62. A method in accordance with claim 56, wherein the NMN is administered by intravenous.
63. A method in accordance with claim 56, wherein the administrating is enterically administrating.
64. A method in accordance with claim 56, wherein the administrating is parenterally administrating.
65. A method in accordance with claim 56, wherein the subject is a mammal.
66. A method in accordance with claim 56, wherein the subject is a human.
67. A method of treating dry eye in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
68. A method in accordance with claim 67, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, Img, about Img, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg,
400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
69. A method in accordance with claim 67, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
70. A method in accordance with claim 67, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
71. A method in accordance with claim 67, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
72. A method in accordance with claim 67, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
73. A method in accordance with claim 67, wherein the NMN is administered by intravenous.
74. A method in accordance with claim 67, wherein the administrating is enterically administrating.
75. A method in accordance with claim 67, wherein the administrating is parenterally administrating.
76. A method in accordance with claim 67, wherein the subject is a mammal.
77. A method in accordance with claim 67, wherein the subject is a human.
78. A method of treating age-associated defects in neural stem/progenitor cell (NSPC) functionality in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
79. A method in accordance with claim 78, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
80. A method in accordance with claim 78, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
81. A method in accordance with claim 78, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg kg body weight, 500 mg/kg body weight, or about 500 mg kg body weight.
82. A method in accordance with claim 78, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet,
a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
83. A method in accordance with claim 78, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
84. A method in accordance with claim 78, wherein the NMN is administered by intravenous.
85. A method in accordance with claim 78, wherein the administrating is enterically administrating.
86. A method in accordance with claim 78, wherein the administrating is parenterally administrating.
87. A method in accordance with claim 78, wherein the subject is a mammal.
88. A method in accordance with claim 78, wherein the subject is a human.
89. A method of reducing age-associated decrease in a neural stem/progenitor cell (NSPC) population in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
90. A method in accordance with claim 89, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100
mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
91. A method in accordance with claim 89, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
92. A method in accordance with claim 89, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
93. A method in accordance with claim 89, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
94. A method in accordance with claim 89, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
95. A method in accordance with claim 89, wherein the NMN is administered by intravenous.
96. A method in accordance with claim 89, wherein the administrating is enterically administrating.
97. A method in accordance with claim 89, wherein the administrating is parenterally administrating.
98. A method in accordance with claim 89, wherein the subject is a mammal.
99. A method in accordance with claim 89, wherein the subject is a human.
100. A method of promoting neural stem/progenitor cell (NSPC) proliferation in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
101. A method in accordance with claim 100, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 1 0 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
102. A method in accordance with claim 100, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
103. A method in accordance with claim 100, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
104. A method in accordance with claim 100, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an
aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
105. A method in accordance with claim 100, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
106. A method in accordance with claim 100, wherein the NMN is administered by intravenous.
107. A method in accordance with claim 100, wherein the administrating is enterically administrating.
108. A method in accordance with claim 100, wherein the administrating is parenterally administrating.
109. A method in accordance with claim 100, wherein the subject is a mammal.
110. A method in accordance with claim 100, wherein the subject is a human.
111. A method of increasing bone density levels in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide
mononucleotide (NMN).
112. A method in accordance with claim 111, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg,
about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
113. A method in accordance with claim 111, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
114. A method in accordance with claim 111, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
115. A method in accordance with claim 111, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
116. A method in accordance with claim 111, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
117. A method in accordance with claim 111, wherein the NMN is administered by intravenous.
118. A method in accordance with claim 111, wherein the administrating is enterically administrating.
119. A method in accordance with claim 111, wherein the administrating is parenterally administrating.
120. A method in accordance with claim 111, wherein the subject is a mammal.
121. A method in accordance with claim 111, wherein the subject is a human.
122. A method of treating aberrantly low bone density levels in a subject, comprising:
administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
123. A method in accordance with claim 122, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 1 0 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
124. A method in accordance with claim 122, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
125. A method in accordance with claim 122, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg kg body weight, or about 500 mg/kg body weight.
126. A method in accordance with claim 122, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an
effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
127. A method in accordance with claim 122, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
128. A method in accordance with claim 122, wherein the NMN is administered by intravenous.
129. A method in accordance with claim 122, wherein the administrating is enterically administrating.
130. A method in accordance with claim 122, wherein the administrating is parenterally administrating.
131. A method in accordance with claim 122, wherein the subject is a mammal.
132. A method in accordance with claim 122, wherein the subject is a human.
133. A method of treating an age-associated bone density decrease in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
134. A method in accordance with claim 133, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000
mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
135. A method in accordance with claim 133, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
136. A method in accordance with claim 133, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg kg body weight, or about 500 mg/kg body weight.
137. A method in accordance with claim 133, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
138. A method in accordance with claim 133, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
139. A method in accordance with claim 133, wherein the NMN is administered by intravenous.
140. A method in accordance with claim 133, wherein the administrating is enterically administrating.
141. A method in accordance with claim 133, wherein the administrating is parenterally administrating.
142. A method in accordance with claim 133, wherein the subject is a mammal.
143. A method in accordance with claim 133, wherein the subject is a human.
144. A method of treating osteoporosis in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
145. A method in accordance with claim 144, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 1 0 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
146. A method in accordance with claim 144, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
147. A method in accordance with claim 144, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
148. A method in accordance with claim 144, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
149. A method in accordance with claim 144, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
150. A method in accordance with claim 144, wherein the NMN is administered by intravenous.
151. A method in accordance with claim 144, wherein the administrating is enterically administrating.
152. A method in accordance with claim 144, wherein the administrating is parenterally administrating.
153. A method in accordance with claim 144, wherein the subject is a mammal.
154. A method in accordance with claim 144, wherein the subject is a human.
155. A method of treating macular degeneration in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide
mononucleotide (NMN).
156. A method in accordance with claim 156, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about
600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
157. A method in accordance with claim 156, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
158. A method in accordance with claim 156, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg kg body weight, or about 500 mg/kg body weight.
159. A method in accordance with claim 156, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
160. A method in accordance with claim 156, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
161. A method in accordance with claim 156, wherein the NMN is administered by intravenous.
162. A method in accordance with claim 156, wherein the administrating is enterically administrating.
163. A method in accordance with claim 156, wherein the administrating is parenterally administrating.
164. A method in accordance with claim 156, wherein the subject is a mammal.
165. A method in accordance with claim 156, wherein the subject is a human.
166. A method of treating retinal degeneration in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide
mononucleotide (NMN).
167. A method in accordance with claim 166, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
168. A method in accordance with claim 166, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
169. A method in accordance with claim 166, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
170. A method in accordance with claim 166, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
171. A method in accordance with claim 166, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
172. A method in accordance with claim 166, wherein the NMN is administered by intravenous.
173. A method in accordance with claim 166, wherein the administrating is enterically administrating.
174. A method in accordance with claim 166, wherein the administrating is parenterally administrating.
175. A method in accordance with claim 166, wherein the subject is a mammal.
176. A method in accordance with claim 166, wherein the subject is a human.
177. A method of treating photoreceptor damage in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide
mononucleotide (NMN).
178. A method in accordance with claim 177, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg,
150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
179. A method in accordance with claim 177, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
180. A method in accordance with claim 177, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg kg body weight, or about 500 mg/kg body weight.
181. A method in accordance with claim 177, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
182. A method in accordance with claim 177, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
183. A method in accordance with claim 177, wherein the NMN is administered by intravenous.
184. A method in accordance with claim 177, wherein the administrating is enterically administrating.
185. A method in accordance with claim 177, wherein the administrating is parenterally administrating.
186. A method in accordance with claim 177, wherein the subject is a mammal.
187. A method in accordance with claim 177, wherein the subject is a human.
188. A method of treating photoreceptor degeneration in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
189. A method in accordance with claim 188, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 1 0 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
190. A method in accordance with claim 188, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
191. A method in accordance with claim 188, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
192. A method in accordance with claim 188, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
193. A method in accordance with claim 188, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
194. A method in accordance with claim 188, wherein the NMN is administered by intravenous.
195. A method in accordance with claim 188, wherein the administrating is enterically administrating.
196. A method in accordance with claim 188, wherein the administrating is parenterally administrating.
197. A method in accordance with claim 188, wherein the subject is a mammal.
198. A method in accordance with claim 188, wherein the subject is a human.
199. A method of treating vision loss associated with retinal degeneration in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
200. A method in accordance with claim 199, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg,
150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
201. A method in accordance with claim 199, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
202. A method in accordance with claim 199, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg kg body weight, or about 500 mg/kg body weight.
203. A method in accordance with claim 199, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
204. A method in accordance with claim 199, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
205. A method in accordance with claim 199, wherein the NMN is administered by intravenous.
206. A method in accordance with claim 199, wherein the administrating is enterically administrating.
207. A method in accordance with claim 199, wherein the administrating is parenterally administrating.
208. A method in accordance with claim 199, wherein the subject is a mammal.
209. A method in accordance with claim 199, wherein the subject is a human.
210. A method of treating aberrant retinal structure in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
211. A method in accordance with claim 210, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 1 0 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
212. A method in accordance with claim 210, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
213. A method in accordance with claim 210, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
214. A method in accordance with claim 210, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
215. A method in accordance with claim 210, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
216. A method in accordance with claim 210, wherein the NMN is administered by intravenous.
217. A method in accordance with claim 210, wherein the administrating is enterically administrating.
218. A method in accordance with claim 210, wherein the administrating is parenterally administrating.
219. A method in accordance with claim 210, wherein the subject is a mammal.
220. A method in accordance with claim 210, wherein the subject is a human.
221. A method of treating aberrant retinal function in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
222. A method in accordance with claim 221, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60
mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
223. A method in accordance with claim 221, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
224. A method in accordance with claim 221, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
225. A method in accordance with claim 221, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
226. A method in accordance with claim 221, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
227. A method in accordance with claim 221, wherein the NMN is administered by intravenous.
228. A method in accordance with claim 221, wherein the administrating is enterically administrating.
229. A method in accordance with claim 221, wherein the administrating is parenterally administrating.
230. A method in accordance with claim 221, wherein the subject is a mammal.
231. A method in accordance with claim 221, wherein the subject is a human.
232. A method of reducing risk of developing macular degeneration in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
233. A method in accordance with claim 232, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 1 0 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
234. A method in accordance with claim 232, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
235. A method in accordance with claim 232, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
236. A method in accordance with claim 232, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
237. A method in accordance with claim 232, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
238. A method in accordance with claim 232, wherein the NMN is administered by intravenous.
239. A method in accordance with claim 232, wherein the administrating is enterically administrating.
240. A method in accordance with claim 232, wherein the administrating is parenterally administrating.
241. A method in accordance with claim 232, wherein the subject is a mammal.
242. A method in accordance with claim 232, wherein the subject is a human.
243. A method of reducing risk of developing aberrant retinal NAD levels in a subject, comprising: administering to a subject in need of treatment NMN in an amount effective for increasing retinal NAD levels.
244. A method in accordance with claim 243, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg,
150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
245. A method in accordance with claim 243, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
246. A method in accordance with claim 243, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg kg body weight, or about 500 mg/kg body weight.
247. A method in accordance with claim 243, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
248. A method in accordance with claim 243, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
249. A method in accordance with claim 243, wherein the NMN is administered by intravenous.
250. A method in accordance with claim 243, wherein the administrating is enterically administrating.
2 1. A method in accordance with claim 243, wherein the administrating is parenterally administrating.
252. A method in accordance with claim 243, wherein the subject is a mammal.
253. A method in accordance with claim 243, wherein the subject is a human.
254. A method of reducing risk of developing retinal degeneration in a subject, comprising administering to a subject in need of treatment NMN in an amount effective for increasing retinal NAD levels.
255. A method in accordance with claim 254, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
256. A method in accordance with claim 254, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
257. A method in accordance with claim 254, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg kg body weight, or about 500 mg/kg body weight.
258. A method in accordance with claim 254, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
259. A method in accordance with claim 254, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
260. A method in accordance with claim 254, wherein the NMN is administered by intravenous.
261. A method in accordance with claim 254, wherein the administrating is enterically administrating.
262. A method in accordance with claim 254, wherein the administrating is parenterally administrating.
263. A method in accordance with claim 254, wherein the subject is a mammal.
264. A method in accordance with claim 254, wherein the subject is a human.
265. A method of reducing risk of developing photoreceptor damage in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective.
266. A method in accordance with claim 265, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg,
about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
267. A method in accordance with claim 265, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
268. A method in accordance with claim 265, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg kg body weight, from 100 mg kg body weight to 300 mg/kg body weight, 500 mg kg body weight, or about 500 mg/kg body weight.
269. A method in accordance with claim 265, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
270. A method in accordance with claim 265, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized
aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
271. A method in accordance with claim 265, wherein the NMN is administered by intravenous.
272. A method in accordance with claim 265, wherein the administrating is enterically administrating.
273. A method in accordance with claim 265, wherein the administrating is parenterally administrating.
274. A method in accordance with claim 265, wherein the subject is a mammal.
275. A method in accordance with claim 265, wherein the subject is a human.
276. A method of reducing risk of developing photoreceptor degeneration in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
277. A method in accordance with claim 276, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
278. A method in accordance with claim 276, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
279. A method in accordance with claim 276, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg kg body weight, or about 500 mg/kg body weight.
280. A method in accordance with claim 276, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
281. A method in accordance with claim 276, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
282. A method in accordance with claim 276, wherein the NMN is administered by intravenous.
283. A method in accordance with claim 276, wherein the administrating is enterically administrating.
284. A method in accordance with claim 276, wherein the administrating is parenterally administrating.
285. A method in accordance with claim 276, wherein the subject is a mammal.
286. A method in accordance with claim 276, wherein the subject is a human.
287. A method of reducing risk of developing vision loss associated with retinal degeneration in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
288. A method in accordance with claim 287, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 1 0 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
289. A method in accordance with claim 287, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
290. A method in accordance with claim 287, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
291. A method in accordance with claim 287, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
292. A method in accordance with claim 287, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
293. A method in accordance with claim 287, wherein the NMN is administered by intravenous.
294. A method in accordance with claim 287, wherein the administrating is enterically administrating.
295. A method in accordance with claim 287, wherein the administrating is parenterally administrating.
296. A method in accordance with claim 287, wherein the subject is a mammal.
297. A method in accordance with claim 287, wherein the subject is a human.
298. A method of reducing risk of developing aberrant retinal structure in a subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
299. A method in accordance with claim 298, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about
5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
300. A method in accordance with claim 298, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
301. A method in accordance with claim 298, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg kg body weight, from 100 mg/kg body weight to 300 mg/kg body weight, 500 mg kg body weight, or about 500 mg/kg body weight.
302. A method in accordance with claim 298, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
303. A method in accordance with claim 298, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
304. A method in accordance with claim 298, wherein the NMN is administered by intravenous.
305. A method in accordance with claim 298, wherein the administrating is enterically administrating.
306. A method in accordance with claim 298, wherein the administrating is parenterally administrating.
307. A method in accordance with claim 298, wherein the subject is a mammal.
308. A method in accordance with claim 298, wherein the subject is a human.
309. A method of reducing risk of developing aberrant retinal function in a
subject, comprising: administering to a subject in need of treatment a pharmaceutically effective amount of nicotinamide mononucleotide (NMN).
310. A method in accordance with claim 309, wherein the NMN is administered at a dosage of 0.5 mg, about 0.5 mg, lmg, about lmg, 5 mg, about 5 mg, lOmg, about 10 mg, 20 mg, about 20 mg, 30 mg, about 30 mg, 40 mg, about 40 mg, 50 mg, about 50 mg, 60 mg, about 60 mg, 70 mg, about 70 mg, 80 mg, about 80 mg, 90 mg, about 90 mg, 100 mg, about 100 mg, 150 mg, about 150 mg, 200 mg, about 200 mg, 250 mg, about 250 mg, 300 mg, about 300 mg, 400 mg, about 400 mg, 450 mg, about 450 mg, 500 mg, about 500 mg, 600 mg, about 600 mg, 700 mg, about 700 mg, 800 mg, about 800 mg, 900 mg, about 900 mg, 1000 mg, about 1000 mg, 1100 mg, about 1100 mg, 1200 mg, about 1200 mg, 1300 mg, about 1300 mg, 1400 mg, about 1400 mg, 1500 mg, about 1500 mg, 1600 mg, about 1600 mg, 1700 mg, about 1700 mg, 1800 mg, about 1800 mg, 1900 mg, about 1900 mg, 2000 mg, about 2000 mg, 2100 mg, about 2100 mg, 2200 mg, about 2200 mg, 2300 mg, about 2300 mg, 2400 mg, about 2400 mg, 2500 mg, about 2500 mg, 2600 mg, about 2600 mg, 2700 mg, about 2700 mg, 2800 mg, about 2800 mg, 2900 mg, about 2900 mg, 3000 mg or about 3000 mg, 3500 mg, about 3500 mg, 4000 mg, about 4000 mg, 4500 mg, about 4500 mg, 5000 mg, about 5000 mg, 5500 mg, about 5500 mg, 6000 mg, about 6000 mg, 6500 mg, about 6500 mg, 6800 mg, about 6800 mg, at a rate of once per day, twice per day, three times per day or four times per day.
311. A method in accordance with claim 309, wherein the NMN is administered at a dosage rate of about 0.5 mg per day, from 0.5 mg per day to 6800 mg per day, or about 6800 mg per day.
312. A method in accordance with claim 309, wherein the NMN is administered at a dosage of 100 mg/kg body weight, about 100 mg/kg body weight, from 100 mg kg body weight to 300 mg/kg body weight, 500 mg/kg body weight, or about 500 mg/kg body weight.
313. A method in accordance with claim 309, wherein the NMN is administered orally in a pharmaceutically acceptable formulation selected from the group consisting of a pill, a tablet, a caplet, a capsule, a chewable tablet, a quick dissolve tablet, a powder, a granule, an effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a non-aqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous
suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, and a lyophilized formulation.
314. A method in accordance with claim 309, wherein the NMN is administered parenterally in a pharmaceutically acceptable formulation selected from the group consisting of a nonaqueous liquid, an aqueous liquid, a suspension, a solution, an emulsion, a syrup, a sterilized aqueous suspension, a sterilized aqueous solution, a non-aqueous suspension, a non-aqueous solution, a lyophilized formulation.
315. A method in accordance with claim 309, wherein the NMN is administered by intravenous.
316. A method in accordance with claim 309, wherein the administrating is enterically administrating.
317. A method in accordance with claim 309, wherein the administrating is parenterally administrating.
318. A method in accordance with claim 309, wherein the subject is a mammal.
319. A method in accordance with claim 309, wherein the subject is a human.
320. Nicotinamide mononucleotide (NMN) for use in the treatment of age-associated obesity.
321. Nicotinamide mononucleotide (NMN) for use in the treatment of age-associated increase in blood lipid levels.
322. Nicotinamide mononucleotide (NMN) for use in the treatment of age-associated loss of insulin sensitivity.
323. Nicotinamide mononucleotide (NMN) for use in the treatment of age-associated impairment of memory function.
324. Nicotinamide mononucleotide (NMN) for use in the treatment of age-associated decline in eye function.
325. Nicotinamide mononucleotide (NMN) for use in the treatment of age-associated retinal degeneration.
326. Nicotinamide mononucleotide (NMN) for use in the treatment of dry eye.
327. Nicotinamide mononucleotide (NMN) for use in the treatment of age-associated defects in neural stem/progenitor cell (NSPC) functionality.
328. Nicotinamide mononucleotide (NMN) for use in the treatment of age-associated decrease in a neural stem/progenitor cell (NSPC) population.
329. Nicotinamide mononucleotide (NMN) for use in the treatment of neural stem/progenitor cell (NSPC) deficiency.
330. Nicotinamide mononucleotide (NMN) for use in the treatment of bone density deficiency.
331. Nicotinamide mononucleotide (NMN) for use in the treatment of age-associated bone density decrease.
332. Nicotinamide mononucleotide (NMN) for use in the treatment of osteoporosis.
333. Nicotinamide mononucleotide (NMN) for use in the treatment of macular degeneration.
334. Nicotinamide mononucleotide (NMN) for use in the treatment of retinal degeneration.
335. Nicotinamide mononucleotide (NMN) for use in the treatment of photoreceptor damage.
336. Nicotinamide mononucleotide (NMN) for use in the treatment of photoreceptor degeneration.
337. Nicotinamide mononucleotide (NMN) for use in the treatment of vision loss associated with retinal degeneration.
338. Nicotinamide mononucleotide (NMN) for use in the treatment of aberrant retinal structure.
339. Nicotinamide mononucleotide (NMN) for use in the treatment of aberrant retinal function.
340. Nicotinamide mononucleotide (NMN) for use in a method of reducing risk of developing macular degeneration.
341. Nicotinamide mononucleotide (NMN) for use in a method of reducing risk of developing aberrant retinal NAD levels.
342. Nicotinamide mononucleotide (NMN) for use in preventing photoreceptor
damage/degeneration.
343. Nicotinamide mononucleotide (NMN) for use in reducing risk of developing vision loss associated with retinal degeneration.
345. Nicotinamide mononucleotide (NMN) for use in reducing risk of developing age-related vision loss.
346. Nicotinamide mononucleotide (NMN) for use in reducing risk of developing aberrant retinal structure.
347. Nicotinamide mononucleotide (NMN) for use in reducing risk of developing aberrant retinal function.
347. Nicotinamide mononucleotide (NMN) for use in the treatment of retinitis pigmentosa (RP).
348. Nicotinamide mononucleotide (NMN) for use in the treatment of Leber's congenital amaurosis (LCA).
349. Nicotinamide mononucleotide (NMN) for use in the treatment of rod dystrophy.
350. Nicotinamide mononucleotide (NMN) for use in the treatment of cone dystrophy.
351. Nicotinamide mononucleotide (NMN) for use in the treatment of cone-rod dystrophy.
352. Nicotinamide mononucleotide (NMN) for use in the treatment of age-related macular degeneration.
353. Nicotinamide mononucleotide (NMN) for use in the treatment of photoreceptor degeneration following retinal detachment.
354. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of age-associated obesity.
355. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of age-associated increase in blood lipid levels.
356. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of age-associated loss of insulin sensitivity.
357. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of age-associated impairment of memory function.
358. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of age-associated decline in eye function.
359. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of age-associated retinal degeneration.
360. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of dry eye.
361. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of age-associated defects in neural stem/progenitor cell (NSPC) functionality.
362. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of age-associated decrease in a neural stem/progenitor cell (NSPC) population.
363. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of neural stem/progenitor cell (NSPC) deficiency.
364. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of bone density deficiency.
365. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of age-associated bone density decrease.
366. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of osteoporosis.
367. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of macular degeneration.
368. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of retinal degeneration.
369. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of photoreceptor damage.
370. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of photoreceptor degeneration.
371. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of vision loss associated with retinal degeneration.
372. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of aberrant retinal structure.
373. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of aberrant retinal function.
374. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for reducing risk of developing macular degeneration.
375. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for reducing risk of developing aberrant retinal NAD levels.
376. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for preventing photoreceptor damage/degeneration.
377. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for reducing risk of developing vision loss associated with retinal degeneration.
378. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for reducing risk of developing age-related vision loss.
379. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for reducing risk of developing aberrant retinal structure.
380. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for reducing risk of developing aberrant retinal function.
381. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of retinitis pigmentosa (RP).
382. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of Leber's congenital amaurosis (LCA).
383. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of rod dystrophy.
384. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of cone dystrophy.
385. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of cone-rod dystrophy.
386. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of age-related macular degeneration.
387. Use of Nicotinamide mononucleotide (NMN) for the manufacture of a medicament for the treatment of photoreceptor degeneration following retinal detachment.
388. Use of Nicotinamide mononucleotide (NMN) for the treatment of age-associated obesity.
389. Use of Nicotinamide mononucleotide (NMN) for the treatment of age-associated increase in blood lipid levels.
390. Use of Nicotinamide mononucleotide (NMN) for the treatment of age-associated loss of insulin sensitivity.
391. Use of Nicotinamide mononucleotide (NMN) for the treatment of age-associated impairment of memory function.
392. Use of Nicotinamide mononucleotide (NMN) for the treatment of age-associated decline in eye function.
393. Use of Nicotinamide mononucleotide (NMN) for the treatment of age-associated retinal degeneration.
394. Use of Nicotinamide mononucleotide (NMN) for the treatment of dry eye.
395. Use of Nicotinamide mononucleotide (NMN) for the treatment of age-associated defects in neural stem/progenitor cell (NSPC) functionality.
396. Use of Nicotinamide mononucleotide (NMN) for the treatment of age-associated decrease in a neural stem/progenitor cell (NSPC) population.
397. Use of Nicotinamide mononucleotide (NMN) for the treatment of neural stem/progenitor cell (NSPC) deficiency.
398. Use of Nicotinamide mononucleotide (NMN) for the treatment of bone density deficiency.
399. Use of Nicotinamide mononucleotide (NMN) for the treatment of age-associated bone density decrease.
400. Use of Nicotinamide mononucleotide (NMN) for the treatment of osteoporosis.
401. Use of Nicotinamide mononucleotide (NMN) for the treatment of macular degeneration.
402. Use of Nicotinamide mononucleotide (NMN) for the treatment of retinal degeneration.
403. Use of Nicotinamide mononucleotide (NMN) for the treatment of photoreceptor damage.
404. Use of Nicotinamide mononucleotide (NMN) for the treatment of photoreceptor degeneration.
405. Use of Nicotinamide mononucleotide (NMN) for the treatment of vision loss associated with retinal degeneration.
406. Use of Nicotinamide mononucleotide (NMN) for the treatment of aberrant retinal structure.
407. Use of Nicotinamide mononucleotide (NMN) for the treatment of aberrant retinal function.
408. Use of Nicotinamide mononucleotide (NMN) for reducing risk of developing macular degeneration.
409. Use of Nicotinamide mononucleotide (NMN) for reducing risk of developing aberrant retinal NAD levels.
410. Use of Nicotinamide mononucleotide (NMN) for preventing photoreceptor
damage/degeneration.
411. Use of Nicotinamide mononucleotide (NMN) for reducing risk of developing vision loss associated with retinal degeneration.
412. Use of Nicotinamide mononucleotide (NMN) for reducing risk of developing age- related vision loss.
413. Use of Nicotinamide mononucleotide (NMN) for reducing risk of developing aberrant retinal structure.
414. Use of Nicotinamide mononucleotide (NMN) for reducing risk of developing aberrant retinal function.
415. Use of Nicotinamide mononucleotide (NMN) for the treatment of retinitis pigmentosa (RP).
416. Use of Nicotinamide mononucleotide (NMN) for the treatment of Leber's congenital amaurosis (LCA).
417. Use of Nicotinamide mononucleotide (NMN) for the treatment of rod dystrophy.
418. Use of Nicotinamide mononucleotide (NMN) for the treatment of cone dystrophy.
419. Use of Nicotinamide mononucleotide (NMN) for the treatment of cone-rod dystrophy.
420. Use of Nicotinamide mononucleotide (NMN) for the treatment of age-related macular degeneration.
421. Use of Nicotinamide mononucleotide (NMN) for the treatment of photoreceptor degeneration following retinal detachment.
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14764546.9A EP2968306B1 (en) | 2013-03-15 | 2014-03-17 | Administration of nicotinamide mononucleotide in the treatment of dry eye |
PL14764546.9T PL2968306T3 (en) | 2013-03-15 | 2014-03-17 | Administration of nicotinamide mononucleotide in the treatment of dry eye |
EP23169080.1A EP4233878A1 (en) | 2013-03-15 | 2014-03-17 | Administration of nicotinamide mononucleotide in the treatment of dry eye |
ES14764546T ES2952032T3 (en) | 2013-03-15 | 2014-03-17 | Administration of nicotinamide mononucleotide in the treatment of dry eye |
US14/855,293 US9844561B2 (en) | 2013-03-15 | 2015-09-15 | Administration of nicotinamide mononucleotide in the treatment of disease |
US15/783,845 US10258638B2 (en) | 2013-03-15 | 2017-10-13 | Administration of nicotinamide mononucleotide in the treatment of disease |
US16/290,122 US10925888B2 (en) | 2013-03-15 | 2019-03-01 | Administration of nicotinamide mononucleotide in the treatment of disease |
US17/150,584 US11793824B2 (en) | 2013-03-15 | 2021-01-15 | Administration of nicotinamide mononucleotide in the treatment of disease |
US18/471,764 US20240009222A1 (en) | 2013-03-15 | 2023-09-21 | Administration of nicotinamide mononucleotide in the treatment of disease |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361801188P | 2013-03-15 | 2013-03-15 | |
US61/801,188 | 2013-03-15 | ||
US201461947387P | 2014-03-03 | 2014-03-03 | |
US61/947,387 | 2014-03-03 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/855,293 Continuation US9844561B2 (en) | 2013-03-15 | 2015-09-15 | Administration of nicotinamide mononucleotide in the treatment of disease |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014146044A1 true WO2014146044A1 (en) | 2014-09-18 |
Family
ID=51538175
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2014/030920 WO2014146044A1 (en) | 2013-03-15 | 2014-03-17 | Administration of nicotinamide mononucleotide in the treatment of disease |
Country Status (5)
Country | Link |
---|---|
US (5) | US9844561B2 (en) |
EP (2) | EP4233878A1 (en) |
ES (1) | ES2952032T3 (en) |
PL (1) | PL2968306T3 (en) |
WO (1) | WO2014146044A1 (en) |
Cited By (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016145911A1 (en) * | 2015-03-16 | 2016-09-22 | 邦泰生物工程(深圳)有限公司 | Application of nicotinamide mononucleotide in preparation of anti-aging drug or health care product |
WO2016171152A1 (en) * | 2015-04-20 | 2016-10-27 | 学校法人 慶應義塾 | Therapeutic agent, improving agent, and preventative agent for corneal disorders |
WO2018052019A1 (en) * | 2016-09-13 | 2018-03-22 | めぐみ 田中 | Visual function improvement agent, and method for improving visual function |
WO2018143258A1 (en) | 2017-01-31 | 2018-08-09 | オリエンタル酵母工業株式会社 | Agent for accelerating growth of stem cells with differentiation potential |
WO2018147385A1 (en) | 2017-02-08 | 2018-08-16 | オリエンタル酵母工業株式会社 | Skin pigmentation inhibitor |
JP2018131418A (en) * | 2017-02-16 | 2018-08-23 | ワシントン・ユニバーシティWashington University | Adiponectin secretion enhancer |
WO2019054485A1 (en) * | 2017-09-14 | 2019-03-21 | めぐみ 田中 | Anti-aging agent and anti-aging method |
JPWO2018030389A1 (en) * | 2016-08-08 | 2019-06-13 | 学校法人慶應義塾 | Utilization of NAD-related metabolites |
US10392416B2 (en) | 2015-10-02 | 2019-08-27 | Metro International Biotech, Llc | Crystal forms of beta-nicotinamide mononucleotide |
WO2019181961A1 (en) | 2018-03-20 | 2019-09-26 | 三菱商事ライフサイエンス株式会社 | METHOD FOR PRODUCING β-NMN AND COMPOSITION CONTAINING SAME |
US10548913B2 (en) | 2015-08-05 | 2020-02-04 | Metro International Biotech, Llc | Nicotinamide mononucleotide derivatives and their uses |
WO2020054795A1 (en) * | 2018-09-14 | 2020-03-19 | めぐみ 田中 | Anti-aging agent and anti-aging method |
CN110996967A (en) * | 2017-08-10 | 2020-04-10 | 华盛顿大学 | Compositions and methods of treatment using nicotinamide mononucleotide |
US10618927B1 (en) | 2019-03-22 | 2020-04-14 | Metro International Biotech, Llc | Compositions and methods for modulation of nicotinamide adenine dinucleotide |
KR20200133367A (en) | 2018-03-22 | 2020-11-27 | 오리엔탈고우보고오교가부시끼가이샤 | Multipotent stem cell differentiation promoter |
WO2021187396A1 (en) * | 2020-03-16 | 2021-09-23 | めぐみ 田中 | Coenzyme q production promoter and coenzyme q production promoting method |
CN113508122A (en) * | 2018-05-15 | 2021-10-15 | 江普斯塔特生育有限公司 | Inorganic salts of nicotinamide mononucleotide as anti-ageing agents, in particular for the treatment of infertility |
US11180521B2 (en) | 2018-01-30 | 2021-11-23 | Metro International Biotech, Llc | Nicotinamide riboside analogs, pharmaceutical compositions, and uses thereof |
WO2022142791A1 (en) * | 2020-12-29 | 2022-07-07 | 中科健康产业集团股份有限公司 | Method for preparing lycopene composition with anti-aging effect |
JP2022534165A (en) * | 2019-03-01 | 2022-07-28 | 北京慧宝源生物技▲術▼股▲分▼有限公司 | Compositions containing nicotinamide mononucleotide and mogroside and methods of use thereof |
WO2023276167A1 (en) * | 2021-06-29 | 2023-01-05 | 株式会社常磐植物化学研究所 | Sirtuin activator |
US11787830B2 (en) | 2021-05-27 | 2023-10-17 | Metro International Biotech, Llc | Crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and use |
WO2024013393A1 (en) | 2022-07-15 | 2024-01-18 | Dsm Ip Assets B.V. | Combination of bifidobacterium and fucosylated hmo for use in increasing nmn or nad+ |
US11939348B2 (en) | 2019-03-22 | 2024-03-26 | Metro International Biotech, Llc | Compositions comprising a phosphorus derivative of nicotinamide riboside and methods for modulation of nicotinamide adenine dinucleotide |
RU2822512C2 (en) * | 2019-06-25 | 2024-07-08 | Сэндзю Фармасьютикал Ко., Лтд. | New use of nicotinamide mononucletide (nmn) and nicotinamide riboside (nr) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20180177703A1 (en) * | 2015-06-25 | 2018-06-28 | N.V. Perricone Llc | Niacinamide Mononucleotide Formulations For Skin Aging |
JP6917239B2 (en) * | 2017-08-03 | 2021-08-11 | 旭化成ファーマ株式会社 | Protein and its production method, protein composition and NMN measurement method and measurement composition using it |
WO2020262497A1 (en) * | 2019-06-25 | 2020-12-30 | 千寿製薬株式会社 | Novel use of nicotinamide mononucleotide (nmn) and nicotinamide riboside (nr) |
CN115605207A (en) * | 2020-05-14 | 2023-01-13 | 葡默药物技术有限公司(Us) | Solid dosage form for transmucosal administration |
CN112089706A (en) * | 2020-09-28 | 2020-12-18 | 深圳雾件科技有限公司 | Nicotinamide mononucleotide sustained-release pellet and preparation method thereof |
AU2022207188A1 (en) * | 2021-01-14 | 2023-08-03 | Bioenergy Life Science, Inc. | Methods and compositions for increasing nad+ metabolome in healthy middle-aged population |
CN113133981A (en) * | 2021-04-20 | 2021-07-20 | 北京天玺宝科技有限公司 | Beta-nicotinamide mononucleotide orally disintegrating tablet and preparation method thereof |
US11571438B1 (en) * | 2022-05-23 | 2023-02-07 | Sasan Akhavan | Nutraceutical compositions to up-regulate SIRT1 and methods of use |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013002879A1 (en) * | 2011-06-29 | 2013-01-03 | President And Fellows Of Harvard College | Small molecule cd38 inhibitors and methods of using same |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8017634B2 (en) | 2003-12-29 | 2011-09-13 | President And Fellows Of Harvard College | Compositions for treating obesity and insulin resistance disorders |
AU2005257883A1 (en) | 2004-06-04 | 2006-01-05 | Washington University | Methods and compositions for treating neuropathies |
US8268575B2 (en) | 2004-09-20 | 2012-09-18 | Washington University | NAD biosynthesis systems |
CA2610854A1 (en) | 2005-03-30 | 2006-10-05 | Sirtris Pharmaceuticals, Inc. | Nicotinamide riboside and analogues thereof |
US20070014833A1 (en) | 2005-03-30 | 2007-01-18 | Sirtris Pharmaceuticals, Inc. | Treatment of eye disorders with sirtuin modulators |
AU2006249816A1 (en) * | 2005-05-25 | 2006-11-30 | Sirtris Pharmaceuticals, Inc. | Treatment of eye disorders with sirtuin modulators |
US7737158B2 (en) | 2005-10-11 | 2010-06-15 | Washington University | Processes for regulating blood glucose in a mammal |
MX2009008022A (en) | 2007-01-26 | 2009-12-11 | Univ Washington | Methods and compositions for treating neuropathies. |
EP2057905A1 (en) | 2007-11-12 | 2009-05-13 | TIMA Foundation | Composition for moderating Triglyceride and Cholesterol Levels |
CN101601679B (en) | 2009-03-17 | 2011-08-10 | 中国人民解放军第二军医大学 | Application of nicotinamide mononucleotide |
DE102010030911A1 (en) | 2010-07-02 | 2012-01-05 | Kunststoff-Technik Scherer & Trier Gmbh & Co Kg | Process for producing a molded part and molded part |
WO2012114204A2 (en) | 2011-02-15 | 2012-08-30 | Ecole Polytechnique Federale De Lausanne (Epfl) Epfl-Tto | Methods of treating mitochondrial dysfunction |
AU2012276038B2 (en) | 2011-06-29 | 2017-08-31 | President And Fellows Of Harvard College | Compositions and methods for enhancing bioenergetic status in female germ cells |
-
2014
- 2014-03-17 PL PL14764546.9T patent/PL2968306T3/en unknown
- 2014-03-17 WO PCT/US2014/030920 patent/WO2014146044A1/en active Application Filing
- 2014-03-17 EP EP23169080.1A patent/EP4233878A1/en active Pending
- 2014-03-17 EP EP14764546.9A patent/EP2968306B1/en active Active
- 2014-03-17 ES ES14764546T patent/ES2952032T3/en active Active
-
2015
- 2015-09-15 US US14/855,293 patent/US9844561B2/en active Active
-
2017
- 2017-10-13 US US15/783,845 patent/US10258638B2/en active Active
-
2019
- 2019-03-01 US US16/290,122 patent/US10925888B2/en active Active
-
2021
- 2021-01-15 US US17/150,584 patent/US11793824B2/en active Active
-
2023
- 2023-09-21 US US18/471,764 patent/US20240009222A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013002879A1 (en) * | 2011-06-29 | 2013-01-03 | President And Fellows Of Harvard College | Small molecule cd38 inhibitors and methods of using same |
Non-Patent Citations (3)
Title |
---|
ARTEGIANI B. ET AL.: "Age-related cognitive decline: Can neural stem cells help us?", AGING., vol. 4, no. 3, March 2012 (2012-03-01), pages 176 - 186, XP055281716 * |
BAI S. ET AL.: "NAD(+) maintenance attenuates light induced photoreceptor degeneration.", EXP EYE RES., vol. 108, March 2013 (2013-03-01), pages 76 - 83, XP028980399 * |
FALK M.J. ET AL.: "NMNAT1 mutations cause Leber congenital amaurosis.", NAT GENET., vol. 44, no. 9, September 2012 (2012-09-01), pages 1040 - 1045, XP055281718 * |
Cited By (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016145911A1 (en) * | 2015-03-16 | 2016-09-22 | 邦泰生物工程(深圳)有限公司 | Application of nicotinamide mononucleotide in preparation of anti-aging drug or health care product |
WO2016171152A1 (en) * | 2015-04-20 | 2016-10-27 | 学校法人 慶應義塾 | Therapeutic agent, improving agent, and preventative agent for corneal disorders |
US10548913B2 (en) | 2015-08-05 | 2020-02-04 | Metro International Biotech, Llc | Nicotinamide mononucleotide derivatives and their uses |
US11878027B2 (en) | 2015-08-05 | 2024-01-23 | Metro International Biotech, Llc | Nicotinamide mononucleotide derivatives and their uses |
US11464796B2 (en) | 2015-08-05 | 2022-10-11 | Metro International Biotech, Llc | Nicotinamide mononucleotide derivatives and their uses |
US10392416B2 (en) | 2015-10-02 | 2019-08-27 | Metro International Biotech, Llc | Crystal forms of beta-nicotinamide mononucleotide |
US11059847B2 (en) | 2015-10-02 | 2021-07-13 | Metro International Biotech, Llc | Crystal forms of β-nicotinamide mononucleotide |
JPWO2018030389A1 (en) * | 2016-08-08 | 2019-06-13 | 学校法人慶應義塾 | Utilization of NAD-related metabolites |
JP7090336B2 (en) | 2016-08-08 | 2022-06-24 | 慶應義塾 | Utilization of NAD-related metabolites |
JPWO2018052019A1 (en) * | 2016-09-13 | 2019-06-24 | めぐみ 田中 | Agent for improving visual function and method for improving visual function |
US10898738B2 (en) | 2016-09-13 | 2021-01-26 | Megumi Tanaka | Visual function printing agent, and method for improving visual functions |
WO2018052019A1 (en) * | 2016-09-13 | 2018-03-22 | めぐみ 田中 | Visual function improvement agent, and method for improving visual function |
US11634690B2 (en) | 2017-01-31 | 2023-04-25 | Oriental Yeast Co., Ltd. | Agent for accelerating growth of pluripotent stem cells |
KR20190112760A (en) | 2017-01-31 | 2019-10-07 | 오리엔탈고우보고오교가부시끼가이샤 | Multipotent Stem Cell Proliferation Accelerator |
JPWO2018143258A1 (en) * | 2017-01-31 | 2019-11-21 | オリエンタル酵母工業株式会社 | Multipotent stem cell proliferation promoter |
WO2018143258A1 (en) | 2017-01-31 | 2018-08-09 | オリエンタル酵母工業株式会社 | Agent for accelerating growth of stem cells with differentiation potential |
KR20190112117A (en) | 2017-02-08 | 2019-10-02 | 오리엔탈고우보고오교가부시끼가이샤 | Skin pigmentation inhibitors |
US11219632B2 (en) | 2017-02-08 | 2022-01-11 | Oriental Yeast Co., Ltd. | Skin pigmentation inhibitor |
WO2018147385A1 (en) | 2017-02-08 | 2018-08-16 | オリエンタル酵母工業株式会社 | Skin pigmentation inhibitor |
US10695360B2 (en) | 2017-02-16 | 2020-06-30 | Washington University | Adiponectin secretion enhancer |
JP2018131418A (en) * | 2017-02-16 | 2018-08-23 | ワシントン・ユニバーシティWashington University | Adiponectin secretion enhancer |
US11564936B2 (en) | 2017-08-10 | 2023-01-31 | Washington University | Compositions and methods of treatment using nicotinamide mononucleotide |
EP3664813A4 (en) * | 2017-08-10 | 2021-08-11 | Washington University | Compositions and methods of treatment using nicotinamide mononucleotide |
CN110996967A (en) * | 2017-08-10 | 2020-04-10 | 华盛顿大学 | Compositions and methods of treatment using nicotinamide mononucleotide |
JP7210459B2 (en) | 2017-09-14 | 2023-01-23 | めぐみ 田中 | Antiaging agent and antiaging method |
JPWO2019054485A1 (en) * | 2017-09-14 | 2020-10-15 | めぐみ 田中 | Anti-aging agents and anti-aging methods |
WO2019054485A1 (en) * | 2017-09-14 | 2019-03-21 | めぐみ 田中 | Anti-aging agent and anti-aging method |
CN111093397A (en) * | 2017-09-14 | 2020-05-01 | 田中惠 | Anti-aging agent and anti-aging method |
US11219590B2 (en) * | 2017-09-14 | 2022-01-11 | Megumi Tanaka | Anti-aging agent and anti-aging method |
US11180521B2 (en) | 2018-01-30 | 2021-11-23 | Metro International Biotech, Llc | Nicotinamide riboside analogs, pharmaceutical compositions, and uses thereof |
WO2019181961A1 (en) | 2018-03-20 | 2019-09-26 | 三菱商事ライフサイエンス株式会社 | METHOD FOR PRODUCING β-NMN AND COMPOSITION CONTAINING SAME |
KR20200133367A (en) | 2018-03-22 | 2020-11-27 | 오리엔탈고우보고오교가부시끼가이샤 | Multipotent stem cell differentiation promoter |
US11814652B2 (en) | 2018-03-22 | 2023-11-14 | Oriental Yeast Co., Ltd. | Pluripotent stem cell differentiation-promoting agent |
CN113508122A (en) * | 2018-05-15 | 2021-10-15 | 江普斯塔特生育有限公司 | Inorganic salts of nicotinamide mononucleotide as anti-ageing agents, in particular for the treatment of infertility |
JPWO2020054795A1 (en) * | 2018-09-14 | 2021-08-30 | めぐみ 田中 | Anti-aging agents and anti-aging methods |
WO2020054795A1 (en) * | 2018-09-14 | 2020-03-19 | めぐみ 田中 | Anti-aging agent and anti-aging method |
CN112739222A (en) * | 2018-09-14 | 2021-04-30 | 田中惠 | Anti-aging agent and anti-aging method |
JP2022534165A (en) * | 2019-03-01 | 2022-07-28 | 北京慧宝源生物技▲術▼股▲分▼有限公司 | Compositions containing nicotinamide mononucleotide and mogroside and methods of use thereof |
US10618927B1 (en) | 2019-03-22 | 2020-04-14 | Metro International Biotech, Llc | Compositions and methods for modulation of nicotinamide adenine dinucleotide |
US11939348B2 (en) | 2019-03-22 | 2024-03-26 | Metro International Biotech, Llc | Compositions comprising a phosphorus derivative of nicotinamide riboside and methods for modulation of nicotinamide adenine dinucleotide |
RU2822512C2 (en) * | 2019-06-25 | 2024-07-08 | Сэндзю Фармасьютикал Ко., Лтд. | New use of nicotinamide mononucletide (nmn) and nicotinamide riboside (nr) |
WO2021187396A1 (en) * | 2020-03-16 | 2021-09-23 | めぐみ 田中 | Coenzyme q production promoter and coenzyme q production promoting method |
WO2022142791A1 (en) * | 2020-12-29 | 2022-07-07 | 中科健康产业集团股份有限公司 | Method for preparing lycopene composition with anti-aging effect |
US11787830B2 (en) | 2021-05-27 | 2023-10-17 | Metro International Biotech, Llc | Crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and use |
US11952396B1 (en) | 2021-05-27 | 2024-04-09 | Metro International Biotech, Llc | Crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and use |
WO2023276167A1 (en) * | 2021-06-29 | 2023-01-05 | 株式会社常磐植物化学研究所 | Sirtuin activator |
WO2024013393A1 (en) | 2022-07-15 | 2024-01-18 | Dsm Ip Assets B.V. | Combination of bifidobacterium and fucosylated hmo for use in increasing nmn or nad+ |
Also Published As
Publication number | Publication date |
---|---|
US11793824B2 (en) | 2023-10-24 |
US10925888B2 (en) | 2021-02-23 |
EP2968306A4 (en) | 2016-11-02 |
US10258638B2 (en) | 2019-04-16 |
PL2968306T3 (en) | 2024-01-29 |
EP2968306A1 (en) | 2016-01-20 |
EP4233878A1 (en) | 2023-08-30 |
US20190224223A1 (en) | 2019-07-25 |
US20210346413A1 (en) | 2021-11-11 |
EP2968306B1 (en) | 2023-06-07 |
US20160022712A1 (en) | 2016-01-28 |
ES2952032T3 (en) | 2023-10-26 |
US20180050054A1 (en) | 2018-02-22 |
US20240009222A1 (en) | 2024-01-11 |
US9844561B2 (en) | 2017-12-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11793824B2 (en) | Administration of nicotinamide mononucleotide in the treatment of disease | |
US20240165079A1 (en) | Combination product for the treatment of neurological and/or psychiatric disorders | |
Hu et al. | Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome | |
She et al. | Emerging roles of sirtuins in ischemic stroke | |
Gu et al. | Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming | |
Wu et al. | Ursolic acid improves domoic acid-induced cognitive deficits in mice | |
Wang et al. | Targeting CARD6 attenuates spinal cord injury (SCI) in mice through inhibiting apoptosis, inflammation and oxidative stress associated ROS production | |
Zhang et al. | Resveratrol attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation | |
Tang et al. | Neuroprotective role of an N-acetyl serotonin derivative via activation of tropomyosin-related kinase receptor B after subarachnoid hemorrhage in a rat model | |
Zhang et al. | Inhibiting Jumoji domain containing protein 3 (JMJD3) prevent neuronal apoptosis from stroke | |
Grummisch et al. | tPA promotes cortical neuron survival via mTOR-dependent mechanisms | |
Sun et al. | SIRT1 activation attenuates microglia-mediated synaptic engulfment in postoperative cognitive dysfunction | |
US9486440B2 (en) | Uses of indole-ketones or indolidones as neuro-protective drugs | |
US20220233443A1 (en) | Production and use of extracellular vesicle-contained enampt | |
Gao et al. | Minocycline prevents the inflammatory response after retinal detachment, where microglia phenotypes being regulated through A20 | |
EP3496725A1 (en) | Remyelination therapies | |
TW201932130A (en) | Lipocalin-type prostaglandin D2 synthase production promoter | |
Li et al. | Melatonin regulates microglial polarization to M2 cell via RhoA/ROCK signaling pathway in epilepsy | |
KR101759424B1 (en) | Therapeutic use of low-molecular weight compounds for glioblastoma | |
Class et al. | Patent application title: Administration of Nicotinamide Mononucleotide in the Treatment of Disease Inventors: Shin-Ichiro Imai (Saint Louis, MO, US) Rajendra Apte (Clayton, MO, US) | |
Yang et al. | miR-199a-5p from bone marrow mesenchymal stem cell exosomes promotes the proliferation of neural stem cells by targeting GSK-3β: miR-199a-5p from BMSC exosomes promotes NSC proliferation | |
WO2017209270A1 (en) | Activated t cell- and/or b cell-selective cell death inducer or cell death promoter comprising as active ingredient 25-hydroxycholesterol or cholesterol analogous thereto | |
EP4157268A1 (en) | New therapy for the treatment of tumors | |
Sola et al. | Melatonin and Cancer: New Insights | |
Petrovski | Omics Technologies and Neovascular Ocular Disorders |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14764546 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2014764546 Country of ref document: EP |