COMPOSITIONS AND METHODS FOR SLOWING DOWN AGING AND EXTENDING LIFESPAN

This application claims the benefit of U.S. Provisional Application No. 63/339,107, filed May 6, 2022, the contents of which are incorporated herein by reference.

Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.

Field of the Invention

The present invention relates to compositions and methods for ameliorating one or more aging hallmarks in a subject.

Background of the Invention

Aging, in the physical sense, is characterized by the accumulation of molecular and cellular damage. This damage leads to a deterioration of physiological function and proper homeostasis, and increases the risk of frailty, infirmity, disability, aging-related diseases, and eventually death.

For a long time, one of the main causes of aging was considered to be oxidative damage, as promoted and promulgated by Denham Harman's free radical theory of aging (1). According to this dated theory, antioxidants have the ability to neutralize free radicals, thus slowing the aging process. Yet, research shows that most antioxidants do not slow down aging, and could even shorten lifespan or undo the beneficial effects of exercise (2-6). However, in the last 15 years, a better understanding of the aging process has emerged, leading to an understanding of various mechanisms and causes of aging. These include, for example, epigenetic dysregulation, epitranscriptomic dysregulation, a decline in proteinases (proteotoxicity), mitochondrial dysfunction, genomic damage, telomere shortening and attrition, transcriptom ic dysregulation, lysosomal dysfunction and crosslinking contributing to the formation of senescent cells, a decline in stem cell function and numbers, changes of the extracellular milieu (e.g., a change to a pro-inflammatory milieu), and changes in intercellular communication. These changes contribute to the aging phenotype and an increased risk and an occurrence of aging-related diseases like heart disease, neurodegenerative diseases (e.g., Alzheimer's disease or vascular dementia), osteoporosis, osteoarthritis, macular degeneration, kidney dysfunction, and others.

There remains an unmet need for superior formulations to ameliorate these hallmarks of aging.

Summary of the Invention

This invention provides a composition comprising (i) an HDAC inhibitor; (ii) a retinoid; (iii) ascorbic acid or an ascorbic acid equivalent; and (iv) alpha-ketoglutarate or an alpha-ketoglutarate equivalent.

This invention also provides a pharmaceutical composition comprising (i) the present composition and (ii) a pharmaceutically acceptable carrier.

This invention provides a method for ameliorating at least one aging hallmark in a subject comprising administering to the subject the present composition, wherein the aging hallmark is selected from the group consisting of genomic instability, telomere attrition, an epigenetic alteration, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, transcriptom ic dysregulation, crosslinking, and altered intercellular communication.

This invention further provides a method for ameliorating at least one aging hallmark in a cell comprising contacting the cell with the present composition, wherein the aging hallmark is selected from the group consisting of genomic instability, telomere attrition, an epigenetic alteration, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, transcriptom ic dysregulation, crosslinking, and altered intercellular communication. Finally, this invention also provides an article of manufacture comprising the present composition, wherein (i) the butyrate and/or butyrate equivalent and (ii) other components of the composition are in separate compartments.

Detailed Description of the Invention

This invention provides compositions and methods for ameliorating an array of aging hallmarks in a subject.

Definitions

In this application, certain terms are used which shall have the meanings set forth as follows.

As used herein, the term “adenylyl cyclase activator” includes, without limitation, forskolin, Coleus forskohlii extracts, Coleus Forskohlii standardized to 10% forskolin, Coleus Forskohlii standardized to 20% forskolin, and Coleus forskohlii standardized to 1 % to 99% forskolin.

As used herein, “administer”, with respect to an agent, means to deliver the agent to a subject’s body via any known method. Specific modes of administration include, without limitation, oral, sublingual, parenteral, intraperitoneal, intravenous, intra-arterial, transdermal, intramuscular, rectal, transbuccal, intranasal, liposomal, via inhalation, vaginal, intraocular, local (e.g., via catheter or stent), subcutaneous, intrathecal, or intra-adiposal administration. Preferably, the present compositions are administered orally.

In addition, in this invention, the various compositions can be formulated using one or more routinely used pharmaceutically acceptable carriers. Such carriers are well known to those skilled in the art. For example, oral delivery systems include, for example, tablets, capsules, and powders (such as powders that can be added to water to form a drinkable formulation). These can contain excipients such as binders (e.g., hydroxypropylmethyl-cellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc). In one embodiment, the oral delivery system is a powder and comprises one or more of xylitol, erythritol, malic acid, flavoring, silicon dioxide, calcium silicate, and rebaudioside A.

As used herein, the term “aging hallmark” (used synonymously with “age-related hallmark” and “hallmark related to aging”) includes, without limitation, any of genomic instability, telomere attrition, an epigenetic alteration, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, transcriptom ic dysregulation, crosslinking, and altered intercellular communication. These hallmarks are known, and reviewed in depth by C. Lopez Otin, et al. (7).

As used herein, the term “alpha-ketoglutarate equivalent” includes, without limitation, alpha-ketoglutarate salts (e.g., calcium alpha-ketoglutarate, potassium alpha- ketoglutarate, and sodium alpha-ketoglutarate), amino acid forms of alpha-ketoglutarate (e.g., arginine-alpha-ketoglutarate), and alpha-ketoglutaric acid.

As used herein, the term “ameliorate”, when used in reference to an aging hallmark, includes, without limitation, (i) slowing, stopping, reversing, or preventing the hallmark's progression, (ii) slowing, stopping, reversing, or preventing the progression of the hallmark’s symptoms, (iii) preventing or reducing the likelihood of the hallmark’s recurrence, and/or (iv) preventing or reducing the likelihood that the hallmark’s symptoms will recur. In one embodiment, treating a subject afflicted with an aging hallmark means (i) reversing the hallmark's progression, ideally to the point of eliminating the hallmark, and/or (ii) reversing the progression of the hallmark’s symptoms, ideally to the point of eliminating the symptoms.

As used herein, the term “B vitamin” includes, without limitation, thiamin (vitamin B1 ), riboflavin (vitamin B2), niacin (vitamin B3), nicotinamide, nicotinamide riboside, choline, carnitine, adenine (vitamin B4), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), pyridoxal, pyridoxamine, biotin (vitamin B7), inositol (vitamin B8), myo-inositol, adenosine monophosphate (AMP), folate, folic acid (vitamin B9), methyl folate, cobalamin (vitamin B12), cyanocobalamin, methylcobalamin, choline, dimethylglycine (DMG) (vitamin B16), trimethylglycine or betaine (TMG), benfotiamine, and phosphatidylcholine. As used herein, “BMP modifiers” include, without limitation, flavonoids, flavones, and chaicone compounds. Additional examples of BMP modifiers include, without limitation, isoliquiritigenin, hydroxychaicone, apigenin, luteolin, diosmetin, hydroxyflavone, dihydroxyflavone, fisetin, quercetin, resveratrol, pterostilbene, salidroside, vitamin K, vitamin K1 , vitamin K2, vitamin K-derivatives, vitamin K precursors, and menaquinone.

As used herein, “butyrate equivalent” includes, without limitation, a histone deacetylase (HDAC) inhibitor other than butyrate. These include, for example, butyric acid, butyrate salts (e.g., calcium butyrate, sodium butyrate, potassium butyrate, ammonium butyrate, and lithium butyrate), tributyrate, tributyrin, butyrin, glycerin tri-butyrate, phenylbutyrate, methylbutyrate, sodium phenylbutyrate, glycerol esters of butyric acid, amide derivatives of butyric acid, [3-hydroxybutyrate (BHB), [3-hydroxybutyric acid, [3- hydroxybutyrate (BHB)-derivatives, [3-hydroxybutyrate salts (e.g., potassium [3- hydroxybutyrate, sodium [3-hydroxybutyrate, calcium [3-hydroxybutyrate, and magnesium [3-hydroxybutyrate), [3-hydroxybutyrate-based ketones, [3-hydroxybutyrate- based ketone esters, [3-hydroxybutyrate-based esters, [3-hydroxybutyrate esters, [3- hydroxybutyrate butanediol, [3-hydroxybutyrate glycerol, R-1 ,3-butanediol-R-3- hydroxybutyrate, butanediol, R-1 ,3-butandediol, R-3-hydroxybutyrate, bis-hexanoyl-1 ,3- butanediol, [3-ketopentanoate, [3-hydroxypentanoate, valeric acid, valerian-extract containing valeric acid, valerian root, valproate, valproic acid, an alkyl carboxylic acid, an alkyl carboxylic acid-derivative, precursors of butyrate and butyric acid (e.g., fibers such as inulin, fructo-oligosaccharides (FOS), resistant starch, Hi-maize, potato starch, arabinoxylan, and beta-glucans), and combinations thereof. Butyrate equivalent also includes, without limitation, another alkane carboxylic acid or alkane carboxylic acid derivative (e.g., propionic acid or other short chain fatty acids such as formic acid, acetic acid, isovaleric acid, valeric acid, isocaproic acid, caproic acid, caprylic acid, lactic acid, succinic acid, pyruvic acid, and combinations thereof).

As used herein, the term “calciferol” includes, without limitation, cholecalciferol, ergocalciferol, calcifediol, calcitriol, vitamin D, vitamin D derivatives, calciferol derivatives, secosteroids, and secosteroid derivatives.

As used herein, the term “epigenetic facilitator” includes, without limitation, ascorbic acid (i.e. , vitamin C), and ascorbic acid equivalents (e.g., ascorbyl palmitate, tetrahexyldecyl ascorbate, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, sodium ascorbate, calcium ascorbate, ascorbic acid polypeptide, ascorbic acid peptide, ascorbyl glucosamine, ascorbyl glucoside, tetrahexyldecyl ascorbate, and ascorbyl tetraisopalmitate).

As used herein, the term “glycogen synthase kinase inhibitor”, also referred to as “GSK- I”, includes, without limitation, lithium, paullones (e.g., kenpaullone, cazpaullone, alsterpaullone, and other paullone derivatives), sulforaphane, valproate, valproic acid, butyrate, butyric acid, butyrate derivatives, hymenialdisine, debromohymenialdisine, furanoterpenoids, meridianine, carboline, ircinal A, a [3-carboline alkaloid, a [3-carboline alkaloid derivative, palinurin, CHIRs (e.g., CHIR99021 , CHIR998014, CHIR98023, and CHIR999021 derivatives), manzamine alkaloids, minerals (e.g., copper and zinc), aloisine A, melatonin, luteolin, astaxanthin, curcumin, curcuminoids, curcumin- derivatives, flavonoids (including, without limitation, flavonoids with the OH groups on the B-ring (e.g., sterubin and eriodictyol)), apigenin, berberine, cinnamon, cinnamon extract, resveratrol, pterostilbene, quercetin, and fisetin.

As used herein, the term “histone deacetylase inhibitor”, also referred to as “HDAC-I” and “HDAC inhibitor”, includes, without limitation, butyrate, butyric acid, butyrate salts (e.g., calcium butyrate, sodium butyrate, potassium butyrate, ammonium butyrate, and lithium butyrate), tributyrate, tributyrin, butyrin, glycerin tri-butyrate, phenylbutyrate, methylbutyrate, sodium phenylbutyrate, glycerol esters of butyric acid, amide derivatives of butyric acid, [3-hydroxybutyrate (BHB), [3-hydroxybutyric acid, [3- hydroxybutyrate (BHB)-derivatives, [3-hydroxybutyrate salts (e.g., potassium [3- hydroxybutyrate, sodium [3-hydroxybutyrate, calcium [3-hydroxybutyrate, and magnesium [3-hydroxybutyrate), [3-hydroxybutyrate-based ketones, [3-hydroxybutyrate- based ketone esters, [3-hydroxybutyrate-based esters, [3-hydroxybutyrate butanediol, [3- hydroxybutyrate glycerol, R-1 ,3-butanediol-R-3-hydroxybutyrate, butanediol, R-1 ,3- butandediol, R-3-hydroxybutyrate, bis-hexanoyl-1 ,3-butanediol, [3-ketopentanoate, [3- hydroxypentanoate, valeric acid, valerian-extract containing valeric acid, valerian root, valproate, valproic acid, an alkyl carboxylic acid, an alkyl carboxylic acid-derivative, precursors of butyrate and butyric acid (e.g., inulin, fructo-oligosaccharides (FOS), resistant starch, Hi-maize, potato starch, arabinoxylan, and beta-glucans), non-butyrate alkane carboxylic acid or alkane carboxylic acid derivatives (e.g., propionic acid, formic acid, acetic acid, isovaleric acid, valeric acid, isocaproic acid, caproic acid, caprylic acid, lactic acid, succinic acid, and pyruvic acid). As used herein, “klf4 activators” include, without limitation, flavonoids, flavones, and chaicone compounds. Additional examples of klf4 activators include, without limitation, isoliquiritigenin, hydroxychaicone, apigenin, luteolin, diosmetin, hydroxyflavone, dihydroxyflavone, fisetin, quercetin, resveratrol, pterostilbene, salidroside, vitamin K, vitamin K1 , vitamin K2, vitamin K-derivatives, vitamin K precursors, and menaquinone.

As used herein, the term “melatonin agent” includes, without limitation, melatonin, melatonin derivatives, and precursors to melatonin. Melatonin agents include, without limitation, serotonin, tryptophan, and 5-hydroxytryptophan (5-HTP).

As used herein, the term “NAD+ booster” includes, without limitation, any molecule that can increase the NAD+ level in a cell or an organism. NAD+ boosters include, without limitation, nicotinamide riboside (NR), niacin, niacinamide, nicotinamide, nicotinic acid, vitamin B3, nicotinamide mononucleotide (NMN), nicotinic acid mononucleotide (NaMN), nicotinic acid riboside (NaR), nicotinamide adenine dinucleotide (NAD), NADH, tryptophan, N-formylkynurenine, quinolinic acid, nicotinamide riboside kinase (NRK), and salts and prodrugs thereof.

As used herein, the term “retinoid”, also referred to as “retinoic acid receptor agonist”, includes, without limitation, vitamin A, a vitamin A derivative, retinol, retinal, retinaldehyde, tretinoin (i.e., retinoic acid), isotretinoin, 9-cis retinoic acid, 13-cis retinoic acid, all-trans retinoic acid, 4-oxoretinol, 4-oxoretinaldehyde, a retinyl ester (e.g., retinyl propionate, retinyl acetate, and retinyl palmitate), adapalene, tazarotene, carotenoids, carotenes, and vitamin A precursors.

As used herein, the term “royal jelly agent” includes, without limitation, royal jelly, royal jelly extract, royal jelly derived peptides, royal jelly derived proteins, royal jelly derived molecules, royalactin, major royal jelly protein 1 (MRJP1 ), major royal jelly proteins 2 to 9, royalactin-based peptides, aspimin, royalisin, jelleines, 10-hydroxydecanoic acid (10HDA), 10-hydroxy-2 -decenoic acid (102HDA), 10-hydroxydecanoic acid, suberoylanilide hydroxamic acid (SAHA), sebacic acid, phenols, phospholipids, butyrate, butyric acid, a butyric acid derivative, B vitamins (e.g., vitamin B1 , vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B8, vitamin B9, and vitamin B12), flavonoids, hesperetin, naringenin, acacetin, kaempferol, coumestrol, formononetin, genistein, free bases (e.g., adenosine, iridin, uridine, and guanosine), and nucleic acid base phosphates.

As used herein, the term “subject” includes, without limitation, a mammal such as a human, a non-human primate, a dog, a cat, a horse, a sheep, a goat, a cow, a rabbit, a pig, a rat, and a rodent (such as a mouse). Where the subject is human, the subject can be of any age. For example, the subject can be 60 years or older, 65 or older, 70 or older, 75 or older, 80 or older, 85 or older, or 90 or older. Alternatively, the subject can be 50 years or younger, 45 or younger, 40 or younger, 35 or younger, 30 or younger, 25 or younger, or 20 or younger.

As used herein, the term “ten eleven translocase modifier”, also known as a “TET modifier”, includes, without limitation, alpha-ketoglutarate, alpha-ketoglutarate equivalents (e.g., salts of alpha-ketoglutarate (such as calcium alpha-ketoglutarate, potassium alpha-ketoglutarate, and sodium alpha-ketoglutarate), amino acid forms of alpha-ketoglutarate (e.g., arginine-alpha-ketoglutarate), and alpha-ketoglutaric acid), ascorbic acid (i.e. , vitamin C), and ascorbic acid equivalents (e.g., ascorbyl palmitate, tetrahexyldecyl ascorbate, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, sodium ascorbate, calcium ascorbate, ascorbic acid polypeptide, ascorbic acid peptide, ascorbyl glucosamine, ascorbyl glucoside, tetrahexyldecyl ascorbate, and ascorbyl tetraisopalmitate).

As used herein, the term “transforming growth factor beta modifier”, also referred to as “TGF-B modifier”, includes, without limitation, cryptotanshinone, resveratrol, flavonoids, oxymatrine, ligustrazine, osthole, codonolactone, betanin, tannic acid, gentiopicroside, paeoniflorin, gambogic acid, Cinnamomum cassia extracts, arctigenin, baicalin, baicalein, betanin, astragalus, astragalus extract, codonolactone, cryptostanshinone, curcuminoids (e.g., curcumin), eupatolide, gambogic acid, isoflavones, genistein, oxymatrine, paeoniflorin, green tea extract, EGCG (epigallocatechin gallate), rosemaric acid, vitamin D, extra virgin olive oil, apigenin, fucoidan, zinc, silymarin, thymoquinone, hesperidin, ginkgo biloba, theanine, quercetin, fisetin, ginseng, berberine, ursolic acid, naringenin, garlic, and garlic extract. As used herein, TGF-B modifier can be a TGF-B inhibitor. Embodiments of the Invention

This invention provides compositions and methods for ameliorating aging hallmarks. These compositions comprise certain combinations of agents that act in concert to address hallmarks of aging such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.

The invention also provides related articles of manufacture.

Specifically, this invention provides a composition comprising (i) an HDAC inhibitor; (ii) a retinoid; (iii) ascorbic acid or an ascorbic acid equivalent; and (iv) alpha-ketoglutarate or an alpha-ketoglutarate equivalent.

In one embodiment, the composition comprises an HDAC inhibitor, a retinoid, ascorbic acid, and alpha-ketoglutarate. Preferably, the HDAC inhibitor is butyrate or a butyrate equivalent (e.g., acetic acid, valproate, or tributyrin), and the retinoid is vitamin A.

In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, and alpha-ketoglutarate.

In one example, the present composition comprises 100 mg - 10,000 mg of butyrate, 100 international units to 25,000 international units of vitamin A, 10 mg - 8,000 mg of ascorbic acid, and 50 mg - 15,000 mg of alpha-ketoglutarate. In a preferred embodiment, the present composition comprises 1 ,200 mg of butyrate, 2,500 international units of vitamin A, 400 mg of ascorbic acid, and 1 ,000 mg of alpha- ketoglutarate.

In another example, the present composition comprises (i) butyrate, vitamin A, ascorbic acid, and alpha-ketoglutarate, and (ii) one or more agents selected from the group consisting of a Klf4 activator, a BMP (bone morphogenic protein) modifier, a glycogen synthase kinase inhibitor (GSK-I), a transforming growth factor-beta (TGF-[3) modifier or inhibitor, a ten eleven translocase (TET) modifier, an adenylyl cyclase activator, an NAD+ booster, a royal jelly agent, zinc, copper, a melatonin agent, and a calciferol. In one preferred embodiment, the present composition comprises (i) 100 mg - 10,000 mg of butyrate, 100 international units to 25,000 international units of vitamin A, 10 mg to 8,000 mg of ascorbic acid, and 50 mg - 15,000 mg of alpha-ketoglutarate, and (ii) one or more agents selected from the group consisting of a Klf4 activator, a BMP (bone morphogenic protein) modifier, a glycogen synthase kinase inhibitor (GSK-I), a transforming growth factor-beta (TGF-|3) modifier or inhibitor, a ten eleven translocase (TET) modifier, an adenylyl cyclase activator, an NAD+ booster, a royal jelly agent, zinc, copper, a melatonin agent, and a calciferol. In another preferred embodiment, the present composition comprises (i) 1 ,200 mg of butyrate, 2,500 international units of vitamin A, 400 mg of ascorbic acid, and 1 ,000 mg of alpha-ketoglutarate, and (ii) one or more agents selected from the group consisting of a Klf4 activator, a BMP (bone morphogenic protein) modifier, a glycogen synthase kinase inhibitor (GSK-I), a transforming growth factor-beta (TGF-|3) modifier or inhibitor, a ten eleven translocase (TET) modifier, an adenylyl cyclase activator, an NAD+ booster, a royal jelly agent, zinc, copper, a melatonin agent, and a calciferol.

In a further example, the present composition comprises (i) butyrate, vitamin A, ascorbic acid, and alpha-ketoglutarate, and (ii) one or more agents selected from the group consisting of one or more flavonoids (e.g., sterubin and eriodictyol), zinc, lithium, copper, fisetin, pterostilbene, resveratrol, salidrosides, apigenin, genistein, theanine, berberine, forskolin, NMN, vitamin D, vitamin K (vitamin K2), royal jelly extract, and 10- HDA (hydroxy-d-decenoic acid). In a preferred embodiment, the present composition comprises (i) 100 mg - 10,000 mg of butyrate, 100 international units to 25,000 international units of vitamin A, 10 mg to 8,000 mg of ascorbic acid, and 50 mg - 15,000 mg of alpha-ketoglutarate, and (ii) one or more agents selected from the group consisting of 10 mg - 2,000 mg of one or more flavonoids (e.g., sterubin and eriodictyol), 1 mg - 50 mg of zinc, 0.01 mg- 1 ,000 mg of lithium, 0.1 mg - 6 mg of copper, 10 mg - 3,000 mg of fisetin, 5 mg - 2,000 mg of pterostilbene, 10 mg - 3,000 mg of resveratrol, 0.1 mg - 100 mg of salidroside or 25 mg - 3,000 mg of Rhodiola rosea extract containing 2 percent salidrosides, 5 mg - 500 mg of apigenin or dried parsley containing 5 mg - 2,000 mg of apigenin, 1 mg - 500 mg of genistein, 5 mg - 2,000 mg of theanine, 20 mg - 4,000 mg of berberine, 1 mg - 250 mg of forskolin or 50 mg - 250 mg of Coleus Forskohlii standardized to 20% forskolin or 100 mg - 500 mg of Coleus Forskohlii standardized to 10% forskolin, 10 mg - 4,000 mg of nicotinamide mononucleotide (NMN), 50 international units - 20,000 units of vitamin D, 10 ug - 2,000 ug of vitamin K (vitamin K2), 20 mg - 10,000 mg of royal jelly extract, and 0.1 mg - 500 mg of 10-HDA (hydroxy-d-decenoic acid). In another preferred embodiment, the present composition comprises (i) 100 mg - 10,000 mg of butyrate, 100 international units to 25,000 international units of vitamin A, 10 mg - 8,000 mg of ascorbic acid, and 50 mg - 15,000 mg of alpha-ketoglutarate, and (ii) one or more agents selected from the group consisting of 10 mg - 3,000 mg of one or more flavonoids, 0.1 mg - 20 mg of zinc, 0.01 mg - 2,000 mg of lithium, 0.1 mg - 10 mg of copper, 10 mg - 2,000 mg of fisetin, 5 mg - 4,000 mg of pterostilbene, 10 mg - 5,000 mg of resveratrol, 0.1 mg - 1 ,000 mg of salidroside or 25 mg - 3,000 mg of Rhodiola rosea extract containing 2 percent salidrosides, 5 mg - 500 mg of apigenin or dried parsley containing 5 mg - 2,000 mg of apigenin, 1 mg - 500 mg of genistein, 5 mg - 4,000 mg of theanine, 20 mg - 4,000 mg of berberine, 1 mg - 250 mg of forskolin or 50 mg - 250 mg of Coleus Forskohlii standardized to 20% forskolin or 100 mg - 500 mg of Coleus Forskohlii standardized to 10% forskolin, 10 mg - 4,000 mg of nicotinamide mononucleotide (NMN), 50 international units - 20,000 international units of vitamin D, 10 ug - 2,000 ug of vitamin K (vitamin K2), 20 mg - 10,000 mg of royal jelly extract, and 0.1 mg - 500 mg of 10-HDA (hydroxy-d-decenoic acid). In another preferred embodiment, the present composition comprises (i) 1 ,200 mg of butyrate, 2,500 international units of vitamin A, 400 mg of ascorbic acid, and 1 ,000 mg of alpha-ketoglutarate, and (ii) one or more agents selected from the group consisting of 200 mg of one or more flavonoids (e.g., sterubin and eriodictyol), 10 mg of zinc, 1 mg of lithium, 2 mg of copper, 100 mg of fisetin, 50 mg of pterostilbene, 250 mg of resveratrol, 4 mg of salidroside or 200 mg of Rhodiola rosea extract containing 2 percent salidrosides, 50 mg of apigenin or dried parsley containing 50 mg of apigenin, 10 mg of genistein, 150 mg of theanine, 500 mg of berberine, 25 mg of forskolin or 125 mg of Coleus Forskohlii standardized to 20% forskolin or 250 mg of Coleus Forskohlii standardized to 10% forskolin, 250 mg of nicotinamide mononucleotide (NMN), 2,000 international units of vitamin D, 100 ug of vitamin K (vitamin K2), 1 ,000 mg of royal jelly extract, and 15 mg of 10-HDA (hydroxy- d-decenoic acid).

In one embodiment of the present composition, the composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and a Klf4 activator. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and a BMP (bone morphogenic protein) modifier. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and a glycogen synthase kinase inhibitor (GSK-I). In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and a transforming growth factor-beta (TGF-[3) modifier or inhibitor. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and a ten eleven translocase (TET) modifier. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and an adenylyl cyclase activator. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha- ketoglutarate, and an NAD+ booster. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and a royal jelly agent. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and zinc. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and copper. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and a melatonin agent. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha- ketoglutarate, and a calciferol. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and one or more flavonoids (e.g., sterubin and eriodictyol). In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and lithium. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and copper. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and fisetin. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and pterostilbene. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and resveratrol. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and one or more salidrosides. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and apigenin. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and genistein. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and theanine. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and berberine. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and forskolin. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha- ketoglutarate, and NMN. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and vitamin D. In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and vitamin K (e.g., vitamin K2). In another embodiment, the present composition comprises butyrate, vitamin A, ascorbic acid, alpha-ketoglutarate, and 10-HDA (hydroxy-d-decenoic acid).

Preferably, one or more of the agents in the present composition is formulated for delayed release and/or extended release. In one embodiment of the present composition, the butyrate, vitamin A, ascorbic acid, and alpha-ketoglutarate are formulated for delayed release and/or extended release. In another embodiment of the present composition, butyrate, and optionally vitamin A, ascorbic acid, and alpha- ketoglutarate, are formulated for delayed release and/or extended release. In another embodiment of the present composition, the composition comprises butyrate or butyrate equivalent formulated for extended-release. In another embodiment of the present composition, the composition comprises ascorbic acid or ascorbic acid equivalent formulated for extended-release. In another embodiment of the present composition, the composition comprises alpha-ketoglutarate formulated for extended- release. In another embodiment of the present composition, each agent is formulated for delayed release and/or extended release. In still a further embodiment, the present composition comprises (i) 1 ,200 mg of delayed release and/or extended release butyrate, 2,500 international units of delayed release and/or extended release vitamin A, 400 mg of delayed release and/or extended release ascorbic acid, and 1 ,000 mg of delayed release and/or extended release alpha-ketoglutarate, and (ii) one or more agents selected from the group consisting of 200 mg of one or more delayed release and/or extended release flavonoids (e.g., sterubin and eriodictyol), 10 mg of delayed release and/or extended release zinc, 1 mg of delayed release and/or extended release lithium, 2 mg of delayed release and/or extended release copper, 100 mg of delayed release and/or extended release fisetin, 50 mg of delayed release and/or extended release pterostilbene, 250 mg of delayed release and/or extended release resveratrol, 4 mg of delayed release and/or extended release salidroside or 200 mg of Rhodiola rosea extract containing 2 percent salidrosides, 50 mg of delayed release and/or extended release apigenin or dried parsley containing 50 mg of apigenin, 10 mg of delayed release and/or extended release genistein, 150 mg of delayed release and/or extended release theanine, 500 mg of delayed release and/or extended release berberine, 25 mg of delayed release and/or extended release forskolin or 125 mg of Coleus Forskoh li i standardized to 20% forskolin or 250 mg of Coleus Forskoh li i standardized to 10% forskolin, 250 mg of delayed release and/or extended release nicotinamide mononucleotide (NMN), 2,000 international units of delayed release and/or extended release vitamin D, 100 ug of delayed release and/or extended release vitamin K (vitamin K2), 1 ,000 mg of royal jelly extract, and 15 mg of delayed release and/or extended release 10-HDA (hydroxy-d-decenoic acid).

Optionally, the present composition comprises one or more sweeteners such as, without limitation, erythritol, maltitol, mannitol, sorbitol, xylitol, isomalt, lactitol, tagatose, monk fruit, inuline, and stevia-derived substances.

Each of the agents in the present composition is commercially available, for example, in oral dosage forms. The following are non-limiting examples.

Butyrate is commercially available, for example, in capsule form. Butyrate is available as the sodium salt, but all other salts of butyrate are envisioned in this invention. Also envisioned for use in this invention, in lieu of butyrate, are other histone deacetylase inhibitors like acetic acid.

Apigenin is commercially available, for example, in 35 mg capsules of liposomal apigenin. Alpha-ketoglutarate, also known as alpha-ketoglutaric acid, is commercially available, for example, in 1 ,000 mg capsules. Alpha-ketoglutarate is available as the calcium salt, but all other forms of alpha-ketoglutarate are envisioned in this invention. They include, for example, potassium alpha-ketoglutarate, sodium alpha-ketoglutarate, other salts of alpha-ketoglutarate, amino acid forms of alpha-ketoglutarate (e.g., arginine-alpha-ketoglutarate, alpha-ketoglutaric acid, and derivatives and combinations thereof).

Ascorbic acid, also known as vitamin C and ascorbate, is commercially available, for example, in 1 ,000 mg tablets. Also envisioned for use in this invention, in lieu of ascorbic acid, is an ascorbic acid equivalent. These equivalents include, without limitation, ascorbyl palmitate, tetrahexyldecyl ascorbate, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, sodium ascorbate, calcium ascorbate, ascorbic acid polypeptide, ascorbic acid peptide, ascorbyl glucosamine, ascorbyl glucoside, tetrahexyldecyl ascorbate, and combinations thereof.

Flavonoids are a diverse group of phytonutrients found in almost all fruits and vegetables. Zinc is commercially available, for example, as 50 mg tablets. Lithium is commercially available, for example, as 1 mg capsules. Copper is commercially available, for example, as amino acid-chelated copper in 2 mg tablets. Fisetin is commercially available, for example, in liposomal gel form at 75 mg per serving.

Pterostilbene is commercially available, for example, as 50 mg capsules. Resveratrol is commercially available, for example, in vegetarian capsule form. Salidroside is commercially available, for example, in 500 mg Rhodiola extract vegetarian capsules. Genistein is commercially available, for example, as 125 mg vegetarian capsules.

Theanine, also known as L-theanine, is commercially available, for example, as 200 mg vegetarian capsules. Berberine is commercially available, for example, in softgel form. Forskolin is commercially available, for example, as 10 mg vegetarian capsules. Nicontinamide mononucleotide, also known as NMN, is commercially available, for example, in powder form at 500 mg per serving. Vitamin D, e.g., vitamin D3, is commercially available, for example, in 125 mcg softgels. Vitamin K2 is commercially available, for example, as 120 mcg vegetarian capsules. Royal jelly extract is commercially available, for example, as 500 mg softgels. 10-HDA (hydroxy-d-decanoic acid) is commercially available, for example, as a component of royal jelly extract.

Natural food products can also serve as a source of agents included in the present composition. For example, carotenoids, retinoids, vitamin A, vitamin A precursors, carotenoid precursors, and retinoid precursors such as retinoic acid receptor agonists, are found in leafy green vegetables, broccoli, kale, mustard greens, Swiss chard, collard greens, natto, spinach, broccoli, Brussels sprouts, lettuce, beans, carrots, pumpkin, tomatoes, cantaloupe, papaya, sweet potatoes, tangerines, squash, and winter squash. As another example, apigenin is found in parsley, celery, chamomile, artichokes, oregano, and vine spinach. As a further example, vitamin K1 , vitamin K2, and vitamin K precursors as klf4 and BMP modifying substances are found in leafy green vegetables, broccoli, kale, mustard greens, Swiss chard, collard greens, natto, spinach, broccoli, Brussels sprouts, and beans. Additional embodiments of the present composition are set forth below in the Examples section.

This invention also provides a pharmaceutical composition comprising (i) the present composition and (ii) a pharmaceutically acceptable carrier.

In a preferred embodiment, the present composition is in a form selected from the group consisting of a food, a powdered drink mix (to be mixed with water and orally consumed), a nutritional supplement, a nutraceutical, and a skincare product (such as a skin cream or serum). Preferably, each of these forms is self-administered daily.

This invention provides a method for ameliorating at least one aging hallmark in a subject comprising administering to the subject the present composition, wherein the aging hallmark is selected from the group consisting of genomic instability, telomere attrition, an epigenetic alteration, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, transcriptom ic dysregulation, crosslinking, and altered intercellular communication.

Preferably, the present method ameliorates genomic instability, loss of proteostasis, one or more epigenetic alterations, telomere attrition, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, transcriptom ic dysregulation, crosslinking, and altered intercellular communication.

In one embodiment, the present method ameliorates genomic instability. In another embodiment, the present method ameliorates telomere attrition. In another embodiment, the present method ameliorates one or more epigenetic alterations. In another embodiment, the present method ameliorates loss of proteostasis. In another embodiment, the present method ameliorates deregulated nutrient sensing. In another embodiment, the present method ameliorates mitochondrial dysfunction. In another embodiment, the present method ameliorates cellular senescence. In another embodiment, the present method ameliorates stem cell exhaustion. In another embodiment, the present method ameliorates transcriptom ic dysregulation. In another embodiment, the present method ameliorates crosslinking. In another embodiment, the present method ameliorates altered intercellular communication. In a further embodiment of the present method, the method ameliorates at least two aging hallmarks in the subject. In another embodiment, the present method ameliorates at least three aging hallmarks in the subject. In another embodiment, the present method ameliorates at least four aging hallmarks in the subject. In another embodiment, the present method ameliorates at least five aging hallmarks in the subject. In another embodiment, the present method ameliorates at least six aging hallmarks in the subject. In another embodiment, the present method ameliorates at least seven aging hallmarks in the subject. In another embodiment, the present method ameliorates at least eight aging hallmarks in the subject. In another embodiment, the present method ameliorates at least nine aging hallmarks in the subject. In another embodiment, the present method ameliorates at least ten aging hallmarks in the subject. In another embodiment, the present method ameliorates at least eleven aging hallmarks in the subject.

For example, in one embodiment, the present method ameliorates at least the following aging hallmarks in the subject: genomic instability, an epigenetic alteration, and loss of proteostasis. In another embodiment, the present method ameliorates at least the following aging hallmarks in the subject: an epigenetic alteration, loss of proteostasis, and mitochondrial dysfunction. In another embodiment, the present method ameliorates at least the following aging hallmarks in the subject: an epigenetic alteration, loss of proteostasis, and deregulated nutrient sensing. In another embodiment, the present method ameliorates cellular senescence or reduces the amount of senescent cells. In another embodiment, the present method ameliorates cellular senescence and stem cell exhaustion. In another embodiment, the present method ameliorates mitochondrial dysfunction and loss of proteostasis. In another embodiment, the present method ameliorates epigenetic alterations and loss of proteostasis. In another embodiment, the present method ameliorates altered intercellular communication and deregulated nutrient sensing. In another embodiment, the present method ameliorates altered intercellular communication and stem cell exhaustion. In another embodiment, the present method ameliorates stem cell exhaustion and epigenetic alterations. In another embodiment, the present method ameliorates epigenetic alterations and mitochondrial dysfunction. In another embodiment, the present method ameliorates epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction. In another embodiment, the present method ameliorates stem cell exhaustion, cellular senescence, and altered intercellular communication. In another embodiment, the present method ameliorates epigenetic alterations, cellular senescence, and mitochondrial dysfunction. In another embodiment, the present method ameliorates deregulated nutrient sensing, mitochondrial dysfunction, and loss or proteostasis. In another embodiment, the present method ameliorates epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, and cellular senescence.

Also envisioned in this invention is administering to a subject the present composition in order to accomplish one or more of the following objectives: (i) increasing lifespan, lengthening healthspan, and/or improving stress resistance; (ii) slowing down aging; (iii) reducing, mitigating, andor slowing down aging-related diseases, aging-related symptoms, and/or age-related impairments; (iv) reducing the risk of, preventing, inhibiting the onset of, or treating a disease such as cardiovascular disease (e.g., atherosclerosis, high blood pressure, cardiac failure, cardiac hypertrophy, coronary syndrome, heart valve dysfunction, calcification of arteries and valves, or stroke), metabolic dysregulation (e.g., metabolic syndrome, high blood cholesterol, high serum triglycerides, increased serum HbA1c, insulin resistance, insulin resistance disorder, hyperglycemia, reduced insulin sensitivity, diabetes, obesity, a thyroid disorder, metabolic syndrome, fatty liver, steatohepatitis, hepatic steatosis, or diabetic retinopathy), cancer, cachexia, frailty, sarcopenia, neurodegenerative disease (e.g., Alzheimer’s disease, vascular dementia, Lewy-body disease, frontotemporal dementia, Parkinson disease, mild cognitive impairment, amyotrophic lateral sclerosis, or Huntington's disease), neuropathy, eye disease (e.g., macular degeneration or cataract), lethargy, musculoskeletal diseases (e.g., rheumatoid arthritis, osteoarthritis, osteoporosis, or muscular dystrophy), lung diseases (e.g., lung fibrosis, chronic obstructive pulmonary disease (COPD), emphysema, aging-related increased susceptibility to lung infections including pneumonia), aging-related gastro-intestinal diseases (e.g., constipation, decreased stomach and gut motility, gastroparesis, polyps, gut dysbiosis, colitis, or inflammatory bowel disease), blood diseases (e.g., leukemia, lymphoma, anemia, platelet disorders, coagulation disorders, multiple myeloma, myelodysplastic syndromes, or myeloproliferative disorders), infertility, reduced fertility, aging-related increased risk of cancer or proliferative diseases, disorders caused or exacerbated by senescent cells, aging-related skin diseases, psoriasis, aging-related kidney diseases, sepsis, or sleep disorders; (v) improving and/or or mitigating the cellular and organismal physiological stress and dysfunction caused by surgery, exercise, combat, or certain work environments; and (vi) inhibiting the origin and progression of weight gain, wrinkles, sagging skin, aged skin, reduced stamina, reduced eyesight, reduced hearing, sarcopenia (i.e. , a decrease in muscle mass), insulin resistance, fat deposition (e.g., abdominal fat deposition), hair graying, hair loss, baldness, loss of libido, erectile dysfunction, memory problems, reduced cognition, concentration problems, memory problems, sleep disorders, or mood disorders.

This invention further provides a method for ameliorating at least one aging hallmark in a cell (e.g., a skin cell (such as a keratinocyte, fibroblast, or melanocyte), a skin stem cell, an endothelial cell, a neuron, a liver cell, a retinal cell, a hematopoetic stem cell, a muscle cell, a satellite cell, a hepatocyte, a chondrocyte, a cardiocyte, a white blood cell (such as a B cell, T cell, lymphocyte, or monocyte), or a gastrointestinal cell) comprising contacting the cell with the present composition, wherein the aging hallmark is selected from the group consisting of genomic instability, telomere attrition, an epigenetic alteration, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, transcriptom ic dysregulation, crosslinking, and altered intercellular communication. The present method is envisioned for this cellbased embodiment, mutatis mutandis, as it is for the subject treatment embodiment in this invention.

In a preferred embodiment of the present method, the subject is a human. In another preferred embodiment, the subject is a rodent, a rabbit, a cat, a dog, or a horse.

Finally, this invention also provides an article of manufacture comprising the present composition, wherein (i) the butyrate and/or butyrate equivalent and (ii) other components of the composition are in separate compartments.

In one embodiment of this article, the butyrate and/or butyrate equivalent is the only agent separately (i.e., individually) encapsulated (e.g., in extended release form, while the other agents are in non-extended release form). In another embodiment, a plurality of agents is separately encapsulated (e.g., in extended release form or as a separate capsule (as with NMN, for example)). For example, the following embodiments are envisioned: (i) each of butyrate, vitamin A, ascorbic acid, and alpha-ketoglutarate is separately encapsulated; (ii) each of butyrate and vitamin A is separately encapsulated; (iii) each of butyrate and ascorbic acid is separately encapsulated; (iv) each of butyrate and alpha-ketoglutarate is separately encapsulated; (v) each of vitamin A and ascorbic acid is separately encapsulated; (vi) each of vitamin A and alpha-ketoglutarate is separately encapsulated; (vii) each of ascorbic acid and alpha-ketoglutarate is separately encapsulated; (viii) each of butyrate, vitamin A, and ascorbic acid is separately encapsulated; (ix) each of butyrate, vitamin A, and alpha-ketoglutarate is separately encapsulated; (x) each of butyrate, ascorbic acid, and alpha-ketoglutarate is separately encapsulated; and (xi) each of vitamin A, ascorbic acid, and alpha- ketoglutarate is separately encapsulated.

One advantage of the present articles is the separation of foul-tasting butyrate and/or its foul-tasting equivalents from the other components of the present composition, thereby facilitating oral administration of the entire composition. In one example, the present article comprises (i) vitamin A, ascorbic acid, and alpha-ketoglutarate (and, optionally, other agents as described herein) blended into a nutrient bar for oral consumption, and (ii) mini-capsules (or mini-spheres) of butyrate and/or a butyrate equivalent in the nutrient bar. In another example, the present article comprises (i) vitamin A, ascorbic acid, and alpha-ketoglutarate (and, optionally, other agents as described herein) formulated as a powdered drink mix for oral consumption after combining with water, and (ii) one or more capsules of butyrate and/or a butyrate equivalent for oral consumption in conjunction with the drink. For instance, in one embodiment, the present article comprises, in separate compartments, (i) a composition (preferably in powder form) comprising 2,500 international units of vitamin A, 400 mg of ascorbic acid, and 1 ,000 mg of alpha-ketoglutarate (and optionally 200 mg of one or more flavonoids (e.g., sterubin and eriodictyol)), 10 mg of zinc, 1 mg of lithium, 2 mg of copper, 100 mg of fisetin, 50 mg of pterostilbene, 250 mg of resveratrol, 4 mg of salidroside or 200 mg of Rhodiola rosea extract containing 2 percent salidrosides, 50 mg of apigenin or dried parsley containing 50 mg of apigenin, 10 mg of genistein, 150 mg of theanine, 500 mg of berberine, 25 mg of forskolin, 250 mg of nicotinamide mononucleotide (NMN), 2,000 international units of vitamin D, 100 ug of vitamin K (vitamin K2), 1 ,000 mg of royal jelly extract, and 15 mg of 10-HDA (hydroxy-d-decenoic acid)), and (ii) 600 mg of butyrate or butyrate equivalent (preferably in capsule form). To reduce the foul smell and taste of butyrate, a triacylglyceride or diacylglyceride form of butyrate (such as tributyrin) can be used. In the present method, it is envisioned that the present composition is orally administered to the subject daily. The following dosages are envisioned, without limitation: (i) 600 mg of butyrate (preferably in separate capsule form) (or optionally, any of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1 g, 2 g, 3 g, 4 g, and 5 g thereof); (ii) 2,500 international units of vitamin A (or optionally, any of 200 international units, 300 international units, 400 international units, 500 international units, 1 ,000 international units, 1 ,500 international units, 2,000 international units, 3,000 international units, 4,000 international units, 5,000 international units, 6,000 international units, 7,000 international units, 8,000 international units, 9,000 international units and 10,000 international units thereof); (iii) 400 mg of ascorbic acid (or optionally, any of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 200 mg, 300 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g, 2 g, 3 g, 4 g, and 5 g thereof); (iv) 1 ,000 mg of alphaketoglutarate (or optionally, any of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 ,500 mg, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 10 g, 12 g, 15g, and 20 g thereof); (v) 200 mg of one or more flavonoids (e.g., sterubin and eriodictyol) (or optionally, any of 20 mg, 50 mg, 100 mg, 150 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, and 1 g thereof); (vi) 10 mg of zinc (or optionally, any of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 30 mg, 40 mg, and 50 mg thereof); (vii) 1 mg of lithium (or optionally, any of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1 .5 mg, 2 mg, 3 mg, 4 mg, and 5 mg thereof); (viii) 2 mg of copper (or optionally, any of 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1 .2 mg, 1 .4 mg, 1 .6 mg, 1 .8 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, and 10 mg thereof); (ix) 100 mg of fisetin (or optionally, any of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 200 mg, 300 mg, 400 mg, and 500 mg thereof); (x) 50 mg of pterostilbene (or optionally, any of 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 130 mg, 140 mg, 150 mg, and 200 mg thereof); (xi) 250 mg of resveratrol (or optionally, any of 20 mg, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, and 1 g thereof); (xii) 4 mg of salidroside (or optionally, any of 0.4 mg, 0.6 mg, 0.8 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, and 20 mg thereof); (xiii) 50 mg of apigenin (or optionally, any of 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 130 mg, 140 mg, 150 mg, and 200 mg thereof); (xiv) 10 mg of genistein (or optionally, any of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 30 mg, 40 mg, and 50 mg thereof); (xv) 150 mg of theanine (or optionally, any of 20 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, and 1 g thereof); (xvi) 500 mg of berberine (or optionally, any of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 ,500 mg, 2 g, 3 g, 4 g, and 5 g thereof); (xvii) 25 mg of forskolin (or optionally, any of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, and 100 mg thereof); (xviii) 250 mg of nicotinamide mononucleotide (NMN) (preferably in separate capsule form) (or optionally, any of 20 mg, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, and 1 g thereof); (xix) 2,000 international units of vitamin D (or optionally, any of 200 international units, 300 international units, 400 international units, 500 international units, 1 ,000 international units, 1 ,500 international units, 2,000 international units, 3,000 international units, 4,000 international units, 5,000 international units, 6,000 international units, 7,000 international units, 8,000 international units, 9,000 and 10,000 international units thereof); (xx) 100 ug of vitamin K (e.g., vitamin K2) (or optionally, any of 10 ug, 20 ug, 50 ug, 150 ug, 200 ug, 250 ug, 300 ug, 350 ug, 400 ug, 450 ug, 500 ug, 550 ug, 650 ug, 700 ug, 750 ug, 800 ug, 850 ug, 900 ug, 950 ug, and 1 mg thereof); (xxi) 1 ,000 mg of royal jelly extract (or optionally, any of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 ,500 mg, 2 g, 3 g, 4 g, and 5 g thereof); and (xxii) 15 mg of 10-HDA (hydroxy-d-decenoic acid) (or optionally, any of 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg thereof).

The following dosages are also envisioned for daily administration, without limitation: (i) 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, 400 mg to 500 mg, 500 mg to 700 mg, 700 mg to 1 g, 1 g to 2 g, and 2 g to 5 g thereof of butyrate (preferably in separate capsule form); (ii) 200 international units to 500 international units, 500 international units to 1 ,000 international units, 1 ,000 international units to 2,000 international units, 2,000 international units to 3,000 international units, 3,000 international units to 5,000 international units, 5,000 international units to 10,000 international units, and 10,000 international units to 25,000 international units of vitamin A; (iii) 10 mg to 50 mg, 50 mg to 150 mg, 150 mg to 500 mg, 500 mg to 1 g, and 1 g to 5 g of ascorbic acid; (iv) 100 mg to 500 mg, 500 mg to 1 ,500 mg, and 1 ,500 to 5 g of alpha-ketoglutarate; (v) 20 mg to 50 mg, 50 mg to 100 mg, 100 mg to 250 mg, 250 mg to 500 mg, and 500 mg to 1 g of one or more flavonoids (e.g., sterubin and eriodictyol); (vi) 1 mg to 5 mg, 5 mg to 15 mg, and 15 mg to 50 mg of zinc; (vii) 0.1 mg to 0.5 mg, 0.5 mg to 1 .5 mg, and 1 .5 mg to 5 mg of lithium; (viii) 0.2 mg to 0.8 mg, 0.8 mg to 1 .4 mg, 1 .4 mg to 2.5 mg, and 2.5 mg to 10 mg of copper; (ix) 10 mg to 50 mg, 50 mg to 150 mg, and 150 mg to 500 mg of fisetin; (x) 5 mg to 30 mg, 30 mg to 70 mg, 70 mg to 100 mg, and 100 mg to 200 mg of pterostilbene; (xi) 20 mg to 100 mg, 100 mg to 400 mg, and 400 mg to 1 g of resveratrol; (xii) 0.4 mg to 2 mg, 2 mg to 5 mg, 5 mg to 20 mg, and 20 mg to 300 mg of salidroside; (xiii) 5 mg to 20 mg, 20 mg to 70 mg, 70 mg to 200 mg, and 200 mg to 500 mg of apigenin; (xiv) 1 mg to 5 mg, 5 mg to 15 mg, and 15 mg to 50 mg of genistein; (xv) 20 mg to 100 mg, 100 mg to 300 mg, and 300 mg to 1 g of theanine; (xvi) 50 mg to 200 mg, 200 mg to 1 g, and 1 g to 5 g of berberine; (xvii) 2 mg to 10 mg, 10 mg to 50 mg, and 50 mg to 100 mg of forskolin; (xviii) 20 mg to 100 mg, 100 mg to 500 mg, and 500 mg to 1 g of nicotinamide mononucleotide (NMN) (preferably in separate capsule form); (xix) 200 international units to 1 ,000 international units, 1 ,000 international units to 3,000 international units, and 3,000 international units to 10,000 international units of vitamin D; (xx) 20 ug to 100 ug, 100 ug to 300 ug, and 300 ug to 1 mg of vitamin K (e.g., vitamin K2); (xxi) 100 mg to 500 mg, 500 mg to 1 ,500 mg, ad 1 ,500 mg to 5 g of royal jelly extract; and (xxii) 2 mg to 10 mg, 10 mg to 30 mg, and 30 mg to 60 mg of 10-HDA (hydroxy-d-decenoic acid).

The following three dosage regimens are (i) also envisioned for daily oral administration (in delayed release and/or extended release form, as well as non- delayed release, non-extended release form) and (ii) envisioned for the present compositions and articles of manufacture. They comprise, without limitation, the following: (i) 150 mg of butyrate (preferably in separate capsule form), 625 international units of vitamin A, 100 mg of ascorbic acid, and 250 mg of alpha-ketoglutarate, 50 mg of one or more flavonoids (e.g., sterubin and eriodictyol), 2.5 mg of zinc, 0.25 mg of lithium, 0.5 mg of copper, 25 mg of fisetin, 12.5 mg of pterostilbene, 62.5 mg of resveratrol, 1 mg of salidroside, 12.5 mg of apigenin, 2.5 mg of genistein, 37.5 mg of theanine, 125 mg of berberine, 6.25 mg of forskolin, 62.5 mg of nicotinamide mononucleotide (NMN) (preferably in separate capsule form), 500 international units of vitamin D, 25 ug of vitamin K (e.g., vitamin K2), 250 mg of royal jelly extract, and 3.75 mg of 10-HDA (hydroxy-d-decenoic acid); (ii) 300 mg of butyrate (preferably in separate capsule form), 1 ,250 international units of vitamin A, 200 mg of ascorbic acid, and 500 mg of alphaketoglutarate, 100 mg of one or more flavonoids (e.g., sterubin and eriodictyol), 5 mg of zinc, 0.5 mg of lithium, 1 mg of copper, 50 mg of fisetin, 25 mg of pterostilbene, 125 mg of resveratrol, 2 mg of salidroside, 25 mg of apigenin, 5 mg of genistein, 75 mg of theanine, 250 mg of berberine, 12.5 mg of forskolin, 125 mg of nicotinamide mononucleotide (NMN) (preferably in separate capsule form), 1 ,000 international units of vitamin D, 500 ug of vitamin K (e.g., vitamin K2), 500 mg of royal jelly extract, and

7.5 mg of 10-HDA (hydroxy-d-decenoic acid); and (iii) 450 mg of butyrate (preferably in separate capsule form), 1 ,875 international units of vitamin A, 300 mg of ascorbic acid, and 750 mg of alpha-ketoglutarate, 150 mg of one or more flavonoids (e.g., sterubin and eriodictyol), 7.5 mg of zinc, 0.75 mg of lithium, 1 .5 mg of copper, 75 mg of fisetin,

37.5 mg of pterostilbene, 187.5 mg of resveratrol, 3 mg of salidroside, 37.5 mg of apigenin, 7.5 mg of genistein, 112.5 mg of theanine, 375 mg of berberine, 18.75 mg of forskolin, 187.5 mg of nicotinamide mononucleotide (NMN) (preferably in separate capsule form), 1 .500 international units of vitamin D, 75 ug of vitamin K (e.g., vitamin K2), 750 mg of royal jelly extract, and 11 .25 mg of 10-HDA (hydroxy-d-decenoic acid).

This invention will be better understood by reference to the examples which follow, but those skilled in the art will readily appreciate that the specific examples detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.

Examples

Example 1 - Additional Embodiments of the Present Compositions

The following additional combinations of agents are envisioned, without limitation, for the present compositions.

One additional combination comprises a histone deacetylase inhibitor (HDAC-I), a retinoic acid receptor (RAR) agonist, a Klf4 activator, a glycogen synthase kinase inhibitor (GSK-I), a transforming growth factor-[3 (TGF-|3) inhibitor, an epigenetic facilitator, a ten eleven translocase (TET) modifier, an adenylyl cyclase activator, an NAD+ booster, a royal jelly agent, zinc, and a melatonin agent. A further additional combination comprises a histone deacetylase inhibitor (HDAC-I), a retinoic acid receptor (RAR) agonist, a glycogen synthase kinase inhibitor (GSK-I), a transforming growth factor-[3 (TGF-|3) inhibitor, and an epigenetic facilitator like vitamin C.

A further additional combination comprises a histone deacetylase inhibitor (HDAC-I), a retinoic acid receptor (RAR) agonist, a Klf4 activator, a glycogen synthase kinase inhibitor (GSK-I), and a transforming growth factor-[3 (TGF-|3) inhibitor.

A further additional combination comprises a retinoic acid receptor (RAR) agonist, glycogen synthase kinase inhibitor (GSK-I), a transforming growth factor-[3 (TGF-|3) inhibitor, an epigenetic facilitator like an ascorbic acid derivative, a ten eleven translocase (TET) modifier, an NAD+ booster, zinc, and copper.

A further additional combination comprises a glycogen synthase kinase inhibitor (GSK- I), a transforming growth factor-[3 (TGF-|3) inhibitor, an epigenetic facilitator, an NAD+ booster, a royal jelly agent, zinc, and vitamin D.

A further additional combination comprises a histone deacetylase inhibitor (HDAC-I), a retinoic acid receptor (RAR) agonist or a retinoid X receptor (RXR) agonist, a Klf4 activator or BMP (bone morphogenic protein) modifier, a glycogen synthase kinase inhibitor (GSK-I), a ten eleven translocase (TET) modifier, and a royal jelly agent.

A further additional combination comprises a method for epigenetic modification of cells, tissues and organisms consists of using a histone deacetylase inhibitor (HDAC-I), a retinoic acid receptor (RAR), a Klf4 activator or BMP (bone morphogenic protein) modifier, a glycogen synthase kinase inhibitor (GSK-I), a transforming growth factor-[3 (TGF-[3) modifier or inhibitor, an epigenetic facilitator like an ascorbic acid derivative, a ten eleven translocase (TET) modifier, an adenylyl cyclase activator, an NAD+ booster, a royal jelly agent, zinc, copper, a melatonin agent, and a calciferol.

A further additional combination comprises butyrate, retinol, hydroxyflavone, dihydroxyflavone, fisetin, quercetin, resveratrol, pterostilbene, salidroside, apigenin, genistein, theanine, berberine, vitamin K, lithium, copper, zinc, ascorbic acid, alphaketoglutarate, forskolin, NMN, royal jelly extract, melatonin, and vitamin D. A further additional combination comprises butyrate, retinol, fisetin, resveratrol, lithium, copper, zinc, ascorbic acid, alpha-ketoglutarate, forskolin, NMN, and royal jelly extract.

A further additional combination comprises butyrate, retinol, lithium, copper, zinc, ascorbic acid, alpha-ketoglutarate, vitamin K, vitamin D, and NMN.

A further additional combination comprises butyrate, retinol, lithium, copper, zinc, ascorbic acid, alpha-ketoglutarate, and NMN.

A further additional combination comprises butyrate, tretinoin, copper, zinc, ascorbic acid, alpha-ketoglutarate, and NMN.

A further additional combination comprises butyrate, a retinyl ester like propionate, retinyl acetate, retinyl palmitate, lithium, zinc, ascorbic acid, alpha-ketoglutarate, and NMN.

A further additional combination comprises beta-hydroxy butyrate, retinol, lithium, zinc, ascorbic acid, alpha-ketoglutarate, and NMN.

A further additional combination comprises butyrate, retinol, lithium, copper, zinc, ascorbic acid, and alpha-ketoglutarate.

A further additional combination comprises butyrate, retinol, lithium, fisetin, apigenin, copper, zinc, ascorbic acid, alpha-ketoglutarate, NMN, royal jelly extract, and melatonin.

A further additional combination comprises butyrate, retinol, lithium, fisetin, apigenin, copper, zinc, ascorbic acid, alpha-ketoglutarate, NMN, and melatonin.

A further additional combination comprises butyrate, retinol, lithium, fisetin, apigenin, copper, zinc, ascorbic acid, and alpha-ketoglutarate.

A further additional combination comprises butyrate, retinol, copper, zinc, ascorbic acid, and alpha-ketoglutarate. A further additional combination comprises butyrate, retinol, ascorbic acid, and alphaketoglutarate.

A further additional combination comprises butyrate, ascorbic acid, and alphaketoglutarate.

A further additional combination comprises (i) an HDAC inhibitor; (ii) a retinoid; (iii) ascorbic acid or an ascorbic acid equivalent; (iv) alpha-ketoglutarate or an alphaketoglutarate equivalent; and (v) a B vitamin (e.g., phosphatidylcholine). Alternatively, this combination comprises one or more of phosphatidylcholine, phosphatidylserine, choline, and trimethylglycine.

A further additional combination comprises (i) an HDAC inhibitor; (ii) a retinoid; (iii) ascorbic acid; (iv) alpha-ketoglutarate; and (v) a B vitamin (e.g., phosphatidylcholine). Alternatively, this combination comprises one or more of phosphatidylcholine, phosphatidylserine, choline, and trimethylglycine.

A further additional combination comprises a food supplement containing butyrate, vitamin A, lithium, copper, zinc, fisetin, pterostilbene, resveratrol, apigenin, ascorbic acid, alpha-ketoglutarate, forskolin, an NMN-derivative like NMN, royal jelly extract, vitamin D, vitamin K, B vitamins, and melatonin.

A further additional combination comprises a food supplement containing butyrate, vitamin A, lithium, copper, zinc, fisetin, apigenin, ascorbic acid, alpha-ketoglutarate, NMN, vitamin D, vitamin K, and B vitamins.

A further additional combination comprises a food supplement containing butyrate, vitamin A, lithium, zinc, fisetin, apigenin, ascorbic acid, alpha-ketoglutarate, vitamin D, vitamin K, and B vitamins.

A further additional combination comprises a food supplement containing beta-hydroxy butyrate, vitamin A, lithium, pterostilbene, ascorbic acid, alpha-ketoglutarate, an NMN- derivative like NMN, royal jelly extract, vitamin D, vitamin K, and B vitamins. A further additional combination comprises a food supplement containing tributyrate, vitamin A, lithium, copper, zinc, fisetin, apigenin, ascorbic acid, alpha-ketoglutarate, NMN, vitamin D, vitamin K, and B vitamins.

A further additional combination comprises a food supplement containing butyrate, vitamin A, lithium, apigenin, ascorbic acid, alpha-ketoglutarate, NMN, vitamin D, vitamin K, and B vitamins.

A further additional combination comprises a food supplement containing butyrate, vitamin A, lithium, ascorbic acid, alpha-ketoglutarate, NMN, vitamin D, vitamin K, and B vitamins.

A further additional combination comprises a food supplement containing (i) an HDAC inhibitor; (ii) a retinoid; (iii) ascorbic acid or an ascorbic acid equivalent; (iv) alpha- ketoglutarate or an alpha-ketoglutarate equivalent; and (v) a B vitamin (e.g., phosphatidylcholine).

A further additional combination comprises a food supplement containing (i) an HDAC inhibitor; (ii) a retinoid; (iii) ascorbic acid; (iv) alpha-ketoglutarate; and (v) a B vitamin (e.g., phosphatidylcholine).

A further additional combination comprises a skin cream, skin serum or other skincare product containing a retinoid (for example retinol or a retinyl ester), lithium, copper, zinc, fisetin, pterostilbene, resveratrol, apigenin, ascorbic acid, alpha-ketoglutarate, forskolin, an NMN-derivative like NMN, royal jelly extract, vitamin D, vitamin K, B vitamins, and melatonin.

A further additional combination comprises a skin cream, skin serum or other skincare product containing butyrate, retinol, lithium, copper, zinc, resveratrol, ascorbic acid, alpha-ketoglutarate, NMN, royal jelly extract, vitamin D, vitamin K, and melatonin.

A further additional combination comprises a skin cream, skin serum or other skincare product containing a butyrate equivalent, a retinoid, lithium, copper, zinc, an ascorbic acid equivalent, an alpha-ketoglutarate equivalent, a flavonoid, genistein, apigenin, fisetin, an NAD+ booster, vitamin D, and vitamin K. A further additional combination comprises a skin cream, skin serum or other skincare product containing a butyrate equivalent, lithium, copper, zinc, an ascorbic acid equivalent, an alpha-ketoglutarate equivalent, a flavonoid, genistein, apigenin, fisetin, an NAD+ booster, vitamin D, and vitamin K.

A further additional combination comprises a skin cream, skin serum or other skincare product containing a butyrate equivalent, a retinoid, lithium, copper, zinc, an ascorbic acid equivalent, an alpha-ketoglutarate equivalent, a flavonoid, genistein, flavonoids, an NAD+ booster, vitamin D, and vitamin K.

A further additional combination comprises a skin cream, skin serum or other skincare product containing beta-hydroxybutyric acid, a retinoid (for example retinol), lithium, copper, zinc, resveratrol, apigenin, ascorbic acid, alpha-ketoglutarate, NMN, vitamin D, and vitamin K.

A further additional combination comprises a skin cream, skin serum or other skincare product containing retinol, lithium, copper, zinc, resveratrol, ascorbic acid or an ascorbic acid equivalent, alpha-ketoglutarate, NMN, royal jelly extract, vitamin D, vitamin K, and melatonin.

A further additional combination comprises a skin cream, skin serum or other skincare product containing a retinoid (for example retinol), lithium, copper, zinc, resveratrol, apigenin, ascorbic acid or an ascorbic acid equivalent, alpha-ketoglutarate, NMN, vitamin D, and vitamin K.

A further additional combination comprises a skin cream, skin serum or other skincare product containing retinol, lithium, resveratrol, ascorbic acid or an ascorbic acid equivalent, alpha-ketoglutarate or an alpha-ketoglutarate equivalent, NMN, vitamin D, vitamin K, and melatonin.

A further additional combination comprises a skin cream, skin serum or other skincare product containing retinol, lithium, resveratrol, ascorbic acid, alpha-ketoglutarate, NMN, vitamin D, and vitamin K. A further additional combination comprises a skin cream, skin serum or other skincare product containing retinol, lithium, resveratrol, ascorbic acid, alpha-ketoglutarate, vitamin D, and vitamin K.

A further additional combination comprises a skin cream, skin serum or other skincare product containing retinol, lithium, ascorbic acid, alpha-ketoglutarate, vitamin D, and vitamin K.

A further additional combination comprises a skin cream, skin serum or other skincare product containing retinol, lithium, ascorbic acid, alpha-ketoglutarate, and vitamin K.

A further additional combination comprises a skin cream, skin serum or other skincare product containing retinol, lithium, an ascorbic acid-derivative, alpha-ketoglutarate, and vitamin D.

A further additional combination comprises a skin cream, skin serum or other skincare product containing retinol, lithium, ascorbic acid, alpha-ketoglutarate, and melatonin.

A further additional combination comprises a skin cream, skin serum or other skincare product containing retinol, lithium, copper, zinc, ascorbic acid or an ascorbic acid equivalent, and alpha-ketoglutarate.

A further additional combination comprises a skin cream, skin serum or other skincare product containing retinol, zinc, copper, ascorbic acid or an ascorbic acid equivalent, and alpha-ketoglutarate.

A further additional combination comprises a skin cream, skin serum or other skincare product containing retinol, lithium, zinc, copper, ascorbic acid, and alpha-ketoglutarate.

A further additional combination comprises a skin cream, skin serum or other skincare product containing retinol, lithium, ascorbic acid, and alpha-ketoglutarate.

A further additional combination comprises a skin cream, skin serum or other skincare product containing butyrate, a retinoid (for example retinol or a retinyl ester), lithium, copper, zinc, fisetin, pterostilbene, resveratrol, apigenin, ascorbic acid, alpha- ketoglutarate, forskolin, an NMN-derivative like NMN, royal jelly extract, vitamin D, vitamin K, B vitamins, and melatonin.

A further additional combination comprises a skin cream, skin serum or other skincare product containing beta-hydroxybutyrate, a retinoid (for example retinol or a retinyl ester), lithium, copper, zinc, fisetin, pterostilbene, resveratrol, apigenin, ascorbic acid, alpha-ketoglutarate, forskolin, an NMN-derivative like NMN, royal jelly extract, vitamin D, vitamin K, B vitamins, and melatonin.

A further additional combination comprises a skin cream, skin serum or other skincare product containing (i) an HDAC inhibitor; (ii) a retinoid; (iii) ascorbic acid or an ascorbic acid equivalent; (iv) alpha-ketoglutarate or an alpha-ketoglutarate equivalent; and (v) a B vitamin (e.g., phosphatidylcholine).

A further additional combination comprises a skin cream, skin serum or other skincare product containing (i) an HDAC inhibitor; (ii) a retinoid; (iii) ascorbic acid; (iv) alpha- ketoglutarate; and (v) a B vitamin (e.g., phosphatidylcholine).

A further additional combination comprises a skin cream or product containing 1 % to 5% beta-hydroxybutyrate or 1 % to 5% lithium butyrate or 1 % to 5% tributyrin or 1 % to 5% phenylbutyrate or 1 % to 5% of sodium butyrate or 1 % to 5% of magnesium butyrate, 0.25% to 1 % retinol or 2.5% retinyl palmitate or an equivalent retinoid dose, 0.1 % to 0.5% vitamin K, 0.2 to 1 % melatonin, 1 % to 4% lithium, 1 to 5% alpha-ketoglutarate, 0.1 % to 20% ascorbic acid, 1 % zinc.

A further additional combination comprises a food product containing butyrate, vitamin A, lithium, copper, zinc, fisetin, pterostilbene, resveratrol, apigenin, ascorbic acid, alpha-ketoglutarate, forskolin, an NMN-derivative like NMN, royal jelly extract, vitamin D, vitamin K, B vitamins, and melatonin.

A further additional combination comprises a food product containing butyrate or tributyrate, vitamin A, lithium, copper, zinc, fisetin, pterostilbene, resveratrol, apigenin, ascorbic acid, alpha-ketoglutarate, forskolin, an NMN-derivative like NMN, royal jelly extract, vitamin D, vitamin K, B vitamins, and melatonin. A further additional combination comprises a food product containing butyrate or tributyrate, vitamin A, copper, zinc, fisetin, resveratrol, apigenin, ascorbic acid, alphaketoglutarate, NMN, royal jelly extract, vitamin D, vitamin K, and B vitamins.

A further additional combination comprises a food product containing (i) an HDAC inhibitor; (ii) a retinoid; (iii) ascorbic acid or an ascorbic acid equivalent; (iv) alphaketoglutarate or an alpha-ketoglutarate equivalent; and (v) a B vitamin (e.g., phosphatidylcholine).

A further additional combination comprises a food product containing (i) an HDAC inhibitor; (ii) a retinoid; (iii) ascorbic acid; (iv) alpha-ketoglutarate; and (v) a B vitamin (e.g., phosphatidylcholine).

In yet an additional embodiment of the present method, the daily dose admistered comprises 100 mg to 1200 mg of butyrate, 1 ,000 to 5,000 units of vitamin A (retinyl palmitate), 200 mg of flavonoids (e.g., sterubin and eriodictyol), 10 mg of zinc, 1 mg of lithium, 2 mg of copper, 100 mg of fisetin, 50 mg of pterostilbene, 250 mg of resveratrol, 4 mg of salidroside or 200 mg of Rhodiola rosea extract containing 2 percent salidrosides, 50 mg of apigenin or dried parsley containing 50 mg of apigenin, 10 mg of genistein, 150 mg of theanine, 500 mg of berberine, 100 mg of vitamin C, 1 ,000 mg of alpha-ketoglutarate, 25 mg of forskolin or 125 mg of Coleus Forskohlii standardized to 20% forskolin or 250 mg of Coleus Forskohlii standardized to 10% forskolin, 250 mg of NMN, 2,000 international units of vitamin D, 100 ug of vitamin K (vitamin K2), 1 ,000 mg of royal jelly extract or 15 mg of 10-HDA (hydroxy-d-decenoic acid), and 100 or 300 percent of the RDA of vitamin B.

Example 2 - Measuring Epigenetic Dysrequlation

The success of the present composition in ameliorating epigenetic dysregulation in a subject (e.g., a human subject) can be measured, for example, by making any of the following determinations: (i) the subject’s epigenetic methylation, histonylation, and/or chromatin patterns more closely resemble the patterns of younger persons (e.g., by at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (ii) an epigenetic clock (e.g., a Horvath clock or a Levine clock)-measuring methylation of DNA in different regions of the subject’s DNA more closely resembles the DNA methylation pattern of a younger subject (e.g., by at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (iii) an epigenetic DNA methylation clock (e.g., a Horvath clock or a Levine clock) shows that an adult human subject has been rejuvenated by at least 3 months, one year, at least two years, or at least three years after being administered the present composition (or of which the epigenetic age or biological age has been decreased by at least 1 %, at least 2%, at least 3%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to a subject’s chronological age); (iv) the subject’s chromatin distribution more closely resembles that of a younger subject (e.g., by at least 0.2%, at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (v) the subject’s transcriptome resembles the transcriptome of a younger subject (e.g., by at least 0.2%, at least 0.5%, at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (vi) the subject’s expression profile of ribosome-related proteins and/or ribosome-related RNA more closely resembles that of a younger organism (e.g., by at least 0.2%, at least 0.5%, at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); or (vii) the subject’s levels of sirtuins have increased (e.g., by at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%).

The success of the present composition in ameliorating epigenetic dysregulation in a subject (e.g., a human subject) can also be measured, for example, by making any of the following determinations: (i) an increase in the level of H3K9me3 in the subject (e.g., by at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); or (ii) an increase in the level of heterochromatin protein (Hp1y) in the subject (e.g., by at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%). Example 3 - Measuring Cell Senescence

The success of the present composition in ameliorating cell senescence in a subject (e.g., a human subject) can be measured, for example, by making any of the following determinations: (i) a delay in the occurrence of senescent cells or a delay in the transition of normal cells into senescent cells in vitro or in vivo (e.g., by at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); and/or (ii) a decrease in the number of senescent cells in vitro or in vivo (e.g., by at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%). Senescence or senescent-like status of cells can be measured, for example, via one or more of the following: (i) epigenetic profiling such as measuring epigenetic markers of senescence (e.g., changes in histone H3 lysine 9 and 27 trimethylation (changed levels of H3K9me3 and H3K27me3), changed heterochromatin protein 1 (HP1 ) family protein levels, increased histone variant macroH2A levels, and/or chromatin remodeling enzyme ATRX levels); (ii) changes in cell morphology resembling the morphology of senescent cells, (e.g., enlarged size, a more flattened shape, polyploid nuclei, or accumulation of DNA damage foci); (iii) changes in levels of nuclear lamina-associated proteins such as lamins (e.g., a decline lamin B1); (iv) heterochromatin changes more resembling the heterochromatin status of senescent cells (e.g., an increase in senescence-associated heterochromatic foci (SAHF)); (v) an increase of senescence-associated distention of satellites (SADS) or other changes in pericentric satellite DNA more resembling that of senescent cells; and (vi) changes in secretory phenotype corresponding to that of senescent cells (e.g., the occurrence of a more senescence-associated secretome including, without limitation, cytokines, interleukins (e.g., IL-1 , IL-2, IL-6, II-8, and TNF- alpha), matrix metalloproteinases, pro angiogenetic factors, pro-inflammatory substances, and growth factors (e.g., vascular endothelial growth factor, insulin like growth factor, and GM-CSF)).

The success of the present composition in ameliorating cell senescence in a subject (e.g., a human subject) can also be measured, for example, by making any of the following determinations: (i) an increase in the level of H3K9me3 in the subject (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (ii) an increase in the level of H3K27me3 in the subject (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (iii) a decrease in the level of P16INK4A in the subject (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); or (iv) a decrease in the level of one or more of p16, p53, p21 , p14, p15, and beta-galactosidase activity in the subject (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%).

Example 4 - Measuring Altered Intercellular Communication

The success of the present composition in ameliorating altered intercellular communication in a subject (e.g., a human subject) can be measured, for example, by determining a decrease in the level of one or more of IL-1 , IL-2, IL-6, IL-8, IL-17a, and TNF-alpha signaling in the subject (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%).

Example 5 - Measuring Autophagy

The success of the present composition in ameliorating decreased autophagy in a subject (e.g., a human subject) can be measured, for example, by determining any of the following: (i) an increase in the level of one or more of LC3, p62, Ulk1 , Parkin, PINK1 , LAMP2A, Atg, FIP200, Vps15, Beclin, Lamp-1 , Lamp-2, Hsp70, Hsp90, and SQSTM1 in the subject (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (ii) an increase (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%) in any of phagophore formation, autophagosome formation, lysosome numbers, lysosomal activity, LC3 puncta, lysosomal content (as determined, for example, using immunochemistry, electron microscopy, Western blotting, or flow cytometry); (iii) increased lysosome acidity (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (iv) upregulation of the ubiguitin-proteasome system (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); or (v) inhibition of mTOR or the mTOR pathway (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%).

Example 6 - Measuring Cell Oxidation

The success of the present composition in ameliorating cell oxidation in a subject (e.g., a human subject) can be measured, for example, by making any of the following determinations: (i) a decrease in the level of 8-isoprostane in the subject (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (ii) a decrease in the level of 8-hydroxydeoxyguanosine (8-OHdG) in the subject (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); or (iii) a decrease in the subject of levels of any of oxidized LDL, malondialdehyde (MDA), 4-HNA, lipid hydroperoxides, oxidized proteins, protein carbonylation and protein nitration (3-nitrotyrosines), advanced glycation end products (AGEs), and advanced oxidation protein products (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%).

Example 7 - Measuring Telomere Fitness

The success of the present composition in ameliorating telomere attrition in a subject (e.g., a human subject) can be measured, for example, by making any of the following determinations: (i) an increase in telomere length in the subject (e.g., by at least 0.01 %, at least 0.1 %, at least 0.5%, at least 1.0%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%); or (ii) an increase in mRNA expression of telomerase, TERT, TERC, or telomerase-related genes (e.g., by at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%). Example 8 - Measuring Stem Cell Fitness

The success of the present composition in ameliorating stem cell exhaustion in a subject (e.g., a human subject) can be measured, for example, by determining an increase in the number of stem cells in vivo (e.g., by at least 1 %, at least 2%, at least 5%). This increase can be measured in vitro or in vivo via, for example, one or more of the following biomarkers (i) muscle satellite stem cell biomarkers (e.g., PAX7, LMNA, and emerin); (ii) neuronal stem cell biomarkers (e.g., Nestin, Sox2, ASCL1/Mash1 , ABCG2, BMI-1 , beta-Catenin, Brg1 , N-Cadherin, Calcitonin R, CD15/Lewis X, CD133, CDCP1 , COUP-TF I/NR2F1 , CXCR4, FABP7/B-FABP, FABP8/M-FABP, FGFR2, FGFR4, FoxD3, Frizzled-9, GCNF/NR6A1 , GFAP, Glutl , HOXB1 , ID2, LRTM1 , Meteorin, MSX1 , Musashi-1 , Musashi-2, Nestin, NeuroDI , Noggin, Notch-1 , Notch-2, Nrf2, Nucleostemin, Numb, Otx2, Pax3, Pax6, PDGF R alpha, PKC zeta, Prominin 2, ROR2, RUNX1/CBFA2, RXR alpha/NR2B1 sFRP-2, SLAIN1 , SOX1 , SOX2, SOX9, SOX11 , SOX21 , SSEA-1 , SSEA-4, TRAF-4, Vimentin, and ZIC1 ); (iii) pluripotency stem cell markers (e.g., Oct4, NANOG, Sox2, and Myc); (iv) hematopoietic stem cell markers (e.g., CD34, CD59, and CD90/Thy1 ); and (v) mesenchymal stem cell markers (e.g., CD105, CD90, CD73, CD44, CD45, CD29, CD166, Stro-1 , CD106, and GSTT1 ).

Since measuring stem cells in vivo is difficult and costly, success of the present composition in ameliorating stem cell exhaustion can also be measured, for example, by making the following preferred in vitro (“lab dish”) determinations (as well as in vivo determinations): (i) an increase in the number of stem cells (e.g., by at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (ii) increased viability of the stem cells (e.g., by at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (iii) an increase in potency of the stem cells in vitro (and in vivo as well) (e.g., by at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (iv) an increase in the quality of stem cells, measured for example by an increase in growth of the stem cells, an increase in the ability to proliferate, an increase in the ability to form colonies, or an increase in the ability to produce cells (e.g., by at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (v) an increased lifespan of stem cells, as measured in hours (e.g., by at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); or (vi) an increased resistance of stem cells against cellular stressors (e.g., heat, cold, or toxins) (e.g., by at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%).

The success of the present composition in ameliorating stem cell exhaustion in a subject (e.g., a human subject) can further be measured, for example, by making any of the following determinations in vitro, but also in vivo: (i) improved stem cell function as measured, for example, by replication ability, potency, proliferation capability, survival (as measured, for example, temporally (e.g., number of extra hours of survival), by exposing stem cells to physiological stressors and toxins), potency, and quality (e.g., stem cells have an increased number of replications or can generate/produce larger numbers of cells stemming from the stem cells or display increase cell division markers (e.g., cyclin D1 or increased B-catechin) (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (ii) improved stem cell transcriptome (i.e., the stem cell’s transcriptome is more similar to the transcriptome of a younger stem cell or a more functional stem cell) (e.g., by at least 0.5%, at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); (iii) improved stem cell proteome (i.e., the stem cell’s proteome is more similar to the proteome of a younger stem cell or more functional stem cell) (e.g., by at least 0.5%, at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); or (iv) an improved stem cell epigenome (i.e., the stem cell’s epigenome is more similar to the epigenome of a younger stem cell or more functional stem cell) (e.g., by at least 0.5%, at least 1 %, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%), as assessed, for example, by measuring methylation or histonylation patterns and comparing them to those of younger, more functional, or more potent stem cells. Example 9 - Measuring Physiological Biomarkers as Indicators of Stem Cell Fitness and Senescent Cell Levels in an Organism

The success of the present composition in ameliorating adverse physiological events in a subject (e.g., a human subject) can be measured, for example, by making any of the following determinations: (i) a decrease in the number and/or severity of skin wrinkles as measured, for example, via wrinkle surface area (e.g., via 3D topography or profi lorn etry); (ii) an increase in skin radiance as measured, for example, via an identometer, cutometer, transepidermal water loss meter, corneometer, or a skin transcriptome or proteome biomarker panel that shows improved skin functioning; (iii) improved cognition as measured, for example, via a cognitive test; (iv) improved feelings of happiness as measured, for example, via the Depressive Symptoms Scale; (v) reduced frailty, as measured, for example, via an international frailty scale or mobility scale (such as the Canadian Study on Health & Aging Clinical Frailty Scale (CSHA-CFS)); (vi) improved reaction time; (vii) improved neuromuscular capability and strength (e.g., increased stamina, improved balance, improved proprioception, improved mobility (measured by 6-minute walk test (6MWT), 4-m gait speed test (4MGST), improved short physical performance battery (SPPB) score, or tests measuring balance, gait speed tests, chair stand tests or other markers of physical function), increased grip strength, increased power, increased activity levels, improved 400 m walk test, and improved arm curl test results); (viii) improved blood flow, as measured by increase of unit of blood per mm ³ of tissue; (ix) reduced blood pressure; (x) improved vascular health, as measured, for example, via pulse wave velocity of the blood vessels or flow-mediated vasodilatation; (xi) induced weight loss, a reduction in waist circumference or BMI, or a reduction in abdominal fat volume; (xii) improvement in heart rate variability (HRV); and (xiii) improvement in an Al-assessed facial aging profile (e.g., as measured via facial Al software that for example assesses wrinkle area, blood flow, or skin sagging).

Importantly, if stem cell health is improved and cell senescence is reduced, the various physiological biomarkers discussed in this example will also improve. This is particularly the case with stem cells in that reducing the aging hallmark of stem cell decline (the measurement of which is discussed above) improves physiological biomarkers. Example 10 - Measuring Genomic Fitness

The success of the present composition in ameliorating genomic instability in a subject (e.g., a human subject) can be measured, for example, by determining a decrease in the level of 8-hydroxydeoxyguanosine (8-OHdG), gamma-H2AX, or biomarkers of DNA mutations (e.g., double strand breaks) in the subject (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%).

Example 11 - Measuring Improvement in Deregulated Nutrient Sensing

The success of the present composition in ameliorating deregulated nutrient sensing in a subject (e.g., a human subject) can be measured, for example, by making any of the following determinations: (i) an increase in the level of insulin sensitivity in the subject (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%); or (ii) a decrease in the level of fasting glucose, fasting insulin, LDL, HbA1c, mTOR activity, or mitochondrial reactive oxygen species in the subject (e.g., by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%).

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