US20050096256A1 - Compositions for manipulating the lifespan and stress response of cells and organisms - Google Patents

Compositions for manipulating the lifespan and stress response of cells and organisms Download PDF

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US20050096256A1
US20050096256A1 US10/884,022 US88402204A US2005096256A1 US 20050096256 A1 US20050096256 A1 US 20050096256A1 US 88402204 A US88402204 A US 88402204A US 2005096256 A1 US2005096256 A1 US 2005096256A1
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David Sinclair
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Definitions

  • Yeast lifespan extension is governed by PNC1, a calorie restriction (CR)- and stress-responsive gene that depletes nicotinamide, a potent inhibitor of the longevity protein Sir2.
  • PNC1 and SIR2 are required for lifespan extension by CR or mild stress 5,6 and additional copies of these genes extend lifespan 30-70% 5,7 . Based on these results we proposed that CR may confer health benefits in a variety of species because it is a mild stress that induces a sirtuin-mediated organismal defense response 6 .
  • Sir2 a histone deacetylase (HDAC), is the founding member of the sirtuin deacetylase family, which is characterized by a requirement for NAD + as a co-substrate 8,13 .
  • SIR2 was originally identified as a gene required for the formation of transcriptionally silent heterochromatin at yeast mating-type loci 14 .
  • Subsequent studies have shown that Sir2 suppresses recombination between repetitive DNA sequences at ribosomal RNA genes (rDNA) 15-17 .
  • rDNA ribosomal RNA genes
  • sirtuins are conserved 19-22 .
  • additional copies of sir-2.1 extend lifespan by 50% via the insulin/IGF-1 signalling pathway, the same pathway recently shown to regulate lifespan in rodents 23-25 .
  • the method may comprise contacting a sirtuin deacetylase protein family member with a compound having a structure selected from the group consisting of formulas 1-25, 30 and 32-65.
  • a compound having a structure selected from the group consisting of formulas 1-25, 30 and 32-65 Compounds falling within formulas 1-25, 30 and 32-65 and activating a sirtuin protein are referred to herein as “activating compounds.”
  • the activating compound may b e a polyphenol compound, such as a plant polyphenol or an analog or derivative thereof.
  • Exemplary compounds are selected from the group consisting of flavones, stilbenes, flavanones, isoflavones, catechins, chalcones, tannins and anthocyanidins or analog or derivative thereof.
  • compounds are selected from the group consisting of resveratrol, butein, piceatannol, isoliquiritgenin, fisetin, luteolin, 3,6,3′,4′-tetrahydroxyfalvone, quercetin, and analogs and derivatives thereof.
  • the activating compound is a naturally occurring compound, it may not in a form in which it is naturally occurring.
  • the sirtuin deacetylase protein family member may be the human SIRT1 protein or the yeast Sir2 protein.
  • the sirtuin deacetylase protein family member may be in a cell, in which case the method may comprise contacting the cell with an activating compound or introducing a compound into the cell.
  • the cell may be in vitro.
  • the cell may be a cell of a subject.
  • the cell may be in a subject and the method may comprise administering the activating compound to the subject.
  • Methods may further comprise determining the activity of the sirtuin deacetylase protein family member.
  • a cell may be contacted with an activating compound at a concentration of about 0.1-100 ⁇ M. In certain embodiments, a cell is further contacted with an additional activating compound. In other embodiments, a cell is contacted with a least three different activating compounds.
  • Other methods encompassed herein include methods for inhibiting the activity of p53 in a cell and optionally protecting the cell against apoptosis, e.g., comprising contacting the cell with an activating compound at a concentration of less than about 0.5 ⁇ M.
  • Another method comprises stimulating the activity of p53 in a cell and optionally inducing apoptosis in the cell, comprising contacting the cell with an activating compound at a concentration of at least about 50 ⁇ M.
  • a compound selected from the group consisting of stilbene, flavone and chalcone family members Such compounds are referred to as “lifespan extending compounds.”
  • the compound may have the structure set forth in formula 7.
  • Other compounds may be activating compounds having a structure set forth in any of formulas 1-25, 30 and 32-65, provided they extend lifespan or increase resistance to stress.
  • the compound may be selected from the group consisting of resveratrol, butein and fisetin and analogs and derivatives thereof.
  • the lifespan extending compound is a naturally occurring compound, it is not in a form in which it is naturally occurring.
  • the method may further comprise determining the lifespan of the cell.
  • the method may also further comprise contacting the cell with an additional compound or with at least three compounds selected from the group consisting of stilbene, flavone and chalcone family members or other lifespan extending compound.
  • the cell may be contacted with a compound at a concentration of less than about 10 ⁇ M or at a concentration of about 10-100 ⁇ M.
  • the cell may be in vitro or in vivo, it may be a yeast cell or a mammalian cell. If the cell is in a subject, the method may comprise administering the compound to the subject.
  • One method comprises contacting a sirtuin or cell or organism comprising such with an inhibitory compound having a formula selected from the group of formulas 26-29, 31 and 66-68.
  • compositions comprising, e.g., at least one or at least two compounds each having a formula selected from the group consisting of formulas 1-68. Further provided herein a rescreening methods for identifying compounds, e.g., small molecules, that modulate sirtuins and/or modulate the life span or resistance to stress of cells.
  • Methods may comprise (i) contacting a cell comprising a SIRT1 protein with a peptide of p53 comprising an acetylated residue 382 in the presence of an inhibitor of class I and class II HDAC under conditions appropriate for SIRT1 to deacetylate the peptide and (ii) determining the level of acetylation of the peptide, wherein a different level of acetylation of the peptide in the presence of the test compound relative to the absence of the test compound indicates that the test compound modulates SIRT1 in vivo.
  • FIG. 1 shows the effects of resveratrol on the kinetics of recombinant human SIRT1.
  • a Resveratrol dose-response of SIRT1 catalytic rate at 25 ⁇ M NAD + , 25 ⁇ M p53-382 acetylated peptide.
  • Relative initial rates are the mean of two determinations, each derived from the slopes of fluorescence (arbitrary fluorescence units, AFU) vs. time plots with data obtained at 0, 5, 10 and 20 min. of deacetylation.
  • FIG. 2 shows the effects of polyphenols on Sir2 and S. cerevisiae lifespan.
  • a Initial deacetylation rate of recombinant GST-Sir2 as a function of resveratrol concentration. Rates were determined at the indicated resveratrol concentrations, either with 100 ⁇ M ‘Fluor de Lys’ acetylated lysine substrate (FdL) plus 3 mM NAD + ( ⁇ ) or with 200 ⁇ M p53-382 acetylated peptide substrate plus 200 ⁇ M NAD + ( ⁇ ).
  • FdL acetylated lysine substrate
  • ⁇ acetylated lysine substrate
  • ⁇ 200 ⁇ M p53-382 acetylated peptide substrate plus 200 ⁇ M NAD +
  • Lifespan analyses were determined by micro-manipulating individual yeast cells as described 37 on complete 2% glucose medium with 10 ⁇ M of each compound, unless otherwise stated.
  • c Average lifespan for wild type, 22.9 generations; fisetin, 30.0; butein, 35.5; resveratrol, 36.8.
  • d Average lifespan for wild type untreated, 21.0 generations; growth on resveratrol, 10 ⁇ M, 35.7; 100 ⁇ M, 29.4; 500 ⁇ M, 29.3.
  • FIG. 3 shows that resveratrol extends lifespan by mimicking CR and suppressing rDNA recombination.
  • Yeast lifespans were determined as in FIG. 2 .
  • a Average lifespan for wild type (wt) untreated, 19.0 generations; wild type+resveratrol (wt+R) 37.8; glucose-restricted+resveratrol (CR+R), 39.9.
  • b Average lifespans for wild type sir2 ⁇ , 9.9; sir2 ⁇ +resveratrol, 10.0; pnc1 ⁇ , 19.2; pnc1 ⁇ + resveratrol, 33.1.
  • Resveratrol suppresses the frequency of ribosomal DNA recombination in the presence and absence of nicotinamide (NAM). Frequencies were determined by loss of the ADE2 marker gene from the rDNA locus (RDN1). d, Resveratrol does not suppress rDNA recombination in a sir2 strain. e, Resveratrol and other sirtuin activators do not significantly increase rDNA silencing compared to a 2 ⁇ SIR2 strain. Pre-treated cells (RDN1::URA3) were harvested and spotted as 10-fold serial dilutions on either SC or SC with 5-fluororotic acid (5-FOA). In this assay, increased rDNA silencing results in increased survival on 5-FOA medium. f, Quantitation of the effect of resveratrol on rDNA silencing by counting numbers of surviving cells on FOA/total plated.
  • NAM nicotinamide
  • FIG. 4 shows that resveratrol and other polyphenols stimulate SIRT1 activity in human cells.
  • SIRT1 activating polyphenols can stimulate TSA-insensitive, FdL deacetylation by HeLa S3 cells.
  • Cells were grown adherently in DMEM/10% FCS and treated for 1 hour with 200 ⁇ M FdL, 1 ⁇ M TSA and either vehicle (0.5% final DMSO, Control) or 500 ⁇ M of the indicated compound. Intracellular accumulation of deAc-FdL was then determined as described briefly in a.
  • U2OS cells cultured as above were pre-treated with the indicated amounts of resveratrol or a 0.5% DMSO blank for 4 hours after which cells were exposed to 0 or 50 J/cm 2 of UV radiation.
  • Lysates were prepared and analyzed by Western blot as in c. e, Human embryonic kidney cells (HEK 293) expressing wild type SIRT1 or dominant negative SIRT1-H363Y (SIRT1-HY) protein were cultured as above, pre-treated with the indicated amounts of resveratrol or a 0.5% DMSO blank for 4 hours and exposed to 50 J/cm 2 of UV radiation as above. Lysates were prepared and analyzed as above.
  • FIG. 5 shows that intracellular deacetylation activity may be measured with a cell-permeable, fluorogenic HDAC and sirtuin substrate.
  • HeLa S3 cells were grown to confluence in DMEM/10% FCS and then incubated with fresh medium containing 200 ⁇ M FdL for the indicated times, 37° C.
  • Intracellular and medium levels of deacetylated substrate (deAc-FdL) were determined according to the manufacturer's instructions (HDAC assay kit, BIOMOL). All data points represent the mean of two determinations.
  • a Concentration ratio of intracellular ([deAc-FdL] i ) to medium ([deAc-FdL] o ) concentrations in the presence ( ⁇ ) or absence ( ⁇ ) of 1 ⁇ M trichostatin A (TSA).
  • TSA trichostatin A
  • b Total accumulation of deacetylated substrate (deAc-FdL) in the presence ( ⁇ ) or absence ( ⁇ ) of 1 ⁇ M TSA.
  • c Intracellular accumulation of deacetylated substrate (deAc-FdL) in the presence ( ⁇ ) or absence ( ⁇ ) of 1 ⁇ M TSA.
  • FIG. 6 shows that deacetylation site preferences of recombinant SIRT1.
  • Initial rates of deacetylation were determined for a series of fluorogenic acetylated peptide substrates based on short stretches of human histone H3, H4 and p53 sequence (see key to substrate name and single letter peptide sequence below the bar graph).
  • Recombinant human SIRT1(1 ⁇ g, BIOMOL) was incubated 10 min, 37° C., with 25 ⁇ M of the indicated fluorogenic acetylated peptide substrate and 500 ⁇ M NAD + . Reactions were stopped by the addition of 1 mM nicotinamide and the deacetylation-dependent fluorescent signal was determined.
  • FIG. 7 is a graph representing SIRT2 activity as a function of resveratrol concentration.
  • FIG. 8 shows an alignment of the amino acid sequences of hSIRT2, hSIRT1 and S. cerevisiae Sir2.
  • FIG. 9A shows resveratrol and BML-230 dose responses of SIRT1 catalytic rate.
  • FIG. 9B shows the ratio of BML-230-activated to resveratrol-activated SIRT1 rates as a function of activator concentration (the ratios were calculated from data of FIG. 9A ).
  • FIG. 10 shows the effect of polyphenolic STACs on metazoan sirtuins.
  • a Schematic of Sir2 polypeptides from human, yeast, C. elegans and D. melanogaster aligned to show conserved regions. Amino acids forming the NAD + -binding pocket (grey) and substrate binding groove (black) are indicated. Percentages refer to the homology to SIRT1.
  • b Effect of polyphenolic STACs (500 ⁇ M) on NAD + -dependent, trichostatin A (TSA)-insensitive deacetylase activity in Drosophila S2 cells.
  • TSA trichostatin A
  • d Fold stimulation of recombinant dSir2 by STACs (10 ⁇ M). Values are the mean of at least three determinations (+/ ⁇ standard error).
  • e Dose-dependent activation of C. elegans SIR-2.1 by resveratrol. Rates were determined using a fluorigenic acetylated lysine substrate (Fluor de Lys).
  • f Dose-dependent activation of Drosophila dSir2 by resveratrol.
  • g SIR-2.1 initial rate at 10 ⁇ M Fluor de Lys as a function of NAD + concentration, in the presence or absence of 100 ⁇ M resveratrol.
  • AFU arbitrary fluorescence units.
  • FIG. 11 shows the C. elegans survival on resveratrol.
  • b Survivorship of sir-2.1 mutants treated with resveratrol fed with heat-killed OP50.
  • e Fecundity of adult hermaphrodites treated with 1000M resveratrol. Controls: 106 eggs/5 worms/5 hours (s.d. 10.0); resveratrol-treated: 99 eggs/5 worms/5 hours (s.d. 13.0).
  • f Feeding rates of L4 larval and adult hermaphrodites treated with 100 ⁇ M resveratrol.
  • FIG. 12 shows wild-type female D. melanogaster survival with adults fed resveratrol or fisetin.
  • a Canton-S on 15% SY media.
  • b Canton-S on 5% SY media with resveratrol at two concentrations.
  • c Strain yw on 3% CSY media.
  • d Strain yw on 2% CSY media with resveratol at two concentrations.
  • e Strain yw on 3% CSY media with 100 ⁇ M resveratrol or fisetin.
  • f Strain yw on 2% CSY media with 100 ⁇ M resveratrol or fisetin. Life table statistics for this figure, for males and for additional trials are in Table 20.
  • g Mean daily fecundity per female (s.e.) estimated over 5-day intervals of Canton-S on 15% SY media with 0 or 10 ⁇ M resveratrol.
  • h Proportion (s.e.) of yw females feeding on diet with and without resveratrol in crop-filling assay.
  • i Mean (s.e.) body mass of Canton-S males and females feeding on diet without and with resveratrol (10 ⁇ M).
  • FIG. 13 shows the survivorship of D. melanogaster adults with mutant alleles of dSir2 when fed resveratrol (100 ⁇ M).
  • FIG. 14 shows the mortality rates of control and resveratrol treated adults. Mortality was estimated as ln( ⁇ ln(p x )) where p x is the survival probability at day x to x+1.
  • a C. elegans wild-type N2 on heat-killed OP50 E. coli .
  • b C. elegans wild-type N2 on live OP50 E. coli .
  • mortality is plotted only at days with observed mortality.
  • c D. melanogaster wildtype females of Trial 1 at effective doses of resveratrol on 15% SY diet.
  • d D. melanogaster wildtype males of Trial 1 at effective doses of resveratrol on 15% SY diet.
  • c and d mortality is smoothed from 3-day running average of p x .
  • FIG. 15 shows the stimulation of SIRT 1 catalytic rate by 100 ⁇ M plant polyphenols (Table 1).
  • FIG. 16 shows the effect of 100 ⁇ M stilbenes and chalcones on SIRT 1 catalytic rate (Supplementary Table 1).
  • FIG. 17 shows the effect of 100 ⁇ M flavones on SIRT 1 catalytic rate (Supplementary Table 2).
  • FIG. 18 shows the effect of 100 ⁇ M flavones on SIRT 1 catalytic rate (Supplementary Table 3).
  • FIG. 19 shows the effect of 100 ⁇ M isoflavones, flavanones and anthocyanidins on SIRT 1 catalytic rate (Supplementary Table 4).
  • FIG. 20 shows the effect of 100 ⁇ M catechins (Flavan-3-ols) on SIRT 1 catalytic rate (Supplementary Table 5).
  • FIG. 21 shows the effect of 100 ⁇ M free radical protective compounds on SIRT 1 catalytic rate (Supplementary Table 6).
  • FIG. 22 shows the effect of 100 ⁇ M miscellaneous compounds on SIRT 1 catalytic rate (Supplementary Table 7).
  • FIG. 23 shows the effect of 100 ⁇ M of various modulators on SIRT 1 catalytic rate (Supplementary Table 8).
  • FIG. 24 shows the effect of 100 ⁇ M of new resveratrol analogs on SIRT 1 catalytic rate (Table 9).
  • FIG. 25 shows the effect of 100 ⁇ M of new resveratrol analogs on SIRT 1 catalytic rate (Table 10).
  • FIG. 26 shows the effect of 100 ⁇ M of new resveratrol analogs on SIRT 1 catalytic rate (Table 11).
  • FIG. 27 shows the effect of 100 ⁇ M of new resveratrol analogs on SIRT 1 catalytic rate (Table 12).
  • FIG. 28 shows the effect of 100 ⁇ M of new resveratrol analogs on SIRT 1 catalytic rate (Table 13).
  • FIG. 29 shows synthetic intermediates of resveratrol analog synthesis (Table 14).
  • FIG. 30 shows synthetic intermediates of resveratrol analog synthesis (Table 15).
  • FIG. 31 shows synthetic intermediates of resveratrol analog synthesis (Table 16).
  • FIG. 32 shows synthetic intermediates of resveratrol analog synthesis (Table 17).
  • FIG. 33 shows synthetic intermediates of resveratrol analog synthesis (Table 18).
  • FIG. 34 shows the effect of resveratrol on Drosophila melanogaster (Table 20).
  • FIGS. 35 A-G shows sirtuin activators and the fold activation of SIRT1 (Table 21).
  • FIG. 36 shows sirtuin inhibitors and the fold inhibition of SIRT1 (Table 22).
  • Activating a sirtuin protein refers to the action of producing an activated sirtuin protein, i.e., a sirtuin protein that is capable of performing at least one of its biological activities to at least some extent, e.g., with an increase of activity of at least about 10%, 50%, 2 fold or more.
  • Biological activities of sirtuin proteins include deacetylation, e.g., of histones and p53; extending lifespan; increasing genomic stability; silencing transcription; and controlling the segregation of oxidized proteins between mother and daughter cells.
  • activating compound or a “sirtuin activating compound” refers to a compound that activates a sirtuin protein or stimulates or increases at least one of its activities. Activating compounds may have a formula selected from the group of formulas 1-25, 30 and 32-65.
  • a “form that is naturally occurring” when referring to a compound means a compound that is in a form, e.g., a composition, in which it can be found naturally. For example, since resveratrol can be found in red wine, it is present in red wine in a form that is naturally occurring. A compound is not in a form that is naturally occurring if, e.g., the compound has been purified and separated from at least some of the other molecules that are found with the compound in nature.
  • “Inhibiting a sirtuin protein” refers to the action of reducing at least one of the biological activities of a sirtuin protein to at least some extent, e.g., at least about 10%, 50%, 2 fold or more.
  • inhibitory compound refers to a compound that inhibits a sirtuin protein. Inhibitory compounds may have a formula selected from the group of formulas 26-29, 31 and 66-68.
  • a “naturally occurring compound” refers to a compound that can be found in nature, i.e., a compound that has not been designed by man.
  • a naturally occurring compound may have been made by man or by nature.
  • resveratrol is a naturally-occurring compound.
  • a “non-naturally occurring compound” is a compound that is not known to exist in nature or that does not occur in nature.
  • Replicative lifespan of a cell refers to the number of daughter cells produced by an individual “mother cell.”
  • “Sirtuin deacetylase protein family members;” “Sir2 family members;” “Sir2 protein family members;” or “sirtuin proteins” includes yeast Sir2, Sir-2.1, and human SIRT1 and SIRT2 proteins.
  • the nucleotide and amino acid sequences of the human sirtuin, SIRT1 (silent mating type information regulation 2 homolog), are set forth as SEQ ID NOs: 1 and 2, respectively (corresponding to GenBank Accession numbers NM — 012238 and NP — 036370, respectively).
  • HST genes additional yeast Sir2-like genes termed “HST genes” (homologues of Sir two) HST1, HST2, HST3 and HST4, and the five other human homologues hSIRT3, hSIRT4, hSIRT5, hSIRT6 and hSIRT7 (Brachmann et al. (1995) Genes Dev. 9:2888 and Frye et al. (1999) BBRC 260:273).
  • HST genes homologues of Sir two HST1, HST2, HST3 and HST4
  • Preferred sirtuins are those that share more similarities with SIRT1, i.e., hSIRT1, and/or Sir2 than with SIRT2, such as those members having at least part of the N-terminal sequence present in SIRT1 and absent in SIRT2 such as SIRT3 has.
  • Biologically active portion of a sirtuin refers to a portion of a sirtuin protein having a biological activity, such as the ability to deacetylate.
  • Biologically active portions of sirtuins may comprise the core domain of sirtuins.
  • amino acids 62-293 of SIRT1 having SEQ ID NO: 2, which are encoded by nucleotides 237 to 932 of SEQ ID NO: 1 encompass the NAD + binding domain and the substrate binding domain. Therefore, this region is sometimes referred to as the core domain.
  • SIRT1 also sometimes referred to as core domains
  • core domains include about amino acids 261 to 447 of SEQ ID NO: 2, which are encoded by nucleotides 834 to 1394 of SEQ ID NO: 1; about amino acids 242 to 493 of SEQ ID NO: 2, which are encoded by nucleotides 777 to 1532 of SEQ ID NO: 1; or about amino acids 254 to 495 of SEQ ID NO: 2, which are encoded by nucleotides 813 to 1538 of SEQ ID NO: 1.
  • Cis configurations are often labeled as (Z) configurations.
  • Trans is art-recognized and refers to the arrangement of two atoms or groups around a double bond such that the atoms or groups are on the opposite sides of a double bond.
  • Trans configurations are often labeled as (E) configurations.
  • covalent bond is art-recognized and refers to a bond between two atoms where electrons are attracted electrostatically to both nuclei of the two atoms, and the net effect of increased electron density between the nuclei counterbalances the internuclear repulsion.
  • covalent bond includes coordinate bonds when the bond is with a metal ion.
  • therapeutic agent is art-recognized and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject.
  • the term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and/or conditions in an animal or human.
  • therapeutic effect is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance.
  • therapeutically-effective amount means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment.
  • the therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • certain compositions described herein may be administered in a sufficient amount to produce a at a reasonable benefit/risk ratio applicable to such treatment.
  • synthetic is art-recognized and refers to production by in vitro chemical or enzymatic synthesis.
  • meso compound is art-recognized and refers to a chemical compound which has at least two chiral centers but is achiral due to a plane or point of symmetry.
  • chiral is art-recognized and refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • a “prochiral molecule” is a molecule which has the potential to be converted to a chiral molecule in a particular process.
  • stereoisomers is art-recognized and refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • Diastereomers refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another.
  • a “stereoselective process” is one which produces a particular stereoisomer of a reaction product in preference to other possible stereoisomers of that product.
  • An “enantioselective process” is one which favors production of one of the two possible enantiomers of a reaction product.
  • regioisomers is art-recognized and refers to compounds which have the same molecular formula but differ in the connectivity of the atoms. Accordingly, a “regioselective process” is one which favors the production of a particular regioisomer over others, e.g., the reaction produces a statistically significant increase in the yield of a certain regioisomer.
  • esters are art-recognized and refers to molecules with identical chemical constitution and containing more than one stereocenter, but which differ in configuration at only one of these stereocenters.
  • ED 50 means the dose of a drug which produces 50% of its maximum response or effect, or alternatively, the dose which produces a pre-determined response in 50% of test subjects or preparations.
  • LD 50 means the dose of a drug which is lethal in 50% of test subjects.
  • therapeutic index is an art-recognized term which refers to the therapeutic index of a drug, defined as LD 5 O/ED 50 .
  • structure-activity relationship or “(SAR)” is art-recognized and refers to the way in which altering the molecular structure of a drug or other compound alters its biological activity, e.g., its interaction with a receptor, enzyme, nucleic acid or other target and the like.
  • aliphatic is art-recognized and refers to a linear, branched, cyclic alkane, alkene, or alkyne.
  • aliphatic groups in the present compounds are linear or branched and have from 1 to about 20 carbon atoms.
  • alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for straight chain, C 3 -C 30 for branched chain), and alternatively, about 20 or fewer.
  • cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
  • alkyl is also defined to include halosubstituted alkyls.
  • aralkyl is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • aryl is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphtalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles” or “heteroaromatics.”
  • the aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, —CF 3 , —CN, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively.
  • 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
  • heterocyclyl or “heterocyclic group” are a rt-recognized and refer to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be polycycles.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
  • the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF 3 , —CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • polycyclyl or “polycyclic group” are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are “fused rings”. Rings that are joined through non-adjacent atoms are termed “bridged” rings.
  • Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF 3 , —CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, si
  • carrier is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • nitro is art-recognized and refers to —NO 2 ;
  • halogen is art-recognized and refers to —F, —Cl, —Br or —I;
  • sulfhydryl is art-recognized and refers to —SH;
  • hydroxyl means —OH;
  • sulfonyl is art-recognized and refers to —SO 2 —.
  • Halide designates the corresponding anion of the halogens, and “pseudohalide” has the definition set forth on 560 of “ Advanced Inorganic Chemistry ” by Cotton and Wilkinson.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas: wherein R 50 , R 51 and R 52 each independently represent a hydrogen, an alkyl, an alkenyl, —(CH 2 ) m —R 61 , or R 50 and R 51 , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R 61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
  • R 50 or R 51 may be a carbonyl, e.g., R 50 , R 51 and the nitrogen together do not form an imide.
  • R 50 and R 51 (and optionally R 52 ) each independently represent a hydrogen, an alkyl, an alkenyl, or —(CH 2 ) m —R 61 .
  • alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R 50 and R 51 is an alkyl group.
  • acylamino is art-recognized and refers to a moiety that may be represented by the general formula: wherein R 50 is as defined above, and R 54 represents a hydrogen, an alkyl, an alkenyl or —(CH 2 ) m —R 61 , where m and R 61 are as defined above.
  • amide is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula: wherein R 50 and R 51 are as defined above. Certain embodiments of amides may not include imides which may be unstable.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the “alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl, —S-alkynyl, and —S—(CH 2 ) m —R 61 , wherein m and R 61 are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • carbonyl is art recognized and includes such moieties as may be represented by the general formulas: wherein X50 is a bond or represents an oxygen or a sulfur, and R 55 and R 56 represents a hydrogen, an alkyl, an alkenyl, —(CH 2 ) m —R 61 or a pharmaceutically acceptable salt, R 56 represents a hydrogen, an alkyl, an alkenyl or —(CH 2 ) m —R 61 , where m and R 61 are defined above. Where X50 is an oxygen and R 55 or R 56 is not hydrogen, the formula represents an “ester”.
  • X50 is an oxygen
  • R 55 is as defined above
  • the moiety is referred to herein as a carboxyl group, and particularly when R 55 is a hydrogen, the formula represents a “carboxylic acid”.
  • R 56 is hydrogen
  • the formula represents a “formate”.
  • the oxygen atom of the above formula is replaced by sulfur
  • the formula represents a “thiolcarbonyl” group.
  • X50 is a sulfur and R 55 or R 56 is not hydrogen
  • the formula represents a “thiolester.”
  • X50 is a sulfur and R 55 is hydrogen
  • the formula represents a “thiolcarboxylic acid.”
  • X50 is a sulfur and R 56 is hydrogen
  • the formula represents a “thiolformate.”
  • X50 is a bond, and R 55 is not hydrogen
  • the above formula represents a “ketone” group.
  • X50 is a bond, and R 55 is hydrogen
  • the above formula represents an “aldehyde” group.
  • alkoxyl or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH 2 ) m —R 61 , where m and R 61 are described above.
  • sulfonate is art recognized and refers to a moiety that may be represented by the general formula: in which R 57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • sulfamoyl is art-recognized and refers to a moiety that may be represented by the general formula: in which R 50 and R 51 are as defined above.
  • sulfonyl is art-recognized and refers to a moiety that may be represented by the general formula: in which R 58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
  • sulfoxido is art-recognized and refers to a moiety that may be represented by the general formula: in which R 58 is defined above.
  • phosphoryl is art-recognized and may in general be represented by the formula: wherein Q50 represents S or O, and R 59 represents hydrogen, a lower alkyl or an aryl.
  • the phosphoryl group of the phosphorylalkyl may be represented by the general formulas: wherein Q50 and R 59 , each independently, are defined above, and Q51 represents O, S or N.
  • Q50 is S
  • the phosphoryl moiety is a “phosphorothioate”.
  • phosphoramidite is art-recognized and may be represented in the general formulas: wherein Q51, R 50 , R 51 and R 59 are as defined above.
  • phosphonamidite is art-recognized and may be represented in the general formulas: wherein Q51, R 50 , R 51 and R 59 are as defined above, and R 60 represents a lower alkyl or an aryl.
  • Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • each expression e.g. alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • selenoalkyl is art-recognized and refers to an alkyl group having a substituted seleno group attached thereto.
  • exemplary “selenoethers” which may be substituted on the alkyl are selected from one of —Se-alkyl, —Se-alkenyl, —Se-alkynyl, and —Se—(CH 2 ) m —R 61 , m and R 61 being defined above.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry ; this list is typically presented in a table entitled Standard List of Abbreviations.
  • compositions described herein may exist in particular geometric or stereoisomeric forms.
  • compounds may also be optically active. Contemplated herein are all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, ( D )-isomers, ( L )-isomers, the racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are encompassed herein.
  • a particular enantiomer of a compound may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Compounds are not intended to be limited in any manner by the permissible substituents of organic compounds.
  • protecting group is art-recognized and refers to temporary substituents that protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed by Greene and Wuts in Protective Groups in Organic Synthesis (2 nd ed., Wiley: New York, 1991).
  • hydroxyl-protecting group is art-recognized and refers to those groups intended to protect a hydroxyl group against undesirable reactions during synthetic procedures and includes, for example, benzyl or other suitable esters or ethers groups known in the art.
  • carboxyl-protecting group refers to those groups intended to protect a carboxylic acid group, such as the C-terminus of an amino acid or peptide or an acidic or hydroxyl azepine ring substituent, against undesirable reactions during synthetic procedures and includes.
  • Examples for protecting groups for carboxyl groups involve, for example, benzyl ester, cyclohexyl ester, 4-nitrobenzyl ester, t-butyl ester, 4-pyridylmethyl ester, and the like.
  • amino-blocking group refers to a group which will prevent an amino group from participating in a reaction carried out on some other functional group, but which can be removed from the amine when desired.
  • amino-blocking group refers to a group which will prevent an amino group from participating in a reaction carried out on some other functional group, but which can be removed from the amine when desired.
  • Such groups are discussed by in Ch. 7 of Greene and Wuts, cited above, and by Barton, Protective Groups in Organic Chemistry ch. 2 (McOmie, ed., Plenum Press, New York, 1973).
  • acyl protecting groups such as, to illustrate, formyl, dansyl, acetyl, benzoyl, trifluoroacetyl, succinyl, methoxysuccinyl, benzyl and substituted benzyl such as 3,4-dimethoxybenzyl, o-nitrobenzyl, and triphenylmethyl; those of the formula —COOR where R includes such groups as methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, 1-methyl-1-phenylethyl, isobutyl, t-butyl, t-amyl, vinyl, allyl, phenyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, and 2,4-dichlorobenzyl; acyl groups and substituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl,
  • Preferred amino-blocking groups are benzyl (—CH 2 C 6 H 5 ), acyl [C(O)R1] or SiR1 3 where R 1 is C 1 -C 4 alkyl, halomethyl, or 2-halo-substituted-(C 2 -C 4 alkoxy), aromatic urethane protecting groups as, for example, carbonylbenzyloxy (Cbz); and aliphatic urethane protecting groups such as t-butyloxycarbonyl (Boc) or 9-fluorenylmethoxycarbonyl (FMOC).
  • each expression e.g. lower alkyl, m, n, p and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • electron-withdrawing group is art-recognized, and refers to the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms.
  • ⁇ Hammett sigma
  • Exemplary electron-withdrawing groups include nitro, acyl, formyl, sulfonyl, trifluoromethyl, cyano, chloride, and the like.
  • Exemplary electron-donating groups include amino, methoxy, and the like.
  • small molecule is art-recognized and refers to a composition which has a molecular weight of less than about 2000 amu, or less than about 1000 amu, and even less than about 500 amu.
  • Small molecules may be, for example, nucleic acids, peptides, polypeptides, peptide nucleic acids, peptidomimetics, carbohydrates, lipids or other organic (carbon containing) or inorganic molecules.
  • Many pharmaceutical companies have extensive libraries of chemical and/or biological mixtures, often fungal, bacterial, or algal extracts, which can be screened with any of the assays described herein.
  • small organic molecule refers to a small molecule that is often identified as being an organic or medicinal compound, and does not include molecules that are exclusively nucleic acids, peptides or polypeptides.
  • modulation is art-recognized and refers to up regulation (i.e., activation or stimulation), down regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart.
  • treating is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disease or preventing a condition or disease from worsening.
  • prophylactic or therapeutic treatment refers to administration of a drug to a host. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate or maintain the existing unwanted condition or side effects therefrom).
  • the unwanted condition e.g., disease or other unwanted state of the host animal
  • a “patient,” “subject” or “host” to be treated by the subject method may mean either a human or non-human animal.
  • mammals include humans, primates, bovines, porcines, canines, felines, and rodents (e.g., mice and rats).
  • bioavailable when referring to a compound is art-recognized and refers to a form of a compound that allows for it, or a portion of the amount of compound administered, to be absorbed by, incorporated to, or otherwise physiologically available to a subject or patient to whom it is administered.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, including, for example, those contained in compositions described herein.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
  • materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • systemic administration refers to the administration of a subject composition, therapeutic or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.
  • parenteral administration and “administered parenterally” are art-recognized and refer to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
  • sirtuin deacetylase protein family member referred to as a “sirtuin protein”.
  • the methods may comprise contacting the sirtuin deacetylase protein family member with a compound, such as a polyphenol, e.g. a plant polyphenol, and referred to herein as “activation compound” or “activating compound.”
  • a compound such as a polyphenol, e.g. a plant polyphenol, and referred to herein as “activation compound” or “activating compound.”
  • exemplary sirtuin deacetylase proteins include the yeast silent information regulator 2 (Sir2) and human SIRT1.
  • Other family members include proteins having a significant amino acid sequence homology and biological activity, e.g., the ability to deacetylate target proteins, such as histones and p53, to those of Sir2 and SIRT1.
  • Exemplary activating compounds are those selected from the group consisting of flavones, stilbenes, flavanones, isoflavanones, catechins, chalcones, tannins and anthocyanidins.
  • Exemplary stilbenes include hydroxystilbenes, such as trihydroxystilbenes, e.g., 3,5,4′-trihydroxystilbene (“resveratrol”). Resveratrol is also known as 3,4′,5-stilbenetriol. Tetrahydroxystilbenes, e.g., piceatannol, are also encompassed. Hydroxychalones including trihydroxychalones, such as isoliquiritigenin, and tetrahydroxychalones, such as butein, can also be used.
  • Hydroxyflavones including tetrahydroxyflavones, such as fisetin, and pentahydroxyflavones, such as quercetin, can also be used.
  • Exemplary compounds are set forth in Tables 1-13 and 21 (compounds for which the ratio to control rate is >1).
  • the compounds of Tables 1-8 may be obtained from Biomol, Sigma/Aldrich or Indofine.
  • methods for activating a sirtuin protein comprise using an activating compound that is a stilbene or chalcone compound of formula 1: wherein, independently for each occurrence,
  • the methods comprise a compound of formula 1 and the attendant definitions, wherein n is 0. In a further embodiment, the methods comprise a compound of formula 1 and the attendant definitions, wherein n is 1. In a further embodiment, the methods comprise a compound of formula 1 and the attendant definitions, wherein A-B is ethenyl. In a further embodiment, the methods comprise a compound of formula 1 and the attendant definitions, wherein A-B is —CH 2 CH(Me)CH(Me)CH 2 —. In a further embodiment, the methods comprise a compound of formula 1 and the attendant definitions, wherein M is O.
  • the methods comprises a compound of formula 1 and the attendant definitions, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 1 and the attendant definitions, wherein R 2 , R 4 , and R′ 3 are OH.
  • the methods comprise a compound of formula 1 and the attendant definitions, wherein R 2 , R 4 , R′ 2 and R′ 3 are OH.
  • the methods comprise a compound of formula 1 and the attendant definitions, wherein R 3 , R 5 , R′ 2 and R′ 3 are OH. In a further embodiment, the methods comprise a compound of formula 1 and the attendant definitions, wherein R 1 , R 3 , R 5 , R′ 2 and R′ 3 are OH. In a further embodiment, the methods comprise a compound of formula 1 and the attendant definitions, wherein R 2 and R′ 2 are OH; R 4 is O- ⁇ -D-glucoside; and R′ 3 is OCH 3 . In a further embodiment, the methods comprise a compound of formula 1 and the attendant definitions, wherein R 2 is OH; R 4 is O- ⁇ -D-glucoside; and R′ 3 is OCH 3 .
  • the methods comprise a compound of formula 1 and the attendant definitions, wherein n is 0; A-B is ethenyl; and R 1 , R 2 , R 3 , R 4 , R 5 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , and R′ 5 are H (trans stilbene).
  • the methods comprise a compound of formula 1 and the attendant definitions, wherein n is 1; A-B is ethenyl; M is O; and R 1 , R 2 , R 3 , R 4 , R 5 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , and R′ 5 are H (chalcone).
  • the methods comprise a compound of formula 1 and the attendant definitions, wherein n is 0; A-B is ethenyl; R 2 , R 4 , and R′ 3 are OH; and R 1 , R 3 , R 5 , R′ 1 , R′ 2 , R′ 4 , and R′ 5 are H (resveratrol).
  • the methods comprise a compound of formula 1 and the attendant definitions, wherein n is 0; A-B is ethenyl; R 2 , R 4 , R′ 2 and R′ 3 are OH; and R 1 , R 3 , R 5 , R′ 1 , R′ 4 and R′ 5 are H (piceatannol).
  • the methods comprise a compound of formula 1 and the attendant definitions, wherein n is 1; A-B is ethenyl; M is O; R 3 , R 5 , R 12 and R 13 are OH; and R 1 , R 2 , R 4 , R′ 1 , R′ 4 , and R′ 5 are H (butein).
  • the methods comprise a compound of formula 1 and the attendant definitions, wherein n is 1; A-B is ethenyl; M is O; R 1 , R 3 , R 5 , R′ 2 and R′ 3 are OH; and R 2 , R 4 , R′ 1 , R′ 4 , and R′ 5 are H (3,4,2′,4′,6′-pentahydroxychalcone).
  • the methods comprise a compound of formula 1 and the attendant definitions, wherein n is 0; A-B is —CH 2 CH(Me)CH(Me)CH 2 —; R 2 , R 3 , R 12 , and R 13 are OH; and R 1 , R 4 , R 5 , R′ 1 , R′ 4 , and R′ 5 are H (NDGA).
  • methods for activating a sirtuin protein comprise using an activating compound that is a flavanone compound of formula 2:
  • the methods comprise a compound of formula 2 and the attendant definitions, wherein X and Y are both CH. In a further embodiment, the methods comprise a compound of formula 2 and the attendant definitions, wherein M is O. In a further embodiment, the methods comprise a compound of formula 2 and the attendant definitions, wherein M is H 2 . In a further embodiment, the methods comprise a compound of formula 2 and the attendant definitions, wherein Z is O. In a further embodiment, the methods comprise a compound of formula 2 and the attendant definitions, wherein R′′ is H. In a further embodiment, the methods comprise a compound of formula 2 and the attendant definitions, wherein R′′ is OH.
  • the methods comprise a compound of formula 2 and the attendant definitions, wherein R′′ is an alkoxycarbonyl.
  • the methods comprise a compound of formula 2 and the attendant definitions, wherein R 1 is In a further embodiment, the methods comprise a compound of formula 2 and the attendant definitions, wherein R 1 , R 2 , R 3 , R 4 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , R′ 5 and R′′ are H.
  • the methods comprise a compound of formula 2 and the attendant definitions, wherein R 2 , R 4 , and R′ 3 are OH.
  • the methods comprise a compound of formula 2 and the attendant definitions, wherein X and Y are CH; M is H 2 ; Z and O; R′′ is OH; R 2 , R 4 , R′ 2 , R′ 3 , and R′ 4 are OH; and R 1 , R 3 , R′ 1 , and R′ 5 are H (gallocatechin).
  • the methods comprise a compound of formula 2 and the attendant definitions, wherein X and Y are CH; M is H 2 ; Z and O; R′′ is R 2 , R 4 , R′ 2 , R′ 3 , R′ 4 , and R′′ are OH; and R 1 , R 3 , R′ 1 , and R′ 5 are H (epigallocatechin gallate).
  • methods for activating a sirtuin protein comprise using an activating compound that is an isoflavanone compound of formula 3:
  • methods for activating a sirtuin protein comprise using an activating compound that is a flavone compound of formula 4:
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is C. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein X is CR. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein Z is O. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein M is O. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R′′ is H. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R′′ is OH.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein R 1 , R 2 , R 3 , R 4 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 , R′ 2 , and R 13 are OH.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 , R 4 , R′ 2 , R′ 3 , and R′ 4 are OH.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 , R 4 , R′ 2 , and R′ 3 are OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 3 , R′ 2 , and R′ 3 are OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 , R 4 , R′ 2 , and R′ 3 are OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 , R′ 2 , R′ 3 , and R′ 4 are OH.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 , R 4 , and R′ 3 are OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 , R 3 , R 4 , and R′ 3 are OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 , R 4 , and R′ 3 are OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 3 , R′ 1 , and R′ 3 are OH.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 and R′ 3 are OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 1 , R 2 , R′ 2 , and R′ 3 are OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 3 , R′ 1 , and R′ 2 are OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R′ 3 is OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 4 and R′ 3 are OH.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 and R 4 are OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 , R 4 , R′ 1 , and R′ 3 are OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 4 is OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 , R 4 , R′ 2 , R′ 3 , and R′ 4 are OH.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein R 2 , R′ 2 , R′ 3 , and R 14 are OH. In a further embodiment, the methods comprise a compound of formula 4 and the attendant definitions, wherein R 1 , R 2 , R 4 , R′ 2 , and R′ 3 are OH.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; and R 1 , R 2 , R 3 , R 4 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , and R′ 5 are H (flavone).
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R 2 , R′ 2 , and R′ 3 are OH; and R 1 , R 3 , R 4 , R′ 1 , R′ 4 , and R′ 5 are H (fisetin).
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R 2 , R 4 , R′ 2 , R′ 3 , and R′ 4 are OH; and R 1 , R 3 , R′ 1 , and R′ 5 are H (5,7,3′,4′,5′-pentahydroxyflavone).
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R 2 , R 4 , R′ 2 , and R′ 3 are OH; and R 1 , R 3 , R′ 1 , R′ 4 , and R′ 5 are H (luteolin).
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R 3 , R′ 2 , and R′ 3 are OH; and R 1 , R 2 , R 4 , R′ 1 , R′ 4 , and R′ 5 are H (3,6,3′,4′-tetrahydroxyflavone).
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R 2 , R 4 , R′ 2 , and R′ 3 are OH; and R I , R 3 , R′ 1 , R′ 4 , and R′ 5 are H (quercetin).
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R 2 , R′ 2 , R′ 3 , and R′ 4 are OH; and R 1 , R 3 , R 4 , R′ 1 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R 2 , R 4 , and R′ 3 are OH; and R 1 , R 3 , R′ 1 , R′ 2 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R 2 , R 3 , R 4 , and R′ 3 are OH; and R 1 , R′ 1 , R′ 2 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R 2 , R 4 , and R′ 3 are OH; and R 1 , R 3 , R′ 1 , R′ 2 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R 3 , R′ 1 , and R′ 3 are OH; and R 1 , R 2 , R 4 , R′ 2 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R 2 and R′ 3 are OH; and R 1 , R 3 , R 4 , R′ 1 , R′ 2 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R 1 , R 2 , R′ 2 , and R′ 3 are OH; and R 1 , R 2 , R 4 , R′ 3 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R 3 , R′ 1 , and R′ 2 are OH; and R 1 , R 2 , R 4 ; R′ 3 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R′ 3 is OH; and R 1 , R 2 , R 3 , R 4 , R′ 1 , R′ 2 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R 4 and R′ 3 are OH; and R 1 , R 2 , R 3 , R′ 1 , R′ 2 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R 2 and R 4 are OH; and R 1 , R 3 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R 2 , R 4 , R′ 1 , and R′ 3 are OH; and R 1 , R 3 , R′ 2 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R 4 is OH; and R 1 , R 2 , R 3 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R 2 , R 4 , R′ 2 , R′ 3 , and R′ 4 are OH; and R, R 3 , R′ 1 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R 2 , R′ 2 , R′ 3 , and R′ 4 are OH; and R 1 , R 3 , R 4 , R′ 1 , and R′ 5 are H.
  • the methods comprise a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R 1 , R 2 , R 4 , R′ 2 , and R 13 are OH; and R 3 , R′ 1 , R′ 4 , and R′ 5 are H.
  • methods for activating a sirtuin protein comprise using an activating compound that is an isoflavone compound of formula 5:
  • the methods comprise a compound of formula 5 and the attendant definitions, wherein Y is CR′′. In a further embodiment, the methods comprise a compound of formula 5 and the attendant definitions, wherein Y is CH. In a further embodiment, the methods comprise a compound of formula 5 and the attendant definitions, wherein Z is O. In a further embodiment, the methods comprise a compound of formula 5 and the attendant definitions, wherein M is O. In a further embodiment, the methods comprise a compound of formula 5 and the attendant definitions, wherein R 2 and R′ 3 are OH. In a further embodiment, the methods comprise a compound of formula 5 and the attendant definitions, wherein R 2 , R 4 , and R′ 3 are OH.
  • the methods comprise a compound of formula 5 and the attendant definitions, wherein Y is CH; Z is O; M is O; R 2 and R′ 3 are OH; and R 1 , R 3 , R 4 , R′ 1 , R′ 2 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound of formula 5 and the attendant definitions, wherein Y is CH; Z is O; M is O; R 2 , R 4 , and R′ 3 are OH; and R 1 , R 3 , R′ 1 , R′ 2 , R′ 4 , and R′ 5 are H.
  • methods for activating a sirtuin protein comprise using an activating compound that is an anthocyanidin compound of formula 6:
  • the methods comprise a compound of formula 6 and the attendant definitions, wherein A ⁇ is Cl ⁇ . In a further embodiment, the methods comprise a compound of formula 6 and the attendant definitions, wherein R 3 , R 5 , R 7 , and R′ 4 are OH. In a further embodiment, the methods comprise a compound of formula 6 and the attendant definitions, w herein R 3 , R 5 , R 7 , R′ 3 , a nd R′ 4 are OH. In a further embodiment, the methods comprise a compound of formula 6 and the attendant definitions, wherein R 3 , R 5 , R 7 , R′ 3 , R′ 4 , and R′ 5 are OH.
  • the methods comprise a compound of formula 6 and the attendant definitions, wherein A ⁇ is Cl ⁇ ; R 3 , R 5 , R 7 , and R′ 4 are OH; and R 4 , R 6 , R 8 , R′ 2 , R′ 3 , R′ 5 , and R′ 6 are H.
  • the methods comprise a compound of formula 6 and the attendant definitions, wherein A ⁇ is Cl ⁇ ; R 3 , R 5 , R 7 , R′ 3 , and R′ 4 are OH; and R 4 , R 6 , R 8 , R′ 2 , R′ 5 , and R′ 6 are H.
  • the methods comprise a compound of formula 6 and the attendant definitions, wherein A ⁇ is Cl ⁇ ; R 3 , R 5 , R 7 , R′ 3 , R′ 4 , and R′ 5 are OH; and R 4 , R 6 , R 8 , R′ 2 , and R′ 6 are H.
  • Methods for activating a sirtuin protein may also comprise using a stilbene, chalcone, or flavone compound represented by formula 7:
  • the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein n is 0. In a further embodiment, the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein n is 1. In a further embodiment, the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein M is absent. In a further embodiment, the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein M is O. In a further embodiment, the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein R a is H. In a further embodiment, the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein M is O and the two R a form a bond.
  • the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein R 5 is H. In a further embodiment, the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein R 5 is OH. In a further embodiment, the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein R 1 , R 3 , and R′ 3 are OH. In a further embodiment, the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein R 2 , R 4 , R′ 2 , and R′ 3 are OH. In a further embodiment, the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein R 2 , R′ 2 , and R′ 3 are OH. In a further embodiment, the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein R 2 , R′ 2 , and R′ 3 are OH. In a further embodiment, the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein R 2 and
  • the methods include contacting a cell with an activating compound represented by formula 7 and the attendant definitions, wherein n is 0; M is absent; R a is H; R 5 is H; R 1 , R 3 , and R′ 3 are OH; and R 2 , R 4 , R′ 1 , R′ 2 , R′ 4 , and R′ 5 are H.
  • the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein n is 1; M is absent; R a is H; R 5 is H; R 2 , R 4 , R′ 2 , and R′ 3 are OH; and R 1 , R 3 , R′ 1 , R′ 4 , and R′ 5 are H.
  • the methods comprise an activating compound represented by formula 7 and the attendant definitions, wherein n is 1; M is O; the two R a form a bond; R 5 is OH; R 2 , R′ 2 , and R′ 3 are OH; and R 1 , R 3 , R 4 , R′ 1 , R′ 4 , and R′ 5 are H.
  • sirtuin deacetylase protein family members include compounds having a formula selected from the group consisting of formulas 8-25 and 30 set forth below.
  • Methods for activating a sirtuin protein may also comprise using a stilbene, chalcone, or flavone compound represented by formula 30:
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein D is a phenyl group.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is an ethenylene or imine group.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is an ethenylene group.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein R 2 is OH.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein R 4 is OH.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein R 2 and R 4 are OH.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein D is a phenyl group; and A-B is an ethenylene group.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein D is a phenyl group; A-B is an ethenylene group; and R 2 and R 4 are OH.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is Cl.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is OH.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is H.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is CH 2 CH 3 .
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is F.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is Me.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is an azide.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is SMe.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is NO 2 .
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is CH(CH 3 ) 2 .
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is OMe.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; R′ 2 is OH; and R′ 3 is OMe.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 is OH; R 4 is carboxyl; and R′ 3 is OH.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is carboxyl.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 and R′ 4 taken together form a fused benzene ring.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; and R 4 is OH.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OCH 2 OCH 3 ; and R′ 3 is SMe.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is carboxyl.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a cyclohexyl ring; and R 2 and R 4 are OH.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; and R 3 and R 4 are OMe.
  • the methods include contacting a cell with an activating compound represented by formula 30 and the attendant definitions, wherein A-B is ethenylene; D is a phenyl ring; R 2 and R 4 are OH; and R′ 3 is OH.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 32:
  • the methods comprise a compound of formula 32 and the attendant definitions wherein R is H.
  • the methods comprise a compound of formula 32 and the attendant definitions wherein R 1 is 3-hydroxyphenyl.
  • the methods comprise a compound of formula 32 and the attendant definitions wherein R 2 is methyl.
  • the methods comprise a compound of formula 32 and the attendant definitions wherein R is H and R 1 is 3-hydroxyphenyl.
  • the methods comprise a compound of formula 32 and the attendant definitions wherein R is H, R 1 is 3-hydroxyphenyl, and R 2 is methyl.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 33:
  • the methods comprise a compound of formula 33 and the attendant definitions wherein R is alkynyl.
  • the methods comprise a compound of formula 33 and the attendant definitions wherein R 1 is 2,6-dichlorophenyl.
  • the methods comprise a compound of formula 33 and the attendant definitions wherein R 2 is methyl.
  • the methods comprise a compound of formula 33 and the attendant definitions wherein L is O.
  • the methods comprise a compound of formula 33 and the attendant definitions wherein R is alkynyl and R 1 is 2,6-dichlorophenyl.
  • the methods comprise a compound of formula 33 and the attendant definitions wherein R is alkynyl, R 1 is 2,6-dichlorophenyl, and R 2 is methyl.
  • the methods comprise a compound of formula 33 and the attendant definitions wherein R is alkynyl, R 1 is 2,6-dichlorophenyl, R 2 is methyl, and L is O.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 34:
  • the methods comprise a compound of formula 34 and the attendant definitions wherein R is 3,5-dichloro-2-hydroxyphenyl.
  • the methods comprise a compound of formula 34 and the attendant definitions wherein R 1 is H.
  • the methods comprise a compound of formula 34 and the attendant definitions wherein R 2 is H.
  • the methods comprise a compound of formula 34 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 34 and the attendant definitions wherein R is 3,5-dichloro-2-hydroxyphenyl and R 1 is H.
  • the methods comprise a compound of formula 34 and the attendant definitions wherein R is 3,5-dichloro-2-hydroxyphenyl, R 1 is H, and R 2 is H.
  • the methods comprise a compound of formula 34 and the attendant definitions wherein R is 3,5-dichloro-2-hydroxyphenyl, R 1 is H, R 2 is H, and n is 1.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 35:
  • the methods comprise a compound of formula 35 and the attendant definitions wherein R is phenyl.
  • the methods comprise a compound of formula 35 and the attendant definitions wherein R 1 is pyridine.
  • the methods comprise a compound of formula 35 and the attendant definitions wherein L is S. In a further embodiment, the methods comprise a compound of formula 35 and the attendant definitions wherein m is 0.
  • the methods comprise a compound of formula 35 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 35 and the attendant definitions wherein o is 0.
  • the methods comprise a compound of formula 35 and the attendant definitions wherein R is phenyl and R 1 is pyridine.
  • the methods comprise a compound of formula 35 and the attendant definitions wherein R is phenyl, R 1 is pyridine, and L is S.
  • the methods comprise a compound of formula 35 and the attendant definitions wherein R is phenyl, R 1 is pyridine, L is S, and m is 0.
  • the methods comprise a compound of formula 35 and the attendant definitions wherein R is phenyl, R 1 is pyridine, L is S, m is 0, and n is 1.
  • the methods comprise a compound of formula 35 and the attendant definitions wherein R is phenyl, R 1 is pyridine, L is S, m is 0, n is 1, and o is 0.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 36:
  • the methods comprise a compound of formula 36 and the attendant definitions wherein R is H.
  • the methods comprise a compound of formula 36 and the attendant definitions wherein R 1 is 4-chlorophenyl.
  • the methods comprise a compound of formula 36 and the attendant definitions wherein R 2 is 4-chlorophenyl.
  • the methods comprise a compound of formula 36 and the attendant definitions wherein R 3 is H.
  • the methods comprise a compound of formula 36 and the attendant definitions wherein R 4 is H.
  • the methods comprise a compound of formula 36 and the attendant definitions wherein L 1 is SO 2 .
  • the methods comprise a compound of formula 36 and the attendant definitions wherein L 2 is NH.
  • the methods comprise a compound of formula 36 and the attendant definitions wherein L 3 is O.
  • the methods comprise a compound of formula 36 and the attendant definitions wherein R is H and R 1 is 4-chlorophenyl.
  • the methods comprise a compound of formula 36 and the attendant definitions wherein R is H, R 1 is 4-chlorophenyl, and R 2 is 4-chlorophenyl.
  • the methods comprise a compound of formula 36 and the attendant definitions wherein R is H, R 1 is 4-chlorophenyl, R 2 is 4-chlorophenyl, and R 3 is H.
  • the methods comprise a compound of formula 36 and the attendant definitions wherein R is H, R 1 is 4-chlorophenyl, R 2 is 4-chlorophenyl, R 3 is H, and R 4 is H.
  • the methods comprise a compound of formula 36 and the attendant definitions wherein R is H, R 1 is 4-chlorophenyl, R 2 is 4-chlorophenyl, R 3 is H, R 4 is H, and L 1 is SO 2 .
  • the methods comprise a compound of formula 36 and the attendant definitions wherein R is H, R 1 is 4-chlorophenyl, R 2 is 4-chlorophenyl, R 3 is H, R 4 is H, L 1 is SO 2 , and L 2 is NH.
  • the methods comprise a compound of formula 36 and the attendant definitions wherein R is H, R 1 is 4-chlorophenyl, R 2 is 4-chlorophenyl, R 3 is H, R 4 is H, L 1 is SO 2 , L 2 is NH, and L 3 is O.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 37:
  • the methods comprise a compound of formula 37 and the attendant definitions wherein R is methyl.
  • the methods comprise a compound of formula 37 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 37 and the attendant definitions wherein R 1 is 3-fluorophenyl.
  • the methods comprise a compound of formula 37 and the attendant definitions wherein R 2 is H.
  • the methods comprise a compound of formula 37 and the attendant definitions wherein R 3 is 4-chlorophenyl.
  • the methods comprise a compound of formula 37 and the attendant definitions wherein L is O.
  • the methods comprise a compound of formula 37 and the attendant definitions wherein R is methyl and n is 1.
  • the methods comprise a compound of formula 37 and the attendant definitions wherein R is methyl, n is 1, and R 1 is 3-fluorophenyl.
  • the methods comprise a compound of formula 37 and the attendant definitions wherein R is methyl, n is 1, R 1 is 3-fluorophenyl, and R 2 is H.
  • the methods comprise a compound of formula 37 and the attendant definitions wherein R is methyl, n is 1, R 1 is 3-fluorophenyl, R 2 is H, and R 3 is 4-chlorophenyl.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 38:
  • the methods comprise a compound of formula 38 and the attendant definitions wherein R is 3-methoxyphenyl.
  • the methods comprise a compound of formula 38 and the attendant definitions wherein R 1 is 4-t-butylphenyl.
  • the methods comprise a compound of formula 38 and the attendant definitions wherein L 1 is NH.
  • the methods comprise a compound of formula 38 and the attendant definitions wherein L 2 is O.
  • the methods comprise a compound of formula 38 and the attendant definitions wherein R is 3-methoxyphenyl and R 1 is 4-t-butylphenyl.
  • the methods comprise a compound of formula 38 and the attendant definitions wherein R is 3-methoxyphenyl, R 1 is 4-t-butylphenyl, and L 1 is NH.
  • the methods comprise a compound of formula 38 and the attendant definitions wherein R is 3-methoxyphenyl, R 1 is 4-t-butylphenyl, L 1 is NH, and L 2 is O.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 39:
  • the methods comprise a compound of formula 39 and the attendant definitions wherein R is methyl.
  • the methods comprise a compound of formula 39 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 39 and the attendant definitions wherein R 1 is 3,4,5-trimethoxyphenyl.
  • the methods comprise a compound of formula 39 and the attendant definitions wherein L 1 is S.
  • the methods comprise a compound of formula 39 and the attendant definitions wherein L 2 is NH.
  • the methods comprise a compound of formula 39 and the attendant definitions wherein R is methyl and n is 1.
  • the methods comprise a compound of formula 39 and the attendant definitions wherein R is methyl, n is 1, and R 1 is 3,4,5-trimethoxyphenyl.
  • the methods comprise a compound of formula 39 and the attendant definitions wherein R is methyl, n is 1, R 1 is 3,4,5-trimethoxyphenyl, and L 1 is S.
  • the methods comprise a compound of formula 39 and the attendant definitions wherein R is methyl, n is 1, R 1 is 3,4,5-trimethoxyphenyl, L 1 is S, and L 2 is NH.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 40:
  • the methods comprise a compound of formula 40 and the attendant definitions wherein R is H.
  • the methods comprise a compound of formula 40 and the attendant definitions wherein R 1 is perfluorophenyl.
  • the methods comprise a compound of formula 40 and the attendant definitions wherein R 2 is H.
  • the methods comprise a compound of formula 40 and the attendant definitions wherein R 3 is H.
  • the methods comprise a compound of formula 40 and the attendant definitions wherein L 1 is O.
  • the methods comprise a compound of formula 40 and the attendant definitions wherein L 2 is O.
  • the methods comprise a compound of formula 40 and the attendant definitions wherein n is 0.
  • the methods comprise a compound of formula 40 and the attendant definitions wherein R is H and R 1 is perfluorophenyl.
  • the methods comprise a compound of formula 40 and the attendant definitions wherein R is H, R 1 is perfluorophenyl, and R 2 is H.
  • the methods comprise a compound of formula 40 and the attendant definitions R is H, R 1 is perfluorophenyl, R 2 is H, and R 3 is H.
  • the methods comprise a compound of formula 40 and the attendant definitions wherein R is H, R 1 is perfluorophenyl, R 2 is H, R 3 is H, and L 1 is O.
  • the methods comprise a compound of formula 40 and the attendant definitions wherein R is H, R 1 is perfluorophenyl, R 2 is H, R 3 is H, L 1 is O, and L 2 is O.
  • the methods comprise a compound of formula 40 and the attendant definitions wherein R is H, R 1 is perfluorophenyl, R 2 is H, R 3 is H, L 1 is O, L 2 is O, and n is 0.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 41:
  • the methods comprise a compound of formula 41 and the attendant definitions wherein n is 0.
  • the methods comprise a compound of formula 41 and the attendant definitions wherein R 1 is cyano.
  • the methods comprise a compound of formula 41 and the attendant definitions wherein R 2 is ethyl.
  • the methods comprise a compound of formula 41 and the attendant definitions wherein m is 0.
  • the methods comprise a compound of formula 41 and the attendant definitions wherein L 1 is S.
  • the methods comprise a compound of formula 41 and the attendant definitions wherein L 2 is O.
  • the methods comprise a compound of formula 41 and the attendant definitions wherein L 3 is O.
  • the methods comprise a compound of formula 41 and the attendant definitions wherein n is 0 and R 1 is cyano.
  • the methods comprise a compound of formula 41 and the attendant definitions wherein n is 0, R 1 is cyano, and R 2 is ethyl.
  • the methods comprise a compound of formula 41 and the attendant definitions wherein n is 0, R 1 is cyano, R 2 is ethyl, and m is 0.
  • the methods comprise a compound of formula 41 and the attendant definitions wherein n is 0, R 1 is cyano, R 2 is ethyl, m is 0, and L 1 is S.
  • the methods comprise a compound of formula 41 and the attendant definitions wherein n is 0, R 1 is cyano, R 2 is ethyl, m is 0, L 1 is S, and L 2 is O.
  • the methods comprise a compound of formula 41 and the attendant definitions wherein n is 0, R 1 is cyano, R 2 is ethyl, m is 0, L 1 is S, L 2 is O, and L 3 is O.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 42:
  • the methods comprise a compound of formula 42 and the attendant definitions wherein n is 0.
  • the methods comprise a compound of formula 42 and the attendant definitions wherein R 1 is methyl.
  • the methods comprise a compound of formula 42 and the attendant definitions wherein R 2 is CF 3 and m is 1.
  • the methods comprise a compound of formula 42 and the attendant definitions wherein R 3 is 4-methylphenyl.
  • the methods comprise a compound of formula 42 and the attendant definitions wherein L 1 is S.
  • the methods comprise a compound of formula 42 and the attendant definitions wherein L 2 is O.
  • the methods comprise a compound of formula 42 and the attendant definitions wherein L 3 is NR 1 .
  • the methods comprise a compound of formula 42 and the attendant definitions wherein L 4 is NR 1 .
  • the methods comprise a compound of formula 42 and the attendant definitions wherein n is 0 and R 1 is methyl.
  • the methods comprise a compound of formula 42 and the attendant definitions wherein n is 0, R 1 is methyl, R 2 is CF 3 , and m is 1.
  • the methods comprise a compound of formula 42 and the attendant definitions wherein n is 0, R 1 is methyl, R 2 is CF 3 , m is 1; and R 3 is 4-methylphenyl.
  • the methods comprise a compound of formula 42 and the attendant definitions wherein n is 0, R 1 is methyl, R 2 is CF 3 , m is 1; R 3 is 4-methylphenyl; and L 1 is S.
  • the methods comprise a compound of formula 42 and the attendant definitions wherein n is 0, R 1 is methyl, R 2 is CF 3 , m is 1; R 3 is 4-methylphenyl; L 1 is S, and L 2 is O.
  • the methods comprise a compound of formula 42 and the attendant definitions wherein n is 0, R 1 is methyl, R 2 is CF 3 , m is 1; R 3 is 4-methylphenyl; L 1 is S, L 2 is O; and L 3 is NR 1 .
  • the methods comprise a compound of formula 42 and the attendant definitions wherein n is 0, R 1 is methyl, R 2 is CF 3 , m is 1; R 3 is 4-methylphenyl; L 1 is S, L 2 is O; L 3 is NR 1 , and L 4 is NR 1 .
  • methods for activating a sirtuin protein comprise using an activating compound of formula 43:
  • the methods comprise a compound of formula 43 and the attendant definitions wherein R is cyano.
  • the methods comprise a compound of formula 43 and the attendant definitions wherein R 1 is NH 2 .
  • the methods comprise a compound of formula 43 and the attendant definitions wherein R 2 is 4-bromophenyl.
  • the methods comprise a compound of formula 43 and the attendant definitions wherein R 3 is 3-hydroxy-4-methoxyphenyl.
  • the methods comprise a compound of formula 43 and the attendant definitions wherein L 1 is O.
  • the methods comprise a compound of formula 43 and the attendant definitions wherein L 2 is NR 2 .
  • the methods comprise a compound of formula 43 and the attendant definitions wherein R is cyano and R 1 is NH 2 .
  • the methods comprise a compound of formula 43 and the attendant definitions wherein R is cyano, R 1 is NH 2 , and R 2 is 4-bromophenyl.
  • the methods comprise a compound of formula 43 and the attendant definitions wherein R is cyano, R 1 is NH 2 , R 2 is 4-bromophenyl, and R 3 is 3-hydroxy-4-methoxyphenyl.
  • the methods comprise a compound of formula 43 and the attendant definitions wherein R is cyano, R 1 is NH 2 , R 2 is 4-bromophenyl, R 3 is 3-hydroxy-4-methoxyphenyl, and L 1 is O.
  • the methods comprise a compound of formula 43 and the attendant definitions wherein R is cyano, R 1 is NH 2 , R 2 is 4-bromophenyl, R 3 is 3-hydroxy-4-methoxyphenyl, L 1 is O, and L 2 is NR 2 .
  • methods for activating a sirtuin protein comprise using an activating compound of formula 44:
  • the methods comprise a compound of formula 44 and the attendant definitions wherein R is 3-trifluoromethylphenyl.
  • the methods comprise a compound of formula 44 and the attendant definitions wherein R 1 is C(O)OCH 3 .
  • the methods comprise a compound of formula 44 and the attendant definitions wherein L 1 is NR.
  • the methods comprise a compound of formula 44 and the attendant definitions wherein L 2 is S.
  • the methods comprise a compound of formula 44 and the attendant definitions wherein L 3 is NR.
  • the methods comprise a compound of formula 44 and the attendant definitions wherein n is 2.
  • the methods comprise a compound of formula 44 and the attendant definitions wherein R is 3-trifluoromethylphenyl and R 1 is C(O)OCH 3 .
  • the methods comprise a compound of formula 44 and the attendant definitions wherein R is 3-trifluoromethylphenyl, R 1 is C(O)OCH 3 , and L 1 is NR.
  • the methods comprise a compound of formula 44 and the attendant definitions wherein R is 3-trifluoromethylphenyl, R 1 is C(O)OCH 3 , L 1 is NR, and L 2 is S.
  • the methods comprise a compound of formula 44 and the attendant definitions wherein R is 3-trifluoromethylphenyl, R 1 is C(O)OCH 3 , L 1 is NR, L 2 is S, and L 3 is NR.
  • the methods comprise a compound of formula 44 and the attendant definitions wherein R is 3-trifluoromethylphenyl, R 1 is C(O)OCH 3 , L 1 is NR, L 2 is S, L 3 is NR, and n is 2.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 45:
  • the methods comprise a compound of formula 45 and the attendant definitions wherein n is 0.
  • the methods comprise a compound of formula 45 and the attendant definitions wherein R 1 is 2-tetrahydrofuranylmethyl.
  • the methods comprise a compound of formula 45 and the attendant definitions wherein R 2 is —CH 2 CH 2 C 6 H 4 SO 2 NH 2 .
  • the methods comprise a compound of formula 45 and the attendant definitions wherein L 1 is S.
  • the methods comprise a compound of formula 45 and the attendant definitions wherein L 2 is NR 1 .
  • the methods comprise a compound of formula 45 and the attendant definitions wherein n is 0 and R 1 is 2-tetrahydrofuranylmethyl.
  • the methods comprise a compound of formula 45 and the attendant definitions wherein n is 0, R 1 is 2-tetrahydrofuranylmethyl, and R 2 is —CH 2 CH 2 C 6 H 4 SO 2 NH 2 .
  • the methods comprise a compound of formula 45 and the attendant definitions wherein n is 0, R 1 is 2-tetrahydrofuranylmethyl, R 2 is —CH 2 CH 2 C 6 H 4 SO 2 NH 2 , and L 1 is S.
  • the methods comprise a compound of formula 45 and the attendant definitions wherein n is 0, R 1 is 2-tetrahydrofuranylmethyl, R 2 is —CH 2 CH 2 C 6 H 4 SO 2 NH 2 , L 1 is S, and L 2 is NR 1 .
  • methods for activating a sirtuin protein comprise using an activating compound of formula 46:
  • the methods comprise a compound of formula 46 and the attendant definitions wherein n is 0.
  • the methods comprise a compound of formula 46 and the attendant definitions wherein m is 1.
  • the methods comprise a compound of formula 46 and the attendant definitions wherein R 1 is Cl.
  • the methods comprise a compound of formula 46 and the attendant definitions wherein o is 1.
  • the methods comprise a compound of formula 46 and the attendant definitions wherein R 2 is Cl.
  • the methods comprise a compound of formula 46 and the attendant definitions wherein p is 3.
  • the methods comprise a compound of formula 46 and the attendant definitions wherein R 3 is OH or I.
  • the methods comprise a compound of formula 46 and the attendant definitions wherein n is 0 and m is 1.
  • the methods comprise a compound of formula 46 and the attendant definitions wherein n is 0, m is 1, and o is 1.
  • the methods comprise a compound of formula 46 and the attendant definitions wherein n is 0, m is 1, o is 1, and R 1 is Cl.
  • the methods comprise a compound of formula 46 and the attendant definitions wherein n is 0, m is 1, o is 1, R 1 is Cl, and p is 3.
  • the methods comprise a compound of formula 46 and the attendant definitions wherein n is 0, m is 1, o is 1, R 1 is Cl, p is 3, and R 2 is OH or I.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 47:
  • the methods comprise a compound of formula 47 and the attendant definitions wherein n is 2.
  • the methods comprise a compound of formula 47 and the attendant definitions wherein R is methyl or t-butyl.
  • the methods comprise a compound of formula 47 and the attendant definitions wherein m is 2.
  • the methods comprise a compound of formula 47 and the attendant definitions wherein R 1 is methyl or t-butyl.
  • the methods comprise a compound of formula 47 and the attendant definitions wherein L 1 is O.
  • the methods comprise a compound of formula 47 and the attendant definitions wherein L 2 is O.
  • the methods comprise a compound of formula 47 and the attendant definitions wherein n is 2 and R is methyl or t-butyl.
  • the methods comprise a compound of formula 47 and the attendant definitions wherein n is 2, R is methyl or t-butyl, and m is 2.
  • the methods comprise a compound of formula 47 and the attendant definitions wherein n is 2, R is methyl or t-butyl, m is 2, and R 1 is methyl or t-butyl.
  • the methods comprise a compound of formula 47 and the attendant definitions wherein n is 2, R is methyl or t-butyl, m is 2, R 1 is methyl or t-butyl, and L 1 is O.
  • the methods comprise a compound of formula 47 and the attendant definitions wherein n is 2, R is methyl or t-butyl, m is 2, R 1 is methyl or t-butyl, L 1 is O, and L 2 is O.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 48:
  • the methods comprise a compound of formula 48 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 48 and the attendant definitions wherein R is methyl.
  • the methods comprise a compound of formula 48 and the attendant definitions wherein R 1 is C(O)OCH 3 .
  • the methods comprise a compound of formula 48 and the attendant definitions wherein R 2 is C(O)OCH 3 .
  • the methods comprise a compound of formula 48 and the attendant definitions wherein R 3 is C(O)OCH 3 .
  • the methods comprise a compound of formula 48 and the attendant definitions wherein R 4 is C(O)OCH 3 .
  • the methods comprise a compound of formula 48 and the attendant definitions wherein R 5 is methyl.
  • the methods comprise a compound of formula 48 and the attendant definitions wherein R 6 is methyl.
  • the methods comprise a compound of formula 48 and the attendant definitions wherein R 7 is C(O)CF 3 .
  • the methods comprise a compound of formula 48 and the attendant definitions wherein L 1 is S.
  • the methods comprise a compound of formula 48 and the attendant definitions wherein L 2 is S.
  • the methods comprise a compound of formula 48 and the attendant definitions wherein L 3 is S.
  • the methods comprise a compound of formula 48 and the attendant definitions wherein n is 1 and R is methyl.
  • the methods comprise a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, and R 1 is C(O)OCH 3 .
  • the methods comprise a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , and R 2 is C(O)OCH 3 .
  • the methods comprise a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , and R 3 is C(O)OCH 3 .
  • the methods comprise a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is C(O)OCH 3 , and R 4 is C(O)OCH 3 .
  • the methods comprise a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is C(O)OCH 3 , R 4 is C(O)OCH 3 , and R 5 is methyl.
  • the methods comprise a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is C(O)OCH 3 , R 4 is C(O)OCH 3 , R 5 is methyl, and R 6 is methyl.
  • the methods comprise a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is C(O)OCH 3 , R 4 is C(O)OCH 3 , R 5 is methyl, R 6 is methyl, and R 7 is C(O)CF 3 .
  • the methods comprise a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is C(O)OCH 3 , R 4 is C(O)OCH 3 , R 5 is methyl, R 6 is methyl, R 7 is C(O)CF 3 , and L 1 is S.
  • the methods comprise a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is C(O)OCH 3 , R 4 is C(O)OCH 3 , R 5 is methyl, R 6 is methyl, R 7 is C(O)CF 3 , L 1 is S, and L 2 is S.
  • the methods comprise a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is C(O)OCH 3 , R 4 is C(O)OCH 3 , R 5 is methyl, R 6 is methyl, R 7 is C(O)CF 3 , L 1 is S, L 2 is S, and L 3 is S.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 49:
  • the methods comprise a compound of formula 49 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein R is methyl.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein R 1 is C(O)OCH 3 .
  • the methods comprise a compound of formula 49 and the attendant definitions wherein R 2 is C(O)OCH 3 .
  • the methods comprise a compound of formula 49 and the attendant definitions wherein R 3 is methyl.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein R 4 is methyl.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein R 5 is CH 2 CH(CH 3 ) 2 .
  • the methods comprise a compound of formula 49 and the attendant definitions wherein L 1 is S.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein L 2 is S.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein L 3 is S.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein n is 1 and R is methyl.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, and R 1 is C(O)OCH 3 .
  • the methods comprise a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , and R 2 is C(O)OCH 3 .
  • the methods comprise a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , and R 3 is methyl.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is methyl, and R 4 is methyl.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is methyl, R 4 is methyl, and R 5 is CH 2 CH(CH 3 ) 2 .
  • the methods comprise a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is methyl, R 4 is methyl, R 5 is CH 2 CH(CH 3 ) 2 , and L 1 is S.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is methyl, R 4 is methyl, R 5 is CH 2 CH(CH 3 ) 2 , and L 1 is S.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein n is 0.1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is methyl, R 4 is methyl, R 5 is CH 2 CH(CH 3 ) 2 , L 1 is S, and L 2 is S.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is methyl, R 4 is methyl, R 5 is CH 2 CH(CH 3 ) 2 , L 1 is S, and L 2 is S.
  • the methods comprise a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R 1 is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is methyl, R 4 is methyl, R 5 is CH 2 CH(CH 3 ) 2 , L 1 is S, L 2 is S, and L 3 is S.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 50:
  • the methods comprise a compound of formula 50 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 50 and the attendant definitions wherein R is CO 2 Et.
  • the methods comprise a compound of formula 50 and the attendant definitions wherein m is 0.
  • the methods comprise a compound of formula 50 and the attendant definitions wherein R 2 is cyano.
  • the methods comprise a compound of formula 50 and the attendant definitions wherein L 1 is S.
  • the methods comprise a compound of formula 50 and the attendant definitions wherein L 2 is S.
  • the methods comprise a compound of formula 50 and the attendant definitions wherein n is 1 and R is CO 2 Et.
  • the methods comprise a compound of formula 50 and the attendant definitions wherein n is 1, R is CO 2 Et, and m is 0.
  • the methods comprise a compound of formula 50 and the attendant definitions wherein n is 1, R is CO 2 Et, m is 0, and R 2 is cyano.
  • the methods comprise a compound of formula 50 and the attendant definitions wherein n is 1, R is CO 2 Et, m is 0, R 2 is cyano, and L 1 is S.
  • the methods comprise a compound of formula 50 and the attendant definitions wherein n is 1, R is CO 2 Et, m is 0, R 2 is cyano, L 1 is S, and L 2 is S.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 51:
  • the methods comprise a compound of formula 51 and the attendant definitions wherein n is 2.
  • the methods comprise a compound of formula 51 and the attendant definitions wherein R is Cl or trifluoromethyl.
  • the methods comprise a compound of formula 51 and the attendant definitions wherein m is 2.
  • the methods comprise a compound of formula 51 and the attendant definitions wherein R 1 is phenyl.
  • the methods comprise a compound of formula 51 and the attendant definitions wherein n is 2 and R is Cl or trifluoromethyl.
  • the methods comprise a compound of formula 51 and the attendant definitions wherein n is 2, R is Cl or trifluoromethyl, and m is 2.
  • the methods comprise a compound of formula 51 and the attendant definitions wherein n is 2, R is Cl or trifluoromethyl, m is 2, and R 1 is phenyl.
  • the methods comprise a compound of formula 51 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 51 and the attendant definitions wherein R is F.
  • the methods comprise a compound of formula 51 and the attendant definitions wherein R 1 is 4-methylphenyl.
  • the methods comprise a compound of formula 51 and the attendant definitions wherein n is 1 and R is F.
  • the methods comprise a compound of formula 51 and the attendant definitions wherein n is 1, R is F, and m is 2.
  • the methods comprise a compound of formula 51 and the attendant definitions wherein n is 1, R is F, m is 2, and R 1 is 4-methylphenyl.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 52:
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R 1 is I.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R 2 is alkynylene.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein m is 1.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R 3 is OH.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R 4 is C(O)OEt.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein o is 1.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R 5 is OH.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein p is 0.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein L 1 is NH.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein L 2 is O.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein L 3 is O.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH and n is 1.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH, n is 1, and R 1 is I.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH, n is 1, R 1 is I, and R 2 is alkynylene.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH, n is 1, R 1 is I, R 2 is alkynylene, and m is 1.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH, n is 1, R 1 is I, R 2 is alkynylene, m is 1, and R 3 is OH.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH, n is 1, R 1 is I, R 2 is alkynylene, m is 1, R 3 is OH, and R 4 is C(O)OEt.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH, n is 1, R 1 is I, R 2 is alkynylene, m is 1, R 3 is OH, R 4 is C(O)OEt, and o is 1.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH, n is 1, R 1 is I, R 2 is alkynylene, m is 1, R 3 is OH, R 4 is C(O)OEt, o is 1, and R 5 is OH.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH, n is 1, R 1 is I, R 2 is alkynylene, m is 1, R 3 is OH, R 4 is C(O)OEt, o is 1, R 5 is OH, and p is 0.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH, n is 1, R 1 is I, R 2 is alkynylene, m is 1, R 3 is OH, R 4 is C(O)OEt, o is 1, R 5 is OH, p is O, and L 1 is NH.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH, n is 1, R 1 is I, R 2 is alkynylene, m is 1, R 3 is OH, R 4 is C(O)OEt, o is 1, R 5 is OH, p is O, L 1 is NH, and L 2 is O.
  • the methods comprise a compound of formula 52 and the attendant definitions wherein R is CH 2 CH 2 OH, n is 1, R 1 is I, R 2 is alkynylene, m is 1, R 3 is OH, R 4 is C(O)OEt, o is 1, R 5 is OH, p is O, L 1 is NH, L 2 is O, and L 3 is O.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 53:
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R is O-t-butyl.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R 1 is t-butyl.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R 2 is O-t-butyl.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R 3 is t-butyl.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R 4 is C(O)OMe.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R 5 is C(O)OMe.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein L 1 is NH.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein L 2 is O.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein L 3 is O.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein L 4 is NH.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R is O-t-butyl and R 1 is t-butyl.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R is O-t-butyl, R 1 is t-butyl, and R 2 is O-t-butyl.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R is O-t-butyl, R 1 is t-butyl, R 2 is O-t-butyl, and R 3 is t-butyl.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R is O-t-butyl, R 1 is t-butyl, R 2 is O-t-butyl, R 3 is t-butyl, and R 4 is C(O)OMe.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R is O-t-butyl, R 1 is t-butyl, R 2 is O-t-butyl, R 3 is t-butyl, R 4 is C(O)OMe, and R 5 is C(O)OMe.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R is O-t-butyl, R 1 is t-butyl, R 2 is O-t-butyl, R 3 is t-butyl, R 4 is C(O)OMe, R 5 is C(O)OMe, and L 1 is NH.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R is O-t-butyl, R 1 is t-butyl, R 2 is O-t-butyl, R 3 is t-butyl, R 4 is C(O)OMe, R 5 is C(O)OMe, L 1 is NH, and L 2 is O.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R is O-t-butyl, R 1 is t-butyl, R 2 is O-t-butyl, R 3 is t-butyl, R 4 is C(O)OMe, R 5 is C(O)OMe, L 1 is NH, L 2 is O, and L 3 is O.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R is O-t-butyl, R 1 is t-butyl, R 2 is O-t-butyl, R 3 is t-butyl, R 4 is C(O)OMe, R 5 is C(O)OMe, L 1 is NH, L 2 is O, L 3 is O, and L 4 is NH.
  • the methods comprise a compound of formula 53 and the attendant definitions wherein R is O-t-butyl, R 1 is t-butyl, R 2 is O-t-butyl, R 3 is t-butyl, R 4 is C(O)OMe, R 5 is C(O)OMe, L 1 is NH, L 2 is O, L 3 is O, L 4 is NH, and n is 1.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 54:
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R is ethyl.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R 1 is ethyl.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein m is 0.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R 3 is H.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein o is 0.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R 5 is Cl.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R 6 is H.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R 7 is methyl.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein L is NH.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R is ethyl and R 1 is ethyl.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R is ethyl, R 1 is ethyl, and m is 0.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R is ethyl, R 1 is ethyl, m is 0, and R 3 is H.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R is ethyl, R 1 is ethyl, m is 0, R 3 is H, and o is 0.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R is ethyl, R 1 is ethyl, m is 0, R 3 is H, o is 0, and R 5 is Cl.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R is ethyl, R 1 is ethyl, m is 0, R 3 is H, o is 0, R 5 is Cl, and R 6 is H.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R is ethyl, R 1 is ethyl, m is 0, R 3 is H, o is 0, R 5 is Cl, R 6 is H, and R 7 is methyl.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R is ethyl, R 1 is ethyl, m is 0, R 3 is H, o is 0, R 5 is Cl, R 6 is H, R 7 is methyl, and L is NH.
  • the methods comprise a compound of formula 54 and the attendant definitions wherein R is ethyl, R 1 is ethyl, m is 0, R 3 is H, o is 0, R 5 is Cl, R 6 is H, R 7 is methyl, L is NH, and n is 1.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 55:
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R is H.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R 1 is H.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R 2 is OEt.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R 3 is methyl.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R 4 is H.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R 5 is H.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein L 1 is S.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein L 2 is NH.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein L 3 is NH.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein L 4 is S.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R is H and R 1 is H.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R is H, R 1 is H, and R 2 is OEt.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R is H, R 1 is H, R 2 is OEt, and R 3 is methyl.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R is H, R 1 is H, R 2 is OEt, R 3 is methyl, and R 4 is H.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R is H, R 1 is H, R 2 is OEt, R 3 is methyl, R 4 is H, and R 5 is H.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R is H, R 1 is H, R 2 is OEt, R 3 is methyl, R 4 is H, R 5 is H, and L 1 is S.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R is H, R 1 is H, R 2 is OEt, R 3 is methyl, R 4 is H, R 5 is H, L 1 is S, and L 2 is NH.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R is H, R 1 is H, R 2 is OEt, R 3 is methyl, 4 is H, R 5 is H, L 1 is S, L 2 is NH, and L 3 is NH.
  • the methods comprise a compound of formula 55 and the attendant definitions wherein R is H, R 1 is H, R 2 is OEt, R 3 is methyl, R 4 is H, R 5 is H, L 1 is S, L 2 is NH, L 3 is NH, and L 4 is S.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 56:
  • the methods comprise a compound of formula 56 and the attendant definitions wherein n is 0.
  • the methods comprise a compound of formula 56 and the attendant definitions wherein m is 0.
  • the methods comprise a compound of formula 56 and the attendant definitions wherein L 1 is NH.
  • the methods comprise a compound of formula 56 and the attendant definitions wherein L 2 is S.
  • the methods comprise a compound of formula 56 and the attendant definitions wherein L 3 is S.
  • the methods comprise a compound of formula 56 and the attendant definitions wherein m is 0 and n is 0.
  • the methods comprise a compound of formula 56 and the attendant definitions wherein m is 0, n is 0, and L 1 is NH.
  • the methods comprise a compound of formula 56 and the attendant definitions wherein m is 0, n is 0, L 1 is NH, and L 2 is S.
  • the methods comprise a compound of formula 56 and the attendant definitions wherein m is 0, n is 0, L 1 is NH, L 2 is S, and L 3 is S.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 57:
  • the methods comprise a compound of formula 57 and the attendant definitions wherein n is 2.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein R is OH or methyl.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein m is 1.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein R 1 is methyl.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein o is 1.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein R 2 is C(O)CH 3 .
  • the methods comprise a compound of formula 57 and the attendant definitions wherein p is 2.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein R 3 is CO 2 H.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein A is alkenylene.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein n is 2 and R is OH or methyl.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, and m is 1.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, m is 1, and R 1 is methyl.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, m is 1, R 1 is methyl, and o is 1.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, m is 1, R 1 is methyl, o is 1, and R 2 is C(O)CH 3 .
  • the methods comprise a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, m is 1, R 1 is methyl, o is 1, R 2 is C(O)CH 3 , and p is 2.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, m is 1, R 1 is methyl, o is 1, R 2 is C(O)CH 3 , p is 2, and R 3 is CO 2 H.
  • the methods comprise a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, m is 1, R 1 is methyl, o is 1, R 2 is C(O)CH 3 , p is 2, R 3 is CO 2 H, and A is alkenylene.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 58:
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R 1 is CH 2 OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R 2 is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R 3 is methyl.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R 4 is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R 5 is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R 6 is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R 7 is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R 8 is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R 9 is methyl.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein L 1 is O.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein L 2 is O.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein L 3 is O.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH and R 1 is CH 2 OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH, R 1 is CH 2 OH, and R 2 is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH, R 1 is CH 2 OH, R 2 is OH, and R 3 is methyl.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH, R 1 is CH 2 OH, R 2 is OH, R 3 is methyl, and R 4 is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH, R 1 is CH 2 OH, R 2 is OH, R 3 is methyl, R 4 is OH, and R 5 is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH, R 1 is CH 2 OH, R 2 is OH, R 3 is methyl, R 4 is OH, R 5 is OH, and R 6 is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH, R 1 is CH 2 OH, R 2 is OH, R 3 is methyl, R 4 is OH, R 5 is OH, R 6 is OH, and R 7 is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH, R 1 is CH 2 OH, R 2 is OH, R 3 is methyl, R 4 is OH, R 5 is OH, R 6 is OH, R 7 is OH, and R 8 is OH.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH, R 1 is CH 2 OH, R 2 is OH, R 3 is methyl, R 4 is OH, R 5 is OH, R 6 is OH, R 7 is OH, R 8 is OH, and R 9 is methyl.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH, R 1 is CH 2 OH, R 2 is OH, R 3 is methyl, R 4 is OH, R 5 is OH, R 6 is OH, R 7 is OH, R 9 is OH, R 9 is methyl, and L 1 is O.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH, R 1 is CH 2 OH, R 2 is OH, R 3 is methyl, R 4 is OH, R 5 is OH, R 6 is OH, R 7 is OH, R 8 is OH, R 9 is methyl, L 1 is O, and L 2 is O.
  • the methods comprise a compound of formula 58 and the attendant definitions wherein R is OH, R 1 is CH 2 OH, R 2 is OH, R 3 is methyl, R 4 is OH, R 5 is OH, R 6 is OH, R 7 is OH, R 8 is OH, R 9 is methyl, L 1 is O, L 2 is O, and L 3 is O.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 59:
  • the methods comprise a compound of formula 59 and the attendant definitions wherein R is H.
  • the methods comprise a compound of formula 59 and the attendant definitions wherein R 1 is H.
  • the methods comprise a compound of formula 59 and the attendant definitions wherein R 2 is H.
  • the methods comprise a compound of formula 59 and the attendant definitions wherein R 3 is H.
  • the methods comprise a compound of formula 59 and the attendant definitions wherein L is Se.
  • the methods comprise a compound of formula 59 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 59 and the attendant definitions wherein m is 1.
  • the methods comprise a compound of formula 59 and the attendant definitions wherein R is H and R 1 is H.
  • the methods comprise a compound of formula 59 and the attendant definitions wherein R is H, R 1 is H, and R 2 is H.
  • the methods comprise a compound of formula 59 and the attendant definitions wherein R is H, R 1 is H, R 2 is H, and R 3 is H.
  • the methods comprise a compound of formula 59 and the attendant definitions wherein R is H, R 1 is H, R 2 is H, R 3 is H, and L is Se.
  • the methods comprise a compound of formula 59 and the attendant definitions wherein R is H, R 1 is H, R 2 is H, R 3 is H, L is Se, and n is 1.
  • the methods comprise a compound of formula 59 and the attendant definitions wherein R is H, R 1 is H, R 2 is H, R 3 is H, L is Se, n is 1, and m is 1.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 60:
  • the methods comprise a compound of formula 60 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 60 and the attendant definitions wherein R is Cl.
  • the methods comprise a compound of formula 60 and the attendant definitions wherein R 1 is NH 2 .
  • the methods comprise a compound of formula 60 and the attendant definitions wherein R 2 is CO 2 H.
  • the methods comprise a compound of formula 60 and the attendant definitions wherein L is SO 2 .
  • the methods comprise a compound of formula 60 and the attendant definitions wherein m is 1.
  • the methods comprise a compound of formula 60 and the attendant definitions wherein n is 1 and R is Cl.
  • the methods comprise a compound of formula 60 and the attendant definitions wherein n is 1, R is Cl, and R 1 is NH 2 .
  • the methods comprise a compound of formula 60 and the attendant definitions wherein n is 1, R is Cl, R 1 is NH 2 , and R 2 is CO 2 H.
  • the methods comprise a compound of formula 60 and the attendant definitions wherein n is 1, R is Cl, R 1 is NH 2 , R 2 is CO 2 H, and L is SO 2 .
  • the methods comprise a compound of formula 60 and the attendant definitions wherein n is 1, R is Cl, R 1 is NH 2 , R 2 is CO 2 H, L is SO 2 , and m is 1.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 61:
  • the methods comprise a compound of formula 61 and the attendant definitions wherein n is 2.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein R is 3-hydroxy and 5-hydroxy.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein R 1 is H.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein R 2 is H.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein m is 0.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein m is 1.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein R 3 is 4-hydroxy.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein R 3 is 4-methoxy.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein n is 2 and R is 3-hydroxy and 5-hydroxy.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein n is 2, R is 3-hydroxy and 5-hydroxy, and R 1 is H.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein n is 2, R is 3-hydroxy and 5-hydroxy, R 1 is H, and R 2 is H.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein n is 2, R is 3-hydroxy and 5-hydroxy, R 1 is H, R 2 is H, and m is 0.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein n is 2, R is 3-hydroxy and 5-hydroxy, R 1 is H, R 2 is H, and m is 1.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein n is 2, R is 3-hydroxy and 5-hydroxy, R 1 is H, R 2 is H, m is 1, and R 3 is 4-hydroxy.
  • the methods comprise a compound of formula 61 and the attendant definitions wherein n is 2, R is 3-hydroxy and 5-hydroxy, R 1 is H, R 2 is H, m is 1, and R 3 is 4-methoxy.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 62:
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R is OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R 1 is OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R 2 is CH 2 OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R 3 is OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R 4 is OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R 5 is OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R 6 is CH 2 OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein L is O.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R is OH and R 1 is OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R is OH, R 1 is OH, and R 2 is CH 2 OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R is OH, R 1 is OH, R 2 is CH 2 OH, and R 3 is OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R is OH, R 1 is OH, R 2 is CH 2 OH, R 3 is OH, and R 4 is OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R is OH, R 1 is OH, R 2 is CH 2 OH, R 3 is OH, R 4 is OH, and R 5 is OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R is OH, R 1 is OH, R 2 is CH 2 OH, R 3 is OH, R 4 is OH, R 5 is OH, and R 6 is CH 2 OH.
  • the methods comprise a compound of formula 62 and the attendant definitions wherein R is OH, R 1 is OH, R 2 is CH 2 OH, R 3 is OH, R 4 is OH, R 5 is OH, R 6 is CH 2 OH, and L is O.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 63: wherein, independently for each occurrence:
  • the methods comprise a compound of formula 63 and the attendant definitions wherein R is CO 2 H.
  • the methods comprise a compound of formula 63 and the attendant definitions wherein R 1 is ethyl.
  • the methods comprise a compound of formula 63 and the attendant definitions wherein R 2 is N-1-pyrrolidine.
  • the methods comprise a compound of formula 63 and the attendant definitions wherein R is CO 2 H and R 1 is ethyl.
  • the methods comprise a compound of formula 63 and the attendant definitions wherein R is CO 2 H and R 2 is N-1-pyrrolidine.
  • the methods comprise a compound of formula 63 and the attendant definitions wherein R 1 is ethyl and R 2 is N-1-pyrrolidine.
  • the methods comprise a compound of formula 63 and the attendant definitions wherein R is CO 2 H, R 1 is ethyl, and R 2 is N-1-pyrrolidine.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 64: wherein, independently for each occurrence:
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is Cl.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is H.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R 1 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R 2 is N(Me) 2 .
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R 3 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R 4 is C(O)NH 2 .
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R 5 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R 6 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R 7 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein L 1 is CH 2 .
  • the methods comprise a compound of formula 64 and the attendant definitions wherein L 2 is O.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein L 3 is O.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is Cl and R 1 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is Cl, R 1 is OH, and R 2 is N(Me) 2 .
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is Cl, R 1 is OH, R 2 is N(Me) 2 , and R 3 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is Cl, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, and R 4 is C(O)NH 2 .
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is Cl, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , and R 5 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is Cl, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, and R 6 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is Cl, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, and R 7 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is Cl, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, R 7 is OH, and L 1 is CH 2 .
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is Cl, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, R 7 is OH, L 1 is CH 2 , and L 2 is O.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is Cl, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, R 7 is OH, L 1 is CH 2 , L 2 is 0, and L 3 is O.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is H and R 1 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is H, R 1 is OH, and R 2 is N(Me) 2 .
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is H, R 1 is OH, R 2 is N(Me) 2 , and R 3 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is H, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, and R 4 is C(O)NH 2 .
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is H, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , and R 5 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is H, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, and R 6 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is H, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, and R 7 is OH.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is H, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, R 7 is OH, and L 1 is CH 2 .
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is H, R 1 is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, R 7 is OH, L 1 is CH 2 , and L 2 is O.
  • the methods comprise a compound of formula 64 and the attendant definitions wherein R is H, R is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, R 7 is OH, L 1 is CH 2 , L 2 is 0, and L 3 is O.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 65:
  • the methods comprise a compound of formula 65 and the attendant definitions wherein R is methyl.
  • the methods comprise a compound of formula 65 and the attendant definitions wherein R 1 is methyl.
  • the methods comprise a compound of formula 65 and the attendant definitions wherein R 2 is CO 2 H.
  • the methods comprise a compound of formula 65 and the attendant definitions wherein R 3 is F.
  • the methods comprise a compound of formula 65 and the attendant definitions wherein L 1 is O.
  • the methods comprise a compound of formula 65 and the attendant definitions wherein L 2 is O.
  • the methods comprise a compound of formula 65 and the attendant definitions wherein R is methyl and R 1 is methyl.
  • the methods comprise a compound of formula 65 and the attendant definitions wherein R is methyl, R 1 is methyl, and R 2 is CO 2 H.
  • the methods comprise a compound of formula 65 and the attendant definitions wherein R is methyl, R 1 is methyl, R 2 is CO 2 H, and R 3 is F.
  • the methods comprise a compound of formula 65 and the attendant definitions wherein R is methyl, R 1 is methyl, R 2 is CO 2 H, R 3 is F, and L 1 is O.
  • the methods comprise a compound of formula 65 and the attendant definitions wherein R is methyl, R 1 is methyl, R 2 is CO 2 H, R 3 is F, L 1 is O, and L 2 is O.
  • activating compounds are those listed in the appended Tables having a ratio to control rate of more than one.
  • a preferred compound of formula 8 is Dipyridamole; a preferred compound of formula 12 is Hinokitiol; a preferred compound of formula 13 is L-(+)-Ergothioneine; a preferred compound of formula 19 is Caffeic Acid Phenol Ester; a preferred compound of formula 20 is MCI-186 and a preferred compound of formula 21 is HBED (Supplementary Table 6).
  • Activating compounds may also be oxidized forms of the compounds of Table 21.
  • compositions 1-25, 30, and 32-65 are also included.
  • the compounds contemplated herein may be a single stereoisomer or racemic mixtures of stereoisomers.
  • prodrugs of the compounds of formulas 1-25, 30, and 32-65 are also included in the methods presented herein. Prodrugs are considered to be any covalently bonded carriers that release the active parent drug in vivo.
  • Analogs and derivatives of the above-described compounds can also be used for activating a member of the sirtuin protein family.
  • derivatives or analogs may make the compounds more stable or improve their ability to traverse cell membranes or being phagocytosed or pinocytosed.
  • Exemplary derivatives include glycosylated derivatives, as described, e.g., in U.S. Pat. No. 6,361,815 for resveratrol.
  • Other derivatives of resveratrol include cis- and trans-resveratrol and conjugates thereof with a saccharide, such as to form a glucoside (see, e.g., U.S. Pat. No. 6,414,037).
  • Glucoside polydatin referred to as piceid or resveratrol 3-O-beta-D-glucopyranoside
  • Saccharides to which compounds may be conjugated include glucose, galactose, maltose, lactose and sucrose.
  • Glycosylated stilbenes are further described in Regev-Shoshani et al. Biochemical J. (published on Apr. 16, 2003 as BJ20030141).
  • Other derivatives of compounds described herein are esters, amides and prodrugs. Esters of resveratrol are described, e.g., in U.S. Pat. No. 6,572,882.
  • Resveratrol and derivatives thereof can be prepared as described in the art, e.g., in U.S. Pat. Nos. 6,414,037; 6,361,815; 6,270,780; 6,572,882; and Brandolini et al. (2002) J. Agric. Food. Chem.50:7407. Derivatives of hydroxyflavones are described, e.g., in U.S. Pat. No. 4,591,600. Resveratrol and other activating compounds can also be obtained commercially, e.g., from Sigma.
  • an activating compound may be at least partially isolated from its natural environment prior to use.
  • a plant polyphenol may be isolated from a plant and partially or significantly purified prior to use in the methods described herein.
  • An activating compound may also be prepared synthetically, in which case it would be free of other compounds with which it is naturally associated.
  • an activating composition comprises, or an activating compound is associated with, less than about 50%, 10%, 1%, 0.1%, 10 ⁇ 2 % or 10 ⁇ 3 % of a compound with which it is naturally associated.
  • Sirtuin proteins may be activated in vitro, e.g., in a solution or in a cell.
  • a sirtuin protein is contacted with an activating compound in a solution.
  • a sirtuin is activated by a compound when at least one of its biological activities, e.g., deacetylation activity, is higher in the presence of the compound than in its absence. Activation may be by a factor of at least about 10%, 30%, 50%, 100% (i.e., a factor of two), 3, 10, 30, or 100.
  • the extent of activation can be determined, e.g., by contacting the activated sirtuin with a deacetylation substrate and determining the extent of deacetylation of the substrate, as further described herein.
  • the observation of a lower level of acetylation of the substrate in the presence of a test sirtuin relative to the presence of a non activated control sirtuin indicates that the test sirtuin is activated.
  • the solution may be a reaction mixture.
  • the solution may be in a dish, e.g., a multiwell dish.
  • Sirtuin proteins may be prepared recombinantly or isolated from cells according to methods known in the art.
  • a cell comprising a sirtuin deacetylase protein is contacted with an activating compound.
  • the cell may be a eukaryotic cell, e.g., a mammalian cell, such as a human cell, a yeast cell, a non-human primate cell, a bovine cell, an ovine cell, an equine cell, a porcine cell, a sheep cell, a bird (e.g., chicken or fowl) cell, a canine cell, a feline cell or a rodent (mouse or rat) cell. It can also be a non-mammalian cell, e.g., a fish cell.
  • Yeast cells include S.
  • the cell may also be a prokaryotic cell, e.g., a bacterial cell.
  • the cell may also be a single-cell microorganism, e.g., a protozoan.
  • the cell may also be a metazoan cell, a plant cell or an insect cell.
  • the cells are in vitro.
  • a cell may be contacted with a solution having a concentration of an activating compound of less than about 0.1 ⁇ M; 0.5 ⁇ M; less than about 1 ⁇ M; less than about 10 ⁇ M or less than about 100 ⁇ M.
  • concentration of the activating compound may also be in the range of about 0.1 to 1 M, about 1 to 10 ⁇ M or about 10 to 100 ⁇ M. The appropriate concentration may depend on the particular compound and the particular cell used as well as the desired effect.
  • a cell may be contacted with a “sirtuin activating” concentration of an activating compound, e.g., a concentration sufficient for activating the sirtuin by a factor of at least 10%, 30%, 50%, 100%, 3, 10, 30, or 100.
  • a “sirtuin activating” concentration of an activating compound e.g., a concentration sufficient for activating the sirtuin by a factor of at least 10%, 30%, 50%, 100%, 3, 10, 30, or 100.
  • a cell is contacted with an activating compound in vivo, such as in a subject.
  • the subject can be a human, a non-human primate, a bovine, an ovine, an equine, a porcine, a sheep, a canine, a feline or a rodent (mouse or rat).
  • an activating compound may be administered to a subject. Administration may be local, e.g., topical, parenteral, oral, or other depending on the desired result of the administration (as further described herein). Administration may be followed by measuring a factor in the subject or the cell, such as the activity of the sirtuin, lifespan or stress resistance.
  • a cell is obtained from a subject following administration of an activating compound to the subject, such as by obtaining a biopsy, and the activity of the sirtuin is determined in the biopsy.
  • the cell may be any cell of the subject, but in cases in which an activating compound is administered locally, the cell is preferably a cell that is located in the vicinity of the site of administration.
  • lysine 382 of p53 proteins in cells is deacetylated following incubation of cells in the presence of low concentrations of resveratrol.
  • concentrations include, e.g., concentrations of less than about 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 3 ⁇ M, 50 ⁇ M, 100 ⁇ M or 300 ⁇ M. It has also been shown herein that p53 proteins in cells are acetylated in the presence of higher concentrations of resveratrol.
  • p53 acetylating concentrations include, e.g., concentrations of at least about 10 ⁇ M, 30 ⁇ M, 100 ⁇ M or 300 ⁇ M.
  • concentrations of at least about 10 ⁇ M, 30 ⁇ M, 100 ⁇ M or 300 ⁇ M The level of acetylation of p53 can be determined by methods known in the art, e.g., as further described in the Examples.
  • a cell can be protected from apoptosis by activating sirtuins by contacting the cell with an amount of an activating compound sufficient or adequate for protecting against apoptosis, e.g., less than about 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 3 ⁇ M or 10 ⁇ M.
  • An amount sufficient or adequate for protection against apoptosis can also be determined experimentally, such as by incubating a cell with different amounts of an activating compound, subjecting the cell to an agent or condition that induces apoptosis, and comparing the extent of apoptosis in the presence of different concentrations or the absence of an enhancing compound and determining the concentration that provides the desired protection. Determining the level of apoptosis in a population of cells can be performed according to methods known in the art.
  • Apoptosis inducing concentrations of compounds may be, e.g., at least about 10 ⁇ M, 30 ⁇ M, 100 ⁇ M or 300 ⁇ M.
  • concentrations for modulating p53 deacetylation and apoptosis can be determined according to methods, e.g., those described herein. Concentrations may vary slightly from one cell to another, from one activating compound to another and whether the cell is isolated or in an organism.
  • Cells in which p53 acetylation and apoptosis may be modulated can be in vitro, e.g., in cell culture, or in vivo, e.g., in a subject.
  • Administration of an activating compound to a subject can be conducted as further described herein.
  • the level of p53 acetylation and/or apoptosis in cells of the subject can be determined, e.g., by obtaining a sample of cells from the subject and conducting an in vitro analysis of the level of p53 acetylation and/or apoptosis.
  • Also provided herein are methods for extending the lifespan of a eukaryotic cell and/or increasing its resistance to stress comprising, e.g., contacting the eukaryotic cell with a compound, e.g., a polyphenol compound.
  • exemplary compounds include the activating compounds described herein, such as compounds of the stilbene, flavone and chalcone families.
  • quercetin and piceatannol which activate sirtuins, were not found to significantly affect the lifespan of eukaryotic cells, it is believed that this may be the result of a lack of entry of the compounds into the cell or potentially the existence of another pathway overriding activation of sirtuins.
  • Derivatives and analogs of these compounds or administration of these compounds to other cells or by other methods are expected to activate sirtuins.
  • methods for extending the lifespan of a eukaryotic cell and/or increasing its resistance to stress comprise contacting the cell with a stilbene, chalcone, or flavone compound represented by formula 7:
  • the methods comprise a compound represented by formula 7 and the attendant definitions, wherein n is 0. In a further embodiment, the methods comprise a compound represented by formula 7 and the attendant definitions, wherein n is 1. In a further embodiment, the methods comprise a compound represented by formula 7 and the attendant definitions, wherein M is absent. In a further embodiment, the methods comprise a compound represented by formula 7 and the attendant definitions, wherein M is O. In a further embodiment, the methods comprise a compound represented by formula 7 and the attendant definitions, wherein R a is H. In a further embodiment, the methods comprise a compound represented by formula 7 and the attendant definitions, wherein M is O and the two R a form a bond.
  • the methods comprise a compound represented by formula 7 and the attendant definitions, wherein R 5 is H. In a further embodiment, the methods comprise a compound represented by formula 7 and the attendant definitions, wherein R 5 is OH. In a further embodiment, the methods comprise a compound represented by formula 7 and the attendant definitions, wherein R 1 , R 3 , and R′ 3 are OH. In a further embodiment, the methods comprise a compound represented by formula 7 and the attendant definitions, wherein R 2 , R 4 , R′ 2 , and R′ 3 are OH. In a further embodiment, the methods comprise a compound represented by formula 7 and the attendant definitions, wherein R 2 , R′ 2 , and R′ 3 are OH.
  • methods for extending the lifespan of a eukaryotic cell comprise contacting the cell with a compound represented by formula 7 and the attendant definitions, wherein n is 0; M is absent; R a is H; R 5 is H; R 1 , R 3 , and R′ 3 are OH; and R 2 , R 4 , R′ 1 , R′ 2 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound represented by formula 7 and the attendant definitions, wherein n is 1; M is absent; R a is H; R 5 is H; R 2 , R 4 , R′ 2 , and R′ 3 are OH; and R 1 , R 3 , R′ 1 , R′ 4 , and R′ 5 are H.
  • the methods comprise a compound represented by formula 7 and the attendant definitions, wherein n is 1; M is O; the two R a form a bond; R 5 is OH; R 2 , R′ 2 , and R′ 3 are OH; and R 1 , R 3 , R 4 , R′ 1 , R′ 4 , and R′ 5 are H.
  • the eukaryotic cell whose lifespan may be extended can be a human, a non-human primate, a bovine, an ovine, an equine, a porcine, a sheep, a canine, a feline, a rodent (mouse or rat) or a yeast cell.
  • a yeast cell may be Saccharomyces cerevisiae or Candida albicans . Concentrations of compounds for this purpose may be about 0.1 ⁇ M, 0.3 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, 30 ⁇ M, 100 ⁇ M or 300 ⁇ M. Based at least on the high conservation of Sir2 proteins in various organisms, lifespan can also be prolonged in prokaryotes, protozoans, metazoans, insects and plants.
  • the cell may be in vitro or in vivo.
  • a life extending compound is administered to an organism (e.g., a subject) such as to induce hormesis, i.e., an increasing resistance to mild stress that results in increasing the lifespan of the organism.
  • hormesis i.e., an increasing resistance to mild stress that results in increasing the lifespan of the organism.
  • Sir2 is essential for the increased longevity provided by calorie restriction, a mild stress, that extends the lifespan of every organism it has been tested on (Lin et al. (2000) Science 249:2126).
  • a Caenorhabditis elegans Sit2 homologue, sir-2.1 increases lifespan via a forkhead transcription factor, DAF-16, and a Sir2 gene has recently been implicated in lifespan regulation in Drosophila melanogaster (Rogina et al. Science (2002) 298:1745).
  • the closest human Sir2 homologue, SIRT1 promotes survival in human cells by down-regulating the activity of the tumor suppressor p53 (Tissenbaum et al. Nature 410, 227-30 (2001); Rogina et al. Science 298:1745 (2002); and Vaziri, H. et al. Cell 107, 149-59. (2001)).
  • PNC1 a calorie restriction- and stress-responsive gene that increases lifespan and stress resistance of cells by depleting intracellular nicotinamide (Anderson et al. (2003) Nature 423:181 and Bitterman et al. (2002) J. Biol. Chem. 277: 45099). Accordingly, compounds may be administered to a subject for protecting the cells of the subject from stresses and thereby extending the lifespan of the cells of the subject.
  • Methods may include contacting a cell or a molecule, such as a sirtuin or a p53 protein, with a compound that inhibits sirtuins, i.e., an “inhibiting compound” or “sirtuin inhibitory compound.”
  • a compound that inhibits sirtuins i.e., an “inhibiting compound” or “sirtuin inhibitory compound.”
  • Exemplary inhibiting compounds are set forth in Tables 1-13 and 22 (compounds for which the ratio to control rate is ⁇ 1).
  • Another compound is Mercury, (2-hydroxy-5-nitrophenyl)(6-thioguanosinato-N7,S6).
  • the compounds of Tables 1-8 may be obtained from Biomol, Sigma/Aldrich or Indofine.
  • a sirtuin inhibitory compound may have a formula selected from the group of formulas 26-29, 31, and 67-68:
  • the inhibiting compound is represented by formula 31 and the attendant definitions, wherein R 3 is OH, A-B is ethenylene, and R′ 3 is H.
  • the inhibiting compound is represented by formula 31 and the attendant definitions, wherein R 2 and R 4 are OH, A-B is an amido group, and R′ 3 is H.
  • the inhibiting compound is represented by formula 31 and the attendant definitions, wherein R 2 and R 4 are OMe, A-B is ethenylene, and R′ 3 is NO 2 .
  • the inhibiting compound is represented by formula 31 and the attendant definitions, wherein R 3 is OMe, A-B is ethenylene, and R′ 3 is H.
  • methods for activating a sirtuin protein comprise using an activating compound of formula 66:
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R is OH.
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R 1 is OH.
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R 2 is OH.
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R 3 is C(O)NH 2 .
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R 4 is OH.
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R 5 is NMe 2 .
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R 6 is methyl.
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R 7 is OH.
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R 8 is Cl.
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R is OH and R 1 is OH.
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R is OH, R 1 is OH, and R 2 is OH.
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R is OH, R 1 is OH, R 2 is OH, and R 3 is C(O)NH 2 .
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R is OH, R 1 is OH, R 2 is OH, R 3 is C(O)NH 2 , and R 4 is OH.
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R is OH, R 1 is OH, R 2 is OH, R 3 is C(O)NH 2 , R 4 is OH, and R 5 is NMe 2 .
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R is OH, R 1 is OH, R 2 is OH, R 3 is C(O)NH 2 , R 4 is OH, R 5 is NMe 2 , and R 6 is methyl.
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R is OH, R 1 is OH, R 2 is OH, R 3 is C(O)NH 2 , R 4 is OH, R 5 is NMe 2 , R 6 is methyl, and R 7 is OH.
  • the methods comprise a compound of formula 66 and the attendant definitions wherein R is OH, R 1 is OH, R 2 is OH, R 3 is C(O)NH 2 , R 4 is OH, R 5 is NMe 2 , R 6 is methyl, R 7 is OH, and R 8 is Cl.
  • methods for inhibiting a sirtuin protein comprise using an inhibiting compound of formula 67:
  • the methods comprise a compound of formula 67 and the attendant definitions wherein R is Cl.
  • the methods comprise a compound of formula 67 and the attendant definitions wherein R 1 is H.
  • the methods comprise a compound of formula 67 and the attendant definitions wherein R 2 is H.
  • the methods comprise a compound of formula 67 and the attendant definitions wherein R 3 is Br.
  • the methods comprise a compound of formula 67 and the attendant definitions wherein R is Cl and R 1 is H.
  • the methods comprise a compound of formula 67 and the attendant definitions wherein R is Cl, R 1 is H, and R 2 is H.
  • the methods comprise a compound of formula 67 and the attendant definitions wherein R is Cl, R 1 is H, R 2 is H, and R 3 is Br.
  • methods for inhibiting a sirtuin protein comprise using an inhibiting compound of formula 68:
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R is H.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R 1 is H.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R 2 is methyl.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein m is 0.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R 4 is OH.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R 5 is OH.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R 6 is H.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R 7 is H.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein L is NH.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein n is 1.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein o is 1.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R is H and R 1 is H.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R is H, R 1 is H, and R 2 is methyl.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R is H, R 1 is H, R 2 is methyl, and m is 0.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R is H, R 1 is H, R 2 is methyl, m is 0, and R 4 is OH.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R is H, R 1 is H, R 2 is methyl, m is 0, R 4 is OH, and R 5 is OH.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R is H, R 1 is H, R 2 is methyl, m is 0, R 4 is OH, R 5 is OH, and R 6 is H.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R is H, R 1 is H, R 2 is methyl, m is 0, R 4 is OH, R 5 is OH, R 6 is H, and R 7 is H.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R is H, R 1 is H, R 2 is methyl, m is 0, R 4 is OH, R 5 is OH, R 6 is H, R 7 is H, and L is NH.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R is H, R 1 is H, R 2 is methyl, m is 0, R 4 is OH, R 5 is OH, R 6 is H, R 7 is H, L is NH, and n is 1.
  • the methods comprise a compound of formula 68 and the attendant definitions wherein R is H, R 1 is H, R 2 is methyl, m is 0, R 4 is OH, R 5 is OH, R 6 is H, R 7 is H, L is NH, n is 1, and o is 1.
  • Inhibitory compounds may also be oxidized forms of the compounds of Table 22.
  • An oxidized form of chlortetracyclin may be an activator.
  • Exemplary inhibitory compounds are those set forth in the appended Tables for which the “ratio to control rate” is lower than one.
  • prodrugs of the compounds of formulas 26-29, 31 and 66-68 are included in the methods presented herein. Prodrugs are considered to be any covalently bonded carriers that release the active parent drug in vivo.
  • Inhibitory compounds may be contacted with a cell, administered to a subject, or contacted with one or more molecules, such as a sirtuin protein and a p53 protein. Doses of inhibitory compounds may be similar to those of activating compounds.
  • a cell may also be contacted with more than one compound (whether an activating compound or an inhibiting compound).
  • a cell may be contacted with at least 2, 3, 5, or 10 different compounds.
  • a cell may be contacted simultaneously or sequentially with different compounds.
  • compositions comprising one or more activating or inhibiting compounds having a formula selected from the group of formulas 1-68.
  • Compounds may be in a pharmaceutical composition, such as a pill or other formulation for oral administration, further described herein.
  • compositions may also comprise or consist of extracts of plants, red wine or other source of the compounds.
  • a certain biological function is modulated by any one of a compound of a genus of compounds (e.g., having formula I), with the proviso that the genus does not include one or more specific compounds.
  • a sirtuin activator compound may be a compound of any one of formulas 1-25, 30 and 32-65 with the proviso that the compound is not resveratrol, flavone or any of the other compounds specifically cited herein.
  • an agent may be a nucleic acid, such as an aptamer.
  • Assays may be conducted in a cell based or cell free format.
  • an assay may comprise incubating (or contacting) a sirtuin with a test agent under conditions in which a sirtuin can be activated by an agent known to activate the sirtuin, and monitoring or determining the level of activation of the sirtuin in the presence of the test agent relative to the absence of the test agent.
  • the level of activation of a sirtuin can be determined by determining its ability to deacetylate a substrate.
  • Exemplary substrates are acetylated peptides, e.g., those set forth in FIG. 5 , which can be obtained from BIOMOL (Plymouth Meeting, Pa.).
  • Preferred substrates include peptides of p53, such as those comprising an acetylated K382.
  • a particularly preferred substrate is the Fluor de Lys-SIRT1(BIOMOL), i.e., the acetylated peptide Arg-His-Lys-Lys.
  • Other substrates are peptides from human histones H3 and H4 or an acetylated amino acid (see FIG. 5 ). Substrates may be fluorogenic.
  • the sirtuin may be SIRT1 or SIR2 or a portion thereof.
  • recombinant SIRT1 can be obtained from BIOMOL.
  • the reaction may be conducted for about 30 minutes and stopped, e.g., with nicotinamide.
  • the HDAC fluorescent activity assay/drug discovery kit (AK-500, BIOMOL Research Laboratories) may be used to determine the level of acetylation. Similar assays are described in Bitterman et al. (2002) J. Biol. Chem. 277:45099.
  • the level of activation of the sirtuin in an assay may be compared to the level of activation of the sirtuin in the presence of one or more (separately or simultaneously) compounds described herein, which may serve as positive or negative controls.
  • Sirtuins for use in the assays may be full length sirtuin proteins or portions thereof. Since it has been shown herein that activating compounds appear to interact with the N-terminus of SIRT1, proteins for use in the assays include N-terminal portions of sirtuins, e.g., about amino acids 1-176 or 1-255 of SIRT1; about amino acids 1-174 or 1-252 of Sir2.
  • a screening assay comprises (i) contacting a sirtuin with a test agent and an acetylated substrate under conditions appropriate for the sirtuin to deacetylate the substrate in the absence of the test agent; and (ii) determining the level of acetylation of the substrate, wherein a lower level of acetylation of the substrate in the presence of the test agent relative to the absence of the test agent indicates that the test agent stimulates deacetylation by the sirtuin, whereas a higher level of acetylation of the substrate in the presence of the test agent relative to the absence of the test agent indicates that the test agent inhibits deacetylation by the sirtuin.
  • Methods for identifying an agent that modulates, e.g., stimulate or inhibit, sirtuins in vivo may comprise (i) contacting a cell with a test agent and a substrate that is capable of entering a cell in the presence of an inhibitor of class I and class II HDACs under conditions appropriate for the sirtuin to deacetylate the substrate in the absence of the test agent; and (ii) determining the level of acetylation of the substrate, wherein a lower level of acetylation of the substrate in the presence of the test agent relative to the absence of the test agent indicates that the test agent stimulates deacetylation by the sirtuin, whereas a higher level of acetylation of the substrate in the presence of the test agent relative to the absence of the test agent indicates that the test agent inhibits deacetylation by the sirtuin.
  • a preferred substrate is an acetylated peptide, which is also prefeably fluorogenic, as further described herein (Examples).
  • the method may further comprise lysing the cells to determine the level of acetylation of the substrate.
  • Substrates may be added to cells at a concentration ranging from about 1 ⁇ M to about 10 mM, preferably from about 10 ⁇ M to 1 mM, even more preferably from about 100 ⁇ M to 1 mM, such as about 200 ⁇ M.
  • a preferred substrate is an acetylated lysine, e.g., ⁇ -acetyl lysine (Fluor de Lys, FdL) or Fluor de Lys-SIRT1.
  • a preferred inhibitor of class I and class II HDACs is trichostatin A (TSA), which may be used at concentrations ranging from about 0.01 to 100 ⁇ M, preferably from about 0.1 to 10 ⁇ M, such as 1 ⁇ M.
  • TSA trichostatin A
  • Incubation of cells with the test compound and the substrate may be conducted for about 10 minutes to 5 hours, preferably for about 1-3 hours. Since TSA inhibits all class I and class II HDACs, and that certain substrates, e.g., Fluor de Lys, is a poor substrate for SIRT2 and even less a substrate for SIRT3-7, such an assay may be used to identify modulators of SIRT1 in vivo.
  • An exemplary assay is further described in the Examples and shown in FIG. 4 a.
  • a method may comprise incubating cells with a test agent and determining the effect of the test agent on rDNA silencing and rDNA recombination, wherein an increase in the frequency of rDNA recombination and an absence of effect on rDNA silencing in the presence of the test agent relative to the absence of the test agent indicates that the test agent extends lifespan.
  • This assay is based at least on the observation that resveratrol reduced the frequency of rDNA recombination by about 60% in a SIR2 dependent manner, but did not increase rDNA silencing.
  • BML-232 (Table 10) is used.
  • BML-232 has very similar SIRT1 activating properties to resveratrol and contains a phenylazide function. Phenylazide groups may be activated by the absorption of ultraviolet light to form reactive nitrenes. When a protein-bound phenylazide is light-activated it can react to form covalent adducts with various protein functional groups in the site to which it is bound. The photo cross-linked protein may then be analyzed by proteolysis/mass spectrometry to identify amino acid residues which may form part of the binding site for the compound. This information, in combination with published three dimensional structural information on SIRT1 homologs could be used to aid the design of new, possibly higher affinity, SIRT1 activating ligands.
  • cells are treated in vitro as described herein to mimic caloric restriction, such as to extend their lifespan, e.g., to keep them proliferating longer and/or increasing their resistance to stress or prevent apoptosis.
  • That compounds described herein may increase resistance to stress is based at least on the observation that Sir2 provides stress resistance and that PNC1 modulates Sir2 activity in response to cell stress (Anderson et al. (2003) Nature 423:181). This is particularly useful for primary cell cultures (i.e., cells obtained from an organism, e.g., a human), which are known to have only a limited lifespan in culture.
  • Embryonic stem (ES) cells and pluripotent cells, and cells differentiated therefrom can also be treated according to the methods described herein such as to keep the cells or progeny thereof in culture for longer periods of time.
  • Primary cultures of cells, ES cells, pluripotent cells and progeny thereof can be used, e.g., to identify compounds having particular biological effects on the cells or for testing the toxicity of compounds on the cells (i.e., cytotoxicity assays).
  • Such cells can also be used for transplantation into a subject, e.g., after ex vivo modification.
  • cells that are intended to be preserved for long periods of time are treated as described herein.
  • the cells can be cells in suspension, e.g., blood cells, serum, biological growth media, or tissues or organs.
  • blood collected from an individual for administering to an individual can be treated as described herein, such as to preserve the blood cells for longer periods of time, such as for forensic purposes.
  • Other cells that one may treat for extending their lifespan or protect against apoptosis include cells for consumption, e.g., cells from non-human mammals (such as meat), or plant cells (such as vegetables).
  • sirtuin-activating compounds may be used for extending the lifespan of a cell; extending the proliferative capacity of a cell; slowing ageing of a cell; promoting the survival of a cell; delaying cellular senescence in a cell; or mimicking the effects of calorie restriction.
  • a sirtuin-activating compound does not significantly increase the resistance of a cell to oxidative stress, although it may increase its resistance to other types of stresses.
  • a compound may increase the resistance of a cell to oxidative stress less than about 2, 5, 10, 30, or 100 fold relative to another compound, e.g., reseveratrol.
  • Compounds may also be applied during developmental and growth phases in mammals, plants, insects or microorganisms, in order to, e.g., alter, retard or accelerate the developmental and/or growth process.
  • cells obtained from a subject are treated according to methods described herein and then administered to the same or a different subject.
  • cells or tissues obtained from a donor for use as a graft can be treated as described herein prior to administering to the recipient of the graft.
  • bone marrow cells can be obtained from a subject, treated ex vivo, e.g., to extend their lifespan, and then administered to a recipient.
  • the graft can be an organ, a tissue or loose cells.
  • cells are treated in vivo, e.g., to increase their lifespan or prevent apoptosis.
  • skin can be protected from aging, e.g., developing wrinkles, by treating skin, e.g., epithelial cells, as described herein.
  • skin is contacted with a pharmaceutical or cosmetic composition comprising a compound described herein.
  • exemplary skin afflictions or skin conditions include disorders or diseases associated with or caused by inflammation, sun damage or natural aging.
  • compositions find utility in the prevention or treatment of contact dermatitis (including irritant contact dermatitis and allergic contact dermatitis), atopic dermatitis (also known as allergic eczema), actinic keratosis, keratinization disorders (including eczema), epidermolysis bullosa diseases (including penfigus), exfoliative dermatitis, seborrheic dermatitis, erythemas (including erythema multiforme and erythema nodosum), damage caused by the sun or other light sources, discoid lupus erythematosus, dermatomyositis, skin cancer and the effects of natural aging.
  • contact dermatitis including irritant contact dermatitis and allergic contact dermatitis
  • atopic dermatitis also known as allergic eczema
  • actinic keratosis also known as allergic eczema
  • keratinization disorders including
  • the formulations may be administered topically, to the skin or mucosal tissue, as an ointment, lotion, cream, microemulsion, gel, solution or the like, as further described herein, within the context of a dosing regimen effective to bring about the desired result.
  • a dose of active agent may be in the range of about 0.005 to about 1 micromoles per kg per day, preferably about 0.05 to about 0.75 micromoles per kg per day, more typically about 0.075 to about 0.5 micromoles per kg per day. It will be recognized by those skilled in the art that the optimal quantity and spacing of individual dosages will be determined by the nature and extent of the condition being treated, the site of administration, and the particular individual undergoing treatment, and that such optimums can be determined by conventional techniques.
  • an optimal dosing regimen for any particular patient i.e., the number and frequency of doses
  • a dosing regimen involves administration of the topical formulation at least once daily, and preferably one to four times daily, until symptoms have subsided.
  • Topical formulations may also be used as preventive, e.g., chemopreventive, compositions.
  • preventive e.g., chemopreventive
  • susceptible skin is treated prior to any visible condition in a particular individual.
  • Compounds can also be delivered locally, e.g., to a tissue or organ within a subject, such as by injection, e.g., to extend the lifespan of the cells; protect against apoptosis or induce apoptosis.
  • sirtuin-activating compounds may be used in methods for treating or preventing a disease or condition induced or exacerbated by cellular senescence in a subject; methods for decreasing the rate of senescence of a subject, e.g., after onset of senescence; methods for extending the lifespan of a subject; methods for treating or preventing a disease or condition relating to lifespan; methods for treating or preventing a disease or condition relating to the proliferative capacity of cells; and methods for treating or preventing a disease or condition resulting from cell damage or death.
  • the disease or condition does not result from oxidative stress.
  • a method does not significantly increase the resistance of the subject to oxidative stress.
  • the method does not act by decreasing the rate of occurrence of diseases that shorten the lifespan of a subject.
  • a method does not act by reducing the lethality caused by a disease, such as cancer.
  • a sirtuin activating compound is administered to a subject, such as to generally increase the lifespan of its cells and to protect its cells against stress and/or against apoptosis. It is believed that treating a subject with a compound described herein is similar to subjecting the subject to hormesis, i.e., mild stress that is beneficial to organisms and may extend their lifespan.
  • a compound can be taken by subjects as a food or dietary supplement.
  • such a compound is a component of a multi-vitamin complex.
  • Compounds can also be added to existing formulations that are taken on a daily basis, e.g., statins and aspirin. Compounds may also be used as food additives.
  • this multi-drug complex or regimen would include drugs or compounds for the treatment or prevention of aging-related diseases, e.g., stroke, heart disease, arthritis, high blood pressure, Alzheimer's.
  • this multi-drug regimen would include chemotherapeutic drugs for the treatment of cancer.
  • a compound could be used to protect non-cancerous cells from the effects of chemotherapy.
  • Sirtuin-activating compounds may be administered to a subject to prevent aging and aging-related consequences or diseases, such as stroke, heart disease, such as heart failure, arthritis, high blood pressure, and Alzheimer's disease.
  • Other conditions that can be treated include ocular disorders, e.g., associated with the aging of the eye, such as cataracts, glaucoma, and macular degeneration.
  • Sirtuin-activating compounds described herein can also be administered to subjects for treatment of diseases, e.g., chronic diseases, associated with cell death, such as to protect the cells from cell death.
  • Exemplary diseases include those associated with neural cell death or muscular cell death, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amniotropic lateral sclerosis, and muscular dystrophy; AIDS; fulminant hepatitis; diseases linked to degeneration of the brain, such as Creutzfeld-Jakob disease, retinitis pigmentosa and cerebellar degeneration; myelodysplasis such as aplastic anemia; ischemic diseases such as myocardial infarction and stroke; hepatic diseases such as alcoholic hepatitis, hepatitis B and hepatitis C; joint-diseases such as osteoarthritis; atherosclerosis; alopecia; damage to the skin due to UV light; lichen planus; atrophy of the skin; cataract; and graft rejections.
  • neural cell death or muscular cell death such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amniotropic lateral sclerosis, and muscular dystrophy
  • Cardiovascular diseases that can be treated or prevented include cardiomyopathy or myocarditis; such as idiopathic cardiomyopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, drug-induced cardiomyopathy, ischemic cardiomyopathy, and hypertensive cardiomyopathy.
  • cardiomyopathy or myocarditis such as idiopathic cardiomyopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, drug-induced cardiomyopathy, ischemic cardiomyopathy, and hypertensive cardiomyopathy.
  • atheromatous disorders of the major blood vessels such as the aorta, the coronary arteries, the carotid arteries, the cerebrovascular arteries, the renal arteries, the iliac arteries, the femoral arteries, and the popliteal arteries.
  • vascular diseases that can be treated or prevented include those related to the retinal arterioles, the glomerular arterioles, the vasa nervorum, cardiac arterioles, and associated capillary beds of the eye, the kidney, the heart, and the central and peripheral nervous systems.
  • the compounds may also be used for increasing HDL levels in plasma of an individual.
  • sirtuin activators include restenosis, e.g., following coronary intervention, and disorders relating to an abnormal level of high density and low density cholesterol.
  • Sirtuin activators may also be used for treating or preventing viral infections, such as infections by influenza, herpes or papilloma virus. They may also be used as antifungal agents, anti-inflammatory agents and neuroprotective agents.
  • Sirtuin-activating compounds described herein can also be administered to a subject suffering from an acute disease, e.g., damage to an organ or tissue, e.g., a subject suffering from stroke or myocardial infarction or a subject suffering from a spinal cord injury.
  • Compounds can also be used to repair an alcoholic's liver.
  • Sirtuin-activating compounds can also be administered to subjects who have recently received or are likely to receive a dose of radiation.
  • the dose of radiation is received as part of a work-related or medical procedure, e.g., working in a nuclear power plant, flying an airplane, an X-ray, CAT scan, or the administration of a radioactive dye for medical imaging; in such an embodiment, the compound is administered as a prophylactic measure.
  • the radiation exposure is received unintentionally, e.g., as a result of an industrial accident, terrorist act, or act of war involving radioactive material.
  • the compound is preferably administered as soon as possible after the exposure to inhibit apoptosis and the subsequent development of acute radiation syndrome.
  • the activating compounds can also be administed to a subject in conditions in which apoptosis of certain cells is desired.
  • cancer may be treated or prevented.
  • Exemplary cancers are those of the brain and kidney; hormone-dependent cancers including breast, prostate, testicular, and ovarian cancers; lymphomas, and leukemias.
  • a activating compound may be administered directly into the tumor.
  • Cancer of blood cells e.g., leukemia can be treated by administering a activating compound into the blood stream or into the bone marrow.
  • Benign cell growth can also be treated, e.g., warts.
  • Other diseases that can be treated include autoimmune diseases, e.g., systemic lupus erythematosus, scleroderma, and arthritis, in which autoimmune cells should be removed.
  • Viral infections such as herpes, HIV, adenovirus, and HTLV-1 associated malignant and benign disorders can also be treated by administration of compounds.
  • cells can be obtained from a subject, treated ex vivo to remove certain undesirable cells, e.g., cancer cells, and administered back to the same or a different subject.
  • Chemotherapeutic agents that may be coadministered with compounds described herein as having anti-cancer activity (e.g., compounds that induce apoptosis, compounds that reduce lifespan or compounds that render cells sensitive to stress) include: aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg, bicalutamide, bleomycin, buserelin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgras
  • chemotherapeutic agents may be categorized by their mechanism of action into, for example, following groups: anti-metabolites/anti-cancer agents, such as pyrimidine analogs (5-fluorouracil, floxuridine, capecitabine, gemcitabine and cytarabine) and purine analogs, folate antagonists and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine)); antiproliferative/antimitotic agents including natural products such as vinca alkaloids (vinblastine, vincristine, and vinorelbine), microtubule disruptors such as taxane (paclitaxel, docetaxel), vincristin, vinblastin, nocodazole, epothilones and navelbine, epidipodophyllotoxins (teniposide), DNA damaging agents (actinomycin, amsacrine, anthracyclines, bleomycin, busulfan
  • chemotherapeutic agents may be used by themselves with a compound described herein as inducing cell death or reducing lifespan or increasing sensitivity to stress and/or in combination with other chemotherapeutics agents.
  • Many combinatorial therapies have been developed, including but not limited to those listed in Table 23.
  • RNAi RNAi other polynucleotides to inhibit the expression of the cellular components that contribute to unwanted cellular proliferation that are targets of conventional chemotherapy.
  • targets are, merely to illustrate, growth factors, growth factor receptors, cell cycle regulatory proteins, transcription factors, or signal transduction kinases.
  • the methods may be advantageous over combination therapies known in the art because it allows conventional chemotherapeutic agent to exert greater effect at lower dosage.
  • the effective dose (ED 50 ) for a chemotherapeutic agent or combination of conventional chemotherapeutic agents when used in combination with a compound described herein is at least 2 fold less than the ED 50 for the chemotherapeutic agent alone, and even more preferably at 5 fold, 10 fold or even 25 fold less.
  • the therapeutic index (TI) for such chemotherapeutic agent or combination of such chemotherapeutic agent when used in combination with a compound described herein can be at least 2 fold greater than the TI for conventional chemotherapeutic regimen alone, and even more preferably at 5 fold, 10 fold or even 25 fold greater.
  • combination therapies include conjoint administration with nicotinamide, NAD + or salts thereof, or other Vitamin B3 analogs.
  • Carnitines such as L-carnitine
  • Cyclooxygenase inhibitors e.g., a COX-2 inhibitor
  • compositions or coformulations comprising a sirtuin activator or inhibitor and another agent, e.g., a chemotherapeutic agent, an antiviral agent, nicotinamide, NAD + or salts thereof, Vitamin B3 analogs, retinoids, alpha-hydroxy acid, ascorbic acid, are also encompassed herein.
  • a chemotherapeutic agent e.g., an antiviral agent, nicotinamide, NAD + or salts thereof, Vitamin B3 analogs, retinoids, alpha-hydroxy acid, ascorbic acid
  • the subject sirtuin activators do not have any substantial ability to inhibit PI3-kinase, inhibit aldoreductase and/or inhibit tyrosine protein kinases at concentrations (e.g., in vivo) effective for activating the deacetylase activity of the sirtuin, e.g., SIRT1.
  • the sirtuin activator is chosen to have an EC 50 for activating sirtuin deacetylase activity that is at least 5 fold less than the EC 50 for inhibition of one or more of aldoreductase and/or tyrosine protein kinases, and even more preferably at least 10 fold, 100 fold or even 1000 fold less.
  • the subject sirtuin activators do not have any substantial ability to transactivate EGFR tyrosine kinase activity at concentrations (e.g., in vivo) effective for activating the deacetylase activity of the sirtuin.
  • the sirtuin activator is chosen to have an EC 50 for activating sirtuin deacetylase activity that is at least 5 fold less than the EC 50 for transactivating EGFR tyrosine kinase activity, and even more preferably at least 10 fold, 100 fold or even 1000 fold less.
  • the subject sirtuin activators do not have any substantial ability to cause coronary dilation at concentrations (e.g., in vivo) effective for activating the deacetylase activity of the sirtuin.
  • the sirtuin activator is chosen to have an EC 50 for activating sirtuin deacetylase activity that is at least 5 fold less than the EC 50 for coronary dilation, and even more preferably at least 10 fold, 100 fold or even 1000 fold less.
  • the subject sirtuin activators do not have any substantial spasmolytic activity at concentrations (e.g., in vivo) effective for activating the deacetylase activity of the sirtuin.
  • the sirtuin activator is chosen to have an EC 50 for activating sirtuin deacetylase activity that is at least 5 fold less than the EC 50 for spasmolytic effects (such as on gastrointestinal muscle), and even more preferably at least 10 fold, 100 fold or even 1000 fold less.
  • the subject sirtuin activators do not have any substantial ability to inhibit hepatic cytochrome P450 1B1 (CYP) at concentrations (e.g., in vivo) effective for activating the deacetylase activity of the sirtuin.
  • CYP hepatic cytochrome P450 1B1
  • the sirtuin activator is chosen to have an EC 50 for activating sirtuin deacetylase activity that is at least 5 fold less than the EC 50 for inhibition of P450 1B1, and even more preferably at least 10 fold, 100 fold or even 1000 fold less.
  • the subject sirtuin activators do not have any substantial ability to inhibit nuclear factor-kappaB (NF- ⁇ B) at concentrations (e.g., in vivo) effective for activating the deacetylase activity of the sirtuin.
  • NF- ⁇ B nuclear factor-kappaB
  • the sirtuin activator is chosen to have an EC 50 for activating sirtuin deacetylase activity that is at least 5 fold less than the EC 50 for inhibition of NF- ⁇ B, and even more preferably at least 10 fold, 100 fold or even 1000 fold less.
  • the subject SIRT1 activators do not have any substantial ability to activate SIRT1 orthologs in lower eukaryotes, particularly yeast or human pathogens, at concentrations (e.g., in vivo) effective for activating the deacetylase activity of human SIRT1.
  • the SIRT1 activator is chosen to have an EC50 for activating human SIRT1 deacetylase activity that is at least 5 fold less than the EC50 for activating yeast Sir2 (such as Candida, S. cerevisiae , etc), and even more preferably at least 10 fold, 100 fold or even 1000 fold less.
  • the subject sirtuin activators do not have any substantial ability to inhibit protein kinases; to phosphorylate mitogen activated protein (MAP) kinases; to inhibit the catalytic or transcriptional activity of cyclo-oxygenases, such as COX-2; to inhibit nitric oxide synthase (iNOS); or to inhibit platelet adhesion to type I collagen at concentrations (e.g., in vivo) effective for activating the deacetylase activity of the sirtuin.
  • MAP mitogen activated protein
  • COX-2 cyclo-oxygenases
  • iNOS nitric oxide synthase
  • platelet adhesion to type I collagen at concentrations (e.g., in vivo) effective for activating the deacetylase activity of the sirtuin.
  • the sirtuin activator is chosen to have an EC 50 for activating sirtuin deacetylase activity that is at least 5 fold less than the EC 50 for performing any of these activities, and even more preferably at least 10 fold, 100 fold or even 1000 fold less.
  • a compound described herein e.g., a sirtuin activator or inhibitor, does not have significant or detectable anti-oxidant activities, as determined by any of the standard assays known in the art.
  • a compound does not significantly scavenge free-radicals, such as O 2 radicals.
  • a compound may have less than about 2, 3, 5, 10, 30 or 100 fold anti-oxidant activity relative to another compound, e.g., resveratrol.
  • a compound may also have a binding affinity for a sirtuin of about 10 ⁇ 9 M, 10 ⁇ 10 M, 10 ⁇ 1 M, 10 ⁇ 12 M or less.
  • a compound may reduce the K m of a sirtuin for its substrate or NAD + by a factor of at least about 2, 3, 4, 5, 10, 20, 30, 50 or 100.
  • a compound may have an EC 50 for activating the deacetylase activity of a sirtuin of less than about 1 nM, less than about 10 nM, less than about 100 nM, less than about 1 ⁇ M, less than about 10 ⁇ M, less than about 100 ⁇ M, or from about 1-10 nM, from about 10-100 nM, from about 0.1-1 ⁇ M, from about 1-10 ⁇ M or from a bout 10-100 ⁇ M.
  • a compound may activate the deacetylase activity of a sirtuin by a factor of at least about 5, 10, 20, 30, 50, or 100, as measured in an acellular assay or in a cell based assay as described in the Examples.
  • a compound may cause at least a 10%, 30%, 50%, 80%, 2 fold, 5 fold, 10 fold, 50 fold or 100 fold greater induction of the deacetylase activity of SIRT1relative to the same concentration of resveratrol or other compound described herein.
  • a compound may also have an EC 50 for activating SIRT5 that is at least about 10 fold, 20 fold, 30 fold, 50 fold greater than that for activating SIRT1.
  • a compound may traverse the cytoplasmic membrane of a cell.
  • a compound may have a cell-permeability of at least about 20%, 50%, 75%, 80%, 90% or 95%.
  • the compound may be essentially non-toxic to a cell or subject; the compound may be an organic molecule or a small molecule of 2000 amu or less, 1000 amu or less; a compound may have a half-life under normal atmospheric conditions of at least about 30 days, 60 days, 120 days, 6 months or 1 year; the compound may have a half-life in solution of at least about 30 days, 60 days, 120 days, 6 months or 1 year; a compound may be more stable in solution than resveratrol by at least a factor of about 50%, 2 fold, 5 fold, 10 fold, 30 fold, 50 fold or 100 fold; a compound may promote deacetylation of the DNA repair factor Ku70; a compound may promote deacetylation of RelA/p65; a compound may increase general turnover rates and enhance the sensitivity of cells to TNF-induced apoptosis.
  • methods described herein are applied to yeast cells.
  • Situations in which it may be desirable to extend the lifespan of yeast cells include any process in which yeast is used, e.g., the making of beer, yogurt, and bakery items, e.g., bread.
  • Use of yeast having an extended lifespan can result in using less yeast or in having the yeast be active for longer periods of time.
  • Yeast or other mammalian cells used for recombinantly producing proteins may also be treated as described herein.
  • Sirtuin activators may also be used for treating or preventing viral infections, such as infections by influenz, herpes or papillomavirus. They may also be used as antifungal agents, anti-inflammatory agents and neuroprotective agents.
  • Subjects that may be treated as described herein include eukaryotes, such as mammals, e.g., humans, ovines, bovines, equines, porcines, canines, felines, non-human primate, mice, and rats.
  • Cells that may be treated include eukaryotic cells, e.g., from a subject described above, or plant cells, yeast cells and prokaryotic cells, e.g., bacterial cells.
  • activating compounds may be administered to farm animals to improve their ability to withstand farming conditions longer.
  • Compounds may also be used to increase lifespan, stress resistance, and resistance to apoptosis in plants.
  • a compound is applied to plants, e.g., on a periodic basis, or to fungi.
  • plants are genetically modified to produce a compound.
  • plants and fruits are treated with a compound prior to picking and shipping to increase resistance to damage during shipping.
  • Plant seeds may also be contacted with compounds described herein, e.g., to preverse them.
  • Compounds may also be used to increase lifespan, stress resistance and resistance to apoptosis in insects.
  • compounds would be applied to useful insects, e.g., bees and other insects that are involved in pollination of plants.
  • a compound would be applied to bees involved in the production of honey.
  • the methods described herein may be applied to any organism, e.g., eukaryote, that may have commercial importance. For example, they can be applied to fish (aquaculture) and birds (e.g., chicken and fowl).
  • a compound may be applied to plants using a method known in the art that ensures the compound is bio-available to insect larvae, and not to plants.
  • Activated sirtuin proteins that are in vitro outside of a cell may be used, e.g., for deacetylating target proteins, thereby, e.g., activating the target proteins.
  • Activated sirtuins may be used, e.g., for the identification, in vitro, of previously unknown targets of sirtuin deacetylation, for example using 2D electrophoresis of acetyl labeled proteins.
  • the compounds can be applied to affect the reproduction of organisms such as insects, animals and microorganisms.
  • Inhibitory compounds may be used for similar purposes as those described herein for high concentrations of activating compounds.
  • inhibitory compounds may be used to stimulate acetylation of substrates such as p53 and thereby increase apoptosis, as well as to reduce the lifespan of cells and organisms and/or rendering them more sensitive to stress.
  • inhibitory compounds may be used, e.g., for treating cancer.
  • compositions for use in accordance with the present methods may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients.
  • activating compounds and their physiologically acceptable salts and solvates may be formulated for administration by, for example, injection, inhalation or insufflation (either through the mouth or the nose) or oral, buccal, parenteral or rectal administration.
  • the compound is administered locally, at the site where the target cells, e.g., diseased cells, are present, i.e., in the blood or in a joint.
  • Compounds can be formulated for a variety of loads of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in Remmington's Pharmaceutical Sciences, Meade Publishing Co., Easton, Pa.
  • injection is preferred, including intramuscular, intravenous, intraperitoneal, and subcutaneous.
  • the compounds can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution.
  • the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms are also included.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozanges, or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., ationd oil, oily esters, ethyl alcohol or fractionated vegetable oils); preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • the compounds may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may comprise from about 0.00001 to 100% such as from 0.001 to 10% or from 0.1% to 5% by weight of one or more compounds described herein.
  • a compound described herein is incorporated into a topical formulation containing a topical carrier that is generally suited to topical drug administration and comprising any such material known in the art.
  • the topical carrier may be selected so as to provide the composition in the desired form, e.g., as an ointment, lotion, cream, microemulsion, gel, oil, solution, or the like, and may be comprised of a material of either naturally occurring or synthetic origin. It is preferable that the selected carrier not adversely affect the active agent or other components of the topical formulation.
  • suitable topical carriers for use herein include water, alcohols and other nontoxic organic solvents, glycerin, mineral oil, silicone, petroleum jelly, lanolin, fatty acids, vegetable oils, parabens, waxes, and the like.
  • Formulations may be colorless, odorless ointments, lotions, creams, microemulsions and gels.
  • ointments which generally are semisolid preparations which are typically based on petrolatum or other petroleum derivatives.
  • the specific ointment base to be used is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency or the like.
  • an ointment base should be inert, stable, nonirritating and nonsensitizing.
  • ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.
  • Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
  • Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
  • Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.
  • Exemplary water-soluble ointment bases are prepared from polyethylene glycols (PEGs) of varying molecular weight; again, reference may be had to Remington's, supra, for further information.
  • Lotions may be incorporated into lotions, which generally are preparations to be applied to the skin surface without friction, and are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base.
  • Lotions are usually suspensions of solids, and may comprise a liquid oily emulsion of the oil-in-water type. Lotions are preferred formulations for treating large body areas, because of the ease of applying a more fluid composition. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethylcellulose, or the like.
  • An exemplary lotion formulation for use in conjunction with the present method contains propylene glycol mixed with a hydrophilic petrolatum such as that which may be obtained under the trademark Aquaphor RTM from Beiersdorf, Inc. (Norwalk, Conn.).
  • Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
  • microemulsions which generally are thermodynamically stable, isotropically clear dispersions of two immiscible liquids, such as oil and water, stabilized by an interfacial film of surfactant molecules (Encyclopedia of Pharmaceutical Technology (New York: Marcel Dekker, 1992), volume 9).
  • surfactant emulsifier
  • co-surfactant co-emulsifier
  • an oil phase and a water phase are necessary.
  • Suitable surfactants include any surfactants that are useful in the preparation of emulsions, e.g., emulsifiers that are typically used in the preparation of creams.
  • the co-surfactant is generally selected from the group of polyglycerol derivatives, glycerol derivatives and fatty alcohols.
  • Preferred emulsifier/co-emulsifier combinations are generally although not necessarily selected from the group consisting of: glyceryl monostearate and polyoxyethylene stearate; polyethylene glycol and ethylene glycol palmitostearate; and caprilic and capric triglycerides and oleoyl macrogolglycerides.
  • the water phase includes not only water but also, typically, buffers, glucose, propylene glycol, polyethylene glycols, preferably lower molecular weight polyethylene glycols (e.g., PEG 300 and PEG 400), and/or glycerol, and the like, while the oil phase will generally comprise, for example, fatty acid esters, modified vegetable oils, silicone oils, mixtures of mono- di- and triglycerides, mono- and di-esters of PEG (e.g., oleoyl macrogol glycerides), etc.
  • buffers glucose, propylene glycol, polyethylene glycols, preferably lower molecular weight polyethylene glycols (e.g., PEG 300 and PEG 400), and/or glycerol, and the like
  • the oil phase will generally comprise, for example, fatty acid esters, modified vegetable oils, silicone oils, mixtures of mono- di- and triglycerides, mono- and di-esters of PEG (e.g., ole
  • Gel formulations which generally are semisolid systems consisting of either suspensions made up of small inorganic particles (two-phase systems) or large organic molecules distributed substantially uniformly throughout a carrier liquid (single phase gels).
  • Single phase gels can be made, for example, by combining the active agent, a carrier liquid and a suitable gelling agent such as tragacanth (at 2 to 5%), sodium alginate (at 2-10%), gelatin (at 2-15%), methylcellulose (at 3-5%), sodium carboxymethylcellulose (at 2-5%), carbomer (at 0.3-5%) or polyvinyl alcohol (at 10-20%) together and mixing until a characteristic semisolid product is produced.
  • suitable gelling agents include methylhydroxycellulose, polyoxyethylene-polyoxypropylene, hydroxyethylcellulose and gelatin.
  • additives may be included in formulations, e.g., topical formulations.
  • additives include, but are not limited to, solubilizers, skin permeation enhancers, opacifiers, preservatives (e.g., anti-oxidants), gelling agents, buffering agents, surfactants (particularly nonionic and amphoteric surfactants), emulsifiers, emollients, thickening agents, stabilizers, humectants, colorants, fragrance, and the like.
  • solubilizers and/or skin permeation enhancers is particularly preferred, along with emulsifiers, emollients and preservatives.
  • An optimum topical formulation comprises approximately: 2 wt. % to 60 wt. %, preferably 2 wt. % to 50 wt. %, solubilizer and/or skin permeation enhancer; 2 wt. % to 50 wt. %, preferably 2 wt. % to 20 wt. %, emulsifiers; 2 wt. % to 20 wt. % emollient; and 0.01 to 0.2 wt. % preservative, with the active agent and carrier (e.g., water) making of the remainder of the formulation.
  • the active agent and carrier e.g., water
  • a skin permeation enhancer serves to facilitate passage of therapeutic levels of active agent to pass through a reasonably sized area of unbroken skin.
  • Suitable enhancers include, for example: lower alkanols such as methanol ethanol and 2-propanol; alkyl methyl sulfoxides such as dimethylsulfoxide (DMSO), decylmethylsulfoxide (C.sub.10 MSO) and tetradecylmethyl sulfboxide; pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone and N-(-hydroxyethyl)pyrrolidone; urea; N,N-diethyl-m-toluamide; C.sub.2-C.sub.6 alkanediols; miscellaneous solvents such as dimethyl formamide (DMF), N,N-dimethylacetamide (DMA) and tetrahydrofurfuryl alcohol; and the 1-substi
  • solubilizers include, but are not limited to, the following: hydrophilic ethers such as diethylene glycol monoethyl ether (ethoxydiglycol, available commercially as Transcutol RTM ) and diethylene glycol monoethyl ether oleate (available commercially as Softcutol RTM ); polyethylene castor oil derivatives such as polyoxy 35 castor oil, polyoxy 40 hydrogenated castor oil, etc.; polyethylene glycol, particularly lower molecular weight polyethylene glycols such as PEG 300 and PEG 400, and polyethylene glycol derivatives such as PEG-8 caprylic/capric glycerides (available commercially as Labrasol RTM ); alkyl methyl sulfoxides such as DMSO; pyrrolidones such as 2-pyrrolidone and N-methyl-2-pyrrolidone; and DMA. Many solubilizers can also act as absorption enhancers. A single solubilizer may be incorporated into the formulation, or a
  • Suitable emulsifiers and co-emulsifiers include, without limitation, those emulsifiers and co-emulsifiers described with respect to microemulsion formulations.
  • Emollients include, for example, propylene glycol, glycerol, isopropyl myristate, polypropylene glycol-2 (PPG-2) myristyl ether propionate, and the like.
  • sunscreen formulations e.g., other anti-inflammatory agents, analgesics, antimicrobial agents, antifungal agents, antibiotics, vitamins, antioxidants, and sunblock agents commonly found in sunscreen formulations including, but not limited to, anthranilates, benzophenones (particularly benzophenone-3), camphor derivatives, cinnamates (e.g., octyl methoxycinnamate), dibenzoyl methanes (e.g., butyl methoxydibenzoyl methane), p-aminobenzoic acid (PABA) and derivatives thereof, and salicylates (e.g., octyl salicylate).
  • sunscreen formulations including, but not limited to, anthranilates, benzophenones (particularly benzophenone-3), camphor derivatives, cinnamates (e.g., octyl methoxycinnamate), dibenzoyl methanes (e.g.,
  • the active agent is present in an amount in the range of approximately 0.25 wt. % to 75 wt. % of the formulation, preferably in the range of approximately 0.25 wt. % to 30 wt. % of the formulation, more preferably in the range of approximately 0.5 wt. % to 15 wt. % of the formulation, and most preferably in the range of approximately 1.0 wt. % to 10 wt. % of the formulation.
  • Topical skin treatment compositions can be packaged in a suitable container to suit its viscosity and intended use by the consumer.
  • a lotion or cream can be packaged in a bottle or a roll-ball applicator, or a propellant-driven aerosol device or a container fitted with a pump suitable for finger operation.
  • the composition When the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a lidded jar.
  • the composition may also be included in capsules such as those described in U.S. Pat. No. 5,063,507. Accordingly, also provided are closed containers containing a cosmetically acceptable composition as herein defined.
  • a pharmaceutical formulation for oral or parenteral administration, in which case the formulation may comprises an activating compound-containing microemulsion as described above, but may contain alternative pharmaceutically acceptable carriers, vehicles, additives, etc. particularly suited to oral or parenteral drug administration.
  • an activating compound-containing microemulsion may be administered orally or parenterally substantially as described above, without modification.
  • Phospholipids complexes e.g., resveratrol-phospholipid complexes, and their preparation are described in US2004116386.
  • Methods for stabilizing active components using polyol/polymer microcapsules, and their preparation are described in US20040108608.
  • Processes for dissolving lipophilic compounds in aqueous solution with amphiphilic block copolymers are described in WO 04/035013.
  • Conditions of the eye can be treated or prevented by, e.g., systemic, topical, intraocular injection of a compound described herein, or by insertion of a sustained release device that releases a compound described herein.
  • resveratrol or analog thereof can be prepared in an airtight capusule for oral administration, such as Capsugel from Pfizer, Inc.
  • Cells e.g., treated ex vivo with a compound described herein, can be administered according to methods for administering a graft to a subject, which may be accompanied, e.g., by administration of an immunosuppressant drug, e.g., cyclosporin A.
  • an immunosuppressant drug e.g., cyclosporin A.
  • the reader is referred to Cell Therapy: Stem Cell Transplantation, Gene Therapy, and Cellular Immunotherapy, by G. Morstyn & W. Sheridan eds, Cambridge University Press, 1996; and Hematopoietic Stem Cell Therapy, E. D. Ball, J. Lister & P. Law, Churchill Livingstone, 2000.
  • Toxicity and therapeutic efficacy of compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals.
  • the LD 50 is the dose lethal to 50% of the population).
  • the ED 50 is the dose therapeutically effective in 50% of the population.
  • the dose ratio between toxic and therapeutic effects (LD 50 /ED 50 ) is the therapeutic index.
  • Compounds that exhibit large therapeutic indexes are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds may lie within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC 50 i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • kits e.g., kits for therapeutic purposes or kits for modulating the lifespan of cells or modulating apoptosis.
  • a kit may comprise one or more activating or inhibitory compounds described herein, e.g., in premeasured doses.
  • a kit may optionally comprise devices for contacting c ells with the compounds and instructions for use. Devices include syringes, stents and other devices for introducing a compound into a subject or applying it to the skin of a subject.
  • the substrate used in the assay was a fluorogenic peptide based on the sequence encompassing the p53-K382 acetylation site, a known target of SIRT1 in vivo 20,21,27 . This substrate was preferred over a variety of other fluorogenic peptide substrates that were based on other known HDAC targets ( FIG. 5 ).
  • the small molecule libraries included analogues of nicotinamide, ⁇ -acetyl lysine, NAD + , nucleotides, nucleotide analogues and purinergic ligands.
  • Piceatannol comprises two phenyl groups trans to one another across a linking ethylene moiety.
  • the trans-stilbene ring structures of piceatannol are superimposable on the flavonoid A and B rings of quercetin, with the ether oxygen and carbon-2 of the C ring aligning with the ethylene carbons in piceatannol (see structures, Table 1). Further, the 5, 7, 3′ and 4′ hydroxyl group positions in quercetin can be aligned, respectively, with the 3, 5, 3′ and 4′ hydroxyls of piceatannol.
  • Both quercetin and piceatannol are polyphenols, members of a large and diverse group of plant secondary metabolites that includes flavones, stilbenes, flavanones, isoflavones, catechins (flavan-3-ols), chalcones, tannins and anthocyanidins 30,31 .
  • Polyphenols noteworthy with respect to potential longevity-enhancing effects include resveratrol, a stilbene found in red wine and epigallocatechin gallate (EGCG) from green tea.
  • resveratrol acts only on K m , it could be classified as an allosteric effector of ‘K system’ type 34 . This can imply that only the substrate binding affinity of the enzyme has been altered, rather than a rate-limiting catalytic step.
  • Nicotinamide in contrast to resveratrol, affects the SIRT1V max (note 30% and 36% V max decreases in absence of resveratrol, FIG. 1 d and see ref. 26 ).
  • resveratrol appears to have complex, concentration-dependent effects on the kinetics of SIRT1 ( FIG. 1 d ).
  • Apparent K m for NAD + and acetylated substrate appear to actually be raised by 5 ⁇ M resveratrol when nicotinamide is present.
  • Resveratrol and four other potent sirtuin activators were tested for their effect on yeast lifespan. Due to the potential impediment by the yeast cell wall or plasma membrane and suspected slow oxidation of the compound in the medium, we chose to use a concentration (10 ⁇ M) slightly higher than the optimal resveratrol concentration in vitro. As shown in FIG. 2 b , quercetin and piceatannol had no significant effect on lifespan. In contrast, butein, fisetin and resveratrol increased average lifespan by 31, 55 and 70%, respectively, and all three significantly increased maximum lifespan ( FIG. 2 c ). Concentrations of resveratrol higher than 10 ⁇ M provided no added lifespan benefit and there was no lasting effect of the compound on the lifespan of pre-treated young cells ( FIG. 2 d and data not shown).
  • yeast aging A major cause of yeast aging is thought to stem from the inherent instability of the repetitive rDNA locus 2,5,37-39 . Homologous recombination between rDNA repeats can generate an extrachromosomal circular form of rDNA (ERC) that is replicated until it reaches toxic levels in old cells.
  • ERC extrachromosomal circular form of rDNA
  • Sir2 is thought to extend lifespan by suppressing recombination at the replication fork barrier of rDNA 40 . Consistent with the lifespan extension we observed for resveratrol, this compound reduced the frequency of rDNA recombination by ⁇ 60% ( FIG. 3 c ), in a SIR2-dependent manner ( FIG. 3 d ).
  • Another measure of lifespan in S. cerevisiae is the length of time cells can survive in a metabolically active but nutrient deprived state. Aging under these conditions (i.e. chronological aging) is primarily due to oxidative damage 41 . Resveratrol (10 ⁇ M or 100 ⁇ M) failed to extend chronological lifespan (not shown), indicating that the sirtuin-stimulatory effect of resveratrol may be more relevant in vivo than its antioxidant activity 30,31 .
  • FIG. 4 a A schematic of the assay procedure is depicted in FIG. 4 a .
  • Cells are incubated with media containing the fluorogenic ⁇ -acetyl-lysine substrate, ‘Fluor de Lys’ (FdL).
  • FdL fluorogenic ⁇ -acetyl-lysine substrate
  • This substrate neutral when acetylated, becomes positively charged upon deacetylation and accumulates within cells (see FIG. 6 a ). Lysis of the cells and addition of the non-cell-permeable ‘Developer’ reagent releases a fluorophor specifically from those substrate molecules that have been deacetylated ( FIG. 4 a and see Methods).
  • TSA trichostatin A
  • FIG. 4 b A selection of SIRT1-stimulatory and non-stimulatory polyphenols were tested for their effects on this TSA-insensitive signal.
  • FIG. 4 b Cellular deacetylation signals in the presence of each compound (y-axis, FIG. 4 b ) were plotted against their fold-stimulations of SIRT1 in vitro (x-axis, FIG. 4 b , data from Supplementary Tables 1-3).
  • the in vitro activity roughly corresponded to the cellular signal.
  • Compounds with little or no in vitro activity clustered around the negative control (Group A, FIG. 4 b ).
  • Another grouping, of strong in vitro activators is clearly distanced from the low activity cluster in both dimensions (Group B, FIG. 4 b ).
  • lysine 382 of p53 One known target of SIRT1 in vivo is lysine 382 of p53. Deacetylation of this residue by SIRT1decreases the activity and half-life of p53 20,21,27 .
  • K382 To follow the acetylation status of K382 we generated a rabbit polyclonal antibody that recognizes the acetylated form of K382 (Ac-K382) on Western blots of whole cell lysates. As a control we showed that the signal was specifically detected in extracts from cells exposed to ionizing radiation ( FIG. 4 c ), but not in extracts from cells lacking p53 or where arginine had been substituted for lysine 382 (data not shown).
  • U2OS osteosarcoma cells were pre-treated for 4 hours with resveratrol (0.5 and 50 ⁇ M) and exposed to UV radiation.
  • resveratrol 0.5 and 50 ⁇ M
  • concentrations of resveratrol >50 ⁇ M
  • the ability of low concentrations of resveratrol to promote deacetylation of p53 was diminished in cells expressing a dominant-negative SIRT1 allele (H363Y) ( FIG.
  • sirtuin activators all of which are plant polyphenols. These compounds can dramatically stimulate sirtuin activity in vitro and promote effects consistent with increased sirtuin activity in vivo.
  • resveratrol promotes SIRT1-mediated p53 deacetylation of K382.
  • yeast the effect of resveratrol on lifespan is as great as any longevity-promoting genetic manipulation 6 and has been linked convincingly to the direct activation of Sir2.
  • Sirtuins have been found in diverse eukaryotes, including fungi, protozoans, metazoans and plants 46,47 , and likely evolved early in life's history 1 . Plants are known to produce a variety of polyphenols, including resveratrol, in response to stresses such as dehydration, nutrient deprivation, UV radiation and pathogens 48,49 . Therefore it is plausible that these compounds may be synthesized to regulate a sirtuin-mediated plant stress response. This would be consistent with the recently discovered relationship between environmental stress and Sir2 activity in yeast 6 .
  • sirtuins from fungi and animals because they mimic an endogenous activator, as is the case for the opiates/endorphins, cannabinols/endocannabinoids and various polyphenols with estrogen-like activity 30,31 .
  • animal and fungal sirtuins may have retained or developed an ability to respond to these plant metabolites because they are a useful indicator of a deteriorating environment and/or food supply.
  • SIRT1 and GST-tagged recombinant Sir2 were prepared as previously described 26 . From 0.1 to 1 ⁇ g of SIRT1 and 1.5 ⁇ g of Sir2 were used per deacetylation assay (in 50 ⁇ l total reaction) as previously described 26 . SIRT1 assays and certain of those for Sir2 employed the p53-382 acetylated substrate (‘Fluor de Lys-SIRT1’, BIOMOL) rather than FdL.
  • p53-382 acetylated substrate ‘Fluor de Lys-SIRT1’, BIOMOL
  • DMSO dimethylsulfoxide
  • HeLa cells were grown and the cellular deacetylation assays were performed and read, as above, but in full-volume 96-well microplates (Corning Costar 3595). Unless otherwise indicated all initial rate measurements were means of three or more replicates, obtained with single incubation times, at which point 5% or less of the substrate initially present had been deacetylated. Calculation of net fluorescence increases included subtraction of a blank value, which in the case of Sir2 was obtained by omitting the enzyme from the reaction and in the case of SIRT1 by adding an inhibitor (200 ⁇ M suramin or 1 mM nicotinamide) to the reaction prior to the acetylated substrate.
  • an inhibitor 200 ⁇ M suramin or 1 mM nicotinamide
  • yeast strains were grown at 30° C. in complete yeast extract/bactopeptone, 2.0% (w/v) glucose (YPD) medium except where stated otherwise. Calorie restriction was induced in 0.5% glucose.
  • Synthetic complete (SC) medium consisted of 1.67% yeast nitrogen base, 2% glucose, 40 mg/litre each of auxotrophic markers. SIR 2 was integrated in extra copy and disrupted as described 5 . Other strains are described elsewhere 26 .
  • HEK 293 cells were cultured adherently in Dulbecco's Modified Eagle's Medium (DMEM) containing 10% fetal calf serum (FCS) with 1.0% glutamine and 1.0% penecillin/streptomycin.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FCS fetal calf serum
  • HEK 293 overexpressing dominant negative SIRT1H363Y was a gift of R. Frye (U. Pittsburgh).
  • Lifespan measurements were performed using PSY316AT MAT ⁇ as previously described 35 . All compounds for lifespan analyses were dissolved in 95% ethanol and plates were dried and used within 24 hours. Prior to lifespan analysis, cells were pre-incubated on their respective media for at least 15 hours. Following transfer to a new plate, cells were equilibrated on the medium for a minimum of 4 hours prior to micro-manipulating them. At least 30 cells were examined per experiment and each experiment was performed at least twice. Statistical significance of lifespan differences was determined using the Wilcoxon rank sum test. Differences are stated to be significant when the confidence is higher than 95%.
  • Ribosomal DNA silencing assays using the URA3 reporters were performed as previously described 26 .
  • Ribosomal DNA recombination frequencies were determined by plating W303AR cells 37 on YPD medium with low adenine/histidine and counting the fraction of half-red sectored colonies using Bio-Rad Quantity One software as previously described 35 . At least 6000 cells were analyzed per experiment and all experiments were performed in triplicate. All strains were pre-grown for 15 hours with the relevant compound prior to plating.
  • Recombinant Sir2-GST was expressed and purified from E. coli as previously described except that lysates were prepared using sonication 26 .
  • Recombinant SIRT1 from E. coli was prepared as previously described 26 .
  • Polyclonal antiserum against p53-AcK382 was generated using an acetylated peptide antigen as previously described 20 , with the following modifications.
  • Anti-Ac-K382 antibody was affinity purified using non-acetylated p53-K382 peptides and stored in PBS at ⁇ 70° C. and recognized an acetylated but not a non-acetylated p53 peptide.
  • Yeast Sir2 and human SIRT1 are very homologous and differ from human SIRT2 by the addition of an N-terminal domain that is absent in SIRT2.
  • the effect of resveratrol was assayed on human recombinant SIRT2 as follows. Human recombinant SIRT2 was incubated at a concentration of 1.25 ⁇ g/well with 25 ⁇ M of Fluor de Lys-SIRT2 (BIOMOL cat. # KI-179) and 25 ⁇ M NAD + for 20 minutes at 37° C., as described above. The results, which are shown in FIG. 7 , indicate that, in contrast to SIRT1, increasing concentrations of resveratrol decrease SIRT2 activity.
  • SIRT1 and SIRT2 based on the difference in structure of SIRT1 and SIRT2, i.e., the absence of an N-terminal domain (see FIG. 8 ), it is believed that the N-terminal domain of SIRT1 and Sir2 is necessary for activation by the compounds described herein. In particular, it is likely that the activator compounds described herein interact with the N-terminal portion of sirtuins.
  • the N-terminal portion of SIRT1 that is necessary for the action of the compounds is from about amino acid 1 to about amino acid 176, and that of Sir2 is from about amino acid 1 to about amino acid 175.

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