Formulations for extending life and healthspan

Abstract

Described herein are compositions for delaying the onset or slowing the progression of frailty, reversing the aging phenotype, extending healthy lifespan, reducing morbidity, extending lifespan, and reducing the formation of senescent cells. [Selected figure] Figure 11A

Description

[Technical Field]

[0001] <Cross reference> This application claims the benefit of U.S. Provisional Application No. 62 / 489,884, filed April 25, 2017; and U.S. Provisional Application No. 62 / 646,734, filed March 22, 2018, which are incorporated by reference herein in their entireties. [Background technology]

[0002] Pharmacological treatment and prevention of natural declines of age and age-related diseases present challenges to the medical community, in part due to the stringent properties required of drugs for this purpose. The elderly patient population places an unusually high burden on pharmaceutical therapies to be bioavailable, non-toxic, and free of long-term adverse effects. Prevention requires treatment of patients who may be at risk for age-related disorders but who have no or mild symptoms and require drugs that do not harm their existing health. Treatment of patients with existing age-related diseases necessitates high demands for non-toxicity so as not to worsen existing health conditions. Furthermore, treatment or prevention of age-related diseases is generally likely to require years of drug treatment, and therefore such drugs must be free of cumulative toxicity or long-term adverse effects on organ systems.

[0003] Therefore, there is a need to find drugs and drug combinations that are non-toxic and suitable for administration to subjects before age-related diseases become evident or acute, or for longer-term administration.

[0004] The primary and secondary metabolites present in edible fruits and vegetables are a chemically diverse pharmacopeia that meet the criteria for the treatment of age-related diseases. Many of these compounds have very low toxicity and well-understood pharmacokinetic parameters due to their long-standing presence in the diet. Therefore, screening of compounds from these sources offers great potential for the treatment of ageing and age-related diseases. Summary of the Invention

[0005] In some embodiments, a method for extending the lifespan of a subject in need thereof is disclosed herein, comprising administering to the subject therapeutically effective amounts of berberine, a vitamin A compound, and α-ketoglutaric acid (AKG). In some examples, the berberine, the vitamin A compound, and AKG are administered to the subject as a single composition. In some examples, the berberine, the vitamin A compound, and α-ketoglutaric acid are administered to the subject individually. In some examples, the berberine, the vitamin A compound, and α-ketoglutaric acid are administered to the subject within 24 hours. In some examples, the vitamin A compound is a combination of retinol, retinal, and retinoic acid. (retinoic acid) , retinol palmitate, alpha-carotene, beta-carotene, and gamma-carotene. In some examples, the vitamin A compound is retinoic acid or retinol palmitate. In some examples, AKG is formulated as a calcium salt. In some examples, the subject is a mammal. In some examples, the mammal is a human. In some examples, the mammal is a dog. In some examples, the mammal is a cat. In some examples, the mammal is livestock. In some examples, the livestock is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses. In some examples, the berberine, vitamin A compound, and alpha-ketoglutaric acid are administered once daily. In some examples, the berberine, vitamin A compound, and alpha-ketoglutaric acid are administered twice daily. In some examples, the berberine, vitamin A compound, and alpha-ketoglutaric acid are administered in the morning and evening. In some examples, the berberine, vitamin A compound, and alpha-ketoglutaric acid are administered once weekly. In some instances, berberine, vitamin A compounds, and alpha-ketoglutaric acid are administered monthly.

[0006] In some embodiments, disclosed herein are methods for delaying the onset or progression of frailty in a subject in need thereof, the methods comprising administering to the subject therapeutically effective amounts of berberine, a vitamin A compound, and α-ketoglutaric acid (AKG). In some examples, the berberine, the vitamin A compound, and AKG are administered to the subject as a single composition. In some examples, the berberine, the vitamin A compound, and α-ketoglutaric acid are administered to the subject separately. In some examples, the berberine, the vitamin A compound, and α-ketoglutaric acid are administered to the subject within 24 hours. In some examples, the vitamin A compound is selected from the group consisting of retinol, retinal, retinoic acid, retinol palmitate, α-carotene, β-carotene, and γ-carotene. In some examples, the vitamin A compound is retinoic acid or retinol palmitate. In some examples, the AKG is formulated as a calcium salt. In some examples, the subject is a mammal. In some examples, the mammal is a human. In some examples, the mammal is a dog. In some examples, the mammal is a cat. In some examples, the mammal is a livestock animal. In some examples, the livestock animal is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses. In some examples, the berberine, vitamin A compound, and α-ketoglutaric acid are administered once daily. In some examples, the berberine, vitamin A compound, and α-ketoglutaric acid are administered twice daily. In some examples, the berberine, vitamin A compound, and α-ketoglutaric acid are administered in the morning and evening. In some examples, the berberine, vitamin A compound, and α-ketoglutaric acid are administered once weekly. In some examples, the berberine, vitamin A compound, and α-ketoglutaric acid are administered once monthly.

[0007] In some embodiments, compositions are disclosed herein that include a therapeutically effective amount of berberine, a therapeutically effective amount of a vitamin A compound, a therapeutically effective amount of AKG, and a pharmaceutically acceptable excipient. In some examples, the vitamin A compound is selected from the group consisting of retinol, retinal, retinoic acid, retinol palmitate, alpha-carotene, beta-carotene, and gamma-carotene. In some examples, the vitamin A compound is retinoic acid or retinol palmitate. In some examples, AKG is formulated as a calcium salt. In some examples, the composition further includes silymarin. In some examples, the therapeutically effective amount of berberine is at least 1,000 mg and not more than 5,000 mg. In some examples, the therapeutically effective amount of the vitamin A compound is at least 10,000 IU and not more than 20,000 IU. In some examples, the therapeutically effective amount of alpha-ketoglutaric acid is at least 350 mg and not more than 750 mg. In some examples, the composition is formulated into an oral dosage form. In some examples, the oral dosage form comprises a tablet, powder, suspension, serum, emulsion, capsule, granule, pill, gel, solution, or syrup. In some examples, the oral dosage form is a sustained release dosage form. In some examples, the oral dosage form is formulated into animal feed. In some examples, the oral dosage form is a gel. In some examples, the composition is formulated into an injectable dosage form. In some examples, the injectable dosage form comprises a liquid, suspension, or solution. In some examples, the injectable dosage form is a sustained release dosage form. In some examples, the composition is formulated into a topical dosage form. In some examples, the topical dosage form is a cream, foam, gel, lotion, ointment, or serum. In some examples, the composition is formulated into a hair care product. In some examples, the hair care product is formulated into a shampoo, conditioner, hair spray, or moisturizer. In some examples, the pharmaceutically acceptable excipient comprises an anti-adherent, a binder, a coating, a dye, a disintegrant, a flavoring, a glidant, a lubricant, a preservative, an adsorbent, or a vehicle.

[0008] In some embodiments, disclosed herein are methods for delaying the onset or progression of frailty in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of AKG and a vitamin A compound. In some examples, the AKG and the vitamin A compound are administered to the subject as a single composition. In some examples, the AKG and the vitamin A compound are administered to the subject separately. In some examples, the AKG and the vitamin A compound are administered to the subject within 24 hours. In some examples, the vitamin A compound is selected from the group consisting of retinol, retinal, retinoic acid, retinol palmitate, alpha-carotene, beta-carotene, and gamma-carotene. In some examples, the vitamin A compound is retinoic acid or retinol palmitate. In some examples, the AKG is formulated as a calcium salt. In some examples, the subject is a mammal. In some examples, the mammal is a human. In some examples, the mammal is a dog. In some examples, the mammal is a cat. In some examples, the mammal is a livestock. In some examples, the livestock is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses. In some examples, the AKG and vitamin A compound are administered once daily. In some examples, the AKG and vitamin A compound are administered twice daily. In some examples, the AKG and vitamin A compound are administered in the morning and evening. In some examples, the AKG and vitamin A compound are administered once weekly. In some examples, the AKG and vitamin A compound are administered once monthly. In some examples, the subject is female.

[0009] In some embodiments, disclosed herein is a method for treating or preventing alopecia in a subject, the method comprising administering a therapeutically effective amount of AKG and a vitamin A compound to the subject.In some examples, AKG and the vitamin A compound are administered to the subject as a single composition.In some examples, AKG and the vitamin A compound are administered to the subject separately.In some examples, AKG and the vitamin A compound are administered to the subject within 24 hours.In some examples, the vitamin A compound is selected from the group consisting of retinol, retinal, retinoic acid, retinol palmitate, alpha-carotene, beta-carotene, and gamma-carotene.In some examples, the vitamin A compound is retinoic acid or retinol palmitate.In some examples, AKG is formulated as a calcium salt.In some examples, the subject is a mammal.In some examples, the mammal is a human.In some examples, the mammal is a dog.In some examples, the mammal is a cat.In some examples, the mammal is a livestock. In some examples, the livestock is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses. In some examples, the AKG and vitamin A compound are administered once daily. In some examples, the AKG and vitamin A compound are administered twice daily. In some examples, the AKG and vitamin A compound are administered in the morning and evening. In some examples, the AKG and vitamin A compound are administered once weekly. In some examples, the AKG and vitamin A compound are administered once monthly.

[0010] In some embodiments, disclosed herein are methods for extending the lifespan of a subject, the methods comprising administering to the subject a therapeutically effective amount of AKG and vitamin D. In some examples, the AKG and vitamin D are administered to the subject as a single composition. In some examples, the AKG and vitamin D are administered to the subject separately. In some examples, the AKG and vitamin D are administered to the subject within 24 hours. In some examples, the AKG is formulated as a calcium salt. In some examples, the subject is a mammal. In some examples, the mammal is a human. In some examples, the mammal is a dog. In some examples, the mammal is a cat. In some examples, the mammal is livestock. In some examples, the livestock is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses. In some examples, the AKG and vitamin D are administered once daily. In some examples, the AKG and vitamin D are administered twice daily. In some examples, the AKG and vitamin D are administered in the morning and evening. In some examples, the AKG and vitamin D are administered once weekly. In some examples, the AKG and vitamin D are administered monthly. In some examples, the subject is female.

[0011] In some embodiments, disclosed herein are methods for delaying the onset or progression of frailty in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of AKG and vitamin D. In some examples, the AKG and vitamin D are administered to the subject as a single composition. In some examples, the AKG and vitamin D are administered to the subject separately. In some examples, the AKG and vitamin D are administered to the subject within 24 hours. In some examples, the AKG is formulated as a calcium salt. In some examples, the subject is a mammal. In some examples, the mammal is a human. In some examples, the mammal is a dog. In some examples, the mammal is a cat. In some examples, the mammal is livestock. In some examples, the livestock is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses. In some examples, the AKG and vitamin D are administered once daily. In some examples, the AKG and vitamin D are administered twice daily. In some examples, the AKG and vitamin D are administered in the morning and evening. In some examples, the AKG and vitamin D are administered weekly. In some examples, the AKG and vitamin D are administered monthly. In some examples, the subject is female.

[0012] In some embodiments, disclosed herein are methods for extending the lifespan of a subject, the method comprising administering to the subject a composition comprising a therapeutically effective amount of calcium salt of α-ketoglutaric acid (Ca-AKG). In some examples, the composition consists essentially of a therapeutically effective amount of calcium salt of α-ketoglutaric acid (Ca-AKG). In some examples, the subject is a mammal. In some examples, the mammal is a human. In some examples, the mammal is a dog. In some examples, the mammal is a cat. In some examples, the mammal is a livestock animal. In some examples, the livestock animal is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses. In some examples, the composition is administered once daily. In some examples, the composition is administered twice daily. In some examples, the composition is administered in the morning and evening. In some instances, the composition is administered once weekly. In some instances, the composition is administered once monthly. In some examples, the subject is female.

[0013] In some embodiments, disclosed herein are methods for delaying the onset or progression of frailty in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a composition comprising the calcium salt of alpha-ketoglutaric acid (Ca-AKG). In some examples, delaying the onset or progression of frailty comprises delaying the onset or progression of a frailty phenotype. In some examples, the frailty phenotype is selected from the group consisting of dermatitis, hunchback, tremor, and alopecia. In some instances, the frailty phenotype is dermatitis. In some instances, the frailty phenotype is hunchback. In some instances, the frailty phenotype is tremor. In some instances, the frailty phenotype is alopecia. In some examples, the composition consists essentially of a therapeutically effective amount of the calcium salt of alpha-ketoglutaric acid (Ca-AKG). In some examples, the subject is a mammal. In some examples, the mammal is a human. In some examples, the mammal is a dog. In some examples, the mammal is a cat. In some examples, the mammal is a livestock. In some examples, the livestock is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses. In some examples, the composition is administered once daily. In some examples, the composition is administered twice daily. In some examples, the composition is administered in the morning and evening. In some examples, the composition is administered once weekly. In some examples, the composition is administered once monthly. In some examples, the subject is female. In some examples, the composition is formulated into an oral dosage form. In some examples, the oral dosage form comprises a tablet, powder, suspension, serum, emulsion, capsule, granule, pill, gel, solution, or syrup. In some examples, the oral dosage form is a sustained release dosage form. In some examples, the oral dosage form is formulated into animal feed. In some examples, the oral dosage form is a gel. In some examples, the composition is formulated into an injectable dosage form. In some examples, the injectable dosage form comprises a liquid, suspension, or solution. In some examples, the injectable dosage form is a sustained release dosage form. In some examples, the composition is formulated into a topical dosage form.In some examples, the topical dosage form is a cream, foam, gel, lotion, ointment, or serum. In some examples, the composition is formulated into a hair care product. In some examples, the hair care product is formulated into a shampoo, conditioner, hair spray, or moisturizer. In some examples, the composition further comprises a pharmaceutically acceptable excipient selected from the group consisting of an anti-adhesion agent, a binder, a coating, a dye, a disintegrant, a flavoring, a glidant, a lubricant, a preservative, an adsorbent, or a vehicle. In some examples, the composition is administered to the subject for at least 4 months. In some examples, the composition is administered to the subject for at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 14 months, at least 16 months, or at least 18 months.

[0014] In some embodiments, disclosed herein are methods for extending the healthspan of a subject, the method comprising administering to the subject a composition comprising a therapeutically effective amount of calcium salt of α-ketoglutaric acid (Ca-AKG). In some examples, extending the healthspan comprises delaying the onset and progression of an aging-associated phenotype. In some examples, the aging-associated phenotype is selected from the group consisting of graying of hair, hair loss, and increased cellular senescence. In some examples, the aging-associated phenotype is graying of hair. In some examples, the aging-associated phenotype is hair loss. In some examples, the aging-associated phenotype is increased cellular senescence. In some examples, the composition consists essentially of a therapeutically effective amount of calcium salt of α-ketoglutaric acid (Ca-AKG). In some examples, the subject is a mammal. In some examples, the mammal is a human. In some examples, the mammal is a dog. In some examples, the mammal is a cat. In some examples, the mammal is livestock. In some examples, the livestock is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses. In some examples, the composition is administered once daily. In some examples, the composition is administered twice daily. In some examples, the composition is administered in the morning and evening. In some examples, the composition is administered once weekly. In some examples, the composition is administered once monthly. In some examples, the subject is female. In some examples, the composition is formulated into an oral dosage form. In some examples, the oral dosage form comprises a tablet, powder, suspension, serum, emulsion, capsule, granules, pill, gel, solution, or syrup. In some examples, the oral dosage form is a sustained release dosage form. In some examples, the oral dosage form is formulated into animal feed. In some examples, the oral dosage form is a gel. In some examples, the composition is formulated into an injectable dosage form. In some examples, the injectable dosage form comprises a liquid, suspension, or solution. In some examples, the injectable dosage form is a sustained release dosage form. In some examples, the composition is formulated into a topical dosage form. In some examples, the topical dosage form is a cream, foam, gel, lotion, ointment, or serum. In some examples, the composition is formulated into a hair care product.In some examples, the hair care product is formulated into a shampoo, conditioner, hair spray, or moisturizer. In some examples, the composition further comprises a pharmaceutically acceptable excipient selected from the group consisting of an anti-adhesion agent, a binder, a coating, a dye, a disintegrant, a flavoring, a glidant, a lubricant, a preservative, an adsorbent, or a vehicle. In some examples, the composition is administered to the subject for at least 4 months. In some examples, the composition is administered to the subject for at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 14 months, at least 16 months, or at least 18 months.

[0015] In some embodiments, a method for supporting the maintenance of health in a subject is disclosed herein, the method comprising administering to the subject a therapeutically effective amount of a composition comprising berberine, a vitamin A compound, and α-ketoglutaric acid (AKG). In some examples, the vitamin A compound is selected from the group consisting of retinol, retinal, retinoic acid, retinol palmitate, α-carotene, β-carotene, and γ-carotene. In some examples, the vitamin A compound is retinoic acid or retinol palmitate. In some examples, the AKG is formulated as a calcium salt. In some examples, supporting the maintenance of health includes supporting the maintenance of a healthy musculoskeletal system. In some examples, the composition is formulated into an oral dosage form. In some examples, the oral dosage form includes a tablet, powder, suspension, serum, emulsion, capsule, granule, pill, gel, solution, or syrup. In some examples, the subject is human. In some examples, the composition is administered to the subject once daily. In some examples, the composition is administered to the subject twice daily.

[0016] In some embodiments, disclosed herein are methods for supporting the maintenance of health in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a vitamin A compound and alpha-ketoglutarate (AKG). In some examples, the vitamin A compound is selected from the group consisting of retinol, retinal, retinoic acid, retinol palmitate, alpha-carotene, beta-carotene, and gamma-carotene. In some examples, the vitamin A compound is retinoic acid or retinol palmitate. In some examples, the AKG is formulated as a calcium salt. In some examples, supporting the maintenance of health comprises supporting the maintenance of a healthy musculoskeletal system. In some examples, the composition is formulated into an oral dosage form. In some examples, the oral dosage form comprises a tablet, powder, suspension, serum, emulsion, capsule, granule, pill, gel, solution, or syrup. In some examples, the subject is human. In some examples, the composition is administered to the subject once daily. In some examples, the composition is administered to the subject twice daily.

[0017] In some embodiments, a method of supporting the maintenance of health in a subject is disclosed herein, the method comprising administering to the subject a composition comprising a therapeutically effective amount of vitamin D and alpha-ketoglutarate (AKG). In some examples, the AKG is formulated as a calcium salt. In some examples, supporting the maintenance of health comprises supporting the maintenance of a healthy musculoskeletal system. In some examples, the composition is formulated into an oral dosage form. In some examples, the oral dosage form comprises a tablet, powder, suspension, serum, emulsion, capsule, granule, pill, gel, solution, or syrup. In some examples, the subject is a human. In some examples, the composition is administered to the subject once daily. In some examples, the composition is administered to the subject twice daily.

[0018] In some embodiments, disclosed herein are methods of supporting the maintenance of health in a subject, the methods comprising administering to the subject a therapeutically effective amount of a composition comprising the calcium salt of alpha-ketoglutarate (Ca-AKG). In some examples, supporting the maintenance of health includes supporting the maintenance of a healthy musculoskeletal system. In some examples, the composition is formulated into an oral dosage form. In some examples, the oral dosage form includes a tablet, powder, suspension, serum, emulsion, capsule, granule, pill, gel, solution, or syrup. In some examples, the subject is a human. In some examples, the composition is administered to the subject once daily. In some examples, the composition is administered to the subject twice daily. In some examples, supporting the maintenance of health includes supporting the maintenance of hair density. In some examples, supporting the maintenance of health includes supporting the maintenance of hair pigmentation. In some examples, supporting the maintenance of health includes supporting the maintenance of skin health. In some examples, supporting the maintenance of health includes supporting the maintenance of normal spinal curvature.

[0019] In some embodiments, disclosed herein are methods for treating or preventing alopecia in a subject in need thereof, the method comprising administering a therapeutically effective amount of AKG and vitamin D to the subject. In some examples, AKG and vitamin D are administered to the subject as a single composition. In some examples, AKG and vitamin D are administered to the subject separately. In some examples, AKG and vitamin D are administered to the subject within 24 hours. In some examples, AKG is formulated as a calcium salt. In some examples, the subject is a mammal. In some examples, the mammal is a human. In some examples, the mammal is a dog. In some examples, the mammal is a cat. In some examples, the mammal is livestock. In some examples, the livestock is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses. In some examples, AKG and vitamin D are administered once daily. In some examples, AKG and vitamin D are administered twice daily. In some examples, AKG and vitamin D are administered in the morning and evening. In some examples, AKG and vitamin D are administered once weekly. In some instances, AKG and vitamin D are administered monthly.

[0020] In some embodiments, disclosed herein are methods for extending the lifespan of a subject in need thereof, the method comprising administering to the subject therapeutically effective amounts of a vitamin A compound and α-ketoglutaric acid (AKG). In some examples, the vitamin A compound and AKG are administered to the subject as a single composition. In some examples, the vitamin A compound and α-ketoglutaric acid are administered to the subject separately. In some examples, the vitamin A compound and α-ketoglutaric acid are administered to the subject within 24 hours. In some examples, the vitamin A compound is selected from the group consisting of retinol, retinal, retinoic acid, retinol palmitate, alpha-carotene, beta-carotene, and gamma-carotene. In some examples, the vitamin A compound is retinoic acid or retinol palmitate. In some examples, the AKG is formulated as a calcium salt. In some examples, the subject is a mammal. In some examples, the mammal is a human. In some examples, the mammal is a dog. In some examples, the mammal is a cat. In some examples, the mammal is a livestock animal. In some examples, the livestock is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses. In some examples, the vitamin A compound and α-ketoglutaric acid are administered once daily. In some examples, the vitamin A compound and α-ketoglutaric acid are administered twice daily. In some examples, the vitamin A compound and α-ketoglutaric acid are administered in the morning and evening. In some examples, the vitamin A compound and α-ketoglutaric acid are administered once weekly. In some examples, the vitamin A compound and α-ketoglutaric acid are administered once monthly.

[0021] In some embodiments, disclosed herein are methods for extending the healthspan of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a vitamin A compound and α-ketoglutaric acid (AKG). In some examples, the vitamin A compound and AKG are administered to the subject as a single composition. In some examples, the vitamin A compound and α-ketoglutaric acid are administered to the subject separately. In some examples, the vitamin A compound and α-ketoglutaric acid are administered to the subject within 24 hours. In some examples, the vitamin A compound is selected from the group consisting of retinol, retinal, retinoic acid, retinol palmitate, α-carotene, β-carotene, and γ-carotene. In some examples, the vitamin A compound is retinoic acid or retinol palmitate. In some examples, AKG is formulated as a calcium salt. In some examples, extending the healthspan includes delaying the onset and progression of aging-related phenotypes. In some examples, the aging-associated phenotype is selected from the group consisting of graying, hair loss, and increased cellular senescence. In some examples, the aging-associated phenotype is graying. In some examples, the aging-associated phenotype is hair loss. In some examples, the aging-associated phenotype is increased cellular senescence. In some examples, the subject is a mammal. In some examples, the mammal is a human.

[0022] In some embodiments, disclosed herein are methods for extending the healthy lifespan of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of vitamin D and α-ketoglutarate (AKG). In some examples, vitamin D and AKG are administered to the subject as a single composition. In some examples, vitamin D and AKG are administered to the subject separately. In some examples, vitamin D and α-ketoglutarate are administered to the subject within 24 hours. In some examples, AKG is formulated as a calcium salt. In some examples, extending the healthy lifespan includes delaying the onset and progression of an aging-associated phenotype. In some examples, the aging-associated phenotype is selected from the group consisting of graying of hair, hair loss, and increased cellular senescence. In some examples, the aging-associated phenotype is graying of hair. In some examples, the aging-associated phenotype is hair loss. In some examples, the aging-associated phenotype is increased cellular senescence. In some examples, the subject is a mammal. In some examples, the mammal is a human.

[0023] In one embodiment, a method for assisting a subject in maintaining good health is disclosed herein, the method comprising administering to the subject a therapeutically effective amount of a composition comprising berberine, a vitamin A compound, and alpha-ketoglutarate (AKG), the composition modulating pathways associated with the normal aging process.

[0024] In one embodiment, disclosed herein is a method for assisting a subject in maintaining good health, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a vitamin A compound and alpha-ketoglutarate (AKG), the composition modulating a pathway associated with the normal aging process.

[0025] In one embodiment, a method for assisting a subject in maintaining good health is disclosed herein, the method comprising administering to the subject a composition comprising a therapeutically effective amount of vitamin D and alpha-ketoglutarate (AKG), the composition modulating a pathway associated with the normal aging process.

[0026] In one embodiment, disclosed herein is a method of assisting a subject in maintaining good health, the method comprising administering to the subject a therapeutically effective amount of a composition comprising the calcium salt of alpha-ketoglutarate (Ca-AKG), the composition modulating a pathway associated with the normal aging process.

[0027] In one embodiment, disclosed herein is a method for assisting a subject in maintaining good health, the method comprising administering to the subject a composition comprising a therapeutically effective amount of nicotinamide mononucleotide (NMN) and alpha-ketoglutarate (AKG), the composition modulating a pathway associated with the normal aging process.

[0028] <incorporation by reference> All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawings]

[0029] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth embodiments in which the principles of the invention are utilized, and the accompanying drawings in which:

[0030] [Figure 1] Figure 1 shows the longevity effects of the indicated compounds on aging in C. elegans. Compound 1 is Ca-AKG. Compound 2 is retinoic acid (RA), a metabolite of vitamin A that mediates its function. Compound 3 is berberine. Both Ca-AKG + RA and the combination of all three compounds have strong effects on longevity. [Figure 2] The combination of berberine, Ca-AKG, and retinoic acid (RA) shows beneficial effects on survival in female mice compared to control female mice (Cohort 1). [Figure 3]The combination of berberine, Ca-AKG, and vitamin A has an effect on frailty scores in female mice (top line) compared to control female mice (bottom line). (Cohort 1) [Figure 4] Effect of berberine, control, or retinoic acid (RA) on lifespan in female mice (Cohort 1). [Figure 5] Figure 1 shows the effects of a combination of berberine, Ca-AKG, and retinoic acid (RA) (3-fold), and a combination of Ca-AKG and berberine (2-fold) on the lifespan of female mice. (Cohort 1) [Figure 6] The effects of Ca-AKG + RP, Ca-AKG + vitamin D, vitamin D, retinol palmitate (RP), Ca-AKG, and control on lifespan in female mice (left) and Ca-AKG + RP, vitamin D, RP, Ca-AKG, and control on lifespan in male mice (right) (Cohort 2). [Figure 7] Figure 1 shows the effects of Ca-AKG, vitamin D, RP, and the combination of Ca-AKG + RP on frailty scores in combined female and male mice compared to controls. (Cohort 2) [Figure 8] The effects of Ca-AKG, vitamin D, RP, Ca-AKG + RP, Ca-AKG + vitamin D, and control on frailty scores in female mice after 2 months of treatment (left), and the effects of Ca-AKG, vitamin D, RP, Ca-AKG + RP, and control on frailty scores in male mice after 2 months of treatment (right) are shown (Cohort 2). [Figure 9]The effects of Ca-AKG, retinol palmitate (RP), and the combination of Ca-AKG and RP on frailty scores in female mice compared to controls (left) after 4 months of treatment. Starting at 18 months of age, female mice were fed the natural products as indicated. Frailty was monitored at the start of the experiment and after 4 months of treatment. The bar graph shows the median cumulative frailty measurements for each set of mice. The data show that only the combined RP and Ca-AKG treatment resulted in a statistically significant reduction in frailty. Statistical analysis is provided on the right, where combined Ca-AKG and RP treatment showed a statistically significant reduction compared to all other treatments, indicating a synergistic effect of the two compounds in reducing frailty. (Cohort 2) [Figure 10] A-C show frailty index mice after 2 months of treatment with the indicated compounds. A shows the effect of Ca-AKG, vitamin D3, and the combination of Ca-AKG + vitamin D3 on frailty scores in female mice (>20 mice per cohort) compared to controls (left) after 2 months of treatment. Both vitamin D3 and Ca-AKG + vitamin D3 have lower frailty. In B, the p-values ​​for each comparison are shown, demonstrating the statistical significance of vitamin D3 and Ca-AKG + vitamin D3 in the various conditions. In C, a similar approach was taken with male mice, demonstrating no significant reduction in frailty with vitamin D3. This indicates a gender-specific benefit of vitamin D3 in females. (Cohort 2) [Figure 11A] The effect of Ca-AKG on the mouse frailty phenotype is shown. A shows a control comparison of cages of female C57BL6 mice treated with placebo (right) or Ca-AKG (left). In cages where mice were treated with Ca-AKG, graying of the coat was dramatically reduced. [Figure 11B] The effect of Ca-AKG on the murine frailty phenotype is shown. Control comparisons of individual mice treated with placebo (right) or Ca-AKG (left) are shown. (Cohort 1) [Figure 12]The effect of irradiation (IR) on cells and the expression of senescence-associated β-galactosidase (β-gal), a marker of cellular senescence, are shown. As shown, cells upon exposure to irradiation demonstrate increased expression of β-galactosidase. When cells are pre-treated with Ca-AKG before exposure to irradiation, β-galactosidase expression is reduced compared to controls. (Cohort 1) [Figure 13] Figure 1 shows the effect of Ca-AKG on survival of female mice compared to control female mice (Cohort 1). [Figure 14] Figure 1 shows the effect of Ca-AKG on survival of male mice compared to control male mice (Cohort 1). [Figure 15] The effects of Ca-AKG and control on the lifespan of mice of both sexes are shown. (Cohort 1) [Figure 16] Effect of Ca-AKG on frailty scores in female mice (bottom line) compared to control female mice (top line). (Cohort 1) [Figure 17] Estimated lifespan extension in mice treated with Ca-AKG (Cohort 1). [Figure 18] Data demonstrating reduced hair graying in female mice with Ca-AKG treatment compared to controls measured at 23 months of age (Cohort 1) are presented. [Figure 19] A photograph of a mouse treated with Ca-AKG (left) next to a control mouse is shown. As shown in the photograph, the mice treated with Ca-AKG have fewer gray hairs than the control mice. (Cohort 1) [Figure 20] A photograph of a Ca-AKG-treated mouse (left) is shown next to a control mouse. As shown in the photograph, the Ca-AKG-treated mice had fewer gray hairs and experienced reduced hair loss than the control mice. (Cohort 1) [Figure 21] 1 shows data demonstrating reduced hair loss in mice treated with Ca-AKG compared to control mice (Cohort 1). [Figure 22]Figure 1 shows data demonstrating a reduction in kyphosis in mice treated with Ca-AKG compared to control mice (Cohort 1). [Figure 23] 1 shows data demonstrating a reduction in tremor in mice treated with Ca-AKG compared to control mice (Cohort 1). [Figure 24] This figure shows that 3 months of treatment of mice starting at 18 months of age is sufficient to dramatically reduce the levels of inflammatory cytokines. Each horizontal line represents the relative level of one protein. The first column represents cytokine levels after 3 months of treatment; these values ​​were normalized to 1. The middle column represents cytokine levels in 18-month-old animals. Notably, most values ​​are <1, indicating that the levels of these inflammatory factors increase between 18 and 21 months of age. The right column represents Ca-AKG-treated animals at 21 months of age, demonstrating that Ca-AKG (almost exclusively) prevents or, in some cases, reverses the increase in inflammatory cytokine levels. (Cohort 2) [Figure 25] FIG. 1 shows an exemplary schematic for the study of cellular senescence in irradiated cells either before or after treatment with Ca-AKG. [Figure 26] The effect of Ca-AKG on frailty scores in male mice compared to control male mice (left) is shown. The effect of Ca-AKG on frailty scores in female mice compared to control female mice (right) is also shown. (Cohort 1) [Figure 27] Effect of Ca-AKG on frailty scores compared to controls in combined female and male mice (Cohort 1). [Figure 28] Effect of Ca-AKG on kyphosis compared to control in combined female and male mice (Cohort 1). [Figure 29] Effect of Ca-AKG on dermatitis compared to control in paired female and male mice (Cohort 1). [Figure 30]Figure 1 shows the effect of Ca-AKG on body condition compared to controls in combined female and male mice. Body condition scores include visual scores and / or palpitations to assess the health of the animals. Signs of frailty result in higher frailty scores. (Cohort 1) [Figure 31] Figure 1 shows the effect of Ca-AKG on alopecia compared to control in combined female and male mice. (Cohort 1) [Figure 32] The effect of Ca-AKG on alopecia scores in male mice compared to control male mice (left) is shown. The effect of Ca-AKG on alopecia scores in female mice compared to control female mice (right) is also shown. (Cohort 1) [Figure 33] The effect of Ca-AKG on coat color (greying) in male mice compared to control male mice (left) and female mice compared to control female mice (right) is shown (Cohort 1). [Figure 34] Hunchback scores at 2 months are shown. 18-month-old mice were treated with the indicated compounds. After 2 months of treatment, vitamin D3 was found to significantly reduce the hunchback index (p<0.05). In this study, male and female mice were paired, with over 40 mice per gender-balanced cohort. [Figure 35] The effects of Ca-AKG, RP, vitamin D3, and the combination of Ca-AKG and RP on alopecia scores in female mice compared to control female mice after 4 months of treatment are shown. Alopecia was scored in female mice after 4 months of treatment with the indicated compounds, starting at 18 months of age. Neither Ca-AKG nor RP had a significant effect on their own, while the combination dramatically reduced alopecia. In contrast, vitamin D3 was sufficient to reduce alopecia on its own. The p-value matrix is ​​shown on the right, with both Ca-AKG and RP and vitamin D3 showing significant reductions (p<0.05). [Figure 36]The effects of Ca-AKG, RP, vitamin D3, and combinations of Ca-AKG + RP and Ca-AKG + vitamin D3 on fur color are shown. Several compound combinations prevent or reverse age-related changes in coat color. Female mice were treated with the indicated compounds for four months after birth, starting at 18 months of age. Ca-AKG + RP demonstrated a synergistic effect, and mice treated with vitamin D3 had a more youthful coat color, regardless of whether Ca-AKG was added. [Figure 37] The effects of Ca-AKG, RP, and the combination of Ca-AKG+RP on piloerection in female mice are shown. Four months of treatment with Ca-AKG+RP resulted in a reduction in piloerection in female mice (>20 per cohort). Neither compound was effective alone, nor was vitamin D3 (data not shown). Piloerection is defined as involuntary hair standing up and can be thought of as similar to "goosebumps." It increases with age and can also be caused by cold, reflecting the mice's inability to maintain body temperature. Ca-AKG+RP mice had elevated body temperatures compared to controls, but this did not reach statistical significance (data not shown). Piloerection can also be caused by fear or shock. DETAILED DESCRIPTION OF THE INVENTION

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used to practice or test the present invention, suitable methods and materials are described below. In case of conflict, the present patent specification, including definitions, will control. Furthermore, the materials, methods, and examples are merely illustrative and are not intended to be limiting.

[0032] <specific term> The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the bounds of good medical practice, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0033] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or sealing material. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and is not harmful to the patient. Some examples of materials that can act as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0034] In certain embodiments, the term "prevent" or "preventing" in relation to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disease or condition in a treated sample compared to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disease or condition compared to an untreated control sample.

[0035] As used herein, the terms "treat", "treating" or "treatment" include alleviating, relieving or ameliorating the symptoms of a disease or condition, ameliorating the underlying cause of a condition, inhibiting a disease or condition, e.g., halting the progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or prophylactically and / or therapeutically arresting the symptoms of a disease or condition.

[0036] In certain embodiments, the term "modulator" in reference to a protein or cellular process may refer to a compound that directly or indirectly alters the level of activity associated with the protein or cellular process.

[0037] In certain embodiments, the term "delay" or "delaying" in relation to a disease or disorder may refer to a compound that delays or postpones the onset of a disease or disorder in a statistical sample compared to an untreated control sample, or that delays the onset or reduces the severity of one or more symptoms of a disease or disorder compared to an untreated control sample.

[0038] As used herein, "α-ketoglutaric acid" or AKG includes derivatives of α-ketoglutaric acid (e.g., those described in MacKenzie, et al. (2007) Mol Cell Biol 27(9):3282-3289), analogs of α-ketoglutaric acid (e.g., phosphonate analogs (e.g., those described in Bunik, et al. (2005) Biochemistry 44(31):10552-61)), esters of α-ketoglutaric acid (e.g., dimethyl α-ketoglutarate and octyl α-ketoglutarate), and specific analogs of various species (e.g., human α-ketoglutaric acid, porcine α-ketoglutarate, mouse α-ketoglutarate, bovine α-ketoglutarate, etc.).

[0039] <Composition> Methods and compositions for lifespan, healthspan, and pharmacological treatment of age-related diseases are described herein. In some embodiments, methods and compositions for delaying the onset, slowing the progression of disorders, reversing aging-related phenotypes, extending healthspan, reducing pathologies, and reducing the formation of senescent cells are further disclosed herein.

[0040] In some embodiments, the present disclosure provides compositions comprising two or more compounds (individually referred to as "active ingredients") that are suitable for human consumption without FDA approval or that are generally recognized as safe (GRAS). In some embodiments, the present disclosure provides compositions comprising berberine, α-ketoglutaric acid (AKG), and vitamin A. In some embodiments, the present disclosure provides compositions comprising berberine, α-ketoglutaric acid (AKG), and retinoic acid (RA). In some embodiments, the present disclosure provides compositions comprising berberine, α-ketoglutaric acid (AKG), and retinol palmitate (RP). In some embodiments, the present disclosure provides compositions comprising AKG and vitamin A. In some embodiments, the present disclosure provides compositions comprising AKG and retinoic acid (RA). In some embodiments, the present disclosure provides compositions comprising AKG and retinol palmitate (RP). In some embodiments, the present disclosure provides compositions comprising AKG and vitamin D. In some embodiments, the present disclosure provides compositions comprising AKG and vitamin D3. In some embodiments, the present disclosure provides a composition comprising AKG and nicotinamide mononucleotide (NMN). In some examples, the AKG in the composition is a salt of AKG. In some examples, the AKG provided in the composition is a calcium salt of AKG (Ca-AKG). In some embodiments, the present disclosure provides a composition comprising a compound (e.g., AKG) that can be consumed by humans without FDA approval or is generally recognized as safe (GRAS). In some embodiments, AKG is provided as a salt. In some embodiments, AKG is provided as a calcium salt (Ca-AKG). These compounds can be classified as such because: a) they are present in the FDA SCOGS database and are generally recognized as safe by the U.S. Food and Drug Administration; or b) they are derived from plants (e.g., fruits, vegetables, herbs) present in traditional diets and are therefore recognized by the scientific community as safe for consumption. In some embodiments, a GRAS compound is a compound that can be consumed by humans without FDA approval.

[0041] The active ingredients may be in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of such compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Furthermore, the compounds described herein include unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0042] Disclosed herein (in some embodiments) are compositions comprising a senescence modulator. In some embodiments, the compound modulating the composition (e.g., AKG or Ca-AKG) is an agent that modulates two or more senescence pathways. In some embodiments, the senescence modulator is an agent that modulates the mTOR pathway, the insulin / insulin-like growth factor (IGF) pathway, an inflammatory pathway, a senescence pathway, a dietary pathway, or mitochondrial bioenergetics. In some embodiments, the senescence modulator modulates senescence associated with calorie restriction. In some embodiments, the senescence modulator modulates senescence associated with fasting. In some embodiments, the senescence modulator modulates mitochondrial biogenesis, mitochondrial repair, and mitophagy. In some embodiments, the senescence modulator modulates protein homeostasis and oxidative damage. In some embodiments, the senescence modulator enhances adult stem cell function. In some embodiments, the senescence modulator blocks the effects of senescent cells.

[0043] Further described herein are compositions comprising at least two senescence modulators. In some embodiments, the same compound modulates two or more senescence pathways. In some embodiments, the senescence modulator is an agent that modulates the mTOR pathway, the insulin / insulin-like growth factor (IGF) pathway, an inflammatory pathway, a senescence pathway, a dietary pathway, or mitochondrial bioenergetics. In some embodiments, the senescence modulator modulates senescence associated with calorie restriction. In some embodiments, the senescence modulator modulates senescence associated with fasting. In some embodiments, the senescence modulator modulates mitochondrial biogenesis, mitochondrial repair, and mitophagy. In some embodiments, the senescence modulator modulates protein homeostasis and oxidative damage. In some embodiments, the senescence modulator enhances adult stem cell function. In some embodiments, the senescence modulator blocks the effects of senescent cells.

[0044] In some embodiments, the composition comprises a therapeutically effective amount of an agent that modulates mTOR signaling and a therapeutically effective amount of an agent that modulates IGF signaling. In some embodiments, the composition comprises a therapeutically effective amount of an agent that modulates mTOR signaling and a therapeutically effective amount of an agent that modulates AMPK signaling. In some embodiments, the composition comprises a therapeutically effective amount of an agent that modulates mTOR signaling and a therapeutically effective amount of an agent that modulates mitochondrial bioenergetics.

[0045] In some embodiments, the composition comprises at least three aging modulators. In some embodiments, the composition comprises a therapeutically effective amount of an agent that modulates mTOR signaling, a therapeutically effective amount of an agent that modulates IGF signaling, and a therapeutically effective amount of an agent that modulates AMPK signaling. In some embodiments, the composition comprises a therapeutically effective amount of an agent that modulates mTOR signaling, a therapeutically effective amount of an agent that modulates IGF signaling, and a therapeutically effective amount of an agent that modulates mitochondrial bioenergetics. In some embodiments, the composition comprises a therapeutically effective amount of an agent that modulates mTOR signaling, a therapeutically effective amount of an agent that modulates AMPK signaling, and a therapeutically effective amount of an agent that modulates mitochondrial bioenergetics.

[0046] <Active Agent> Examples of active agents acting in the mTOR pathway include, but are not limited to, vitamin A (e.g., as an activator, see Chen et al. Stem Cells 2010:57-63(2010) and Berry et al. Proc Natl Acad Sci USA 108:4340-5(2011)), berberine (e.g., as an inhibitor, see Ming et al. PLoS One 9: e114573(2014) and Liu et al. Mol Cell Endocrinol 317:148-53(2010)), α-ketoglutarate (e.g., as an inhibitor, see Chin et al. Nature 510:397-401(2014)), resveratrol (e.g., as an inhibitor, see Park et al. Sci Rep. 6:21772(2016)), caffeine (e.g., as an inhibitor, see Saiki et al. Autophagy 7:176-87(2011)), aspirin (e.g., as an inhibitor, see Gao et al. J Biol Chem 278:24944-50(2003)), 5-aminoimidazole-4-carboxamide-1β-d-ribonucleoside (AICAR, e.g., as an inhibitor, see Bolster et al. J Biol Chem 277:23977-23980(2002)), and rapamycin.

[0047] Examples of active agents acting in the IGF pathway include, but are not limited to, vitamin A (e.g., as an activator, see Chen et al. Stem Cells 2010:57-63(2010) and Berry et al. Proc Natl Acad Sci USA 108:4340-5(2011)), aspirin (e.g., as an inhibitor, see Gao et al. J Biol Chem 278:24944-50(2003)), 2-deoxyglucose (e.g., as an activator, see Zhong et al. J Biol Chem 284: 23225-23233(2009)), apigenin (e.g., as an inhibitor, see Shukla et al. Pharm Res 29:1506-17(2012)), and berberine (e.g., as an inhibitor, see Ming et al. PLoS One 9:e114573(2014) and Liu et al. Mol Cell Endocrinol 317:148-53(2010)).

[0048] Examples of active agents acting in the AMPK pathway include, but are not limited to, α-ketoglutarate (e.g., as an activator, see Chin et al. Nature 510:397-401(2014)), metformin (e.g., as an activator, see Onken et al. PLoS One 5: e8758(2010)), rosaglitazone (e.g., as an activator, see LeBrasseur et al. Am J Physiol Endocrinol Metab 291:E175-E181(2006)), quercetin (e.g., as an activator, see LeBrasseur et al. Am J Physiol Endocrinol Metab 291:E175-E181(2006)), and AICAR (e.g., as an activator, see Bolster et al. J Biol Chem 277:23977-23980 (2002)).

[0049] Examples of active agents acting in the inflammatory pathway include, but are not limited to, berberine (e.g., as an anti-inflammatory agent, see Kuo et al. Cancer Lett 203:127-37(2004)), α-ketoglutaric acid (e.g., as an anti-inflammatory agent, see Wang et al. Amino Acids 47:1309-18(2015) and Hou et al. Amino Acids 39:555-64(2010)), and aminoguanidine (e.g., as an anti-inflammatory agent, see Calixto et al. PloS One 8:e76786(2013)).

[0050] Examples of active agents acting in the dietary restriction pathway include, but are not limited to, berberine (e.g., as a SIRT1 activator, see Gomes et al. Biochim Biophys Acta 1822:185-95(2012)) and α-ketoglutarate (e.g., as a dietary restriction mimetic, see Chin et al. Nature 510:397-401(2014)), reservatrol, metformin, and rapamycin.

[0051] Examples of active agents acting in mitochondrial bioenergetics include, but are not limited to, vitamin A (e.g., as an activator of mitochondrial oxygen consumption, see Actin-perez et al. FASEB J 24:627-636(2010)), vitamin D3 (e.g., as an inhibitor of the mitochondrial permeability transition pore, see Uberti et al. J Clin Endocrinol Metab 99:1367-1374(2014)), nicotinamide mononucleotide (NMN, e.g., as an activator of mitochondrial respiration, see Long et al. BMC Neurology 15:19(2015)), quercetin (e.g., as a scavenger of O2 radicals, see Gibellini et al. Evid Based Complement Alternat Med. 2015:527209(2015)), resveratrol (e.g., as a scavenger of H2O2, see Gibellini et al. Evid Based Complement Alternat Med. 2015:527209(2015)), and the like. Complement Alternat Med. 2015:527209(2015)), and curcumin (e.g., via upregulation of antioxidant enzymes, see Gibellini et al. Evid Based Complement Alternat Med. 2015:527209(2015)), and metformin.

[0052] In some embodiments, the active agent combination comprises two or more active agents selected from the group consisting of α-ketoglutaric acid, berberine, vitamin A, vitamin D, and nicotinamide mononucleotide (NMN). In some embodiments, the present disclosure provides a composition comprising berberine, α-ketoglutaric acid (AKG), and vitamin A. In some embodiments, the present disclosure provides a composition comprising berberine, α-ketoglutaric acid (AKG), and retinoic acid (RA). In some embodiments, the present disclosure provides a composition comprising berberine, α-ketoglutaric acid (AKG), and retinol palmitate (RP). In some embodiments, the present disclosure provides a composition comprising AKG and vitamin A. In some embodiments, the present disclosure provides a composition comprising AKG and retinoic acid (RA). In some embodiments, the present disclosure provides a composition comprising AKG and retinol palmitate (RP). In some embodiments, the present disclosure provides a composition comprising AKG and vitamin D. In some embodiments, the present disclosure provides a composition comprising AKG and vitamin D3. In some embodiments, the present disclosure provides a composition comprising AKG and nicotinamide mononucleotide (NMN). In some examples, the AKG in the composition is a salt of AKG. In some examples, the AKG provided in the composition is a calcium salt of AKG (Ca-AKG). In certain embodiments, the two or more compounds comprise α-ketoglutaric acid and berberine. In yet other embodiments, the two or more compounds comprise berberine and vitamin A. In some aspects, the present disclosure further provides a composition comprising an active agent selected from the group consisting of α-ketoglutaric acid, berberine, vitamin A, vitamin D, and nicotinamide mononucleotide (NMN). In some embodiments, the compound is AKG. In some embodiments, the AKG is provided as a salt. In some embodiments, the AKG is provided as a calcium salt (Ca-AKG).

[0053] Any of the compositions disclosed herein may further comprise a pharmaceutically acceptable excipient.

[0054] In some embodiments, the compositions of the present disclosure comprise two or more compounds selected from the group consisting of α-ketoglutaric acid, berberine, vitamin A, vitamin D, and nicotinamide mononucleotide (NMN), wherein the composition does not contain a pharmaceutically acceptable excipient. In some embodiments, the composition contains a pharmaceutically acceptable excipient. In some embodiments, the compositions of the present disclosure comprise a compound selected from the group consisting of α-ketoglutaric acid, berberine, vitamin A, vitamin D, and nicotinamide mononucleotide (NMN), wherein the composition does not contain a pharmaceutically acceptable excipient. In some embodiments, the composition contains a pharmaceutically acceptable excipient. In some embodiments, the compound is AKG. In some embodiments, the AKG is provided as a salt. In some embodiments, the AKG is provided as a calcium salt (Ca-AKG).

[0055] The active agents of the present invention have a combined effect on the phenotypes being treated or evaluated herein. In some embodiments, the active agents have an additive effect on lifespan, healthspan, frailty and its components, or age-related diseases. In some embodiments, the active agents have a synergistic effect on lifespan, healthspan, frailty and its components, or age-related diseases. In some embodiments, the active agents do not have a negative synergistic effect on lifespan, healthspan, frailty and its components, or age-related diseases.

[0056] <Berberine> In some embodiments, the compositions disclosed herein comprise berberine. In some embodiments, the compositions disclosed herein comprise berberine in combination with one or more of the active agents disclosed herein (e.g., AKG or Ca-AKG, vitamin A or retinoic acid, or retinol palmitate, vitamin D, NMN).

[0057] Berberine (also known as umbellatine or 5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxole[5,6-a]quinolizinium, Chemical I) is a plant active ingredient in Berberis vulgaris (barberry berry), Berberis aristata (tree turmeric), Mahonia aquifolium (barberry), Goldenseal (green alder root), Mahonia japonica (yellow root plant), Phellodendron bark (Ambergris), Coptis japonica (Chinese goldthread), Guduchi (Tinospora cordifolia), and Argemone It is a benzoisoquinoline alkaloid found in plants such as California poppy, California poppy, and California poppy.

[0058] [ka]

[0059] In some embodiments, berberine is provided in pure synthetic form. Pure synthetic forms of berberine are available from commercial providers (e.g., Sigma-Aldrich). Methods for synthesizing berberine and related benzoisoquinoline analogs from commercially available derivatives of phenylethylamine and benzaldehyde have been described and can be found, for example, in Wang et al. Bioorganic & Medicinal Chemistry 20: 6552-6558 (2012).

[0060] In other embodiments, berberine is provided in the form of an extract from any of the above-mentioned plant species.Methods for high-purity extraction of berberine from plant materials are known, and can be found, for example, in Liu et al. Journal of Pharmaceutical and Biomedical Analysis 41:1056-1060(2006), which describes extraction from Coptis chinensis Franch rhizome using supercritical fluid extraction.

[0061] Both embodiments described for providing berberine are capable of producing highly pure berberine. In some embodiments, the purity is in the range of 80% to 99.9%, or 85% to 99.9%, or 90% to 99.9%, or 95% to 99.9%. In some embodiments, the purity is in the range of about 80% to about 99.9%, or about 85% to about 99.9%, or about 90% to about 99.9%, or about 95% to about 99.9%. In some embodiments, the purity is greater than 80%, greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or greater than 99.9%.

[0062] In some embodiments, berberine is provided as a chloride salt. In other embodiments, berberine is provided as a salt containing other anions listed in the US FDA Orange Book. Such anions include acetate, benzoate, besylate, bromide, camsylate, carbonate, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, iodide, isethionate, lactate, lactobionate, malate, maleate, mesylate, dimethyl sulfate, napsylate, nitrate, oxalate, pamoate, phosphate, stearate, succinate, sulfate, tartrate / bitartrate, and tosylate.

[0063] In some embodiments, the therapeutically effective amount of berberine is about 1,000 mg to about 5,000 mg. In some embodiments, the therapeutically effective amount is at least 1,000 mg, at least 1,500 mg, at least 2,000 mg, at least 2,500 mg, at least 3,000 mg, at least 3,500 mg, or at least 4,000 mg. In other embodiments, the therapeutically effective amount is less than 5,000 mg, less than 5,500 mg, less than 4,000 mg, less than 3,500 mg, less than 3,000 mg, or less than 2,000 mg.

[0064] <α-ketoglutaric acid (AKG)> In some embodiments, the compositions disclosed herein comprise AKG. In some embodiments, the compositions disclosed herein comprise AKG in combination with one or more of the active agents disclosed herein (e.g., berberine, vitamin A or retinoic acid, or retinol palmitate, vitamin D, NMN).

[0065] α-Ketoglutaric acid (Formula 2, also known as 2-oxopentanedioic acid, 2-ketoglutaric acid, 2-oxoglutaric acid, and oxoglutaric acid. At physiological pH, α-ketoglutaric acid exists in the deprotonated form shown as Formula 3). α-Ketoglutaric acid is an intermediate in the eukaryotic Krebs cycle and is biosynthesized in such organisms from isocitrate (the Krebs cycle process) or L-glutamate (via alanine transaminase). Both α-ketoglutaric acid and its corresponding salts are commercially available, either by fermentation culture preparation (see, e.g., U.S. Pat. No. 2,776,926) or by chemical synthesis from closely related compounds.

[0066] [ka]

[0067] Consistent with its role in energy production via the Krebs cycle, α-ketoglutarate is a key regulator of cellular bioenergetics, implicated as an inhibitor of ATP synthase subunit β and an indirect inhibitor of the kinase mTOR, resulting in partial inhibition of the mitochondrial electron transport chain.

[0068] In some embodiments, α-ketoglutaric acid is provided as the free acid (α-ketoglutaric acid). In other embodiments, α-ketoglutaric acid is provided as the monosodium salt, disodium salt, or monopotassium salt. In further embodiments, the disodium salt of α-ketoglutaric acid is provided as an anhydrous salt, a monohydrate salt, or a dihydrate salt. In further embodiments, α-ketoglutaric acid is provided as a monovalent or divalent salt with other cations listed in the US FDA Orange Book. Such cations include calcium, diolamine, lithium, lysine, magnesium, meglumine, olamine, tromethamine, and zinc.

[0069] Further disclosed herein in certain aspects are compositions comprising α-ketoglutarate. In some embodiments, the α-ketoglutarate is provided as a calcium salt. In some embodiments, the calcium α-ketoglutarate may be hydrated calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate may be monohydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate may be hemihydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate may be anhydrous calcium α-ketoglutarate.

[0070] In some embodiments, the therapeutically effective amount of α-ketoglutaric acid is from about 350 mg to about 2000 mg, or at least 350, at least 400, at least 450, at least 500, at least 550, at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, at least 950, at least 1000, at least 1050, at least 1100, at least 1150, at least 1200, at least 1250, at least 1300, at least 1350, at least 1400, at least 1450, at least 1500, at least 1550, at least 1600, at least 1650, at least 1700, at least 1750, at least 1800, at least 1850, at least 1900, or at least 1950 mg. In other embodiments, the therapeutically effective amount is less than 2000, less than 1950, less than 1900, less than 1850, less than 1800, less than 1750, less than 1700, less than 1650, less than 1600, less than 1550, less than 1500, less than 1450, less than 1400, less than 1350, less than 1300, less than 1250, less than 1200, less than 1150, less than 1100, less than 1050, less than 1000, less than 950, less than 900, less than 850, less than 800, less than 750, less than 700, less than 650, less than 600, less than 550, less than 500, less than 450, or 400 mg.

[0071] <Vitamin A> In some embodiments, the compositions disclosed herein include vitamin A. In some embodiments, the compositions disclosed herein include vitamin A in combination with one or more of the active agents disclosed herein (e.g., berberine, AKG or Ca-AKG, vitamin D, NMN). As disclosed herein, vitamin A can also be provided as retinoic acid (RA) or retinol palmitate (RP).

[0072] Vitamin A is an essential organic nutrient for animals, and it is converted between various chemical forms in cells. These forms include retinol esters (Formula 4), retinol (Formula 5), ​​retinal (Formula 6), and retinoic acid (Formula 7). As retinal, vitamin A is essential for the formation of rhodopsin in the eye. As retinoic acid, vitamin A plays an important role as a hormone-like growth factor for epithelial and immune cells. In relation to aging-related symptoms, this study shows that vitamin A in the form of retinoic acid activates AMPK and stimulates glucose uptake in cells (e.g., Yun et al. J Biol Chem 283:33969-33974 (2008)), thus acting as an antidiabetic agent.

[0073] Vitamin A also exists in plants in various provitamin A forms that are converted to retinol in animals. Such forms include alpha-carotene (formula 8), beta-carotene (formula 9), and gamma-carotene (formula 10). Due to the various forms in which vitamin A exists, the nutritional amount of vitamin A is defined in international units (IU), which are independent of the chemical form of vitamin A. For example, 1 IU is biologically equivalent to 0.3 mg of retinol, while 1 IU is biologically equivalent to 0.6 mg of beta-carotene. Information regarding the IU equivalents of various forms of vitamin A is known in the art.

[0074] In some embodiments, vitamin A is provided as a retinol ester, retinol, retinal, retinoic acid, or retinoic acid salt containing a pharmaceutically acceptable cation as described above. In other embodiments, vitamin A is provided as alpha-carotene, beta-carotene, or gamma-carotene, as represented by formulas 8-10.

[0075] [ka]

[0076] [ka]

[0077] [ka]

[0078] [ka]

[0079] [ka]

[0080] [ka]

[0081] [ka]

[0082] A therapeutically effective amount of vitamin A, such as Formulas 4-10, or any derivative described herein, is about 10,000 IU to about 20,000 IU. In some embodiments, the therapeutically effective amount is at least 10,000, at least 12,500, at least 15,000, or at least 17,500 IU. In other embodiments, the therapeutically effective amount is less than 20,000, less than 17,500, less than 15,000, or less than 12,500 IU.

[0083] In some embodiments, the optimal dose of vitamin A is determined using experimental model systems (e.g., C. elegans, Drosophila melanogaster, mouse models). In other embodiments, the optimal dose of berberine is determined using clinical trials. The optimal dose may depend on the subject's body mass, weight, or blood volume.

[0084] <How to use> Described herein are methods for treating, delaying the onset, or slowing the progression of a disorder in a subject in need thereof by administering an active agent compound disclosed herein or a composition thereof. In some embodiments, the present disclosure provides methods for extending the lifespan or survival of a subject in need thereof, delaying the onset or slowing the progression of a disorder, reversing senescence-associated phenotypes, extending healthspan, reducing morbidity, and reducing the formation of senescent cells by administering a composition comprising an active agent of the present disclosure.

[0085] In some embodiments, the composition comprises two or more active agents selected from the group consisting of α-ketoglutaric acid, berberine, vitamin A, vitamin D, and nicotinamide mononucleotide (NMN). In some embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and vitamin A. In some embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and retinoic acid (RA). In some embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and retinol palmitate (RP). In some embodiments, the composition comprises AKG and vitamin A. In some embodiments, the composition comprises AKG and retinoic acid (RA). In some embodiments, the composition comprises AKG and retinol palmitate (RP). In some embodiments, the composition comprises AKG and vitamin D. In some embodiments, the composition comprises AKG and vitamin D3. In some embodiments, the composition comprises AKG and nicotinamide mononucleotide (NMN). In some examples, the AKG in the composition is a salt of AKG. In some examples, the AKG provided in the composition is a calcium salt of AKG (Ca-AKG). In some embodiments, the two or more compounds include α-ketoglutaric acid and berberine. In yet other embodiments, the two or more compounds include berberine and vitamin A. In some aspects, the present disclosure provides a composition comprising an active agent selected from the group consisting of α-ketoglutaric acid, berberine, vitamin A, and vitamin D. In some aspects, the compound is AKG. In some embodiments, the AKG is provided as a salt. In some embodiments, the AKG is provided as a calcium salt (Ca-AKG).

[0086] In some aspects, the present disclosure provides methods for delaying the onset or progression of disorders, reversing senescence-associated phenotypes, extending healthy lifespan, reducing morbidity, and reducing the formation of senescent cells in a subject in need thereof by administering a composition comprising a calcium salt of ketoglutaric acid. In some embodiments, the calcium α-ketoglutarate can be hydrated calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be monohydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be hemihydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be anhydrous calcium α-ketoglutarate. In other aspects, the present disclosure provides methods for delaying the onset or progression of disorders, reversing senescence-associated phenotypes, extending healthy lifespan, and reducing morbidity in a subject in need thereof by administering a composition consisting essentially of a calcium salt of α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be hydrated calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be monohydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be hemihydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be anhydrous calcium α-ketoglutarate.

[0087] <Life span> In one aspect, the present disclosure provides a method for extending lifespan by administering an active agent or composition thereof described herein. In many embodiments, lifespan extension is assessed in a convenient non-human subject, whose lifespan is shorter than that of humans. Examples of non-human animals used to evaluate lifespan extension interventions include C. elegans, Drosophila melanogaster, and Mus musculus. The use of the C. elegans platform to evaluate lifespan or healthspan interventions, along with appropriate methods, is illustrated in Example 1. The use of Drosophila melanogaster or Mus musculus to evaluate lifespan or healthspan interventions can be found, for example, in Bauer et al. Proc Natl Acad Sci US A. 101:12980-5 (2004) and Selman et al. FASEB J 22:807-18 (2008).

[0088] In some embodiments, the present disclosure provides a method for extending lifespan by administering an active agent or composition thereof described herein. In some embodiments, the composition comprises two or more active agents selected from the group consisting of α-ketoglutaric acid, berberine, vitamin A, vitamin D, and nicotinamide mononucleotide (NMN). In some embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and vitamin A. In some embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and retinoic acid (RA). In some embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and retinol palmitate (RP). In some embodiments, the composition comprises AKG and vitamin A. In some embodiments, the composition comprises AKG and retinoic acid (RA). In some embodiments, the composition comprises AKG and retinol palmitate (RP). In some embodiments, the composition comprises AKG and vitamin D. In some embodiments, the composition comprises AKG and vitamin D3. In some embodiments, the composition comprises AKG and nicotinamide mononucleotide (NMN). In some examples, the AKG in the composition is a salt of AKG. In some examples, the AKG provided in the composition is a calcium salt of AKG (Ca-AKG). In some embodiments, the two or more compounds comprise α-ketoglutaric acid and berberine. In yet other embodiments, the two or more compounds comprise berberine and vitamin A. In some aspects, the present disclosure provides a composition comprising an active agent selected from the group consisting of: α-ketoglutaric acid, berberine, vitamin A, and vitamin D. In some embodiments, the compound is AKG. In some embodiments, the AKG is provided as a salt. In some embodiments, the AKG is provided as a calcium salt (Ca-AKG).

[0089] In one aspect, the present disclosure provides a method for extending the lifespan of a subject, comprising administering to the subject a composition comprising a calcium salt of α-ketoglutaric acid. In another aspect, the present disclosure provides a method for extending the lifespan of a subject, comprising administering to the subject a composition consisting essentially of a calcium salt of α-ketoglutaric acid. In some embodiments, the calcium α-ketoglutaric acid can be hydrated calcium α-ketoglutaric acid. In some embodiments, the calcium α-ketoglutaric acid can be monohydrate calcium α-ketoglutaric acid. In some embodiments, the calcium α-ketoglutaric acid can be hemihydrate calcium α-ketoglutaric acid. In some embodiments, the calcium α-ketoglutaric acid can be anhydrous calcium α-ketoglutaric acid.

[0090] In some embodiments, Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg.In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, Ca-AKG is administered in a dosage of at least 350 mg. In some examples, Ca-AKG is administered in a dosage of at least 400 mg. In some examples, Ca-AKG is administered in a dosage of at least 450 mg. In some examples, Ca-AKG is administered in a dosage of at least 500 mg. In some examples, Ca-AKG is administered in a dosage of at least 550 mg. In some examples, Ca-AKG is administered in a dosage of at least 600 mg. In some examples, Ca-AKG is administered in a dosage of at least 650 mg.In some examples, Ca-AKG is administered in a dosage of at least 700 mg. In some examples, Ca-AKG is administered in a dosage of at least 750 mg. In some examples, Ca-AKG is administered in a dosage of at least 800 mg. In some examples, Ca-AKG is administered in a dosage of at least 900 mg. In some examples, Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, Ca-AKG is administered in a dosage of at least 1900 mg. In some examples, Ca-AKG is administered in a dosage of at least 2000 mg.

[0091] In some embodiments, hydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 350 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 400 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 450 mg.In some examples, the hydrated Ca-AKG is administered in a dosage of at least 500 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 550 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 600 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 650 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 700 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 750 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 800 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 900 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1900 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 2000 mg.

[0092] In some embodiments, the monohydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 550 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 450 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 350 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 450 mg.In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 550 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 650 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 700 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 750 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 800 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 900 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1900 mg. In some instances, the monohydrate Ca-AKG is administered in a dosage of at least 2000 mg.

[0093] In some embodiments, hemihydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 350 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 450 mg.In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 500 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 550 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 600 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 650 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 700 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 750 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 800 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 900 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1000 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1100 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1200 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1300 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1400 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1500 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1600 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1700 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1800 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1900 mg. In some instances, hemihydrate Ca-AKG is administered in a dosage of at least about 2000 mg.

[0094] In some embodiments, anhydrous Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg.In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of about 350 mg to about 450 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of about 350 mg to about 400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 350 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 450 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 550 mg.In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 600 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 650 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 700 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 750 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 800 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 900 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1000 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1100 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1200 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1300 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1600 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1700 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1800 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1900 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 2000 mg.

[0095] In some embodiments, administering a composition comprising AKG extends the lifespan or survival of a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A extends the lifespan or survival of a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A extends the lifespan or survival of a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D extends the lifespan or survival of a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN extends the lifespan or survival of a subject in need thereof.

[0096] In some embodiments, administration of an active agent or composition thereof extends the lifespan of the non-human subject relative to a control non-human subject. In certain embodiments, the administration extends the lifespan of the non-human subject by at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% relative to the lifespan of the control non-human subject. In some embodiments, the lifespan comparison is performed on an individual basis, with the lifespan of each non-human subject being compared to those parameters assessed in a control population relative to the dose series or biomarker levels analyzed. In other embodiments, the comparison is performed by assessing and comparing the average lifespan of the test non-human subjects with the average lifespan of a control population.

[0097] In some embodiments, administration of an active agent or composition thereof slows or reverses the progression of biomarkers of aging in non-humans or humans. Biomarker strategies for measuring aging are currently under development and can be used to test the effectiveness of aging interventions. Most notably, the epigenetic clock is likely to measure the biological age of human cells (see, e.g., Chen et al. Aging, 8:1844-1865(2016), PMID 27690265), dogs (see, e.g., Thompson et al. Aging 9:1055-1068(2017), PMID 28373601), and mice (Petkovich et al. Cell Metab 25:954-960(2017), PMID 28380383). Other biomarker strategies include, but are not limited to, inflammatory cytokine levels, p16INK4A protein levels in specific cell populations, telomere length, as well as specific metabolite levels.

[0098] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a livestock animal. In some embodiments, the livestock animal is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses.

[0099] In some embodiments, the composition is formulated into an oral dosage form. In some embodiments, the oral dosage form comprises a tablet, powder, suspension, serum, emulsion, capsule, granule, pill, gel, solution, or syrup. In some examples, the oral dosage form is a sustained release dosage form. In some examples, the oral dosage form is formulated into animal feed. In some examples, the oral dosage form is a gel. In some embodiments, the composition is formulated into an injectable dosage form. In some embodiments, the injectable dosage form comprises a liquid, suspension, or solution. In some examples, the injectable dosage form is a sustained release dosage form. In some embodiments, the composition is formulated into a topical dosage form. In some embodiments, the topical dosage form is a cream, foam, gel, lotion, ointment, or serum. In some embodiments, the composition is formulated into a hair care product. In some embodiments, the hair care product is formulated into a shampoo, conditioner, hair spray, or moisturizer.

[0100] In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In further embodiments, the pharmaceutically acceptable excipient comprises an anti-adhesive agent, a binder, a coating, a dye, a disintegrant, a flavoring agent, a glidant, a lubricant, a preservative, an adsorbent, or a vehicle. In some examples, the composition further comprises silymarin.

[0101] In some embodiments, the composition is administered for a specific period of time. In some embodiments, the composition is administered over a long-term, chronic treatment period, including the entire lifespan of the subject, to ameliorate or otherwise control or limit the symptoms of the subject's disease or disorder. Within the treatment period, the composition is administered on a specific time schedule. In further embodiments, the composition is administered 1, 2, 3, or 4 times daily. In some embodiments, the composition is administered once daily. In some embodiments, the composition is administered twice daily. In some embodiments, the composition is administered in the morning and evening. In some embodiments, the composition is administered 1, 2, 3, or 4 times weekly. In some embodiments, the composition is administered once weekly. In some embodiments, the composition is administered 1, 2, 3, or 4 times monthly. In some embodiments, the composition is administered monthly. In some embodiments, the composition is administered for at least 3 months every year. In some embodiments, the composition is administered one month every six months.

[0102] <Flail> In one aspect, the present disclosure provides a method for treating, delaying the onset, or slowing the progression of frailty using an active agent or composition thereof described herein. The term "frailty" refers to a biological syndrome characterized by a decline in multiple physiological systems, resulting in reduced preparedness or resistance to stressors. Subjects suffering from frailty have improved susceptibility to adverse health effects from events that stress one or more of these physiological systems. In humans, frailty is often manifested by nonspecific symptoms, falls, delirium, fluctuating disability, or a combination thereof. Nonspecific symptoms include extreme fatigue, unexplained weight loss, and frequent infections. Falls include hot falls (a mild illness that reduces postural balance below a threshold to maintain stability) or spontaneous falls (a debilitating decline in critical postural systems resulting from decreased vision, balance, and strength). Delirium refers to the rapid onset of fluctuating confusion and impaired consciousness. Fluctuating disability refers to the day-to-day instability of a patient's ability to function independently.

[0103] Various clinical scoring and rating systems for frailty are known to those skilled in the art and are suitable for assessing the effect of treatment on frailty. In some embodiments, frailty is assessed in humans using the 70-item CSHA Frailty Index (see Theou et al. Age Ageing 42: 614-619 (2013)). A brief description of how the index is used follows:

[0104] Items (see items in Table 1 below) are assessed, including the presence and / or severity of the disorder, daily living abilities, and physical signs from clinical and neurological examinations. Each deficit is divided into two or three categories and mapped to a 0-1 interval (i.e., individual items have scores of 0, 0.33, 0.50, 0.67, or 1.0) to represent the occurrence and severity of the problem. For individuals, a 70-dimensional vector is constructed, such that a person with five deficits has a score of 5 / 70 = 0.071.

[0105] [Table 1]

[0106] Further details about the application of the CSHA Frailty Index (e.g., calculation of scores for individual measurements) can be found in other publications in the field, for example, Searle et al. A standard procedure for creating a frailty index. BMC Geriatrics 8:24 (2008). An example of the use of the CSHA Frailty Index in humans can be found in Example 5, which describes the selection of pre-frail individuals for the treatment of frailty and evaluation of pharmacological treatments thereof.

[0107] In other embodiments, frailty is assessed in non-human animals, such as mice. Recognized signs of frailty in mice correspond to many of those in humans and include metabolic (e.g., body temperature, weight), coat (e.g., alopecia, loss of coat color, dermatitis, loss of whiskers, grooming), physical / musculoskeletal (e.g., tumors, protruding abdomen, hunched back, stiff tail, gait disturbance, tremor, decreased forelimb grip strength, body condition / muscle wasting / obesity), vestibulo-cochlear / auditory (e.g., vestibular impairment, hearing loss), ocular / nasal (e.g., cataracts, corneal opacities, eye discharge, microphthalmos, loss of vision, increased menace reflex, nasal discharge), digestive / genitourinary (e.g., malocclusion, rectal prolapse, vaginal / uterine / penile prolapse, diarrhea), respiratory (e.g., abnormal respiratory rate or depth), and discomfort symptoms (e.g., increased Mouse Grimace Scale, piloerection).

[0108] In some embodiments, frailty is assessed in mice using a 31-item clinical frailty index encompassing the 31 exemplary phenotypes described above, for example, as described in Whitehead et al. J Gerontol A Biol Sci Med Sci 69:621-632 (2014). Clinical examinations are performed at approximately the same time each day, including body weight and abdominal infrared surface temperature measurements, followed by clinical examinations to assess the 31 frailty phenotypes. The severity of each defect is assessed on a scale, with 0 indicating no signs, 0.5 indicating mild defects, and 1 indicating severe defects. Defects in body weight (g) and body surface temperature (°C) are scored on a scale of 0 to 1 (0.25, 0.5, 0.75, and 1.0) based on the number of standard deviations from the baseline value for young adult animals, according to the number of standard deviations by which the score varies from the mean (1 being >3 SD). The sum of the scores for each parameter generates a final 31-item frailty index, which can be compared between individual mice according to standard statistical methods for assessing frailty.

[0109] In some embodiments, frailty is assessed in mice by a simple 8-item functional frailty index, as described, for example, in Whitehead et al. J Gerontol A Biol Sci Med Sci 69:621-632 (2014) and Parks et al. J Gerontol A Biol Sci Med Sci. 67:217-227 (2012). This method assesses seven performance parameters based on the open-field behavior of mouse subjects: 1) total distance traveled in 10 minutes; 2) maximum distance traveled during bouts of inactivity; 3) total time spent moving (seconds); 4) percentage of total time spent moving; 5) change in direction per unit distance traveled, referred to as meandering (degrees / cm; 0°-180°); 6) average speed of movement over 10 minutes (cm / s); and 7) frequency of rearing (number of times / 10 minutes). An eighth non-movement parameter (body weight) is also assessed. Open field assessments were conducted daily from 10:00 AM to noon. Mice were weighed and their activity recorded using automated video tracking software for 10 minutes in the open field arena. Videos were digitized with an analog-to-digital converter and analyzed with video tracking analysis software to obtain values ​​for the parameters used to create an eight-item frailty index. The mean and standard deviation for each of these parameters were calculated and assigned to a score quantile between 0 and 1 (0.25, 0.5, 0.75, and 1.0) according to the number of standard deviations the score varied from the mean (1 being >3 SD). The parameters were added and divided by 8 to obtain a frailty index score for each mouse subject, ranging from 0 to 1. Higher scores correspond to increasingly frail mice.

[0110] In some embodiments, the present disclosure provides methods for treating, delaying the onset of, or slowing the progression of frailty using the compositions described herein. In some embodiments, the compositions comprise two or more active agents selected from the group consisting of α-ketoglutaric acid, berberine, vitamin A, vitamin D, and nicotinamide mononucleotide (NMN). In some embodiments, the compositions comprise berberine, α-ketoglutaric acid (AKG), and vitamin A. In some embodiments, the compositions comprise berberine, α-ketoglutaric acid (AKG), and retinoic acid (RA). In some embodiments, the compositions comprise berberine, α-ketoglutaric acid (AKG), and retinol palmitate (RP). In some embodiments, the compositions comprise AKG and vitamin A. In some embodiments, the compositions comprise AKG and retinoic acid (RA). In some embodiments, the compositions comprise AKG and retinol palmitate (RP). In some embodiments, the compositions comprise AKG and vitamin D. In some embodiments, the compositions comprise AKG and vitamin D3. In some embodiments, the composition comprises AKG and nicotinamide mononucleotide (NMN). In some examples, the AKG in the composition is a salt of AKG. In some examples, the AKG provided in the composition is a calcium salt of AKG (Ca-AKG). In some embodiments, the two or more compounds comprise α-ketoglutaric acid and berberine. In yet other embodiments, the two or more compounds comprise berberine and vitamin A. In some aspects, the present disclosure provides a composition comprising an active agent selected from the group consisting of: α-ketoglutaric acid, berberine, vitamin A, and vitamin D. In some embodiments, the compound is AKG. In some embodiments, the AKG is provided as a salt. In some embodiments, the AKG is provided as a calcium salt (Ca-AKG).

[0111] In certain aspects, the present disclosure provides methods for treating, delaying the onset, or slowing the progression of frailty in a subject, comprising administering to the subject a composition comprising a calcium salt of α-ketoglutaric acid. In other aspects, the present disclosure provides methods for treating, delaying the onset, or slowing the progression of frailty in a subject, comprising administering to the subject a composition consisting essentially of a calcium salt of α-ketoglutaric acid. In some embodiments, the calcium α-ketoglutarate can be hydrated calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be monohydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be hemihydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be anhydrous calcium α-ketoglutarate.

[0112] In some embodiments, Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg.In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, Ca-AKG is administered in a dosage of at least 350 mg. In some examples, Ca-AKG is administered in a dosage of at least 400 mg. In some examples, Ca-AKG is administered in a dosage of at least 450 mg. In some examples, Ca-AKG is administered in a dosage of at least 500 mg. In some examples, Ca-AKG is administered in a dosage of at least 550 mg. In some examples, Ca-AKG is administered in a dosage of at least 600 mg. In some examples, Ca-AKG is administered in a dosage of at least 650 mg.In some examples, Ca-AKG is administered in a dosage of at least 700 mg. In some examples, Ca-AKG is administered in a dosage of at least 750 mg. In some examples, Ca-AKG is administered in a dosage of at least 800 mg. In some examples, Ca-AKG is administered in a dosage of at least 900 mg. In some examples, Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, Ca-AKG is administered in a dosage of at least 1900 mg. In some examples, Ca-AKG is administered in a dosage of at least 2000 mg.

[0113] In some embodiments, hydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 350 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 400 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 450 mg.In some examples, the hydrated Ca-AKG is administered in a dosage of at least 500 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 550 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 600 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 650 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 700 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 750 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 800 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 900 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1900 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 2000 mg.

[0114] In some embodiments, the monohydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 550 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 450 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 350 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 450 mg.In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 550 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 650 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 700 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 750 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 800 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 900 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1900 mg. In some instances, the monohydrate Ca-AKG is administered in a dosage of at least 2000 mg.

[0115] In some embodiments, hemihydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 350 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 450 mg.In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 500 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 550 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 600 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 650 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 700 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 750 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 800 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 900 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1000 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1100 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1200 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1300 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1400 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1500 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1600 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1700 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1800 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1900 mg. In some instances, hemihydrate Ca-AKG is administered in a dosage of at least about 2000 mg.

[0116] In some embodiments, anhydrous Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg.In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of about 350 mg to about 450 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of about 350 mg to about 400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 350 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 450 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 550 mg.In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 600 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 650 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 700 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 750 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 800 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 900 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1000 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1100 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1200 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1300 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1600 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1700 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1800 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1900 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 2000 mg.

[0117] In some embodiments, administering a composition comprising AKG delays the onset or progression of a frailty phenotype in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A delays the onset or progression of a frailty phenotype in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A delays the onset or progression of a frailty phenotype in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D delays the onset or progression of a frailty phenotype in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN delays the onset or progression of a frailty phenotype in a subject in need thereof.

[0118] In some embodiments, delaying the onset or progression of frailty comprises delaying the onset or progression of a frailty phenotype. In some embodiments, the frailty phenotype is selected from the group consisting of hair loss, dermatitis, kyphosis, grip strength, gait disturbance, hearing loss, cataracts, corneal opacity, eye discharge, vision loss, nasal discharge, age-related fat loss, and tremor. In some embodiments, the frailty phenotype is hair loss. In some embodiments, the frailty phenotype is dermatitis. In some embodiments, the frailty phenotype is kyphosis. In some embodiments, the kyphosis is not caused by osteoporosis. In some embodiments, the kyphosis is caused by intervertebral disc degeneration. In some embodiments, the frailty phenotype is grip strength. In some embodiments, the frailty phenotype is gait disturbance. In some embodiments, the frailty phenotype is hearing loss. In some embodiments, the frailty phenotype is cataracts. In some embodiments, the frailty phenotype is corneal opacity. In some embodiments, the frailty phenotype is ocular discharge. In some embodiments, the frailty phenotype is vision loss. In some embodiments, the frailty phenotype is runny nose. In some embodiments, the frailty phenotype is age-related fat loss. In some embodiments, the frailty phenotype is tremor.

[0119] In some embodiments, administering a composition comprising AKG delays the onset or progression of alopecia in a subject in need thereof.In some embodiments, administering a composition comprising berberine, AKG, and vitamin A delays the onset or progression of alopecia in a subject in need thereof.In some embodiments, administering a composition comprising AKG and vitamin A delays the onset or progression of alopecia in a subject in need thereof.In some embodiments, administering a composition comprising AKG and vitamin D delays the onset or progression of alopecia in a subject in need thereof.In some embodiments, administering a composition comprising AKG and NMN delays the onset or progression of alopecia in a subject in need thereof.

[0120] In some embodiments, administering a composition comprising AKG delays the onset or progression of dermatitis in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A delays the onset or progression of dermatitis in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A delays the onset or progression of dermatitis in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D delays the onset or progression of dermatitis in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN delays the onset or progression of dermatitis in a subject in need thereof.

[0121] In some embodiments, administering a composition comprising AKG delays the onset or progression of kyphosis in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A delays the onset or progression of kyphosis in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A delays the onset or progression of kyphosis in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D delays the onset or progression of kyphosis in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN delays the onset or progression of kyphosis in a subject in need thereof.

[0122] In some embodiments, administering a composition comprising AKG delays the onset or progression of tremor in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A delays the onset or progression of tremor in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A delays the onset or progression of tremor in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D delays the onset or progression of tremor in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN delays the onset or progression of tremor in a subject in need thereof.

[0123] In some embodiments, administering a composition comprising AKG delays the onset or progression of alopecia in a subject in need thereof.In some embodiments, administering a composition comprising berberine, AKG, and vitamin A delays the onset or progression of alopecia in a subject in need thereof.In some embodiments, administering a composition comprising AKG and vitamin A delays the onset or progression of alopecia in a subject in need thereof.In some embodiments, administering a composition comprising AKG and vitamin D delays the onset or progression of alopecia in a subject in need thereof.In some embodiments, administering a composition comprising AKG and NMN delays the onset or progression of alopecia in a subject in need thereof.

[0124] In some embodiments, administering a composition comprising AKG delays the onset or progression of coat color loss in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A delays the onset or progression of coat color loss in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A delays the onset or progression of coat color loss in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D delays the onset or progression of coat color loss in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN delays the onset or progression of coat color loss in a subject in need thereof.

[0125] In some embodiments, administering a composition comprising AKG delays the onset or progression of a decline in the physical condition of a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A delays the onset or progression of a decline in the physical condition of a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A delays the onset or progression of a decline in the physical condition of a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D delays the onset or progression of a decline in the physical condition of a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN delays the onset or progression of a decline in the physical condition of a subject in need thereof.

[0126] In some embodiments, administering a composition comprising AKG delays the onset or progression of piloerection in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A delays the onset or progression of piloerection in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A delays the onset or progression of piloerection in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D delays the onset or progression of piloerection in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN delays the onset or progression of piloerection in a subject in need thereof.

[0127] In some embodiments, the progression of the frailty phenotype is delayed for at least one month after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least two months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least three months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least four months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least five months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least six months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least seven months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least eight months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least nine months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least 10 months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least 11 months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least 12 months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least 18 months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least 24 months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least 30 months after administering the composition to the subject. In some embodiments, the progression of the frailty phenotype is delayed for at least 36 months after administering the composition to the subject. In other embodiments, treating frailty includes reversing one or more of the above frailty phenotypes.

[0128] In some embodiments, the composition reduces the frailty phenotype compared to a pre-treatment value of the frailty phenotype, ie, the frailty phenotype is reduced by at least 5%, 10%, 15%, 20%, 25%, 33%, 40%, 45%, 50%, 66%, 75%, or 100% compared to a pre-treatment value.

[0129] In some embodiments, administration of the composition slows or reverses the progression of biomarkers of aging in non-humans or humans. Biomarker strategies for measuring aging are currently under development and can be used to test the effectiveness of aging interventions. Most notably, the epigenetic clock is likely to measure the biological age of human cells (see, e.g., Chen et al. Aging, 8:1844-1865(2016), PMID 27690265), dogs (see, e.g., Thompson et al. Aging 9:1055-1068(2017), PMID 28373601), and mice (Petkovich et al. Cell Metab 25:954-960(2017), PMID 28380383). Other biomarker strategies include, but are not limited to, inflammatory cytokine levels, p16INK4A protein levels in specific cell populations, telomere length, and specific metabolite levels. In some embodiments, the composition modulates biomarkers of DNA methylation.

[0130] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a livestock animal. In some embodiments, the livestock animal is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses.

[0131] In some embodiments, the composition is formulated into an oral dosage form. In some embodiments, the oral dosage form comprises a tablet, powder, suspension, serum, emulsion, capsule, granule, pill, gel, solution, or syrup. In some examples, the oral dosage form is a sustained release dosage form. In some examples, the oral dosage form is formulated into animal feed. In some examples, the oral dosage form is a gel. In some embodiments, the composition is formulated into an injectable dosage form. In some embodiments, the injectable dosage form comprises a liquid, suspension, or solution. In some examples, the injectable dosage form is a sustained release dosage form. In some embodiments, the composition is formulated into a topical dosage form. In some embodiments, the topical dosage form is a cream, foam, gel, lotion, ointment, or serum. In some embodiments, the composition is formulated into a hair care product. In some embodiments, the hair care product is formulated into a shampoo, conditioner, hair spray, or moisturizer.

[0132] In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In further embodiments, the pharmaceutically acceptable excipient comprises an anti-adhesive agent, a binder, a coating, a dye, a disintegrant, a flavoring agent, a glidant, a lubricant, a preservative, an adsorbent, or a vehicle. In some examples, the composition further comprises silymarin.

[0133] In some embodiments, the composition is administered for a specific period of time. In some embodiments, the composition is administered over a long-term, chronic treatment period, including the entire lifespan of the subject, to ameliorate or otherwise control or limit the symptoms of the subject's disease or disorder. Within the treatment period, the composition is administered on a specific time schedule. In further embodiments, the composition is administered 1, 2, 3, or 4 times daily. In some embodiments, the composition is administered once daily. In some embodiments, the composition is administered twice daily. In some embodiments, the composition is administered in the morning and evening. In some embodiments, the composition is administered 1, 2, 3, or 4 times weekly. In some embodiments, the composition is administered once weekly. In some embodiments, the composition is administered 1, 2, 3, or 4 times monthly. In some embodiments, the composition is administered monthly. In some embodiments, the composition is administered for at least 3 months every year. In some embodiments, the composition is administered one month every six months.

[0134] <Aging phenotype> In certain embodiments, the present disclosure provides a treatment method for reversing aging-related phenotypes using an active agent or composition thereof disclosed herein. In some embodiments, the composition comprises two or more active agents selected from the group consisting of α-ketoglutaric acid, berberine, vitamin A, vitamin D, and nicotinamide mononucleotide (NMN). In certain embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and vitamin A. In certain embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and retinoic acid (RA). In certain embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and retinol palmitate (RP). In certain embodiments, the composition comprises AKG and vitamin A. In certain embodiments, the composition comprises AKG and retinoic acid (RA). In certain embodiments, the composition comprises AKG and retinol palmitate (RP). In certain embodiments, the composition comprises AKG and vitamin D. In certain embodiments, the composition comprises AKG and vitamin D3. In some embodiments, the composition comprises AKG and nicotinamide mononucleotide (NMN). In some examples, the AKG in the composition is a salt of AKG. In some examples, the AKG provided in the composition is a calcium salt of AKG (Ca-AKG). In some embodiments, the two or more compounds comprise α-ketoglutaric acid and berberine. In yet other embodiments, the two or more compounds comprise berberine and vitamin A. In some aspects, the present disclosure provides a composition comprising an active agent selected from the group consisting of: α-ketoglutaric acid, berberine, vitamin A, and vitamin D. In some embodiments, the compound is AKG. In some embodiments, the AKG is provided as a salt. In some embodiments, the AKG is provided as a calcium salt (Ca-AKG).

[0135] In some aspects, the present disclosure provides methods for reversing an aging-associated phenotype in a subject, comprising administering to the subject in need thereof a composition comprising the calcium salt of α-ketoglutarate (Ca-AKG). In other aspects, the present disclosure provides methods for reversing an aging-associated phenotype in a subject in need thereof, comprising administering to the subject a composition consisting essentially of the calcium salt of α-ketoglutarate (Ca-AKG). In some embodiments, the calcium α-ketoglutarate can be hydrated calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be monohydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be hemihydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be anhydrous calcium α-ketoglutarate.

[0136] In some embodiments, Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg.In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, Ca-AKG is administered in a dosage of at least 350 mg. In some examples, Ca-AKG is administered in a dosage of at least 400 mg. In some examples, Ca-AKG is administered in a dosage of at least 450 mg. In some examples, Ca-AKG is administered in a dosage of at least 500 mg. In some examples, Ca-AKG is administered in a dosage of at least 550 mg. In some examples, Ca-AKG is administered in a dosage of at least 600 mg. In some examples, Ca-AKG is administered in a dosage of at least 650 mg.In some examples, Ca-AKG is administered in a dosage of at least 700 mg. In some examples, Ca-AKG is administered in a dosage of at least 750 mg. In some examples, Ca-AKG is administered in a dosage of at least 800 mg. In some examples, Ca-AKG is administered in a dosage of at least 900 mg. In some examples, Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, Ca-AKG is administered in a dosage of at least 1900 mg. In some examples, Ca-AKG is administered in a dosage of at least 2000 mg.

[0137] In some embodiments, hydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 350 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 400 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 450 mg.In some examples, the hydrated Ca-AKG is administered in a dosage of at least 500 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 550 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 600 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 650 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 700 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 750 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 800 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 900 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1900 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 2000 mg.

[0138] In some embodiments, the monohydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 550 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 450 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 350 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 450 mg.In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 550 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 650 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 700 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 750 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 800 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 900 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1900 mg. In some instances, the monohydrate Ca-AKG is administered in a dosage of at least 2000 mg.

[0139] In some embodiments, hemihydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 350 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 450 mg.In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 500 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 550 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 600 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 650 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 700 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 750 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 800 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 900 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1000 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1100 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1200 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1300 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1400 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1500 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1600 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1700 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1800 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1900 mg. In some instances, hemihydrate Ca-AKG is administered in a dosage of at least about 2000 mg.

[0140] In some embodiments, anhydrous Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg.In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of about 350 mg to about 450 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of about 350 mg to about 400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 350 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 450 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 550 mg.In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 600 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 650 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 700 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 750 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 800 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 900 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1000 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1100 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1200 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1300 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1600 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1700 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1800 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1900 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 2000 mg.

[0141] In some embodiments, administering a composition comprising AKG reverses an aging-associated phenotype in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A reverses an aging-associated phenotype in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A reverses an aging-associated phenotype in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D reverses an aging-associated phenotype in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN reverses an aging-associated phenotype in a subject in need thereof.

[0142] In some embodiments, the senescence-associated phenotype is selected from the group consisting of decreased stem cell production, increased cellular senescence, increased inflammation, elevated cholesterol, elevated A1C levels, decreased mobility, elevated high-density lipoprotein, elevated blood pressure, graying of hair, hair loss, hair regrowth, increased abdominal obesity, decreased left ventricular diastolic function, increased interleukin-6, cognitive impairment, and modulation of DNA methylation. In some examples, the senescence-associated phenotype is decreased stem cell production. In some examples, the senescence-associated phenotype is increased cellular senescence. In some examples, the senescence-associated phenotype is increased inflammation. In some examples, the senescence-associated phenotype is elevated cholesterol. In some examples, the senescence-associated phenotype is elevated A1C levels. In some examples, the senescence-associated phenotype is decreased mobility. In some examples, the senescence-associated phenotype is increased high-density lipoprotein. In some examples, the senescence-associated phenotype is elevated blood pressure. In some examples, the senescence-associated phenotype is graying of hair. In some examples, the senescence-associated phenotype is hair loss. In some examples, the senescence-associated phenotype is increased abdominal obesity. In some instances, the aging-associated phenotype is a decrease in left ventricular diastolic function. In some instances, the aging-associated phenotype is an increase in interleukin-6. In some instances, the aging-associated phenotype is cognitive impairment. In some instances, the aging-associated phenotype is modulation of DNA methylation.

[0143] In some embodiments, administering a composition comprising AKG delays or reverses cellular aging in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A delays or reverses cellular aging in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A delays or reverses cellular aging in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D delays or reverses cellular aging in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN delays or reverses cellular aging in a subject in need thereof.

[0144] In some embodiments, administering a composition comprising AKG delays or reverses hair graying in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A delays or reverses hair graying in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A delays or reverses hair graying in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D delays or reverses hair graying in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN delays or reverses hair graying in a subject in need thereof.

[0145] In some embodiments, administering a composition comprising AKG slows or reverses hair loss in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A slows or reverses hair loss in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A slows or reverses hair loss in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D slows or reverses hair loss in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN slows or reverses hair loss in a subject in need thereof.

[0146] In some embodiments, administering a composition comprising AKG promotes hair regrowth in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A promotes hair regrowth in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A promotes hair regrowth in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D promotes hair regrowth in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN promotes hair regrowth in a subject in need thereof.

[0147] In some embodiments, the composition reduces a senescence-associated phenotype compared to a pre-treatment value of the senescence-associated phenotype, ie, the senescence-associated phenotype is reduced by at least 5%, 10%, 15%, 20%, 25%, 33%, 40%, 45%, 50%, 66%, 75%, or 100% compared to a pre-treatment value.

[0148] In some embodiments, administration of the composition slows or reverses the progression of biomarkers of aging in non-humans or humans. Biomarker strategies for measuring aging are currently under development and can be used to test the effectiveness of aging interventions. Most notably, the epigenetic clock is likely to measure the biological age of human cells (see, e.g., Chen et al. Aging, 8:1844-1865(2016), PMID 27690265), dogs (see, e.g., Thompson et al. Aging 9:1055-1068(2017), PMID 28373601), and mice (Petkovich et al. Cell Metab 25:954-960(2017), PMID 28380383). Other biomarker strategies include, but are not limited to, inflammatory cytokine levels, p16INK4A protein levels in specific cell populations, telomere length, and specific metabolite levels. In some embodiments, the composition modulates biomarkers of DNA methylation.

[0149] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a livestock animal. In some embodiments, the livestock animal is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses.

[0150] In some embodiments, the composition is formulated into an oral dosage form. In some embodiments, the oral dosage form comprises a tablet, powder, suspension, serum, emulsion, capsule, granule, pill, gel, solution, or syrup. In some examples, the oral dosage form is a sustained release dosage form. In some examples, the oral dosage form is formulated into animal feed. In some examples, the oral dosage form is a gel. In some embodiments, the composition is formulated into an injectable dosage form. In some embodiments, the injectable dosage form comprises a liquid, suspension, or solution. In some examples, the injectable dosage form is a sustained release dosage form. In some embodiments, the composition is formulated into a topical dosage form. In some embodiments, the topical dosage form is a cream, foam, gel, lotion, ointment, or serum. In some embodiments, the composition is formulated into a hair care product. In some embodiments, the hair care product is formulated into a shampoo, conditioner, hair spray, or moisturizer.

[0151] In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In further embodiments, the pharmaceutically acceptable excipient comprises an anti-adhesive agent, a binder, a coating, a dye, a disintegrant, a flavoring agent, a glidant, a lubricant, a preservative, an adsorbent, or a vehicle. In some examples, the composition further comprises silymarin.

[0152] In some embodiments, the composition is administered for a specific period of time. In some embodiments, the composition is administered over a long-term, chronic treatment period, including the entire lifespan of the subject, to ameliorate or otherwise control or limit the symptoms of the subject's disease or disorder. Within the treatment period, the composition is administered on a specific time schedule. In further embodiments, the composition is administered 1, 2, 3, or 4 times daily. In some embodiments, the composition is administered once daily. In some embodiments, the composition is administered twice daily. In some embodiments, the composition is administered in the morning and evening. In some embodiments, the composition is administered 1, 2, 3, or 4 times weekly. In some embodiments, the composition is administered once weekly. In some embodiments, the composition is administered 1, 2, 3, or 4 times monthly. In some embodiments, the composition is administered monthly. In some embodiments, the composition is administered for at least 3 months every year. In some embodiments, the composition is administered one month every six months.

[0153] <Healthy life expectancy> In one aspect, the present disclosure provides a treatment method for extending healthspan using the active agent or composition thereof disclosed herein. Healthspan refers to the period during which an individual meets one or more selected health criteria. An increase in healthspan refers to an extension of healthspan according to such criteria compared to the healthspan of a control population. Examples of selected health criteria that are evaluated in a human population to assess healthspan include energy / material metabolism (e.g., elevated insulin, insulin resistance, elevated fasting blood glucose + GTT, Hb and one or more aging-associated phenotypes such as elevated A1c, adiponectin, DEXA / abdominal obesity, elevated IGF-I, decreased T3, elevated low-density lipoprotein, elevated high-density lipoprotein, elevated triglycerides), skeletal muscle function (e.g., decreased handgrip strength, decreased mobility), cardiopulmonary function (e.g., decreased VO2max, elevated blood pressure, decreased pulse wave velocity, intima-media thickness, decreased left ventricular diastolic function, elevated left ventricular diastolic pressure), inflammation and immune function (e.g., decreased lymphocyte count, decreased lymphocyte / myeloid ratio, increased CRP, increased IL-6, increased TNF-α), sensory function (e.g., decreased visual acuity, decreased nerve conduction velocity), cognition (e.g., decreased scores on cognitive tests such as MMSE / AMTS / GPAC, impaired performance by fMRI), cellular senescence (e.g., graying hair), and pathology (e.g., evaluation of renal, cardiac, pulmonary, breast, or prostate tissue to assess aging-associated tissue hypertrophy or dysplasia).

[0154] Examples of non-human animals used to evaluate lifespan or healthspan interventions include C. elegans, Drosophila melanogaster, and Mus musculus. The use of Drosophila melanogaster or Mus musculus to evaluate lifespan or healthspan interventions can be found, for example, in Bauer et al. Proc Natl Acad Sci U S A. 101:12980-5 (2004) and Selman et al. FASEB J 22:807-18 (2008).

[0155] In some embodiments, the present disclosure provides methods for extending healthspan using the compositions disclosed herein. In some embodiments, the compositions comprise two or more active agents selected from the group consisting of α-ketoglutaric acid, berberine, vitamin A, vitamin D, and nicotinamide mononucleotide (NMN). In some embodiments, the compositions comprise berberine, α-ketoglutaric acid (AKG), and vitamin A. In some embodiments, the compositions comprise berberine, α-ketoglutaric acid (AKG), and retinoic acid (RA). In some embodiments, the compositions comprise berberine, α-ketoglutaric acid (AKG), and retinol palmitate (RP). In some embodiments, the compositions comprise AKG and vitamin A. In some embodiments, the compositions comprise AKG and retinoic acid (RA). In some embodiments, the compositions comprise AKG and retinol palmitate (RP). In some embodiments, the compositions comprise AKG and vitamin D. In some embodiments, the compositions comprise AKG and vitamin D3. In some embodiments, the composition comprises AKG and nicotinamide mononucleotide (NMN). In some examples, the AKG in the composition is a salt of AKG. In some examples, the AKG provided in the composition is a calcium salt of AKG (Ca-AKG). In some embodiments, the two or more compounds comprise α-ketoglutaric acid and berberine. In yet other embodiments, the two or more compounds comprise berberine and vitamin A. In some aspects, the present disclosure provides a composition comprising an active agent selected from the group consisting of: α-ketoglutaric acid, berberine, vitamin A, and vitamin D. In some embodiments, the compound is AKG. In some embodiments, the AKG is provided as a salt. In some embodiments, the AKG is provided as a calcium salt (Ca-AKG).

[0156] In some aspects, the present disclosure provides methods for extending the healthspan of a subject, comprising administering to the subject in need thereof a composition comprising the calcium salt of α-ketoglutaric acid (Ca-AKG). In other aspects, the present disclosure provides methods for extending the healthspan of a subject, comprising administering to the subject in need thereof a composition consisting essentially of the calcium salt of α-ketoglutaric acid (Ca-AKG). In some embodiments, the calcium α-ketoglutarate can be hydrated calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be monohydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be hemihydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be anhydrous calcium α-ketoglutarate.

[0157] In some embodiments, Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg.In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, Ca-AKG is administered in a dosage of at least 350 mg. In some examples, Ca-AKG is administered in a dosage of at least 400 mg. In some examples, Ca-AKG is administered in a dosage of at least 450 mg. In some examples, Ca-AKG is administered in a dosage of at least 500 mg. In some examples, Ca-AKG is administered in a dosage of at least 550 mg. In some examples, Ca-AKG is administered in a dosage of at least 600 mg. In some examples, Ca-AKG is administered in a dosage of at least 650 mg.In some examples, Ca-AKG is administered in a dosage of at least 700 mg. In some examples, Ca-AKG is administered in a dosage of at least 750 mg. In some examples, Ca-AKG is administered in a dosage of at least 800 mg. In some examples, Ca-AKG is administered in a dosage of at least 900 mg. In some examples, Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, Ca-AKG is administered in a dosage of at least 1900 mg. In some examples, Ca-AKG is administered in a dosage of at least 2000 mg.

[0158] In some embodiments, hydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 350 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 400 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 450 mg.In some examples, the hydrated Ca-AKG is administered in a dosage of at least 500 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 550 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 600 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 650 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 700 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 750 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 800 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 900 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1900 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 2000 mg.

[0159] In some embodiments, the monohydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 550 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 450 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 350 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 450 mg.In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 550 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 650 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 700 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 750 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 800 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 900 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1900 mg. In some instances, the monohydrate Ca-AKG is administered in a dosage of at least 2000 mg.

[0160] In some embodiments, hemihydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 350 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 450 mg.In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 500 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 550 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 600 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 650 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 700 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 750 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 800 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 900 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1000 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1100 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1200 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1300 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1400 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1500 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1600 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1700 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1800 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1900 mg. In some instances, hemihydrate Ca-AKG is administered in a dosage of at least about 2000 mg.

[0161] In some embodiments, anhydrous Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg.In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of about 350 mg to about 450 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of about 350 mg to about 400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 350 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 450 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 550 mg.In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 600 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 650 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 700 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 750 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 800 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 900 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1000 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1100 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1200 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1300 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1600 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1700 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1800 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1900 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 2000 mg.

[0162] In some embodiments, administering a composition comprising AKG extends the healthy lifespan of a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A extends the healthy lifespan of a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A extends the healthy lifespan of a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D extends the healthy lifespan of a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN extends the healthy lifespan of a subject in need thereof.

[0163] In some embodiments, extending healthy lifespan includes delaying one or more of the above aging phenotypes. In some embodiments, administering a composition comprising AKG delays or reverses hair graying in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A delays or reverses hair graying in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A delays or reverses hair graying in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D delays or reverses hair graying in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN delays or reverses hair graying in a subject in need thereof.

[0164] In further embodiments, the increased healthspan comprises delaying one or more of the above aging phenotypes for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months after administration of the active agent or composition thereof, hi other embodiments, the increased healthspan comprises reversing one or more of the above aging phenotypes.

[0165] In some embodiments, extending healthy lifespan comprises delaying the onset of one or more aging-associated diseases. In further embodiments, the aging-associated disease is selected from the group consisting of osteoporosis, arthritis, cataracts, cancer, kidney disease, obesity, type 2 diabetes, neurodegenerative diseases (such as Parkinson's and Alzheimer's disease), heart disease, macular degeneration, and autoimmune diseases. In further embodiments, the aging-associated disease is selected from the group consisting of obesity, type 2 diabetes, macular degeneration, and autoimmune diseases. In some examples, the aging-associated disease is cancer. In some examples, the aging-associated disease is kidney disease. In some examples, the aging-associated disease is obesity. In some examples, the aging-associated disease is type 2 diabetes. In some examples, the aging-associated disease is a neurodegenerative disease. In some examples, the aging-associated disease is heart disease. In some examples, the aging-associated disease is macular degeneration. In some examples, the aging-associated disease is an autoimmune disease.

[0166] In some embodiments, the onset of the aging-associated disease is delayed at least one month after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed at least two months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed at least three months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed at least four months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed at least five months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed at least six months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed at least seven months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed at least eight months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed at least nine months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed by at least 10 months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed by at least 11 months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed by at least 12 months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed by at least 18 months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed by at least 24 months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed by at least 30 months after administering the composition to the subject. In some embodiments, the onset of the aging-associated disease is delayed by at least 36 months after administering the composition to the subject. In other embodiments, the extension of healthy lifespan includes reversal of one or more aging-associated diseases.

[0167] In some embodiments, administration of the composition slows or reverses the progression of biomarkers of aging in non-humans or humans. Biomarker strategies for measuring aging are currently under development and can be used to test the effectiveness of aging interventions. Most notably, the epigenetic clock is likely to measure the biological age of human cells (see, e.g., Chen et al. Aging, 8:1844-1865(2016), PMID 27690265), dogs (see, e.g., Thompson et al. Aging 9:1055-1068(2017), PMID 28373601), and mice (Petkovich et al. Cell Metab 25:954-960(2017), PMID 28380383). Other biomarker strategies include, but are not limited to, inflammatory cytokine levels, p16INK4A protein levels in specific cell populations, telomere length, and specific metabolite levels. In some embodiments, the composition modulates biomarkers of DNA methylation.

[0168] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a livestock animal. In some embodiments, the livestock animal is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses.

[0169] In some embodiments, the composition is formulated into an oral dosage form. In some embodiments, the oral dosage form comprises a tablet, powder, suspension, serum, emulsion, capsule, granule, pill, gel, solution, or syrup. In some examples, the oral dosage form is a sustained release dosage form. In some examples, the oral dosage form is formulated into animal feed. In some examples, the oral dosage form is a gel. In some embodiments, the composition is formulated into an injectable dosage form. In some embodiments, the injectable dosage form comprises a liquid, suspension, or solution. In some examples, the injectable dosage form is a sustained release dosage form. In some embodiments, the composition is formulated into a topical dosage form. In some embodiments, the topical dosage form is a cream, foam, gel, lotion, ointment, or serum. In some embodiments, the composition is formulated into a hair care product. In some embodiments, the hair care product is formulated into a shampoo, conditioner, hair spray, or moisturizer.

[0170] In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In further embodiments, the pharmaceutically acceptable excipient comprises an anti-adhesive agent, a binder, a coating, a dye, a disintegrant, a flavoring agent, a glidant, a lubricant, a preservative, an adsorbent, or a vehicle. In some examples, the composition further comprises silymarin.

[0171] In some embodiments, the composition is administered for a specific period of time. In some embodiments, the composition is administered over a long-term, chronic treatment period, including the entire lifespan of the subject, to ameliorate or otherwise control or limit the symptoms of the subject's disease or disorder. Within the treatment period, the composition is administered on a specific time schedule. In further embodiments, the composition is administered 1, 2, 3, or 4 times per day. In some embodiments, the composition is administered once per day. In some embodiments, the composition is administered twice per day. In some embodiments, the composition is administered in the morning and evening. In some embodiments, the composition is administered 1, 2, 3, or 4 times per week. In some embodiments, the composition is administered once per week. In further embodiments, the composition is administered 1, 2, 3, or 4 times per month. In some embodiments, the composition is administered monthly. In some embodiments, the composition is administered for at least 3 months every year. In some embodiments, the composition is administered one month every six months.

[0172] <Compression of pathological conditions> In one aspect, the present disclosure provides a method for compressing pathology by using the active agent or its composition described herein.When the first appearance age of aging signs and chronic disease symptoms rises faster than average lifespan, pathology compression occurs.When the average age of onset of markers rises faster than average lifespan of the same age, the period between markers of pathology (for example, the first heart attack, the first emphysema-induced breathing difficulty, the first osteoarthritis-induced disability, the first memory loss of a certain magnitude) and the end of life shortens.This disproportionately increases healthy lifespan, dramatically reducing the end-of-life costs of health care.

[0173] In one embodiment, the present disclosure provides a method for compressing a pathological condition using the active agents or compositions thereof described herein. In some embodiments, the composition comprises two or more active agents selected from the group consisting of α-ketoglutaric acid, berberine, vitamin A, vitamin D, and nicotinamide mononucleotide (NMN). In some embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and vitamin A. In some embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and retinoic acid (RA). In some embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and retinol palmitate (RP). In some embodiments, the composition comprises AKG and vitamin A. In some embodiments, the composition comprises AKG and retinoic acid (RA). In some embodiments, the composition comprises AKG and retinol palmitate (RP). In some embodiments, the composition comprises AKG and vitamin D. In some embodiments, the composition comprises AKG and vitamin D3. In some embodiments, the composition comprises AKG and nicotinamide mononucleotide (NMN). In some examples, the AKG in the composition is a salt of AKG. In some examples, the AKG provided in the composition is a calcium salt of AKG (Ca-AKG). In some embodiments, the two or more compounds comprise α-ketoglutaric acid and berberine. In yet other embodiments, the two or more compounds comprise berberine and vitamin A. In some aspects, the present disclosure provides a composition comprising an active agent selected from the group consisting of: α-ketoglutaric acid, berberine, vitamin A, and vitamin D. In some embodiments, the compound is AKG. In some embodiments, the AKG is provided as a salt. In some embodiments, the AKG is provided as a calcium salt (Ca-AKG).

[0174] In some aspects, the present disclosure provides methods for compressing a pathological condition in a subject, comprising administering to the subject in need thereof a composition comprising the calcium salt of α-ketoglutarate (Ca-AKG). In other aspects, the present disclosure provides methods for compressing a pathological condition in a subject, comprising administering to the subject in need thereof a composition consisting essentially of the calcium salt of α-ketoglutarate (Ca-AKG). In some embodiments, the calcium α-ketoglutarate can be hydrated calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be monohydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be hemihydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate can be anhydrous calcium α-ketoglutarate.

[0175] In some embodiments, Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg.In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, Ca-AKG is administered in a dosage of at least 350 mg. In some examples, Ca-AKG is administered in a dosage of at least 400 mg. In some examples, Ca-AKG is administered in a dosage of at least 450 mg. In some examples, Ca-AKG is administered in a dosage of at least 500 mg. In some examples, Ca-AKG is administered in a dosage of at least 550 mg. In some examples, Ca-AKG is administered in a dosage of at least 600 mg. In some examples, Ca-AKG is administered in a dosage of at least 650 mg.In some examples, Ca-AKG is administered in a dosage of at least 700 mg. In some examples, Ca-AKG is administered in a dosage of at least 750 mg. In some examples, Ca-AKG is administered in a dosage of at least 800 mg. In some examples, Ca-AKG is administered in a dosage of at least 900 mg. In some examples, Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, Ca-AKG is administered in a dosage of at least 1900 mg. In some examples, Ca-AKG is administered in a dosage of at least 2000 mg.

[0176] In some embodiments, hydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, hydrate Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 350 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 400 mg. In some examples, the hydrated Ca-AKG is administered at a dosage of at least 450 mg.In some examples, the hydrated Ca-AKG is administered in a dosage of at least 500 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 550 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 600 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 650 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 700 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 750 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 800 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 900 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 1900 mg. In some examples, the hydrated Ca-AKG is administered in a dosage of at least 2000 mg.

[0177] In some embodiments, the monohydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, the monohydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, monohydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 550 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 450 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of about 350 mg to about 400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 350 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 450 mg.In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 550 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 650 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 700 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 750 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 800 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 900 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1000 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1100 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1200 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1300 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1400 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1500 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1600 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1700 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1800 mg. In some examples, the monohydrate Ca-AKG is administered in a dosage of at least 1900 mg. In some instances, the monohydrate Ca-AKG is administered in a dosage of at least 2000 mg.

[0178] In some embodiments, hemihydrate Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg.In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 450 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of about 350 mg to about 400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 350 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 400 mg. In some examples, hemihydrate Ca-AKG is administered at a dosage of at least about 450 mg.In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 500 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 550 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 600 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 650 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 700 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 750 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 800 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 900 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1000 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1100 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1200 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1300 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1400 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1500 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1600 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1700 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1800 mg. In some examples, the hemihydrate Ca-AKG is administered in a dosage of at least about 1900 mg. In some instances, hemihydrate Ca-AKG is administered in a dosage of at least about 2000 mg.

[0179] In some embodiments, anhydrous Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg.In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1500 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1400 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1300 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1200 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1100 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 1000 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 900 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 800 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 700 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 650 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 600 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 550 mg. In some examples, anhydrous Ca-AKG is administered at a dosage of about 350 mg to about 500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of about 350 mg to about 450 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of about 350 mg to about 400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 350 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 450 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 550 mg.In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 600 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 650 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 700 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 750 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 800 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 900 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1000 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1100 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1200 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1300 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1400 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1500 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1600 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1700 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1800 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 1900 mg. In some examples, the anhydrous Ca-AKG is administered in a dosage of at least about 2000 mg.

[0180] In some embodiments, administering a composition comprising AKG reduces a pathological condition in a subject in need thereof. In some embodiments, administering a composition comprising berberine, AKG, and vitamin A reduces a pathological condition in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin A reduces a pathological condition in a subject in need thereof. In some embodiments, administering a composition comprising AKG and vitamin D reduces a pathological condition in a subject in need thereof. In some embodiments, administering a composition comprising AKG and NMN reduces a pathological condition in a subject in need thereof.

[0181] In some embodiments, the compression of the pathology comprises a reduction in the amount of time the subject suffers from the pathology before death. In further embodiments, the pathology is an aging-related disease selected from the group consisting of cancer, kidney disease, obesity, type 2 diabetes, neurodegenerative disease, heart disease, macular degeneration, and an autoimmune disease. In further embodiments, the pathology is an aging-related disease selected from the group consisting of obesity, type 2 diabetes, macular degeneration, and an autoimmune disease. In some examples, the aging-related disease is cancer. In some examples, the aging-related disease is kidney disease. In some examples, the aging-related disease is obesity. In some examples, the aging-related disease is type 2 diabetes. In some examples, the aging-related disease is a neurodegenerative disease. In some examples, the aging-related disease is heart disease. In some examples, the aging-related disease is macular degeneration. In some examples, the aging-related disease is an autoimmune disease.

[0182] In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least one month after administering the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least two months after administering the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least three months after administering the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least four months after administering the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least five months after administering the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least six months after administering the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least seven months after administering the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least eight months after administering the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least 9 months after administration of the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least 10 months after administration of the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least 11 months after administration of the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least 12 months after administration of the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least 18 months after administration of the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least 24 months after administration of the composition to the subject. In some embodiments, the reduction in the time the subject suffers from the pathological condition before death is at least 30 months after administration of the composition to the subject. In some embodiments, the reduction in the time that the subject suffers from the pathological condition before death is at least 36 months after administration of the composition to the subject.In some embodiments, the reduction in the time the subject will suffer from the pathological condition before death is at least 4 years after administration of the composition to the subject. In some embodiments, the reduction in the time the subject will suffer from the pathological condition before death is at least 5 years after administration of the composition to the subject. In some embodiments, the reduction in the time the subject will suffer from the pathological condition before death is at least 10 years after administration of the composition to the subject.

[0183] In some embodiments, administration of the composition slows or reverses the progression of biomarkers of aging in non-humans or humans. Biomarker strategies for measuring aging are currently under development and can be used to test the effectiveness of aging interventions. Most notably, the epigenetic clock is likely to measure the biological age of human cells (see, e.g., Chen et al. Aging, 8:1844-1865(2016), PMID 27690265), dogs (see, e.g., Thompson et al. Aging 9:1055-1068(2017), PMID 28373601), and mice (Petkovich et al. Cell Metab 25:954-960(2017), PMID 28380383). Other biomarker strategies include, but are not limited to, inflammatory cytokine levels, p16INK4A protein levels in specific cell populations, telomere length, and specific metabolite levels. In some embodiments, the composition modulates biomarkers of DNA methylation.

[0184] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a livestock animal. In some embodiments, the livestock animal is selected from the group consisting of cattle, sheep, goats, pigs, poultry, and horses.

[0185] In some embodiments, the composition is formulated into an oral dosage form. In some embodiments, the oral dosage form comprises a tablet, powder, suspension, serum, emulsion, capsule, granule, pill, gel, solution, or syrup. In some examples, the oral dosage form is a sustained release dosage form. In some examples, the oral dosage form is formulated into animal feed. In some examples, the oral dosage form is a gel. In some embodiments, the composition is formulated into an injectable dosage form. In some embodiments, the injectable dosage form comprises a liquid, suspension, or solution. In some examples, the injectable dosage form is a sustained release dosage form. In some embodiments, the composition is formulated into a topical dosage form. In some embodiments, the topical dosage form is a cream, foam, gel, lotion, ointment, or serum. In some embodiments, the composition is formulated into a hair care product. In some embodiments, the hair care product is formulated into a shampoo, conditioner, hair spray, or moisturizer.

[0186] In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In further embodiments, the pharmaceutically acceptable excipient comprises an anti-adhesive agent, a binder, a coating, a dye, a disintegrant, a flavoring agent, a glidant, a lubricant, a preservative, an adsorbent, or a vehicle. In some examples, the composition further comprises silymarin.

[0187] In some embodiments, the composition is administered for a specific period of time. In some embodiments, the composition is administered over a long-term, chronic treatment period, including the entire lifespan of the subject, to ameliorate or otherwise control or limit the symptoms of the subject's disease or disorder. Within the treatment period, the composition is administered on a specific time schedule. In further embodiments, the composition is administered 1, 2, 3, or 4 times per day. In some embodiments, the composition is administered once per day. In some embodiments, the composition is administered twice per day. In some embodiments, the composition is administered in the morning and evening. In some embodiments, the composition is administered 1, 2, 3, or 4 times per week. In some embodiments, the composition is administered once per week. In further embodiments, the composition is administered 1, 2, 3, or 4 times per month. In some embodiments, the composition is administered monthly. In some embodiments, the composition is administered for at least 3 months every year. In some embodiments, the composition is administered one month every six months.

[0188] <Inhibition of senescent cell formation> In one aspect, the present disclosure provides a method for reducing the formation of senescent cells using an active agent or composition thereof disclosed herein. "Senescent cells" are generally considered to be derived from a typically replicating cell type, but are no longer able to replicate due to senescence or other events that cause a change in cellular state. The nuclei of senescent cells are often characterized by DNA segments with senescence-associated heterochromatin formation and chromatin modifications that reinforce senescence. They remain metabolically active and typically employ senescence-associated secretory phenomena (SASP). SASP may include a combination of inflammatory cytokines, growth factors, and proteases. Without being bound by theory, SASP secreted by senescent cells contributes to the development and progression of senescence-related diseases.

[0189] In one embodiment, the present disclosure provides a method for reducing the formation of senescent cells using an active agent or composition thereof disclosed herein. In some embodiments, the composition comprises two or more active agents selected from the group consisting of α-ketoglutaric acid, berberine, vitamin A, vitamin D, and nicotinamide mononucleotide (NMN). In some embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and vitamin A. In some embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and retinoic acid (RA). In some embodiments, the composition comprises berberine, α-ketoglutaric acid (AKG), and retinol palmitate (RP). In some embodiments, the composition comprises AKG and vitamin A. In some embodiments, the composition comprises AKG and retinoic acid (RA). In some embodiments, the composition comprises AKG and retinol palmitate (RP). In some embodiments, the composition comprises AKG and vitamin D. In some embodiments, the composition comprises AKG and vitamin D3. In some embodiments, the composition comprises AKG and nicotinamide mononucleotide (NMN). In some examples, the AKG in the composition is a salt of AKG. In some examples, the AKG provided in the composition is a calcium salt of AKG (Ca-AKG). In some embodiments, the two or more compounds comprise α-ketoglutaric acid and berberine. In yet other embodiments, the two or more compounds comprise berberine and vitamin A. In some aspects, the present disclosure provides a composition comprising an active agent selected from the group consisting of: α-ketoglutaric acid, berberine, vitamin A, and vitamin D. In some embodiments, the compound is AKG. In some embodiments, the AKG is provided as a salt. In some embodiments, the AKG is provided as a calcium salt (Ca-AKG).

[0190] In one aspect, the present disclosure provides a method for reducing the formation of senescent cells in a subject caused by a senescent stimulus, comprising administering to the subject an effective amount of a composition comprising Ca-AKG to reduce the formation of senescent cells upon exposure to the senescent stimulus. In another aspect, the present disclosure provides a method for reducing the formation of senescent cells in a subject caused by a senescent stimulus, comprising administering to the subject an effective amount of a composition consisting essentially of Ca-AKG to reduce the formation of senescent cells upon exposure to the senescent stimulus. In some embodiments, the calcium α-ketoglutarate may be hydrated calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate may be monohydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate may be hemihydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate may be anhydrous calcium α-ketoglutarate.

[0191] In some embodiments, Ca-AKG is administered at a dosage of at least 350 mg and no more than 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 400 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 450 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 500 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 550 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 600 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 650 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 700 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 800 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 900 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1000 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1100 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1200 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1300 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1400 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1500 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1600 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1700 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1800 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 1900 mg to about 2000 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1900 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1800 mg.In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1700 mg. In some examples, Ca-AKG is administered at a dosage of about 350 mg to about 1600 mg. In some examples, Ca-AKG is admi...

Claims

1. 1. A pharmaceutical composition comprising calcium salt of alpha-ketoglutaric acid (Ca-AKG), vitamin D3, and a pharmaceutically acceptable excipient for use in delaying the onset or slowing the progression of frailty in a subject in need thereof, wherein the subject is female.

2. 2. The pharmaceutical composition of claim 1, wherein delaying the onset or progression of frailty comprises delaying the onset or progression of a frailty phenotype.

3. 3. The pharmaceutical composition of claim 2, wherein the frailty phenotype is selected from the group consisting of alopecia, dermatitis, kyphosis, grip strength, gait disturbance, hearing loss, cataracts, corneal opacity, eye discharge, vision loss, nasal discharge, age-related fat loss, and tremor.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein said Ca-AKG and said vitamin D3 are administered to said subject in need thereof as a single composition.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein said Ca-AKG and said vitamin D3 are administered separately to said subject in need thereof.

6. 6. The pharmaceutical composition of claim 5, wherein the Ca-AKG and the vitamin D3 are administered to the subject in need thereof within 24 hours.

7. 7. The pharmaceutical composition of claim 1, wherein the Ca-AKG comprises monohydrate calcium alpha-ketoglutarate.

8. The pharmaceutical composition of any one of claims 1-7, wherein the subject in need thereof is a mammal.

9. 9. The pharmaceutical composition of claim 8, wherein the mammal is selected from the group consisting of humans, dogs, cats, and livestock.

10. 10. The pharmaceutical composition of claim 9, wherein the livestock is selected from the group consisting of cattle, sheep, goats, pigs, and horses.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the Ca-AKG and the vitamin D3 are administered once a day.

12. The pharmaceutical composition of any one of claims 1 to 10, wherein the Ca-AKG and the vitamin D3 are administered twice a day.

13. The pharmaceutical composition of claim 12, wherein the Ca-AKG and the vitamin D3 are administered in the morning and evening.

14. The pharmaceutical composition of any one of claims 1 to 10, wherein the Ca-AKG and the vitamin D3 are administered once a week.

15. The pharmaceutical composition of any one of claims 1 to 10, wherein the Ca-AKG and the vitamin D3 are administered once a month.

16. 16. The pharmaceutical composition of any one of claims 1-15, wherein the pharmaceutically acceptable excipient is selected from the group consisting of anti-adherents, binders, coatings, dyes, disintegrants, flavorings, glidants, lubricants, preservatives, adsorbents, vehicles, and any combination thereof.

17. The pharmaceutical composition of any one of claims 1-16, wherein the pharmaceutical composition is formulated for oral administration.

18. 18. The pharmaceutical composition of any one of claims 1-17, wherein the pharmaceutical composition is selected from the group consisting of a tablet, a powder, a suspension, a serum, an emulsion, a capsule, a granule, a pill, a gel, a solution, and a syrup.

19. 19. The pharmaceutical composition of any one of claims 1-18, wherein the pharmaceutical composition is formulated for sustained release.

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