WO2015138607A1 - Compositions and methods comprising sirtuins - Google Patents

Compositions and methods comprising sirtuins Download PDF

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Publication number
WO2015138607A1
WO2015138607A1 PCT/US2015/019971 US2015019971W WO2015138607A1 WO 2015138607 A1 WO2015138607 A1 WO 2015138607A1 US 2015019971 W US2015019971 W US 2015019971W WO 2015138607 A1 WO2015138607 A1 WO 2015138607A1
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WO
WIPO (PCT)
Prior art keywords
sirtuin
cell
composition
sirtuins
cells
Prior art date
Application number
PCT/US2015/019971
Other languages
French (fr)
Inventor
Joseph D. Ceccoli
Brian R. COSTELLO
Sanford R. Simon
Original Assignee
Biocogent, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biocogent, Llc filed Critical Biocogent, Llc
Priority to CN201580023980.XA priority Critical patent/CN106573156A/en
Priority to EP15760722.7A priority patent/EP3116600A4/en
Publication of WO2015138607A1 publication Critical patent/WO2015138607A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64Proteins; Peptides; Derivatives or degradation products thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64Proteins; Peptides; Derivatives or degradation products thereof
    • A61K8/66Enzymes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/08Anti-ageing preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74Biological properties of particular ingredients
    • A61K2800/78Enzyme modulators, e.g. Enzyme agonists

Definitions

  • the present technology relates to cosmetic and pharmaceutical compositions useful for controlling the rate of cell destruction and minimizing the appearance of aging.
  • the present technology relates to compositions and methods comprising a combination of a sirtuin activator with a sirtuin-offsetting agent.
  • Sirtuins are a class of protein deacetylase enzymes that require nicotaminde adenine dinucleotide (NAD) as a cofactor in deacetylating lysine residues in target proteins.
  • NAD nicotaminde adenine dinucleotide
  • Acetylation and deacetylation of certain amino acids is a post-translational modification that controls the activities of some target proteins.
  • the targets that were initially discovered were the histone proteins that package DNA in cell nuclei; thus, these enzymes are commonly referred to as histone deaceteylases (HDACs), despite the fact that many non-histone target proteins have been discovered subsequent to the initial discoveries.
  • HDACs histone deaceteylases
  • Sirtuins have been found to influence various biological phenomena, including cellular stress responses such as DNA repair, replicative senescence and apoptosis (suicide or "programmed cell death” response that cells typically undergo following serious or irreparable damage). Specifically, sirtuins have been found to delay apoptosis of damaged cells, thereby slowing down or eliminating their destruction.
  • sirtuins may slow down aging may possess an inherently dangerous side effect - specifically, the apoptic response protects organisms by eliminating damaged cells that could otherwise become genetically unstable and lose normal growth controls and proper differentiated function.
  • sirtuins might allow them to escape normal checks, resulting in overgrowth of tissues with abnormal progeny cells, which would compromise proper tissue function and possibly even imperil organism survival.
  • the present technology is directed to compositions comprising a sirtuin activator (also referred to herein as a sirtuin stimulator) as well as a sirtuin-offsetting agent.
  • a sirtuin activator also referred to herein as a sirtuin stimulator
  • a sirtuin-offsetting agent also referred to herein as a sirtuin stimulator
  • the present technology is directed to methods of formulating a composition, or of optimizing the efficacy of a composition for a patient, or of optimizing cell maintenance in a patient, the methods comprising selecting a sirtuin stimulator having a known quantitative prolonging effect on a cell, and selecting a sirtuin- offsetting agent having a known quantitative opposite effect on the cell, and optimizing the balance between the two effects based on a known desired ultimate effect on the cell.
  • the present technology is directed to a method of prolonging the life of a cell and simultaneously avoiding proliferation of cell damage, the method comprising the steps of: stimulating Sirtl activity in the cell; and inhibiting a non- sirtuin HDAC in the cell.
  • the present technology is directed to methods of treating a patient, or methods of reducing the appearance of aging in a patient, or methods of optimizing cell maintenance in a patient, comprising applying a composition including sirtuin stimulator and a sirtuin-offsetting agent to the body of a patient.
  • FIG. 1 shows the experimental results of testing regarding the ability of prototype formulation to enhance the apoptotic response of human keratinocytes that had been exposed to DNA-damaging UV radiation.
  • Sirtuin function appears to be affected by metabolic state. More broadly, sirtuins appear to help individual cells (and therefore organisms overall) to survive stress, likely by effecting a delay in the apoptotic response, so as to allow cells the time and opportunity to repair whatever stress-related damage they may suffer. It is presumed that any lengthening of lifetime of a cell that results from enhanced sirtuin activity is a consequence of delayed apoptosis of cells under stressful conditions. The cells of greatest interest in this regard would be stem cells. It is believed that the anti-aging effect of sirtuins is at least partly dependent on maintaining the regenerative capacity of such cells and of the tissues they support.
  • sirtuins may present an inherent danger. For example, they may impair the normal apoptic response that would otherwise eliminate damaged cells, and that by doing so, could encourage overgrowth of abnormal cells and tissues. Further, molecular consequences of sirtuin stimulation, such as down regulation of the tumor suppressor gene p53, may also be a cause for concern about enhancing sirtuin function.
  • sirtuin-offsetting agents In order to offset the negative effects of sirtuins, "sirtuin-offsetting” agents have been proposed.
  • a “sirtuin-offsetting” agent (or “sirtuin-offsetter”) is one that at least partly counteracts the effects of sirtuin as it relates to prolonging cell life.
  • sirtuin-offsetting agents will be discussed in greater detail herein.
  • Class 1, 2 and 4 HDACs have a fundamentally different molecular mechanism and different overall biological effects from the sirtuins, which are Class 3 HDACs.
  • These "non-sirtuin” HDACs do not use NAD as a co-substrate. They also differ from the sirtuins in other ways, e.g., in terms of their target proteins and regulation. Anti-aging or life extension effects have not been demonstrated as consequences of stimulation of non-sirtuin HDACs.
  • HDACi's Non-sirtuin HDAC inhibitors
  • HDACi's have been found to be effective at inhibiting proliferation and promoting differentiation or apoptosis and may be useful for cancer treatment, because, among other reasons, in cancer cells many important genes are abnormally repressed by extreme levels of histone deacetylation; thus, the genes that would otherwise be controlling proliferation and initiating differentiation or apoptosis may be inactivated by the non-sirtuin HDACs.
  • the present technology is directed to compositions that both stimulate Sirtl activity (the human sirtuin that is the homo log of yeast
  • Sir2 in order to obtain anti-aging benefits, and also simultaneously inhibit sirtuin-offsetting agents such as, e.g., the non-sirtuin HDACs to the extent sufficient to avoid poorly controlled growth of damaged cells that could eventually compromise tissue function.
  • sirtuin-offsetting agents such as, e.g., the non-sirtuin HDACs
  • compositions herein provide the dual effect of sirtuin stimulation and inhibition of HDAC (protein (histone) deacetylases).
  • embodiments is balanced in order to optimize the cell maintenance of the patient.
  • cell maintenance means the balance of prolonging the life of cells without over- prolonging that can lead to proliferation of damaged tissue and harm to the patient.
  • the present technology provides methods for optimizing the preservation of body cells by balancing the Sirtl activity of a sirtuin composition with the inhibitory activity of an HDACi.
  • compositions herein may comprise either a sirtuin itself, or a sirtuin stimulator, for example, resveratrol.
  • the compositions are particularly useful for applying to the skin of a patient.
  • compositions discussed herein may be in any form that can be applied to the body of a patient; for example, to the skin.
  • they may be cosmetically or pharmaceutically acceptable forms that can be incorporated into lotions, creams, sprays, gels, serums, liquids, suspensions or the like.
  • Encapsulation technologies such as liposomes, micellar constructs and the like are also contemplated.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Birds (AREA)
  • Epidemiology (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present technology relates to cosmetic and pharmaceutical compositions useful for controlling the rate of cell destruction and minimizing the appearance of aging. In particular, the present technology relates to compositions and methods related to a combination of a sirtuin activator with a sirtuin-offsetting agent.

Description

TITLE
Compositions and Methods Comprising Sirtuins
BACKGROUND
[0001] The present technology relates to cosmetic and pharmaceutical compositions useful for controlling the rate of cell destruction and minimizing the appearance of aging. In particular, the present technology relates to compositions and methods comprising a combination of a sirtuin activator with a sirtuin-offsetting agent.
[0002] Sirtuins are a class of protein deacetylase enzymes that require nicotaminde adenine dinucleotide (NAD) as a cofactor in deacetylating lysine residues in target proteins. Acetylation and deacetylation of certain amino acids is a post-translational modification that controls the activities of some target proteins. The targets that were initially discovered were the histone proteins that package DNA in cell nuclei; thus, these enzymes are commonly referred to as histone deaceteylases (HDACs), despite the fact that many non-histone target proteins have been discovered subsequent to the initial discoveries.
[0003] Sirtuins have been found to influence various biological phenomena, including cellular stress responses such as DNA repair, replicative senescence and apoptosis (suicide or "programmed cell death" response that cells typically undergo following serious or irreparable damage). Specifically, sirtuins have been found to delay apoptosis of damaged cells, thereby slowing down or eliminating their destruction.
[0004] There is concern that the mechanism through which sirtuins may slow down aging may possess an inherently dangerous side effect - specifically, the apoptic response protects organisms by eliminating damaged cells that could otherwise become genetically unstable and lose normal growth controls and proper differentiated function. By having the effect of delaying apoptosis of damaged cells, sirtuins might allow them to escape normal checks, resulting in overgrowth of tissues with abnormal progeny cells, which would compromise proper tissue function and possibly even imperil organism survival.
[0005] Thus, a need exists for "safe" sirtuin compounds and methods - specifically, compositions that harness the anti-aging benefits of sirtuins without the undesirable side effects; as well as methods of optimizing such compositions and of using them in anti-aging applications for patients.
SUMMARY OF THE DISCLOSED TECHNOLOGY
[0006] In certain embodiments, the present technology is directed to compositions comprising a sirtuin activator (also referred to herein as a sirtuin stimulator) as well as a sirtuin-offsetting agent.
[0007] In certain embodiments, the present technology is directed to methods of formulating a composition, or of optimizing the efficacy of a composition for a patient, or of optimizing cell maintenance in a patient, the methods comprising selecting a sirtuin stimulator having a known quantitative prolonging effect on a cell, and selecting a sirtuin- offsetting agent having a known quantitative opposite effect on the cell, and optimizing the balance between the two effects based on a known desired ultimate effect on the cell.
[0008] In certain embodiments, the present technology is directed to a method of prolonging the life of a cell and simultaneously avoiding proliferation of cell damage, the method comprising the steps of: stimulating Sirtl activity in the cell; and inhibiting a non- sirtuin HDAC in the cell.
[0009] In certain embodiments, the present technology is directed to methods of treating a patient, or methods of reducing the appearance of aging in a patient, or methods of optimizing cell maintenance in a patient, comprising applying a composition including sirtuin stimulator and a sirtuin-offsetting agent to the body of a patient. BRIEF DESCRIPTION OF THE DRAWING
[0010] FIG. 1 shows the experimental results of testing regarding the ability of prototype formulation to enhance the apoptotic response of human keratinocytes that had been exposed to DNA-damaging UV radiation.
DETAILED DESCRIPTION
[0011] Sirtuin function appears to be affected by metabolic state. More broadly, sirtuins appear to help individual cells (and therefore organisms overall) to survive stress, likely by effecting a delay in the apoptotic response, so as to allow cells the time and opportunity to repair whatever stress-related damage they may suffer. It is presumed that any lengthening of lifetime of a cell that results from enhanced sirtuin activity is a consequence of delayed apoptosis of cells under stressful conditions. The cells of greatest interest in this regard would be stem cells. It is believed that the anti-aging effect of sirtuins is at least partly dependent on maintaining the regenerative capacity of such cells and of the tissues they support.
[0012] However, as mentioned above, there is concern that the anti-aging
mechanism(s) of sirtuins may present an inherent danger. For example, they may impair the normal apoptic response that would otherwise eliminate damaged cells, and that by doing so, could encourage overgrowth of abnormal cells and tissues. Further, molecular consequences of sirtuin stimulation, such as down regulation of the tumor suppressor gene p53, may also be a cause for concern about enhancing sirtuin function.
[0013] In order to offset the negative effects of sirtuins, "sirtuin-offsetting" agents have been proposed. As used herein, a "sirtuin-offsetting" agent (or "sirtuin-offsetter") is one that at least partly counteracts the effects of sirtuin as it relates to prolonging cell life.
Examples of "sirtuin-offsetting" agents will be discussed in greater detail herein. For example, it has been discovered herein that the decreased activity of certain non-sirtuin HDACs may provide a safeguard. In particular, in certain embodiments of the technology described herein, it has been shown that Class 1, 2 and 4 HDACs have a fundamentally different molecular mechanism and different overall biological effects from the sirtuins, which are Class 3 HDACs. These "non-sirtuin" HDACs do not use NAD as a co-substrate. They also differ from the sirtuins in other ways, e.g., in terms of their target proteins and regulation. Anti-aging or life extension effects have not been demonstrated as consequences of stimulation of non-sirtuin HDACs.
[0014] It has been found herein that these HDACs can be targeted for antiinflammatory benefits and to prevent proliferation of genetically damaged or unstable cells. Non-sirtuin HDAC inhibitors (HDACi's) have been found to be effective at inhibiting proliferation and promoting differentiation or apoptosis and may be useful for cancer treatment, because, among other reasons, in cancer cells many important genes are abnormally repressed by extreme levels of histone deacetylation; thus, the genes that would otherwise be controlling proliferation and initiating differentiation or apoptosis may be inactivated by the non-sirtuin HDACs.
[0015] Therefore, in certain embodiments, the present technology is directed to compositions that both stimulate Sirtl activity (the human sirtuin that is the homo log of yeast
Sir2) in order to obtain anti-aging benefits, and also simultaneously inhibit sirtuin-offsetting agents such as, e.g., the non-sirtuin HDACs to the extent sufficient to avoid poorly controlled growth of damaged cells that could eventually compromise tissue function.
[0016] In certain embodiments, the compositions herein provide the dual effect of sirtuin stimulation and inhibition of HDAC (protein (histone) deacetylases).
[0017] Thus, in certain embodiments, the relative amounts of sirtuin (or sirtuin stimulator) and sirtuin-offsetting agent in a composition according to the present
embodiments is balanced in order to optimize the cell maintenance of the patient. As used herein, "cell maintenance" means the balance of prolonging the life of cells without over- prolonging that can lead to proliferation of damaged tissue and harm to the patient.
[0018] In certain embodiments, the present technology provides methods for optimizing the preservation of body cells by balancing the Sirtl activity of a sirtuin composition with the inhibitory activity of an HDACi.
[0019] Data have been developed herein that demonstrate, in in vitro studies, the ability to inhibit preferentially the growth of cells that are genetically damaged by exposure to UV light using a formulation that includes activity for inhibiting non- sirtuin HDACs. Cells were subjected to a sub-lethal dose of UV, but by applying a composition in accordance with certain embodiments herein, inhibition of further growth was shown. The effect was to provide time for the cells to repair, and if not, hold them in a quasi-senescent state until they expired.
[0020] In certain embodiments, the compositions herein may comprise either a sirtuin itself, or a sirtuin stimulator, for example, resveratrol. In certain embodiments, the compositions are particularly useful for applying to the skin of a patient.
[0021] The compositions discussed herein may be in any form that can be applied to the body of a patient; for example, to the skin. In certain embodiments, they may be cosmetically or pharmaceutically acceptable forms that can be incorporated into lotions, creams, sprays, gels, serums, liquids, suspensions or the like. Encapsulation technologies such as liposomes, micellar constructs and the like are also contemplated.

Claims

CLAIMS What is claimed:
1. A composition comprising:
(a) a sirtuin stimulator; and
(b) a sirtuin-offsetting agent.
2. The composition of claim 1, wherein the amounts of (a) and (b) are selected to
optimize the cell maintenance in a patient.
3. The composition of claim 1, wherein (b) comprises a non-sirtuin histone deacetylase inhibitor (HDACi).
4. A cosmetic composition comprising:
(c) a first composition that comprises a sirtuin stimulator; and
(d) a second composition that comprises a sirtuin-offsetting agent.
5. The composition of claim 4 in the form of a gel, cream, spray, suspension, liquid, paste or lotion.
6. A method of formulating a composition, the method comprising:
(a) selecting a sirtuin or sirtuin stimulator having a known quantitative
prolonging effect on a cell's life; and
(b) selecting a sirtuin-offsetting agent having a known quantitative opposite effect on the cell's life; and
(c) optimizing the balance between the two effects based on a known desired ultimate effect on the cell.
7. A method of prolonging the life of a cell and simultaneously avoiding proliferation of cell damage, the method comprising the steps of:
(a) stimulating Sirtl activity in the cell; and
(b) inhibiting a non-sirtuin HDAC in the cell.
PCT/US2015/019971 2014-03-11 2015-03-11 Compositions and methods comprising sirtuins WO2015138607A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201580023980.XA CN106573156A (en) 2014-03-11 2015-03-11 Compositions and methods comprising sirtuins
EP15760722.7A EP3116600A4 (en) 2014-03-11 2015-03-11 Compositions and methods comprising sirtuins

Applications Claiming Priority (2)

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US201461951256P 2014-03-11 2014-03-11
US61/951,256 2014-03-11

Publications (1)

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WO2015138607A1 true WO2015138607A1 (en) 2015-09-17

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050096256A1 (en) * 2003-07-01 2005-05-05 President And Fellows Of Harvard College Compositions for manipulating the lifespan and stress response of cells and organisms
US20100144885A1 (en) * 2006-09-29 2010-06-10 The Board Of Trustees Of The University Of Illinois Histone acetyl transferase activators and histone deacetylase inhibitors in the treatment of alcoholism
US20130102009A1 (en) * 2010-04-15 2013-04-25 Han Dai Sirtuin activators and activation assays
US20140017341A1 (en) * 2010-10-19 2014-01-16 Brigitte Gourlaouen Composition and method for treating fat tissues and inflammatory processes

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2858932B1 (en) * 2003-08-22 2009-10-30 Oreal COMPOSITION FOR CONTROLLING THE DEGRADATION OF INDUCED COLLAGEN FIBERS IN NATURAL SOLAR EXPOSURE CONDITIONS
FR2883754B1 (en) * 2005-04-01 2008-04-18 Soc Extraction Principes Actif USE OF COMPOUNDS INDUCING THE SYNTHESIS OF SIRT PROTEINS IN OR FOR THE PREPARATION OF A COSMETIC OR PHARMACEUTICAL COMPOSITION
FR2906139A1 (en) * 2006-09-21 2008-03-28 Davines France Sarl Binary treatment to fight against the signs of skin aging and to eliminate undesirable cell growth, comprises applying a night formulation to stimulate and/or activate sirtuins and applying a day formulation to inhibit the same sirtuins
WO2010056831A2 (en) * 2008-11-12 2010-05-20 Nupotential, Inc. Reprogramming a cell by inducing a pluripotent gene through use of an hdac modulator

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050096256A1 (en) * 2003-07-01 2005-05-05 President And Fellows Of Harvard College Compositions for manipulating the lifespan and stress response of cells and organisms
US20100144885A1 (en) * 2006-09-29 2010-06-10 The Board Of Trustees Of The University Of Illinois Histone acetyl transferase activators and histone deacetylase inhibitors in the treatment of alcoholism
US20130102009A1 (en) * 2010-04-15 2013-04-25 Han Dai Sirtuin activators and activation assays
US20140017341A1 (en) * 2010-10-19 2014-01-16 Brigitte Gourlaouen Composition and method for treating fat tissues and inflammatory processes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3116600A4 *

Also Published As

Publication number Publication date
EP3116600A4 (en) 2017-08-23
CN106573156A (en) 2017-04-19
EP3116600A1 (en) 2017-01-18

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