WO2023244685A1

WO2023244685A1 - Treatment of aging-related changes and diseases

Info

Publication number: WO2023244685A1
Application number: PCT/US2023/025333
Authority: WO
Inventors: Jonas O’Gara HANNESTAD; Abhirup Das
Original assignee: Tranquis Therapeutics, Inc.
Priority date: 2022-06-14
Filing date: 2023-06-14
Publication date: 2023-12-21

Abstract

The disclosure provides methods of delaying an aging-related change, increasing lifespan, and reducing risk of, delaying onset of, or treating an aging-related disease in a subject. The methods comprise administering to the subject an effective amount of a compound of Formula I.

Description

TREATMENT OF AGING-RELATED CHANGES AND DISEASES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/352,156, filed June 14, 2022, and to U.S. Provisional Application No. 63/393,747, filed July 29, 2022, which are hereby incorporated by reference in its entirety. BACKGROUND

[0002] Aging involves the accumulation of physical changes, such as decreased muscle mass, increased fat mass, decreased bone mass, decreased mobility, sensory impairment, decreased digestive function, decreased immune function, and increased inflammation. Aging also increases the risk of a variety of diseases and conditions, such as atherosclerosis, cardiovascular disease, cancer, neurodegenerative disease, dementia, diabetes, osteoporosis, and late- life depression. These aging-related changes, diseases, and conditions negatively impact the quality of life and often reduce life expectancy.

[0003] There is therefore a need for methods for delaying aging-related changes, reducing the risk of aging-related diseases, and increasing lifespan. SUMMARY

[0004] TQS -168 (2-(4-tert-butylphenyl)-lH-benzimidazole), previously known as ZLN-005, is known to be an activator of Ppargcla (PGC-la) expression (Zhang el al., Diabetes 62:1297-1307 (2013)). TQS-168 has previously been shown to suppress myeloid-mediated inflammation and reduce disease severity in murine models of neurodegenerative diseases in which neuroinflammation contributes to the underlying pathophysiology, including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS) (US Pat. Nos. 10,272,070; 10,583,125; and 10,653,669, the disclosures of which are incorporated herein by reference in their entireties). TQS-168 has also been shown to suppress metabolic dysfunction in microglia in older mice, inhibit inflammatory cytokine production in microglia in older mice, suppress systemic inflammation in older mice, and alleviate behavioral dysfunction in older mice (US Pat. No. 10,653,669, the disclosure of which is incorporated herein by reference in its entirety). TQS-168 and its analogs have also been shown to suppress acute systemic immune activation, including cytokine release syndrome (CRS) (WO2021/262617, the disclosure of which is incorporated herein by reference in its entirety).

[0005] We have now demonstrated that TQS-168 and its analogs can be administered to delay aging-related changes, increase lifespan, reduce risk of, delay onset of, and/or treat aging-related diseases, and reduce body weight.

[0006] Accordingly, in a first aspect, methods of delaying an aging-related change in a subject are provided. The method comprises administering to the patient an effective amount of a compound of Formula I:

Formula I or a salt, hydrate, deuterated analog, or fluorinated analog thereof, wherein:

W¹ is chosen from N-R¹, O, and S, or when W⁹ is N, W¹ may additionally be C-

R₅°.

W² is C-R² or N;

W³ is C-R³ or N;

W⁴ is C-R⁴ or N;

W⁵ is C-R⁵ or N;

W⁶ is C-R⁶ or N;

W⁷ is C-R⁷ or N;

W⁸ is C-R⁸ or N;

W⁹ is C, or when W¹ is C-R⁵⁰, W⁹ may be N;

R¹ is selected from H, (C1-C3)alkyl, -CH₂OC(=O)R³⁰, -CH₂OP(=O)OR⁴⁰OR⁴¹, - C(=O)OR⁴², and -C(=O)R⁴³; R², R³, R⁴, and R⁵ are selected independently from hydrogen, deuterium, halogen, perfluoro(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, perfluoro(C1-C4)alkoxy, (C1-C4)acyl, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, carboxy, (C1-

C4)alkoxycarbonylamino, carboxamido, (C1-C4)alkylaminocarbonyl, cyano, acetoxy, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, mercapto, (C1-C4)alkylthio, aminosulfonyl, (C1-C4)alkylsulfonyl, and (C1-C4)acylamino;

R⁶ and R¹⁰ are selected independently from hydrogen, deuterium, halo, (C1- C3)alkyl, perfluoro(C1-C3)alkyl, hydroxy, (C1-C3)alkoxy, perfluoro(C1-C3)alkoxy, and amino;

R⁷ and R⁹ are selected independently from hydrogen, deuterium, hydroxy, cyano, amino, halogen, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy,

, and

R⁸ is selected from hydrogen, deuterium, halogen, halo(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, phenoxy, benzyloxy, amino,

R³⁰ is selected from (C1-C10)hydrocarbyl, (C1-C10)hydrocarbyl substituted with amino, (C1-C10)hydrocarbyl substituted with (C1-C4)hydrocarbyl, (C1-C10)hydrocarbyl substituted with carboxyl, carboxy, (C1-C6lalkoxycarbonyl, (C1-C6lalkoxycarbonylamino, methylthio, heterocyclyl, (C1-C10)oxaalkyl, CHR^NHR⁴⁵ and guanidine;

R⁴⁰ and R⁴¹ are selected independently from hydrogen (C1-C6)hydrocarbyl;

R⁴² is (C1-C5)alkyl;

R⁴³ is (C1-C3)alkyl,

R⁴⁴ is selected from any naturally occurring amino acid sidechain;

R⁴⁵ is selected from H, methyl, and (C1-C4)alkoxycarbonyl; and

R⁵⁰ is H or (C1-C3)alkyl.

[0007] In some embodiments, the compound of Formula I is selected from:

Compound 1 Compound 2 Compound 3

Compound 4 Compound 5 Compound 6

Compound 7 Compound 8 Compound 9

or a salt, hydrate, deuterated analog, or fluorinated analog thereof.

[0008] In some embodiments, the compound of Formula I is compound 1 (TQS-168), according to the formula:

Compound 1 or a salt, hydrate, deuterated analog, or fluorinated analog thereof.

[0009] In some embodiments, the compound of Formula I is compound 4 (TQS-621), according to the formula:

Compound 4 or a salt, hydrate, deuterated analog, or fluorinated analog thereof.

[0010] In some embodiments, the subject is a human. In particular embodiments, the human is over 40 years of age. In particular embodiments, the human is over 50 years of age. In particular embodiments, the human is over 60 years of age. In particular embodiments, the human is over 70 years of age. In particular embodiments, the human is over 80 years of age.

[0011] In some embodiments, the subject is a non-human animal. In various embodiments, the non-human animal is selected from the group consisting of a horse, a donkey, a cow, a pig, a sheep, a goat, a dog, a cat, a guinea pig, a hamster, a ferret, a rat, a rabbit, and a parrot. In certain embodiments, the non-human animal is a non- human primate. In some of these embodiments, the non-human primate is a monkey or an ape.

[0012] In some embodiments, the compound of Formula I is administered parenterally. In certain embodiments, the compound of Formula I is administered intravenously. In some embodiments, the compound of Formula I is administered enterally. In some embodiments, the compound of Formula I is mixed with an enteral feeding formula. In certain embodiments, the compound of Formula I is administered by mouth (p.o.). In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 200-800 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 300-700 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 400-600 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 400-500 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 450 mg. In some embodiments, the compound of Formula I is administered to a non-human animal subject at a daily oral dose of 10 mg/kg to 250 mg/kg. In some embodiments, the compound of Formula I is administered as a single daily dose. In some embodiments, the compound of Formula I is administered as a plurality of equally or unequally divided sub-doses.

[0013] In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the expression level of Ppargcla (PGC- la) as compared to pre-treatment levels.

[0014] In some embodiments, the aging-related change is a decrease in muscle mass. In some embodiments, the aging-related change is a decrease in muscle strength. In some embodiments, the aging-related change is a decrease in muscle function. In certain embodiments, the muscle function is skeletal muscle function. In certain embodiments, the muscle function is diaphragmatic muscle function. In certain embodiments, the muscle function is cardiac muscle function. In certain embodiments, the muscle function is vascular muscle function. In certain embodiments, the subject has sarcopenia.

[0015] In some embodiments, the aging-related change is an increase in fat mass. In certain embodiments, the fat mass is total fat mass. In certain embodiments, the fat mass is visceral fat mass. In some embodiments, the aging-related change is an increase in body weight.

[0016] In some embodiments, the aging-related change is a decrease in motor balance. In some embodiments, the aging-related change is a decrease in motor coordination. In some embodiments, the aging-related change is a decrease in gait steadiness or speed. In some embodiments, the aging-related change is an increased number of falls. In some embodiments, the aging-related change is a decrease in mobility.

[0017] In some embodiments, the aging-related change is an increase in fatigue. In some embodiments, the aging-related change is a decrease in exercise endurance. In some embodiments, the aging-related change is a decrease in lung function. In some embodiments, the aging-related change is a decrease in oxygen utilization. In certain embodiments, the oxygen utilization is measured as VO2 max. In some embodiments, the aging-related change is a decrease in cardiac function. In some embodiments, the aging-related change is a decrease in blood circulation.

[0018] In some embodiments, the aging-related change is a sensory impairment. In certain embodiments, the sensory impairment is a hearing impairment, a visual impairment, or an olfactory impairment.

[0019] In some embodiments, the aging-related change is aging of skin. In certain embodiments, the aging of skin is decreased skin elasticity or increased skin wrinkles. In some embodiments, the aging-related change is aging of hair. In certain embodiments, the aging of hair is hair graying or hair thinning.

[0020] In some embodiments, the aging-related change is a decrease in bone mass. In some embodiments, the aging-related change is an increase in bone fractures. In some embodiments, the aging-related change is a decrease in joint flexibility.

[0021] In some embodiments, the aging-related change is a decrease in digestive function. In some embodiments, the aging -related change is an increase in constipation. In some embodiments, the aging-related change is a decrease in insulin sensitivity. [0022] In some embodiments, the aging-related change is a decrease in immune function. In certain embodiments, the decrease in immune function is increased susceptibility to infection. In certain embodiments, the decrease in immune function is reduced antibody titer after vaccination.

[0023] In some embodiments, the aging-related change is an increase in inflammation. In certain embodiments, the increase in inflammation is measured by an increase in serum levels of one or more pro-inflammatory cytokines selected from the group consisting of: IL-6, TNFa, IFNy, IL-17A, IL-17F, IL-2, and monocyte chemoattractant protein 1 (MCP-1). In certain embodiments, the increase in inflammation is measured by an increase in serum level of C-reactive protein (CRP).

[0024] In some embodiments, the aging-related change is a decrease in vestibular function.

[0025] In some embodiments, the aging-related change is a delay or an impairment in wound healing.

[0026] In some embodiments, the aging-related change is an increase in clinical frailty index.

[0027] In another aspect, methods of increasing lifespan of a subject are provided. The method comprises administering to the patient an effective amount of a compound of Formula I:

R5°.

W² is C-R² or N; W³ is C-R³ or N;

W⁴ is C-R⁴ or N;

W⁵ is C-R⁵ or N;

W⁶ is C-R⁶ or N;

W⁷ is C-R⁷ or N;

W⁸ is C-R⁸ or N;

W⁹ is C, or when W¹ is C-R⁵⁰, W⁹ may be N;

R¹ is selected from H, (C1-C3)alkyl, -CH₂OC(=O)R³⁰, -CH₂OP(=O)OR⁴⁰OR⁴¹, - C(=O)OR⁴², and -C(=O)R⁴³;

R², R³, R⁴, and R⁵ are selected independently from hydrogen, deuterium, halogen, perfluoro(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, perfluoro(C1-C4)alkoxy, (C1-C4)acyl, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, carboxy, (C1- C4)alkoxycarbonylamino, carboxamido, (C1-C4)alkylaminocarbonyl, cyano, acetoxy, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, mercapto, (C1-C4)alkylthio, aminosulfonyl, (C1-C4)alkylsulfonyl, and (C1-C4)acylamino;

, and

R⁸ is selected from hydrogen, deuterium, halogen, halo(C1-C4)alkyl, (C1-C4)alkyl,

I /~^OH (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, phenoxy, benzyloxy, amino, ’ X j COOH and * X ;

R³⁰ is selected from (C1-C10)hydrocarbyl, (C1-Cw)hydrocarbyl substituted with amino, (C1-C10)hydrocarbyl substituted with (C1-C4)hydrocarbyl, (C1-C10)hydrocarbyl substituted with carboxyl, carboxy, (C1-C6jalkoxycarbonyl, (C1-C6jalkoxycarbonylamino, methylthio, heterocyclyl, (C1-C10)oxaalkyl, CHR^NHR⁴⁵ and guanidine;

R⁴⁰ and R⁴¹ are selected independently from hydrogen (C1-C6)hydrocarbyl;

R⁴² is (C1-C₅)alkyl;

R⁴³ is (C1-C3)alkyl, R⁴⁴ is selected from any naturally occurring amino acid sidechain;

R⁴⁵ is selected from H, methyl, and (C1-C4)alkoxycarbonyl; and

R⁵⁰ is H or (C1-C3)alkyl.

[0028] In some embodiments, the compound of Formula I is selected from:

Compound 1 Compound 2 Compound 3

Compound 4 Compound 5 Compound 6

Compound 7 Compound 8 Compound 9

Compound 10 Compound 11 Compound 12 or a salt, hydrate, deuterated analog, or fluorinated analog thereof.

[0029] In some embodiments, the compound of Formula I is compound 1 (TQS-168), according to the formula:

[0030] In some embodiments, the compound of Formula I is compound 4 (TQS-621), according to the formula:

[0031] In some embodiments, the subject is a human. In particular embodiments, the human is over 40 years of age. In particular embodiments, the human is over 50 years of age. In particular embodiments, the human is over 60 years of age. In particular embodiments, the human is over 70 years of age. In particular embodiments, the human is over 80 years of age.

[0032] In some embodiments, the subject is a non-human animal. In various embodiments, the non-human animal is selected from the group consisting of a horse, a donkey, a cow, a pig, a sheep, a goat, a dog, a cat, a guinea pig, a hamster, a ferret, a rat, a rabbit, and a parrot. In certain embodiments, the non-human animal is a non- human primate. In some of these embodiments, the non-human primate is a monkey or an ape.

[0033] In some embodiments, the compound of Formula I is administered parenterally. In certain embodiments, the compound of Formula I is administered intravenously. In some embodiments, the compound of Formula I is administered enterally. In some embodiments, the compound of Formula I is mixed with an enteral feeding formula. In certain embodiments, the compound of Formula I is administered by mouth (p.o.). In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 200-800 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 300-700 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 400-600 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 400-500 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 450 mg. In some embodiments, the compound of Formula I is administered to a non-human animal subject at a daily oral dose of 10 mg/kg to 250 mg/kg. In some embodiments, the compound of Formula I is administered as a single daily dose. In some embodiments, the compound of Formula I is administered as a plurality of equally or unequally divided sub-doses. [0034] In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the expression level of Ppargcla (PGC-la) as compared to pre-treatment levels.

[0035] In certain embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the lifespan of a human population by greater than 1 year as compared to an age-matched control human population without the administration. In certain embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the lifespan of a human population by greater than 2 years as compared to an age-matched control human population without the administration. In certain embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the lifespan of a human population by greater than 5 years as compared to an age- matched control human population without the administration. In certain embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the lifespan of a human population by greater than 10 years as compared to an age-matched control human population without the administration.

[0036] In another aspect, methods of reducing risk of, delaying onset of, or treating an aging-related disease in a subject are provided. The method comprises administering to the patient an effective amount of a compound of Formula I:

R⁵⁰;

W² is C-R² or N;

W³ is C-R³ or N;

W⁴ is C-R⁴ or N;

W⁵ is C-R⁵ or N;

W⁶ is C-R⁶ or N;

W⁷ is C-R⁷ or N;

W⁸ is C-R⁸ or N;

W⁹ is C, or when W¹ is C-R⁵⁰, W⁹ may be N;

R², R³, R⁴, and R⁵ are selected independently from hydrogen, deuterium, halogen, perfhioro(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, perfluoro(C1-C4)alkoxy, (C1-C4)acyl, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, carboxy, (C1- C4)alkoxycarbonylamino, carboxamido, (C1-C4)alkylaminocarbonyl, cyano, acetoxy, nitro, amino, (C1-C,4)alkylamino, di(C1-C,4)alkylamino, mercapto, (C1 -Chalky Ithio, aminosulfonyl, (C1-C4)alkylsulfonyl, and (C1-C4)acylamino;

R⁶ and R¹⁰ are selected independently from hydrogen, deuterium, halo, (C1- Qjalkyl, perfluoro(C1-C3)alkyl, hydroxy, (C1-C3)alkoxy, perfluoro(C1-C3)alkoxy, and amino;

, and

R⁸ is selected from hydrogen, deuterium, halogen, halo(C1-C,4)alkyl, (C1-C,4)alkyl, y— °^H (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, phenoxy, benzyloxy, amino, ’ X ,

R³⁰ is selected from (C1-C10)hydrocarbyl, (C1-Cw)hydrocarbyl substituted with amino, (C1-Cw)hydrocarbyl substituted with (C1-C4)hydrocarbyl, (C1-C10)hydrocarbyl substituted with carboxyl, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6jalkoxycarbonylamino, methylthio, heterocyclyl, (C1-C10)oxaalkyl, CHR^NHR⁴⁵ and guanidine; R⁴⁰ and R⁴¹ are selected independently from hydrogen (C1-C6)hydrocarbyl;

R⁴² is (C1-Cs)alkyl;

R⁴³ is (C1-C3)alkyl,

R⁴⁴ is selected from any naturally occurring amino acid sidechain;

R⁴⁵ is selected from H, methyl, and (C1-C4)alkoxycarbonyl; and

R⁵⁰ is H or (C1-C3)alkyl.

[0037] In some embodiments, the compound of Formula I is selected from:

Compound 1 Compound 2 Compound 3

Compound 4 Compound 5 Compound 6

Compound 10 Compound 11

or a salt, hydrate, deuterated analog, or fluorinated analog thereof.

[0038] In some embodiments, the compound of Formula I is compound 1 (TQS-168), according to the formula:

[0039] In some embodiments, the compound of Formula I is compound 4 (TQS-621), according to the formula:

[0040] In some embodiments, the subject is a human. In particular embodiments, the human is over 40 years of age. In particular embodiments, the human is over 50 years of age. In particular embodiments, the human is over 60 years of age. In particular embodiments, the human is over 70 years of age. In particular embodiments, the human is over 80 years of age.

[0041] In some embodiments, the subject is a non-human animal. In various embodiments, the non-human animal is selected from the group consisting of a horse, a donkey, a cow, a pig, a sheep, a goat, a dog, a cat, a guinea pig, a hamster, a ferret, a rat, a rabbit, and a parrot. In certain embodiments, the non-human animal is a non- human primate. In some of these embodiments, the non-human primate is a monkey or an ape.

[0042] In some embodiments, the compound of Formula I is administered parenterally. In certain embodiments, the compound of Formula I is administered intravenously. In some embodiments, the compound of Formula I is administered enterally. In some embodiments, the compound of Formula I is mixed with an enteral feeding formula. In certain embodiments, the compound of Formula I is administered by mouth (p.o.). In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 200-800 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 300-700 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 400-600 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 400-500 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 450 mg. In some embodiments, the compound of Formula I is administered to a non-human animal subject at a daily oral dose of 10 mg/kg to 250 mg/kg. In some embodiments, the compound of Formula I is administered as a single daily dose. In some embodiments, the compound of Formula I is administered as a plurality of equally or unequally divided sub-doses. [0043] In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the expression level of Ppargcla (PGC-la) as compared to pre-treatment levels.

[0044] In some embodiments, the aging-related disease is hypertension. In some embodiments, the aging-related disease is atherosclerosis. In certain embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, decreases serum levels of one or more markers of atherosclerosis risk selected from the group consisting of: LDL-C, triglyceride, ApoB, and Lp(a). In some embodiments, the aging -related disease is cardiovascular disease. In certain embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, decreases serum level of cardiovascular risk marker, N-terminal prohormone-B-type natriuretic peptide (NT- pro-BNP).

[0045] In some embodiments, the aging-related disease is cancer.

[0046] In some embodiments, the aging-related disease is neurodegenerative disease. In some embodiments, the aging-related disease is dementia. In some embodiments, the aging-related disease is cognitive dysfunction.

[0047] In some embodiments, the aging-related disease is diabetes. In some embodiments, the aging-related disease is obesity.

[0048] In some embodiments, the aging-related disease is osteoarthritis. In some embodiments, the aging-related disease is osteoporosis.

[0049] In some embodiments, the aging-related disease is lung fibrosis. In some embodiments, the aging-related disease is lymph node fibrosis.

[0050] In some embodiments, the aging-related disease is skin disease. In some embodiments, the aging-related disease is kidney disease. In some embodiments, the aging -related disease is chronic obstructive pulmonary disease (COPD).

[0051] In some embodiments, the aging-related disease is age-related macular degeneration. In some embodiments, the aging-related disease is cataract. [0052] In some embodiments, the aging-related disease is late-life depression. [0053] In another aspect, methods of reducing body weight of a subject are provided. The method comprises administering to the patient an effective amount of a compound of Formula I:

W¹ is chosen from N-R¹, O, and S, or when W⁹ is N, W¹ may additionally be C- R⁵⁰;

W² is C-R² or N;

W³ is C-R³ or N;

W⁴ is C-R⁴ or N;

W⁵ is C-R⁵ or N;

W⁶ is C-R⁶ or N;

W⁷ is C-R⁷ or N;

W⁸ is C-R⁸ or N;

W⁹ is C, or when W¹ is C-R⁵⁰, W⁹ may be N;

R⁶ and R¹⁰ are selected independently from hydrogen, deuterium, halo, (C1- Cflalkyl, perfluoro(C1-C3)alkyl, hydroxy, (C1-C3)alkoxy, perfluoro(C1-C3)alkoxy, and amino; R⁷ and R⁹ are selected independently from hydrogen, deuterium, hydroxy, cyano, amino, halogen, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, , and

R^s is selected from hydrogen, deuterium, halogen, halo(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, phenoxy, benzyloxy, amino,

R³⁰ is selected from (C1-C10)hydrocarbyl, (C1-C10)hydrocarbyl substituted with amino, (C1-C10)hydrocarbyl substituted with (C1-C4)hydrocarbyl, (C1-C10)hydrocarbyl substituted with carboxyl, carboxy, (C1-C,6)alkoxycarbonyl, (C1-C6jalkoxycarbonylamino, methylthio, heterocyclyl, (C1-C10)oxaalkyl, CHR^NHR⁴⁵ and guanidine;

R⁴⁰ and R⁴¹ are selected independently from hydrogen (C1-C6)hydrocarbyl;

R⁴² is (C1-Cs)alkyl;

R⁴³ is (C1-C3)alkyl,

R⁴⁴ is selected from any naturally occurring amino acid sidechain;

R⁴⁵ is selected from H, methyl, and (C1-C4)alkoxycarbonyl; and R⁵⁰ is H or (C1-C3)alkyl.

[0054] In some embodiments, the compound of Formula 1 is selected from:

Compound 1 Compound 2 Compound 3

Compound 4 Compound 5 Compound 6

Compound 7 Compound 8 Compound 9

or a salt, hydrate, deuterated analog, or fluorinated analog thereof.

[0055] In some embodiments, the compound of Formula I is compound 1 (TQS-168), according to the formula:

[0056] In some embodiments, the compound of Formula I is compound 4 (TQS-621), according to the formula:

[0057] In some embodiments, the subject is a human. In certain embodiments, the human has a body mass index (BMI) equal to or greater than 25 kg/m². In certain embodiments, the human has a body mass index (BMI) equal to or greater than 30 kg/m².

[0058] In some embodiments, the compound of Formula I is administered parenterally. In certain embodiments, the compound of Formula I is administered intravenously. In some embodiments, the compound of Formula I is administered enterally. In some embodiments, the compound of Formula I is mixed with an enteral feeding formula. In certain embodiments, the compound of Formula I is administered by mouth (p.o.). In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 200-800 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 300-700 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 400-600 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 400-500 mg. In particular embodiments, the compound of Formula I is administered to a human subject at a daily oral dose of 450 mg. In some embodiments, the compound of Formula I is administered as a single daily dose. In some embodiments, the compound of Formula I is administered as a plurality of equally or unequally divided sub-doses. [0059] In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the expression level of Ppargcla (PGC-la) as compared to pre-treatment levels.

[0060] In some embodiments, the subject is diagnosed with obesity. In some embodiments, the subject has an eating disorder. In certain embodiments, the eating disorder is binge-eating disorder. In some embodiments, the subject has hyperglycemia. In some embodiments, the subject has hyperlipidemia.

[0061] In some embodiments, the subject has developed or is at risk of developing type 2 diabetes. In some embodiments, the subject has developed or is at risk of developing cardiovascular disease. In some embodiments, the subject has developed or is at risk of developing metabolic syndrome.

[0062] In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces the subject’s body weight by greater than 5%. In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces the subject’s body weight by greater than 10%. In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces the subject’s body weight by greater than 15%.

[0063] In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, aids reduction of the subject’s body weight by greater than 5%. In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, aids reduction of the subject’s body weight by greater than 10%. In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, aids reduction of the subject’s body weight by greater than 15%.

[0064] In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces fat mass of the subject by greater than 5%. In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces fat mass of the subject by greater than 10%. In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces fat mass of the subject by greater than 15%. [0065] In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, aids reduction of fat mass of the subject by greater than 5%. In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, aids reduction of fat mass of the subject by greater than 10%. In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, aids reduction of fat mass of the subject by greater than 15%.

[0066] In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces or aids in the reduction of visceral fat mass of the subject by greater than 5%. In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces or aids in the reduction of visceral fat mass of the subject by greater than 10%. In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces or aids in the reduction of visceral fat mass of the subject by greater than 15%. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0068] FIG. 1 shows the timeline of study for mice in Cohort 1.

[0069] FIG. 2 shows the timeline of study for mice in Cohort 2.

[0070] FIGs. 3A and 3B show the effect of TQS-168 on the body weight of mice in Cohort 1, with FIG. 3A showing the body weight at baseline and FIG. 3B showing the body weight 57 days after the start of treatment with TQS-168 or vehicle.

[0071] FIGs. 4A and 4B show the effect of TQS-168 on the body weight of mice in Cohort 2, with FIG. 4A showing the body weight at baseline and FIG. 4B showing the body weight 57 days after the start of treatment with TQS-168 or vehicle.

[0072] FIGs. 5A and 5B show the effect of TQS-168 on the total fat mass of mice in Cohort 1 as measured by EchoMRI test, with FIG. 5A showing the fat content normalized to body weight at baseline and FIG. 5B showing the fat content normalized to body weight 115 days after the start of treatment with TQS-168 or vehicle. Data are presented as mean ± SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01; ***p<0.001; ns, no significance.

[0073] FIGs. 6A and 6B show the effect of TQS-168 on the total muscle mass of mice in Cohort 1 as measured by EchoMRI test, with FIG. 6A showing the muscle content normalized to body weight at baseline and FIG. 6B showing the muscle content normalized to body weight 115 days after the start of treatment with TQS-168 or vehicle. Data are presented as mean + SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01; ***p<0.001; ns, no significance.

[0074] FIGs. 7A and 7B show the effect of TQS-168 on the total fat mass of mice in Cohort 2 as measured by EchoMRI test, with FIG. 7A showing the fat content normalized to body weight at baseline and FIG. 7B showing the fat content normalized to body weight 115 days after the start of treatment with TQS-168 or vehicle. Data are presented as mean ± SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01; ***p<0.001; ns, no significance.

[0075] FIGs. 8A and 8B show the effect of TQS-168 on the total muscle mass of mice in Cohort 2 as measured by EchoMRI test, with FIG. 8A showing the muscle content normalized to body weight at baseline and FIG. 8B showing the muscle content normalized to body weight 115 days after the start of treatment with TQS-168 or vehicle. Data are presented as mean ± SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01; ***p<0.001; ns, no significance.

[0076] FIGs. 9A and 9B show the effect of TQS-168 on the individual fat percentage change in mice from baseline to 4 months after treatment, with FIG. 9A showing the fat percentage change in mice administrated with vehicle and FIG. 9B showing the fat percentage change in mice administrated with TQS-168.

[0077] FIGs. 10A and 10B show the effect of TQS-168 on the forelimb grip strength of mice in Cohort 1 measured with grip meter, with FIG. 10A showing the forelimb grip strength at baseline and FIG. 10B showing the forelimb grip strength 114 days after the start of treatment with TQS-168 or vehicle. Data are presented as mean ± SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01; ***p<0.001; ns, no significance.

[0078] FIGs. 11A and 11B show the effect of TQS-168 on the forelimb grip strength of mice in Cohort 2 measured with grip meter, with FIG. 11A showing the forelimb grip strength at baseline and FIG. 11B showing the forelimb grip strength 114 days after the start of treatment with TQS-168 or vehicle. Data are presented as mean ± SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01; ***p<0.001; ns, no significance.

[0079] FIGs. 12A and 12B show the effect of TQS-168 on the field distance traveled by mice in Cohort 1 in the open field test for locomotor activities, with FIG. 12A showing the field distance at baseline and FIG. 12B showing the field distance 115 days after the start of treatment with TQS-168 or vehicle. Data are presented as mean ± SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01;

***p<0.001; ns, no significance.

[0080] FIGs. 13A and 13B show the effect of TQS-168 on the field distance traveled by mice in Cohort 2 in the open field test for locomotor activities, with FIG. 13A showing the field distance at baseline and FIG. 13B showing the field distance 115 days after the start of treatment with TQS- 168 or vehicle. Data are presented as mean ± SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01;

***p<0.001; ns, no significance.

[0081] FIGs. 14A and 14B show the effect of TQS-168 on the rearing number of mice in Cohort 1 in the open field test for locomotor activities, with FIG. 14A showing the rearing number at baseline and FIG. 14B showing the rearing number 115 days after the start of treatment with TQS-168 or vehicle. Data are presented as mean ± SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01; ***p<0.001; ns, no significance.

[0082] FIGs. 15A and 15B show the effect of TQS-168 on the rearing number of mice in Cohort 2 in the open field test for locomotor activities, with FIG. ISA showing the rearing number at baseline and FIG. 15B showing the rearing number 115 days after the start of treatment with TQS-168 or vehicle. Data are presented as mean + SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01 ; ***p<0.001 ; ns, no significance.

[0083] FIGs. 16A and 16B show the effect of TQS-168 on the rotarod test of mice in Cohort 1, with FIG. 16A showing the time remaining on the rotarod instrument at baseline and FIG. 16B showing the time remaining on the rotarod instrument 123 days after the start of treatment with TQS-168 or vehicle. Data are presented as mean ± SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01; ***p<0.001; ns, no significance.

[0084] FIGs. 17A and 17B show the effect of TQS-168 on the treadmill test of mice in Cohort 1 on day 4 after three days of training, with FIG. 17A showing the time spent on the treadmill instrument and FIG. 17B showing the distance traveled on the treadmill instrument.

[0085] FIGs. 18A and 18B show the effect of TQS-168 on the open field test of mice in Cohort 1 on day 5 after three days of training, with FIG. 18A showing the time spent on the open field instrument and FIG. 18B showing the distance traveled on the open field instrument.

[0086] FIGs. 19A, 19B, 19C, 19D, and 19E show the effect of TQS-168 on the frailty index in Cohort 1 , with FIG. 19A showing the clinical frailty index at baseline, FIG. 19B showing the clinical frailty index 57 days after the start of treatment with TQS- 168 or vehicle, FIG. 19C showing the clinical frailty index 86 days after the start of treatment with TQS-168 or vehicle, FIG. 19D showing the clinical frailty index 114 days after the start of treatment with TQS-168 or vehicle, and FIG. 19E showing the tendency graph of the clinical frailty index. For FIGs. 19A-19D, data are presented as mean ± SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01;

***p<0.001; ns, no significance. For FIG. 19E, data are presented as mean + SEM, analyzed using two-way ANOVA followed by Tukey’s multiple comparison post hoc test, ns, no significance; ***p<0.001, comparison made between old-vehicle vs old- TQS-168 groups. POD, post days after dosing.

[0087] FIGs. 20A, 20B, 20C, 20D, and 20E show the effect of TQS-168 on the frailty index in Cohort 2, with FIG. 20A showing the clinical frailty index at baseline, FIG. 20B showing the clinical frailty index 57 days after the start of treatment with TQS- 168 or vehicle, FIG. 20C showing the clinical frailty index 86 days after the start of treatment with TQS-168 or vehicle, FIG. 20D showing the clinical frailty index 114 days after the start of treatment with TQS- 168 or vehicle, and FIG. 20E showing the tendency graph of the clinical frailty index. For FIGs. 20A-20D, data are presented as mean ± SD, analyzed using two-tailed Mann Whitney test. * p<0.05; **p<0.01;

***p<0.001; ns, no significance. For FIG. 20E, data are presented as mean ± SEM, analyzed using two-way ANOVA followed by Tukey’s multiple comparison post hoc test, ns, no significance; ***p<0.001, comparison made between old-vehicle vs old- TQS-168 groups. POD, post days after dosing.

[0088] FIGs. 21A and 21B show the effect of TQS-168 on the appearance of mice in Cohort 1, with FIG. 21 A showing a vehicle-treated group and FIG. 21B showing a TQS-168-treated group.

[0089] FIGs. 22A and 22B show the effect of TQS-168 on the appearance of mice in Cohort 2, with FIG. 22A showing a vehicle-treated group and FIG. 22B showing a TQS-168-treated group.

[0090] FIG. 23 shows the Kaplan-Meier plot of mice administered with TQS-168 or vehicle.

[0091] FIG. 24 shows the effect of TQS-168 on 14 selected aging-related variables of the 31 -point frailty test in old mice (18 months) of Cohort 1. DETAILED DESCRIPTION efinitions

[0092] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the invention pertains.

[0093] A “therapeutically effective amount” of a composition is an amount sufficient to achieve a desired therapeutic effect, and therefore does not require cure or complete remission. [0094] The term “subject” refers to a human or non-human animal, including, but not limited to, bovine, equine, canine, ovine, feline, and rodent, including murine and rattus, subjects. A “patient” is a human subject in need of treatment.

[0095] As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to reducing or ameliorating a disorder, and/or signs or symptoms associated therewith, or slowing or halting the progression thereof. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.

[0096] As used herein, “pre-treatment” means prior to the first administration of a compound of Formula I according to the methods described herein. Pre-treatment does not exclude, and often includes, the prior administration of treatments other than a compound of Formula I.

[0097] As used herein, “post-treatment” means after the administration of a compound of Formula I according to the methods described herein. Post-treatment includes after any administration of a compound of Formula I at any dosage described herein. Post-treatment also includes after the treatment phase of a compound of Formula I.

[0098] In this disclosure, “comprises,” “comprising,” “containing,” “having,” “includes,” “including,” and linguistic variants thereof have the meaning ascribed to them in U.S. Patent law, permitting the presence of additional components beyond those explicitly recited.

[0099] The term “biological sample” refers to any tissue, cell, fluid, or other material derived from an organism (e.g., human subject). In certain embodiments, the biological sample is serum or blood. ethods of Treatment .1. Methods of delaying aging-related changes

[0100] In a first aspect, methods of delaying aging-related changes in a subject are presented. The methods comprise administering to the subject an effective amount of a compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof.

[0101] In some embodiments, the aging -related change does not include neurodegenerative disease. In some embodiments, the aging -related change does not include amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, frontotemporal degeneration, dementia with Lewy bodies, motor neuron disease, or demyelinating disease. In some embodiments, the aging-related change does not include cognitive impairment.

[0102] In some embodiments, the aging -related change does not include an increase in systemic immune activation. In some embodiments, the aging-related change does not include an increase in acute systemic inflammation. In some embodiments, the aging-related change does not include cytokine release syndrome (CRS).

[0103] In some embodiments, the aging -related change is a decrease in muscle mass. In some embodiments, the aging-related change is a decrease in muscle strength. In some embodiments, the aging-related change is a decrease in muscle mass and muscle strength. In some embodiments, the aging-related change is a decrease in muscle function. In some of these embodiments, the muscle function is striated muscle function. In certain embodiments, the muscle function is skeletal muscle function. In certain embodiments, the muscle function is diaphragmatic muscle function. In certain embodiments, the muscle function is cardiac muscle function. In some other of these embodiments, the muscle function is smooth muscle function. In certain embodiments, the muscle function is vascular muscle function. In some embodiments, the subject has sarcopenia.

[0104] In some embodiments, the aging-related change is an increase in fat mass. In certain embodiments, the fat mass is total fat mass. In certain embodiments, the fat mass is visceral fat mass. In some embodiments, the aging-related change is an increase in body weight. In some other embodiments, the aging -related change is a decrease in body weight.

[0105] In some embodiments, the aging -related change is a decrease in motor balance. In some embodiments, the aging-related change is a decrease in motor coordination. In some embodiments, the aging-related change is a decrease in gait steadiness or speed. In some embodiments, the aging-related change is a decrease in gait steadiness. In some embodiments, the aging-related change is a decrease in gait speed. In some embodiments, the aging-related change is a decrease in gait steadiness and speed. In some embodiments, the aging-related change is an increased number of falls. In some embodiments, the aging-related change is a decrease in mobility.

[0106] In some embodiments, the aging -related change is an increase in fatigue. In certain embodiment, the fatigue is physical fatigue. In certain embodiments, the fatigue is mental fatigue. In some embodiments, the aging-related change is a decrease in exercise endurance. In certain embodiments, the aging-related change is a decrease in walking endurance. In certain embodiments, the aging-related change is a decrease in running endurance.

[0107] In some embodiments, the aging -related change is a decrease in lung function. In some embodiments, the aging-related change is a decrease in oxygen utilization. In some of these embodiments, the oxygen utilization is measured as VO2 max. In some embodiments, the aging-related change is a decrease in cardiac function. In some embodiments, the aging-related change is a decrease in blood circulation.

[0108] In some embodiments, the aging -related change is a sensory impairment. In various embodiments, the sensory impairment is a hearing impairment, a visual impairment, or an olfactory impairment. In certain embodiment, the sensory impairment is a hearing impairment. In certain embodiment, the sensory impairment is a visual impairment. In certain embodiment, the sensory impairment is an olfactory impairment.

[0109] In some embodiments, the aging -related change is aging of skin. In some of these embodiments, the aging of skin is decreased skin elasticity or increased skin wrinkles. In certain embodiments, the aging of skin is decreased skin elasticity. In certain embodiments, the aging of skin is increased skin wrinkles.

[0110] In some embodiments, the aging -related change is aging of hair. In some of these embodiments, the aging of hair is hair graying or hair thinning. In certain embodiments, the aging of hair is hair graying. In certain embodiments, the aging of hair is hair thinning.

[0111] In some embodiments, the aging-related change is a decrease in bone mass. In some embodiments, the aging-related change is an increase in bone fractures. In some embodiments, the aging-related change is a decrease in joint flexibility.

[0112] In some embodiments, the aging -related change is a decrease in digestive function. In some embodiments, the aging-related change is an increase in constipation. In some embodiments, the aging-related change is a decrease in insulin sensitivity.

[0113] In some embodiments, the aging -related change is a decrease in immune function. In some of these embodiments, the decrease in immune function is increased susceptibility to infection. In some of these embodiments, the decrease in immune function is reduced antibody titer after vaccination. In certain embodiments, the vaccination is an influenza virus or a coronavirus vaccination.

[0114] In some embodiments, the aging -related change is an increase in inflammation. In some of these embodiments, the increase in inflammation is measured by an increase in serum levels of one or more pro-inflammatory cytokines selected from the group consisting of: IL-6, TNFa, IFNy, IL-17A, IL-17F, IL-2, and monocyte chemoattractant protein I (MCP-1). In certain embodiments, the subject has a pre-treatment serum IL-6 level of at least 2 pg/ml. In some of these embodiments, the increase in inflammation is measured by an increase in serum level of C-reactive protein (CRP). In certain embodiments, the subject has a pre-treatment serum CRP level of at least 2 mg/L. In certain embodiments, the subject has a pre-treatment serum IL-6 level of at least 2 pg/ml and a pre-treatment CRP level of at least 2 mg/L. In some embodiments, the increase in inflammation is measured by an increase in serum level of neurofilament light chain.

[0115] In some embodiments, the aging -related change is a decrease in vestibular function. In some embodiments, the aging-related change is a delay or an impairment in wound healing. In certain embodiments, the aging-related change is a delay in wound healing. In certain embodiments, the aging-related change is an impairment in wound healing.

[0116] In some embodiments, the aging -related change is an increase in clinical frailty index. In some of these embodiments, the clinical frailty index is determined according to the method described in Searle et al., BMC Geriatr. 30;8:24 (2008) or Kulminski et al., J Am Geriatr Soc. 56:898-903 (2008), each of which is incorporated herein by reference in its entirety. .2. Methods of increasing lifespan

[0117] In another aspect, methods of increasing lifespan in a subject are presented. The methods comprise administering to the subject an effective amount of a compound of Formula I or a salt, hydrate, deuterated analog, or fluorinated analog thereof.

[0118] In various embodiments, the administration of the compound of Formula I increases the lifespan of a subject population by greater than 1 month, greater than 2 months, greater than 3 months, greater than 4 months, greater than 5 months, greater than 6 months, greater than 7 months, greater than 8 months, greater than 9 months, greater than 10 months, greater than 11 months, or greater than 12 months, as compared to an age-matched control subject population without the administration. [0119] In various embodiments, the administration of the compound of Formula I increases the lifespan of a subject population by greater than 1 year, greater than 2 years, greater than 3 years, greater than 4 years, greater than 5 years, greater than 6 years, greater than 7 years, greater than 8 years, greater than 9 years, or greater than 10 years, as compared to an age-matched control subject population without the administration.

[0120] In various embodiments, the administration of the compound of Formula I increases the lifespan of a subject population by greater than 10 years, greater than 15 years, greater than 20 years, greater than 25 years, greater than 30 years, greater than 35 years, greater than 40 years, greater than 45 years, or greater than 50 years, as compared to an age-matched control subject population without the administration. [0121] In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the lifespan of a human population by greater than 6 months, greater than 1 year, greater than 2 years, greater than 3 years, greater than 4 years, greater than 5 years, greater than 10 years, greater than 15 years, greater than 20 years, or greater than 30 years, as compared to an age-matched control human population without the administration.

[0122] In various embodiments, the administration of the compound of Formula I increases the lifespan of a subject population by greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 40%, greater than 50%, or greater than 100%, as compared to an age-matched control subject population without the administration. .3. Methods of reducing risk of, delaying onset of, or treating aging-related diseases

[0123] In another aspect, methods of reducing risk of, delaying onset of, or treating aging-related diseases in a subject are presented. The methods comprise administering to the subject an effective amount of a compound of Formula I or a salt, hydrate, deuterated analog, or fluorinated analog thereof.

[0124] In some embodiments, the aging -related disease does not include neurodegenerative disease. In some embodiments, the aging -related disease does not include amyotrophic lateral sclerosis (ALS), Alzheimer disease, Parkinson’s disease, Huntington’s disease, frontotemporal degeneration, dementia with Lewy bodies, motor neuron disease, or demyelinating disease. In some embodiments, the aging-related disease does not include cognitive impairment in the central nerve system.

[0125] In some embodiments, the aging -related disease does not include systemic immune activation. In some embodiments, the aging-related disease does not include acute systemic inflammation. In some embodiments, the aging -related disease does not include cytokine release syndrome (CRS).

[0126] In some embodiments, the method reduces the risk of an aging-related disease or condition. In some embodiments, the method delays the onset of an aging-related disease or condition. In some embodiments, the method prevents an aging-related disease or condition. In some embodiments, the method slows the progression of an aging-related disease or condition.

[0127] In some embodiments, the aging -related disease is arterial stiffening. In some embodiments, the aging-related disease is capillary rarefaction. In some embodiments, the aging-related disease is hypertension. In some embodiments, the aging-related disease is atherosclerosis. In some of these embodiments, the administration of the compound of Formula I decreases serum levels of one or more markers of atherosclerosis risk selected from the group consisting of: LDL-C, triglyceride, ApoB, and Lp(a). In some embodiments, the aging-related disease is cardiovascular disease. In some of these embodiments, the administration of the compound of Formula I, decreases serum level of cardiovascular risk marker, N-terminal prohormone-B-type natriuretic peptide (NT-pro-BNP).

[0128] In some embodiments, the aging -related disease is cancer. In some of these embodiments, the cancer is melanoma, breast cancer, lung cancer, prostate cancer, colon cancer, bladder cancer, pancreas cancer, or ovary cancer.

[0129] In some embodiments, the aging -related disease is neurodegenerative disease. In some embodiments, the aging-related disease is dementia. In some embodiments, the aging-related disease is cognitive dysfunction.

[0130] In some embodiments, the aging-related disease is diabetes. In some embodiments, the aging-related disease is obesity.

[0131] In some embodiments, the aging -related disease is osteoarthritis. In some embodiments, the aging-related disease is osteoporosis. [0132] In some embodiments, the aging -related disease is fibrosis. In some embodiments, the aging-related disease is lung fibrosis. In some embodiments, the aging-related disease is lymph node fibrosis.

[0133] In some embodiments, the aging -related disease is skin disease. In some embodiments, the aging-related disease is kidney disease. In some embodiments, the aging-related disease is pulmonary disease. In some embodiments, the aging-related disease is chronic obstructive pulmonary disease (COPD).

[0134] In some embodiments, the aging-related disease is age-related macular degeneration. In some embodiments, the aging-related disease is cataract.

[0135] In some embodiments, the aging-related disease is late-life depression. .4. Methods of reducing body weight

[0136] In another aspect, methods of reducing body weight of a subject are presented. The methods comprise administering to the subject an effective amount of a compound of Formula I or a salt, hydrate, deuterated analog, or fluorinated analog thereof.

[0137] In some embodiments, the subject is a human and the human subject has normal body weight. In certain embodiments, the human has a body mass index (BMI) less than 25 kg/m². In certain embodiments, the human has a body mass index (BMI) less than 24 kg/m². In certain embodiments, the human has a body mass index (BMI) less than 23 kg/m².

[0138] In some embodiments, the human subject is overweight. In various embodiments, the human has a body mass index (BMI) equal to or greater than 23 kg/m², such as greater than 24 kg/m², 25 kg/m², 26 kg/m², 27 kg/m², 28 kg/m², or 29 kg/m². In certain embodiments, the human has a body mass index (BMI) equal to or greater than 25 kg/m².

[0139] In some embodiments, the human subject is obese. In various embodiments, the human has a body mass index (BMI) equal to or greater than 30 kg/m², such as greater than 31 kg/m², 32 kg/m², 33 kg/m², 34 kg/m², 35 kg/m², or 36 kg/m². In certain embodiments, the human has a body mass index (BMI) equal to or greater than 30 kg/m².

[0140] In some embodiments, the subject is diagnosed with obesity. In some embodiments, the subject is at risk of developing obesity. [0141] In some embodiments, the subject has an eating disorder. In some of these embodiments, the eating disorder is binge-eating disorder.

[0142] In some embodiments, the subject has hyperglycemia. In some embodiments, the subject has hyperlipidemia.

[0143] In some embodiments, the subject has developed type 2 diabetes. In some embodiments, the subject is at risk of developing type 2 diabetes.

[0144] In some embodiments, the subject has developed cardiovascular disease. In some embodiments, the subject is at risk of developing cardiovascular disease.

[0145] In some embodiments, the subject has developed metabolic syndrome. In some embodiments, the subject is at risk of developing metabolic syndrome. In some embodiments, the subject has developed metabolic syndrome, as defined by the American Heart Association. In some embodiments, the subject is at risk of developing metabolic syndrome, as defined by the American Heart Association.

[0146] In various embodiments, the administration of the compound of Formula I reduces the subject’s body weight by greater than 2%, such as greater than 3%, greater than 4%, greater than 5%, greater than 7.5%, greater than 10%, greater than 12.5%, greater than 15%, greater than 20%, or greater than 25%, compared to the subject’s pre-treatment body weight. In certain embodiments, the administration of the compound of Formula I reduces the subject’s body weight by greater than 5%, compared to the subject’s pre-treatment body weight. In certain embodiments, the administration of the compound of Formula I reduces the subject’s body weight by greater than 10%, compared to the subject’s pre-treatment body weight. In certain embodiments, the administration of the compound of Formula I reduces the subject’s body weight by greater than 15%, compared to the subject’s pre-treatment body weight.

[0147] In various embodiments, the administration of the compound of Formula I reduces the fat mass of the subject by greater than 2%, such as greater than 3%, greater than 4%, greater than 5%, greater than 7.5%, greater than 10%, greater than 12.5%, greater than 15%, greater than 20%, or greater than 25%, compared to the subject’s pre-treatment fat mass level. In certain embodiments, the administration of the compound of Formula I reduces the fat mass of the subject by greater than 5%, compared to the subject’s pre-treatment fat mass level. In certain embodiments, the administration of the compound of Formula I reduces the fat mass of the subject by greater than 10%, compared to the subject’s pre-treatment fat mass level. In certain embodiments, the administration of the compound of Formula I reduces the fat mass of the subject by greater than 15%, compared to the subject’s pre-treatment fat mass level.

[0148] In various embodiments, the administration of the compound of Formula I reduces the visceral fat mass of the subject by greater than 2%, such as greater than 3%, greater than 4%, greater than 5%, greater than 7.5%, greater than 10%, greater than 12.5%, greater than 15%, greater than 20%, or greater than 25%, compared to the subject’s pre-treatment visceral fat mass level. In certain embodiments, the administration of the compound of Formula I reduces the visceral fat mass of the subject by greater than 5%, compared to the subject’s pre-treatment visceral fat mass level. In certain embodiments, the administration of the compound of Formula I reduces the visceral fat mass of the subject by greater than 10%, compared to the subject’s pre-treatment visceral fat mass level. In certain embodiments, the administration of the compound of Formula I reduces the visceral fat mass of the subject by greater than 15%, compared to the subject’s pre-treatment visceral fat mass level.

[0149] In various embodiments, following administration of the compound of Formula I, the subject’s body weight is reduced by greater than 2%, such as greater than 3%, greater than 4%, greater than 5%, greater than 7.5%, greater than 10%, greater than 12.5%, greater than 15%, greater than 20%, or greater than 25%, compared to the subject’s pre-treatment body weight. In certain embodiments, following administration of the compound of Formula I, the subject’s body weight is reduced by greater than 5%, compared to the subject’s pre-treatment body weight. In certain embodiments, following administration of the compound of Formula I, the subject’s body weight is reduced by greater than 10%, compared to the subject’s pretreatment body weight. In certain embodiments, following the administration of the compound of Formula I, the subject’s body weight is reduced by greater than 15%, compared to the subject’s pre-treatment body weight.

[0150] In various embodiments, following administration of the compound of Formula I, the subject’s fat mass is reduced by greater than 2%, such as greater than 3%, greater than 4%, greater than 5%, greater than 7.5%, greater than 10%, greater than 12.5%, greater than 15%, greater than 20%, or greater than 25%, compared to the subject’s pre-treatment fat mass level. In certain embodiments, following administration of the compound of Formula I, the subject’s fat mass is reduced by greater than 5%, compared to the subject’s pre-treatment fat mass level. In certain embodiments, following the administration of the compound of Formula I, the subject’s fat mass is reduced by greater than 10%, compared to the subject’s pretreatment fat mass level. In certain embodiments, following the administration of the compound of Formula I, the subject’s fat mass is reduced by greater than 15%, compared to the subject’s pre-treatment fat mass level.

[0151] In various embodiments, following administration of the compound of Formula I, the visceral fat mass of the subject is reduced by greater than 2%, such as greater than 3%, greater than 4%, greater than 5%, greater than 7.5%, greater than 10%, greater than 12.5%, greater than 15%, greater than 20%, or greater than 25%, compared to the subject’s pre-treatment visceral fat mass level. In certain embodiments, following administration of the compound of Formula I, the subject’s visceral fat mass is reduced by greater than 5%, compared to the subject’s pretreatment visceral fat mass level. In certain embodiments, following the administration of the compound of Formula I, the subject’s visceral fat mass is reduced by greater than 10%, compared to the subject’s pre-treatment visceral fat mass level. In certain embodiments, following the administration of the compound of Formula I, the subject’s visceral fat mass is reduced by greater than 15%, compared to the subject’s pre-treatment visceral fat mass level. .5. Subjects

[0152] In some embodiments, the subject is a human.

[0153] In some embodiments, the human is no more than 20 years of age. In some embodiments, the human is no more than 30 years of age. In some embodiments, the human is no more than 40 years of age. In some embodiments, the human is no more than 50 years of age. In some embodiments, the human is no more than 60 years of age. In some embodiments, the human is no more than 70 years of age. In some embodiments, the human is no more than 80 years of age.

[0154] In some embodiments, the human is over 20 years of age. In some embodiments, the human is over 30 years of age. In some embodiments, the human is over 40 years of age. In some embodiments, the human is over 45 years of age. In some embodiments, the human is over 50 years of age. In some embodiments, the human is over 55 years of age. In some embodiments, the human is over 60 years of age. In some embodiments, the human is over 65 years of age. In some embodiments, the human is over 70 years of age. In some embodiments, the human is over 75 years of age. In some embodiments, the human is over 80 years of age. In some embodiments, the human is over 85 years of age. In some embodiments, the human is over 90 years of age.

[0155] In various embodiments, the human is 10 to 100 years of age, such as 10 to 20 years, 10 to 30 years, 10 to 40 years, 10 to 50 years, 10 to 60 years, 10 to 70 years, 10 to 80 years, 10 to 90 years, 20 to 30 years, 20 to 40 years, 20 to 50 years, 20 to 60 years, 20 to 70 years, 20 to 80 years, 20 to 90 years, 20 to 100 years, 30 to 40 years, 30 to 50 years, 30 to 60 years, 30 to 70 years, 30 to 80 years, 30 to 90 years, 30 to 100 years, 40 to 50 years, 40 to 60 years, 40 to 70 years, 40 to 80 years, 40 to 90 years, 40 to 100 years, 50 to 60 years, 50 to 70 years, 50 to 80 years, 50 to 90 years, 50 to 100 years, 60 to 70 years, 60 to 80 years, 60 to 90 years, 60 to 100 years, 70 to 80 years, 70 to 90 years, 70 to 100 years, 80 to 90 years, 80 to 100 years, or 90 to 100 years of age. [0156] In some embodiments, the subject is a non-human animal. In various embodiments, the non-human animal is selected from the group consisting of a horse, a donkey, a cow, a pig, a sheep, a goat, a dog, a cat, a guinea pig, a hamster, a ferret, a rat, a rabbit, and a parrot. In certain embodiments, the non-human animal is a horse.

In some of these embodiments, the horse is over 15 years of age, such as over 20 years, 25 years, or 30 years of age. In certain embodiments, the non-human animal is a donkey. In some of these embodiments, the donkey is over 15 years of age, such as over 20 years, 25 years, or 30 years of age. In certain embodiments, the non-human animal is a cow. In some of these embodiments, the cow is over 10 years of age, such as over 15 years, 20 years, or 25 years of age. In certain embodiments, the non-human animal is a pig. In some of these embodiments, the pig is over 10 years of age, such as over 15 years, 20 years, or 25 years of age. In certain embodiments, the non-human animal is a sheep. In some of these embodiments, the sheep is over 6 years of age, such as over 8 years, 10 years, or 12 years of age. In certain embodiments, the non- human animal is a goat. In some of these embodiments, the goat is over 9 years of age, such as over 12 years, 15 years, or 18 years of age. In certain embodiments, the non- human animal is a dog. In some of these embodiments, the dog is over 6 years of age, such as over 8 years, 10 years, or 12 years of age. In certain embodiments, the non- human animal is a cat. In some of these embodiments, the cat is over 8 years of age, such as over 10 years, 12 years, or 14 years of age. In certain embodiments, the non- human animal is a guinea pig. In some of these embodiments, the guinea pig is over 3 years of age, such as over 4 years, 5 years, or 6 years of age. In certain embodiments, the non-human animal is a hamster. In some of these embodiments, the hamster is over 1 year of age, such as over 1.5 years, 2 years, or 2.5 years of age. In certain embodiments, the non-human animal is a ferret. In some of these embodiments, the ferret is over 4 years of age, such as over 5 years, 6 years, or 7 years of age. In certain embodiments, the non-human animal is a rat. In some of these embodiments, the rat is over 1 year of age, such as over 1 .5 years, 2 years, or 2.5 years of age. In certain embodiments, the non-human animal is a rabbit. In some of these embodiments, the rabbit is over 6 years of age, such as over 7 years, 8 years, or 9 years of age. In certain embodiments, the non-human animal is a parrot. In some of these embodiments, the parrot is over 20 years of age, such as over 25 years, 30 years, or 40 years of age.

[0157] In some embodiments, the non-human animal is a non-human mammal. In some embodiments, the non-human animal is a non-human primate. In certain embodiments, the non-human primate is a monkey or an ape. In various embodiments, the non-human primate over 15 years of age, such as over 20 years, over 25 years, over 30 years, over 35 years, or over 40 years of age.

2.6. Compounds

[0158] In some embodiments, the compound administered in the methods described herein is a compound of Formula I:

Ar is

W¹ is chosen from N-R¹, O, and S, or when W⁹ is N, W¹ may additionally be C-R⁵⁰;

W² is C-R² or N;

W³ is C-R³ or N;

W⁴ is C-R⁴ or N;

W⁵ is C-R⁵ or N;

W⁶ is C-R⁶ or N;

W⁷ is C-R⁷ or N;

W⁸ is C-R⁸ or N;

W⁹ is C, or when W¹ is C-R⁵⁰, W⁹ may be N;

R², R³, R⁴, and R⁵ are selected independently from hydrogen, deuterium, halogen, perfhioro(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, perfluoro(C1-C4)alkoxy, (C1-C4)acyl, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, carboxy, (C1-C4)alkoxycarbonylamino, carboxamido, (C1- C4)alkylaminocarbonyl, cyano, acetoxy, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, mercapto, (C1-C4)alkylthio, aminosulfonyl, (C1- C4)alkylsulfonyl, and (C1-C4)acylamino;

R⁶ and R¹⁰ are selected independently from hydrogen, deuterium, halo, (C1-C3)alkyl, perfluoro(C1-C3)alkyl, hydroxy, (C1-C3)alkoxy, perfluoro(C1-C3)alkoxy, and amino;

R³⁰ is selected from (C1-C10)hydrocarbyl, (C1-C10)hydrocarbyl substituted with amino, (C1-C10)hydrocarbyl substituted with (C1-C4)hydrocarbyl, (C1-C10)hydrocarbyl substituted with carboxyl, carboxy, (C1-C6)alkoxycarbonyl, (C1- C6)alkoxycarbonylamino, methylthio, heterocyclyl, (C1-C10)oxaalkyl, CHR^NHR⁴⁵ and guanidine;

R⁴⁰ and R⁴¹ are selected independently from hydrogen (C1-C6)hydrocarbyl;

R⁴² is (C1-C5)alkyl;

R⁴³ is (C1-C3)alkyl,

R⁴⁴ is selected from any naturally occurring amino acid sidechain;

R⁴⁵ is selected from H, methyl, and (C1-C4)alkoxycarbonyl; and

R⁵⁰ is H or (C1-C3)alkyl.

[0159] In some embodiments, the compound of Formula I is selected from:

Compound 1 Compound 2 Compound 3

Compound 4 Compound 5 Compound 6

[0160] In particular embodiments, the compound of Formula I is compound 1 (TQS-

168), according to the formula:

[0161] In particular embodiments, the compound of Formula I is compound 4 (TQS-

621), according to the formula:

[0162] In various embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the expression level of Ppargcla (PGC-la) as compared to pre- treatment levels. In some embodiments, the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, does not increase the expression level of Ppargcla (PGC-la) as compared to pre-treatment levels.

2.7. Pharmaceutical Composition

[0163] The compound of Formula I used in the methods described herein can be formulated in any appropriate pharmaceutical composition for administration by any suitable route of administration. Suitable routes of administration include, but are not limited to, intravenous and oral routes of administration. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy.

[0164] In some embodiments, the route of administration for use in the methods described herein is parental administration. In certain embodiments, the route of administration for use in the methods described herein is intravenous administration. In some embodiments, the route of administration for use in the methods described herein is enteral administration. In some of these enteral administration embodiments, the compound of Formula I is mixed with an enteral feeding formula. In certain embodiments, the route of administration for use in the methods described herein is oral administration.

[0165] All methods include the step of bringing into association a compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof (“active ingredient”), with the carrier which constitutes one or more excipients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0166] Formulations of the present methods suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0167] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed, or controlled release of the active ingredient therein.

[0168] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate- buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0169] The pharmaceutical composition may comprise one or more pharmaceutical excipients. Any suitable pharmaceutical excipient can be used, and one of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, 8th Revised Ed. (2017), incorporated by reference in its entirety.

[0170] The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present methods described herein are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the methods described herein include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucohep tonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, malefic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p- toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.

2.8. Dosage regimens

Unit dose

[0171] In some embodiments, the compound of formula I is administered in a dose that is independent of subject weight or surface area (flat dose).

[0172] In some embodiments, the flat dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg. In some embodiments, the flat dose is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some embodiments, the flat dose is 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some embodiments, the flat dose is 25 mg, 30 mg, 40 mg, or 50 mg. In some embodiments, the flat dose is 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. In some embodiments, the flat dose is 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg.

[0173] In some embodiments, the flat dose is 0.1 - 1 mg, 1 - 10 mg, 10 - 15 mg, 15 - 20 mg, 20 - 30 mg, 30 - 40 mg, or 40 - 50 mg. In some embodiments, the flat dose is 1 - 50 mg, 50 - 100 mg, 100 mg - 200 mg, 200 mg - 300 mg, 300 mg - 400 mg, 400 mg - 500 mg, 500 mg - 600 mg, 600 mg - 700 mg, 700 mg - 800 mg, 800 mg - 900 mg, or 900 mg - 1000 mg.

[0174] In various embodiments, the flat dose is 10 - 5000 mg. In certain embodiments, the dose is 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg. In certain embodiments, the dose is 1500 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg, or 5000 mg.

[0175] In various embodiments, the flat dose is 25 - 2000 mg. In certain embodiments, the dose is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg,

200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg,

700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg.

[0176] In various embodiments, the compound of Formula I is administered using a weight-based dose.

[0177] In some embodiments, the compound of Formula I is administered in an amount of at least 0.5 mg/kg. In certain embodiments, the compound of Formula I is administered in an amount of at least 1 mg/kg. In certain embodiments, the dose is at least 2 mg/kg, at least 3 mg/kg, at least 4 mg/kg, at least 5 mg/kg, at least 6 mg/kg, at least 7 mg/kg, at least 8 mg/kg, at least 9 mg/kg, or at least 10 mg/kg.

[0178] In various embodiments, the dose of the compound of Formula I is at least 10 mg/kg. In certain embodiments, the dose is at least 15 mg/kg, at least 20 mg/kg, at least 25 mg/kg, 30 mg/kg, at least 35 mg/kg, at least 40 mg/kg, at least 45 mg/kg, at least 50 mg/kg, at least 55 mg/kg, at least 60 mg/kg, at least 65 mg/kg, at least 70 mg/kg, at least 75 mg/kg, at least 80 mg/kg, at least 85 mg/kg, at least 90 mg/kg, at least 95 mg/kg, at least 100 mg/kg, at least 150 mg/kg, at least 175 mg/kg, or at least 200 mg/kg.

[0179] In some embodiments, the dose is 0.5 mg/kg to 100 mg/kg. In some embodiments, the dose is 2 mg/kg to 100 mg/kg. In some embodiments, the dose is 10 mg/kg to 250 mg/kg. In some embodiments, the dose is 25 mg/kg to 1000 mg/kg. In certain embodiments, the dose of the compound of Formula I is 25 mg/kg. Dose regimen

[0180] The compound of Formula I can be administered in a single dose or in multiple doses. In various intravenous embodiments, the compound of Formula I is administered once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 14 days, once every 21 days, once every 28 days, or once a month. In various intravenous embodiments, the compound of Formula I is administered twice a day, twice every 2 days, twice every 3 days, twice every 4 days, twice every 5 days, twice every 6 days, twice every 7 days, twice every 14 days, twice every 21 days, twice every 28 days, or twice a month.

[0181] In various enteral embodiments, the compound of Formula I is administered once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 14 days, once every 21 days, once every 28 days, or once a month. In various enteral embodiments, the compound of Formula I is administered twice a day, twice every 2 days, twice every 3 days, twice every 4 days, twice every 5 days, twice every 6 days, twice every 7 days, twice every 14 days, twice every 21 days, twice every 28 days, or twice a month.

[0182] In some embodiments, the compound of Formula I is administered as a single daily dose. In some embodiments, the compound of Formula I is administered as a plurality of equally divided sub-doses. In some embodiments, the compound of Formula I is administered as a plurality of unequally divided sub-doses.

[0183] In some embodiments, the compound of Formula I is administered at a daily oral dose of 100-1000 mg. In some embodiments, the compound of Formula I is administered at a daily oral dose of 200-800 mg. In some embodiments, the compound of Formula I is administered at a daily oral dose of 300-700 mg. In some embodiments, the compound of Formula I is administered at a daily oral dose of 300- 600 mg. In some embodiments, the compound of Formula I is administered at a daily oral dose of 400-600 mg. In some embodiments, the compound of Formula I is administered at a daily oral dose of 400-500 mg.

[0184] In various embodiments, the compound of Formula I is administered at a daily oral dose of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg. In certain embodiments, the compound of Formula I is administered at a daily oral dose of 100 mg. In certain embodiments, the compound of Formula I is administered at a daily oral dose of 200 mg. In certain embodiments, the compound of Formula I is administered at a daily oral dose of 400 mg. In certain embodiments, the compound of Formula I is administered at a daily oral dose of 450 mg. In certain embodiments, the compound of Formula I is administered at a daily oral dose of 500 mg. In certain embodiments, the compound of Formula I is administered at a daily oral dose of 750 mg. In certain embodiments, the compound of Formula I is administered at a daily oral dose of 1000 mg.

[0185] In some embodiments, the compound of Formula I is administered at a daily oral dose of 10 mg/kg to 250 mg/kg, such as 10 mg/kg to 50 mg/kg, 10 mg/kg to 100 mg/kg, 10 mg/kg to 150 mg/kg, 10 mg/kg to 200 mg/kg, 50 mg/kg to 100 mg/kg, 50 mg/kg to 150 mg/kg, 50 mg/kg to 200 mg/kg, 50 mg/kg to 250 mg/kg, 100 mg/kg to 150 mg/kg, 100 mg/kg to 200 mg/kg, 100 mg/kg to 250 mg/kg, 150 mg/kg to 200 mg/kg, 150 mg/kg to 250 mg/kg, or 200 mg/kg to 250 mg/kg.

[0186] In various embodiments, the compound of Formula I is administered at a daily oral dose of 10 mg/kg, 20 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, or 250 mg/kg. In certain embodiments, the compound of Formula I is administered at a daily oral dose of 10 mg/kg. In certain embodiments, the compound of Formula I is administered at a daily oral dose of 25 mg/kg. In certain embodiments, the compound of Formula I is administered at a daily oral dose of 50 mg/kg. In certain embodiments, the compound of Formula I is administered at a daily oral dose of 100 mg/kg. In certain embodiments, the compound of Formula I is administered at a daily oral dose of 250 mg/kg. .9. Additional Agents

[0187] In some embodiments, the methods of the present disclosure include administering an effective amount of at least one second agent. In certain embodiments, the second agent is metformin. In certain embodiments, the second agent is rapamycin. In certain embodiments, the second agent is resveratrol. xamples

[0188] While various specific embodiments have been illustrated and described, the above specification is not restrictive. It will be appreciated that various changes can be made without departing from the spirit and scope of the invention(s). Many variations will become apparent to those skilled in the art upon review of this specification.

3.1. Example 1 - TQS-168 delays aging-related changes in a mouse model study

[0189] Male C57BL/6 mice were housed in groups of four per cage for 7 days’ acclimation. The mice weighed 20-30 g at the beginning of the experiment.

Temperature and humidity were controlled at 23+2°C and 50+5%, respectively. The vivarium was maintained on a 12-h light/dark cycle. Food and water were available ad libitum.

[0190] The testing subjects were divided into two groups: Cohort 1 and Cohort 2.

The total number of mice in each cohort was 32. The information and treatment of mice in Cohort 1 and Cohort 2 are respectively shown in Table 1 and Table 2 below.

[0191] The study timeline for Cohort 1 is shown in FIG. 1. The baseline characteristics of each subject animal was established during the week before the treatment started. Body weight, frailty test and grip strength measurement were performed at day 1 of the week. Locomotion test and EchoMRI were performed the next day (day 2). Locomotion test was performed before EchoMRI. On the third day of the week, rotarod test was performed. The same testing order was repeated at 16 weeks after the treatment started.

[0192] The study timeline for Cohort 2 is shown in FIG. 2. Similar to Cohort 1, the baseline characteristics of each subject animal was established during the week before the treatment started. Body weight, frailty test and grip strength measurement were performed at day 1 of the week. Locomotion test and EchoMRI were performed the next day (day 2). Locomotion test was performed before EchoMRI. The same testing order was repeated at 16 weeks after the treatment started.

[0193] Frailty test. Frailty test was performed by recording the 31 health-related variables based on established clinical signs of aging in mice, as described in Whitehead et al., J Gerontol A Biol Sci Med Sci 69(6):621-632 (2014), the disclosure of which is incorporated herein by reference in its entirety. Clinical assessment included evaluation of the integument, the musculoskeletal system, the vestibulocochlear/auditory systems, the ocular and nasal systems, the digestive system, the urogenital system, the respiratory system, signs of discomfort, the body weight, and the body surface temperature.

[0194] Grip strength test. Grip strength was assessed using a digital grip-strength meter (Linton Instrumentation) as described in Morgan et al. , Proc Natl Acad Sci U S A 111(24):E2482-91 (2014). For measuring forelimb grip strength, the mouse was lowered over the grid while keeping the torso horizontal and allowing only its forepaws to attach to the grid before any measurements were taken. The mouse was then pulled back gently by its tail to ensure that the mouse only gripped the top portion of the grid and the torso remained horizontal. The maximal grip strength value was recorded. The procedure was performed three times for each mouse. The grip strength was assessed before treatment and at 16 weeks post-treatment.

[0195] Locomotion test. Locomotion test was performed by assessing ambulation behavior of mice in an open field maze. The test was performed using the Med Associates box chambers that have 16 infrared emitters and photo detectors on each side of the box. On two sides, there were emitters and detectors in two rows enabling measurement of rearing. Standard sized environment 27 x 27 x 20.3 cm was used. At the beginning of test the mice were placed in the center of the test chamber and allowed to move freely for 10 minutes. When analyzing the results, the chamber was divided into two zones, center area and periphery. Time spent in each zone of the chamber, distance traveled, and number of rearing were recoded and analyzed using the Activity Monitor software.

[0196] Rotarod test. Mice were placed on a rotating rod with either constant rotation or a steady acceleration. During training, subjects learned to balance on a stationary rod, then on a rod constantly rotating at 4 rpm. In the accelerating protocol, mice were subjected to 3 trials on the accelerating roller (4-40 rpm in 5 min) and the time that the mice remained on the rod was recorded. The interval between each trial was 5 min.

[0197] Treadmill test. Mice were placed on the horizontal treadmill and gently pushed to run near the end of the belt during the first session. For three days, mice were acclimatized to the treadmill by running at 10 m/min for 10 + 10 min, with a 5 min pause. On day 4, the speed started at 10 m/min for 5 min and was then increased by 1 m/min every minute until 20 m/min. On day 5, the speed started at 15 m/min for 5 min at 5° inclination. The speed was increased by 5 m/min every 20 min. For both Day 4 and Day 5, the distance and time run until exhausted were recorded. Mice were considered exhausted when they sat on the shock plate for more than 15 sec, without attempting to reinitiate running.

[0198] EchoMRI test. EchoMRI-130H™ Body Composition Analyzer was used to measure the content of fat and muscle tissue respectively. Standard samples were first put into the machine cavity to conduct system calibration and system test. Mice were then placed in appropriate animal holder which was inserted into machine cavity and scanned. Fat content (all fat amount in mouse body) and muscle content (muscle tissue that contains water in mouse body) were scanned and recorded by the analyzer.

[0199] Body metabolic rate test. Mice were measured 48 h in metabolic cages (Oxymax/CLAMS; Columbus Instruments) with ad libitum access to food and water. The first 24h was for acclimation and the following 24h was for index tests. Heat was derived by assessment of the exchange of oxygen for carbon dioxide that occurred during the metabolic process. The relationship between the volume of gas consumed (oxygen) and of that produced (carbon dioxide) revealed the energy content of the food utilized by the subject. This calorific value was then applied to the volume of gases exchanged to compute heat. The relative index recorded included VO2, O2 In/Out, O2 Acc, VCO2, CO2 In/Out, CO2 Acc, RER, Heat, Vi, Feed Status, Feed Acc, VDM, VDM Acc, DT-Acc, Core Temp, and Heat Rate.

[0200] Data were analyzed and graphed using Excel and GraphPad Prism. [0201] Results. As shown in FIGs. 3A and 3B and FIGs. 4A and 4B, old mice (18 months) had increased body weight compared to young mice (2-3 months) at baseline. The administration of TQS-168 decreased the body weight of old mice compared to the administration of vehicle in both cohorts. As shown in FIGs. 5A and SB and FIGs. 7A and 7B, old mice (18 months) had increased fat mass/body weight percentage compared to young mice (2-3 months) at baseline. After 4 months of treatment, the percentage of fat of mice in young groups increased as they aged. The administration of TQS-168 decreased the percentage of fat in old mice compared to the administration of vehicle in both cohorts. After 4 months of TQS-168 treatment, each individual old mouse showed apparent drop in fat percentage, while this trend was not observed in the vehicle-treated group (FIGs. 9A and 9B). As shown in FIGs. 6A and 6B and FIGs. 8A and 8B, old mice (18 months) had decreased muscle mass/body weight percentage compared to young mice (2-3 months) at baseline. The administration of TQS-168 increased the percentage of muscle in old mice compared to the administration of vehicle in both cohorts. In conclusion, TQS-168 decreased the body weight, decreased the fat mass/body weight percentage, and increased the muscle mass/body weight percentage of old mice.

[0202] As shown in FIGs. 10A and 10B and FIGs. 11A and 11B, old mice (18 months) had significantly decreased forelimb grip strength compared to young mice (2-3 months) at baseline. The administration of TQS-168 significantly rescued the forelimb grip strength of old mice compared to the administration of vehicle in both cohorts.

[0203] As shown in FIGs. 12A and 12B and FIGs. 13A and 13B, old mice (18 months) traveled significantly less distance compared to young mice (2-3 months) at baseline in the open field test. The administration of TQS-168 significantly increased the distance traveled by old mice compared to the administration of vehicle in Cohort 1. The rearing number in the open field test is an indicator of exploratory behavior of mice. Although there was no significant difference in the rearing number between old mice (18 months) and young mice (2-3 months) at baseline in the open field test, the administration of TQS-168 significantly increased the rearing number of old mice compared to the administration of vehicle in Cohort 1 (FIGs. 14A and 14B and FIGs. 15A and 15B). In conclusion, TQS-168 increased the locomotor activities and exploratory behaviors of old mice. [0204] As shown in FIGs. 16A and 16B, although without achieving statistically significant difference, old mice (18 months) showed an apparent decline in the time remaining on the rotarod compared to young mice (2-3 months) at baseline. The administration of TQS-168 increased time remaining on the rotarod of old mice compared to the administration of vehicle in Cohort 1, which indicates the effect of TQS-168 on motor balance and coordination skills.

[0205] As shown in FIGs. 17A and 17B and FIGs. 18A and 18B, the administration of TQS-168 increased time and distance traveled by old mice in the treadmill test and the open field test compared to the administration of vehicle in Cohort 1 , which indicates the effect of TQS-168 on the exercise endurance of old mice.

[0206] FIGs. 19A-19E and FIGs. 20A-20E show that the increase of clinical frailty index for old mice was significantly delayed over the course of TQS-168 treatment compared to the vehicle- treated group in both cohorts, which indicates the effects of TQS-168 in delaying aging-related changes. The analysis of selected aging -related variables included in the clinical frailty index (FIG. 24) shows that TQS-168 treatment reduced the incidence of alopecia, piloerection, kyphosis, hearing loss, gait disorder, fur color loss, and eye discharge in old mice. The administration of TQS-168 also decreased the body weight of the treated mice compared to control mice.

[0207] Finally, as shown in FIGs. 21A and 21B and FIGs. 22A and 22B, TQS-168- treated old mice appeared healthier and had less hair loss and graying compared to their vehicle- treated counterparts. .2. Example 2 - TQS-168 increases lifespan in a mouse model study

[0208] 52-week-old male wild-type C57BL/6 mice were treated with TQS-168 (n=6) at 50 mg/kg or vehicle (n=4) 3 times per week by oral gavage until death. No other interventions or testing were performed.

[0209] As shown in FIG. 23, mice dosed with TQS-168 lived -30% longer than vehicle-treated mice. The mean survival time for TQS-168-treated mice was 1009 days, while the mean survival time for vehicle-treated mice was 766 days. QUIVALENTS

[0210] While various specific embodiments have been illustrated and described, the above specification is not restrictive. It will be appreciated that various changes can be made without departing from the spirit and scope of the invention(s). Many variations will become apparent to those skilled in the art upon review of this specification. NCORPORATION BY REFERENCE

[0211] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A method of delaying an aging-related change in a subject, the method comprising: administering to the subject an effective amount of a compound of Formula I:

W¹ is chosen from N-R¹ , O, and S, or when W⁹ is N, W¹ may additionally be C-R⁵⁰;

W² is C-R² or N;

W³ is C-R³ or N;

W⁴ is C-R⁴ or N;

W⁵ is C-R⁵ or N;

W⁶ is C-R⁶ or N;

W⁷ is C-R⁷ or N;

W⁸ is C-R⁸ or N;

W⁹ is C, or when W¹ is C-R⁵⁰, W⁹ may be N;

R¹ is selected from H, (C1-C3)alkyl, -CH₂OC(=O)R³⁰, -CH₂OP(=O)OR⁴⁰OR⁴¹, -C(=O)OR⁴², and -C(=O)R⁴³;

R², R³, R⁴, and R⁵ are selected independently from hydrogen, deuterium, halogen, perfluoro(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, perfhioro(C1-C4)alkoxy, (C1-C4)acyl, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, carboxy, (C1- C4)alkoxycarbonylamino, carboxamide, (C1-C4)alkylaminocarbonyl, cyano, acetoxy, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, mercapto, (C1-C4)alkylthio, aminosulfonyl, (C1-C4)alkylsulfonyl, and (C1-C4)acylamino;

R⁸ is selected from hydrogen, deuterium, halogen, halo(C1-C4)alkyl, (C1- C,4)alkyl, (C1-C4)alkoxy, halo(C1-C,4)alkoxy, cyano, phenyl, phenoxy, benzyloxy,

R³⁰ is selected from (C1-C10)hydrocarbyl, (C1-C10)hydrocarbyl substituted with amino, (C1-C10)hydrocarbyl substituted with (C1-C4)hydrocarbyl, (C1-C10)hydrocarbyl substituted with carboxyl, carboxy, (C1-C6)alkoxycarbonyl, (C1-

Qjalkoxycarbonyl amino, methylthio, heterocyclyl, (C1-Cw)oxaalkyl, CHR^NHR⁴⁵ and guanidine;

R⁴⁰ and R⁴¹ are selected independently from hydrogen (C1-C6)hydrocarbyl;

R⁴² is (C1-C₅)alkyl;

R⁴³ is (C1-C3)alkyl,

R⁴⁴ is selected from any naturally occurring amino acid sidechain;

R⁴⁵ is selected from H, methyl, and (C1-C4)alkoxycarbonyl; and

R⁵⁰ is H or (C1-C3)alkyl. The method of claim 1, wherein the compound of Formula I is selected from:

Compound 1 Compound 2 Compound 3

Compound 4 Compound 5 Compound 6

Compound 7 Compound 8 Compound 9

or a salt, hydrate, deuterated analog, or fluorinated analog thereof.

3. The method of claim 1 or claim 2, wherein the compound of Formula I is compound 1

(TQS-168), according to the formula:

4. The method of claim 1 or claim 2, wherein the compound of Formula I is compound 4 (TQS-621), according to the formula:

5. The method of any one of claims 1 to 4, wherein the subject is a human.

6. The method of claim 5, wherein the human is over 40 years of age.

7. The method of claim 6, wherein the human is over 50 years of age.

8. The method of claim 7, wherein the human is over 60 years of age.

9. The method of claim 8, wherein the human is over 70 years of age.

10. The method of claim 9, wherein the human is over 80 years of age.

11. The method of any one of claims 1 to 4, wherein the subject is a non-human animal.

12. The method of claim 11, wherein the non-human animal is selected from the group consisting of a horse, a donkey, a cow, a pig, a sheep, a goat, a dog, a cat, a guinea pig, a hamster, a ferret, a rat, a rabbit, and a parrot.

13. The method of claim 11, wherein the non-human animal is a non-human primate.

14. The method of claim 13, wherein the non-human primate is a monkey or an ape.

15. The method of any one of claims 1 to 14, wherein the compound of Formula I is administered parenterally.

16. The method of claim 15, wherein the compound of Formula I is administered intravenously.

17. The method of any one of claims 1 to 14, wherein the compound of Formula I is administered enterally.

18. The method of claim 17, wherein the compound of Formula I is mixed with an enteral feeding formula.

19. The method of claim 17 or 18, wherein the compound of Formula I is administered by mouth (p.o.).

20. The method of claim 19, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 200-800 mg.

21. The method of claim 20, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 300-700 mg.

22. The method of claim 21, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 400-600 mg.

23. The method of claim 22, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 400-500 mg.

24. The method of claim 22, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 450 mg.

25. The method of claim 19, wherein the compound of Formula I is administered to a non-human animal subject at a daily oral dose of 10 mg/kg to 250 mg/kg.

26. The method of any one of claims 15 to 25, wherein the compound of Formula I is administered as a single daily dose.

27. The method of any one of claims 15 to 25, wherein the compound of Formula 1 is administered as a plurality of equally or unequally divided sub-doses.

28. The method of any one of claims 1 to 27, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the expression level of Ppargcla (PGC-la) as compared to pre- treatment levels.

29. The method of any one of claims 1 to 28, wherein the aging-related change is a decrease in muscle mass.

30. The method of any one of claims 1 to 28, wherein the aging-related change is a decrease in muscle strength.

31. The method of any one of claims 1 to 28, wherein the aging -related change is a decrease in muscle function.

32. The method of claim 31, wherein the muscle function is skeletal muscle function.

33. The method of claim 31, wherein the muscle function is diaphragmatic muscle function.

34. The method of claim 31, wherein the muscle function is cardiac muscle function.

35. The method of claim 31, wherein the muscle function is vascular muscle function.

36. The method of any one of claims 29 to 35, wherein the subject has sarcopenia.

37. The method of any one of claims 1 to 28, wherein the aging-related change is an increase in fat mass.

38. The method of claim 37, wherein the fat mass is total fat mass.

39. The method of claim 37, wherein the fat mass is visceral fat mass.

40. The method of any one of claims 1 to 28, wherein the aging-related change is an increase in body weight.

41. The method of any one of claims 1 to 28, wherein the aging-related change is a decrease in motor balance.

42. The method of any one of claims 1 to 28, wherein the aging-related change is a decrease in motor coordination.

43. The method of any one of claims 1 to 28, wherein the aging -related change is a decrease in gait steadiness or speed.

44. The method of any one of claims 1 to 28, wherein the aging-related change is an increased number of falls.

45. The method of any one of claims 1 to 28, wherein the aging -related change is a decrease in mobility.

46. The method of any one of claims 1 to 28, wherein the aging-related change is an increase in fatigue.

47. The method of any one of claims 1 to 28, wherein the aging-related change is a decrease in exercise endurance.

48. The method of any one of claims 1 to 28, wherein the aging-related change is a decrease in lung function.

49. The method of any one of claims 1 to 28, wherein the aging-related change is a decrease in oxygen utilization.

50. The method of claim 49, wherein the oxygen utilization is measured as VO2 max.

51. The method of any one of claims 1 to 28, wherein the aging -related change is a decrease in cardiac function.

52. The method of any one of claims 1 to 28, wherein the aging-related change is a decrease in blood circulation.

53. The method of any one of claims 1 to 28, wherein the aging-related change is a sensory impairment.

54. The method of claim 53, wherein the sensory impairment is a hearing impairment, a visual impairment, or an olfactory impairment.

55. The method of any one of claims 1 to 28, wherein the aging -related change is aging of skin.

56. The method of claim 55, wherein aging of skin is decreased skin elasticity or increased skin wrinkles.

57. The method of any one of claims 1 to 28, wherein the aging-related change is aging of hair.

58. The method of claim 57, wherein the aging of hair is hair graying or hair thinning.

59. The method of any one of claims 1 to 28, wherein the aging-related change is a decrease in bone mass.

60. The method of any one of claims 1 to 28, wherein the aging-related change is an increase in bone fractures.

61. The method of any one of claims 1 to 28, wherein the aging-related change is a decrease in joint flexibility.

62. The method of any one of claims 1 to 28, wherein the aging-related change is a decrease in digestive function.

63. The method of any one of claims 1 to 28, wherein the aging -related change is an increase in constipation.

64. The method of any one of claims 1 to 28, wherein the aging-related change is a decrease in insulin sensitivity.

65. The method of any one of claims 1 to 28, wherein the aging -related change is a decrease in immune function.

66. The method of claim 65, wherein the decrease in immune function is increased susceptibility to infection.

67. The method of claim 65, wherein the decrease in immune function is reduced antibody titer after vaccination.

68. The method of any one of claims 1 to 28, wherein the aging-related change is an increase in inflammation.

69. The method of claim 68, wherein the increase in inflammation is measured by an increase in serum levels of one or more pro-inflammatory cytokines selected from the group consisting of: IL-6, TNFa, IFNy, IL-17A, IL-17F, IL-2, and monocyte chemoattractant protein 1 (MCP-1).

70. The method of claim 68, wherein the increase in inflammation is measured by an increase in serum level of C-reactive protein (CRP).

71. The method of any one of claims 1 to 28, wherein the aging -related change is a decrease in vestibular function.

72. The method of any one of claims 1 to 28, wherein the aging-related change is a delay or an impairment in wound healing.

73. The method of any one of claims 1 to 28, wherein the aging -related change is an increase in clinical frailty index.

74. A method of increasing lifespan of a subject, the method comprising: administering to the subject an effective amount of a compound of Formula I:

W² is C-R² or N;

W³ is C-R³ or N;

W⁴ is C-R⁴ or N;

W⁵ is C-R⁵ or N; W⁶ is C-R⁶ or N;

W⁷ is C-R⁷ or N;

W⁸ is C-R⁸ or N;

W⁹ is C, or when W¹ is C-R⁵⁰, W⁹ may be N;

R², R³, R⁴, and R⁵ are selected independendy from hydrogen, deuterium, halogen, perfluoro(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, perfluoro(C1-C4)alkoxy, (C1-C4)acyl, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, carboxy, (C1- C4)alkoxycarbonylamino, carboxamide, (C1-C4)alkylaminocarbonyl, cyano, acetoxy, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, mercapto, (C1-C4)alkylthio, aminosulfonyl, (C1-C4)alkylsulfonyl, and (C1-C4)acylamino;

R⁸ is selected from hydrogen, deuterium, halogen, halo(C1-C4)alkyl, (C1- C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, phenoxy, benzyloxy, amino,

R³⁰ is selected from (C1-C10)hydrocarbyl, (C1-C10)hydrocarbyl substituted with amino, (C1-C10)hydrocarbyl substituted with (C1-C4)hydrocarbyl, (C1-C10)hydrocarbyl substituted with carboxyl, carboxy, (C1-C6lalkoxycarbonyl, (C1- C,6)alkoxycarbonylamino, methylthio, heterocyclyl, (C1-C10)oxaalkyl, CHR^NHR⁴⁵ and guanidine;

R⁴⁰ and R⁴¹ are selected independently from hydrogen (C i-Cejhydrocarbyl;

R⁴² is (C1-Cs)alkyl; R⁴³ is (C1-C3)alkyl,

R⁴⁴ is selected from any naturally occurring amino acid sidechain;

R⁴⁵ is selected from H, methyl, and (C1-C4)alkoxycarbonyl; and

R^5U is H or (C1-C3)alkyl. The method of claim 74, wherein the compound of Formula I is selected from:

Compound 10 Compound 11

or a salt, hydrate, deuterated analog, or fluorinated analog thereof. The method of claim 75, wherein the compound of Formula T is compound 1 (TQS-), according to the formula:

77. The method of claim 75, wherein the compound of Formula I is compound 4 (TQS-

621), according to the formula:

78. The method of any one of claims 74 to 77, wherein the subject is a human.

79. The method of claim 78, wherein the human is over 40 years of age.

80. The method of claim 79, wherein the human is over 50 years of age.

81. The method of claim 80, wherein the human is over 60 years of age.

82. The method of claim 81, wherein the human is over 70 years of age.

83. The method of claim 82, wherein the human is over 80 years of age.

84. The method of any one of claims 74 to 77, wherein the subject is a non-human animal.

85. The method of claim 84, wherein the non-human animal is selected from the group consisting of a horse, a donkey, a cow, a pig, a sheep, a goat, a dog, a cat, a guinea pig, a hamster, a ferret, a rat, a rabbit, and a parrot.

86. The method of claim 84, wherein the non-human animal is a non-human primate.

87. The method of claim 86, wherein the non-human primate is a monkey or an ape.

88. The method of any one of claims 74 to 87, wherein the compound of Formula I is administered parenterally.

89. The method of claim 88, wherein the compound of Formula I is administered intravenously.

90. The method of any one of claims 74 to 87, wherein the compound of Formula I is administered enterally.

91. The method of claim 90, wherein the compound of Formula I is mixed with an enteral feeding formula.

92. The method of claim 90 or 91 , wherein the compound of Formula I is administered by mouth (p.o.).

93. The method of claim 92, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 200-800 mg.

94. The method of claim 93, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 300-700 mg.

95. The method of claim 94, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 400-600 mg.

96. The method of claim 95, wherein the compound of Formula 1 is administered to a human subject at a daily oral dose of 400-500 mg.

97. The method of claim 96, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 450 mg.

98. The method of claim 92, wherein the compound of Formula I is administered to a non-human animal subject at a daily oral dose of 10 mg/kg to 250 mg/kg.

99. The method of any one of claims 88 to 98, wherein the compound of Formula I is administered as a single daily dose.

100. The method of any one of claims 88 to 98, wherein the compound of Formula I is administered as a plurality of equally or unequally divided sub-doses.

101. The method of any one of claims 74 to 100, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the expression level of Ppargclot (PGC-la) as compared to pre-treatment levels.

102. The method of any one of claims 74 to 101, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the lifespan of a human population by greater than 1 year as compared to an age- matched control human population without the administration.

103. The method of claim 102, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the lifespan of a human population by greater than 2 years as compared to an age-matched control human population without the administration.

104. The method of claim 103, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the lifespan of a human population by greater than 5 years as compared to an age-matched control human population without the administration.

105. The method of claim 104, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the lifespan of a human population by greater than 10 years as compared to an age-matched control human population without the administration.

106. A method of reducing risk of, delaying onset of, or treating an aging-related disease in a subject, the method comprising: administering to the subject an effective amount of a compound of Formula I:

W² is C-R² or N;

W³ is C-R³ or N;

W⁴ is C-R⁴ or N;

W⁵ is C-R⁵ or N;

W⁶ is C-R⁶ or N; W⁷ is C-R⁷ or N;

W⁸ is C-R⁸ or N;

W⁹ is C, or when W¹ is C-R⁵⁰, W⁹ may be N;

R¹ is selected from H, (C1-C3)alkyl, -CH₂OC(=O)R³⁰, -CH₂OP(=O)OR^4UOR⁴¹, -C(=O)OR⁴², and -C(=O)R⁴³;

R², R³, R⁴, and R⁵ are selected independently from hydrogen, deuterium, halogen, perfluoro(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, perfluoro(C1-C4)alkoxy, (C1-C4)acyl, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, carboxy, (C1- Cujalkoxycarbonylamino, carboxamide, (C1-C4)alkylaminocarbonyl, cyano, acetoxy, nitro, amino, (C1-C4)alkylamino, di(C1-C,4)alkylamino, mercapto, (C1-C4)alkyllhio, aminosulfonyl, (C1-C4)alkylsulfonyl, and (C1-COacylamino;

R⁶ and R¹⁰ are selected independently from hydrogen, deuterium, halo, (C1- Cdalkyl, perfluoro(C1-C3)alkyl, hydroxy, (C1-C3)alkoxy, perfluoro(C1-C3)alkoxy, and amino;

R⁴⁰ and R⁴¹ are selected independently from hydrogen (C1-C6jhydrocarbyl;

R⁴² is (C1-Cs)alkyl;

R⁴⁵ is selected from H, methyl, and (C1-C4)alkoxycarbonyl; and R⁵⁰ is H or (C1-C3)alkyl. . The method of claim 106, wherein the compound of Formula I is selected from:

Compound 1 Compound 2 Compound 3

Compound 4 Compound 5 Compound 6

Compound 10 Compound 11

or a salt, hydrate, deuterated analog, or fluorinated analog thereof. . The method of claim 107, wherein the compound of Formula I is compound 1 (TQS-), according to the formula:

Compound 1 or a salt, hydrate, deuterated analog, or fluorinated analog thereof. . The method of claim 107, wherein the compound of Formula I is compound 4 (TQS-), according to the formula:

110. The method of any one of claims 106 to 109, wherein the subject is a human.

111. The method of claim 110, wherein the human is over 40 years of age.

112. The method of claim 111, wherein the human is over 50 years of age.

113. The method of claim 112, wherein the human is over 60 years of age.

114. The method of claim 113, wherein the human is over 70 years of age.

115. The method of claim 114, wherein the human is over 80 years of age.

116. The method of any one of claims 106 to 109, wherein the subject is a non-human animal.

117. The method of claim 116, wherein the non-human animal is selected from the group consisting of a horse, a donkey, a cow, a pig, a sheep, a goat, a dog, a cat, a guinea pig, a hamster, a ferret, a rat, a rabbit, and a parrot.

118. The method of claim 116, wherein the non-human animal is a non-human primate.

119. The method of claim 118, wherein the non-human primate is a monkey or an ape.

120. The method of any one of claims 106 to 119, wherein the compound of Formula I is administered parenterally.

121. The method of claim 120, wherein the compound of Formula I is administered intravenously.

122. The method of any one of claims 106 to 119, wherein the compound of Formula I is administered enterally.

123. The method of claim 122, wherein the compound of Formula I is mixed with an enteral feeding formula.

124. The method of claim 122 or 123, wherein the compound of Formula I is administered by mouth (p.o.).

125. The method of claim 124, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 200-800 mg.

126. The method of claim 125, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 300-700 mg.

127. The method of claim 126, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 400-600 mg.

128. The method of claim 127, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 400-500 mg.

129. The method of claim 128, wherein the compound of Formula 1 is administered to a human subject at a daily oral dose of 450 mg.

130. The method of claim 129, wherein the compound of Formula I is administered to a non-human animal subject at a daily oral dose of 10 mg/kg to 250 mg/kg.

131. The method of any one of claims 120 to 130, wherein the compound of Formula I is administered as a single daily dose.

132. The method of any one of claims 120 to 130, wherein the compound of Formula I is administered as a plurality of equally or unequally divided sub-doses.

133. The method of any one of claims 106 to 132, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the expression level of Ppargclot (PGC-la) as compared to pre-treatment levels.

134. The method of any one of claims 106 to 133, wherein the aging-related disease is hypertension.

135. The method of any one of claims 106 to 133, wherein the aging-related disease is atherosclerosis.

136. The method of claim 135, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, decreases serum levels of one or more markers of atherosclerosis risk selected from the group consisting of: LDL-C, triglyceride, ApoB, and Lp(a).

137. The method of any one of claims 106 to 133, wherein the aging-related disease is cardiovascular disease.

138. The method of claim 137, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, decreases serum level of cardiovascular risk marker, N-terminal prohormone-B-type natriuretic peptide (NT-pro- BNP).

139. The method of any one of claims 106 to 133, wherein the aging-related disease is cancer.

140. The method of any one of claims 106 to 133, wherein the aging-related disease is neurodegenerative disease.

141. The method of any one of claims 106 to 133, wherein the aging-related disease is dementia.

142. The method of any one of claims 106 to 133, wherein the aging-related disease is cognitive dysfunction.

143. The method of any one of claims 106 to 133, wherein the aging-related disease is diabetes.

144. The method of any one of claims 106 to 133, wherein the aging-related disease is obesity.

145. The method of any one of claims 106 to 133, wherein the aging-related disease is osteoarthritis.

146. The method of any one of claims 106 to 133, wherein the aging-related disease is osteoporosis.

147. The method of any one of claims 106 to 133, wherein the aging-related disease is lung fibrosis.

148. The method of any one of claims 106 to 133, wherein the aging-related disease is lymph node fibrosis.

149. The method of any one of claims 106 to 133, wherein the aging-related disease is skin disease.

150. The method of any one of claims 106 to 133, wherein the aging-related disease is kidney disease.

151. The method of any one of claims 106 to 133, wherein the aging-related disease is chronic obstructive pulmonary disease (COPD).

152. The method of any one of claims 106 to 133, wherein the aging-related disease is age- related macular degeneration.

153. The method of any one of claims 106 to 133, wherein the aging-related disease is cataract.

154. The method of any one of claims 106 to 133, wherein the aging-related disease is late- life depression.

155. A method of reducing body weight of a subject, the method comprising: administering to the subject an effective amount of a compound of Formula I:

W¹ is chosen from N-R¹, O, and S, or when W⁹ is N, W¹ may additionally be

C-R⁵⁰;

W² is C-R² or N;

W³ is C-R³ or N;

W⁴ is C-R⁴ or N;

W⁵ is C-R⁵ or N;

W⁶ is C-R⁶ or N;

W⁷ is C-R⁷ or N;

W⁸ is C-R⁸ or N; W⁹ is C, or when W¹ is C-R⁵⁰, W⁹ may be N;

R², R³, R⁴, and R⁵ are selected independently from hydrogen, deuterium, halogen, perfluoro(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, perfluoro(C1-C4)alkoxy, (C1-C4)acyl, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, carboxy, (C1- C.4)alkoxycarbonylamino, carboxamide, (C1-C.4)alkylaminocarbonyl, cyano, acetoxy, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, mercapto, (C1-C4)alkylthio, aminosulfonyl, (C1-C4)alkylsulfonyl, and (C1-C4)acylamino;

R⁴⁰ and R⁴¹ are selected independently from hydrogen (C1-C6jhydrocarbyl;

R⁴² is (C1-C₅)alkyl;

R⁴³ is (C1-C3)alkyl,

R⁴⁴ is selected from any naturally occurring amino acid sidechain;

R⁴⁵ is selected from H, methyl, and (C1-C,4)alkoxycarbonyl; and R⁵⁰ is H or (C1-C3)alkyl. . The method of claim 155, wherein the compound of Formula I is selected from:

Compound 1 Compound 2 Compound 3

Compound 10 Compound 11

or a salt, hydrate, deuterated analog, or fluorinated analog thereof. . The method of claim 156, wherein the compound of Formula I is compound 1 (TQS-), according to the formula:

Compound 1 or a salt, hydrate, deuterated analog, or fluorinated analog thereof. . The method of claim 156, wherein the compound of Formula I is compound 4 (TQS-), according to the formula:

159. The method of any one of claims 155 to 158, wherein the subject is a human.

160. The method of claim 159, wherein the human has a body mass index (BMI) equal to or greater than 25 kg/m².

161. The method of claim 160, wherein the human has a body mass index (BMI) equal to or greater than 30 kg/m².

162. The method of any one of claims 155 to 161, wherein the compound of Formula I is administered parenterally.

163. The method of claim 162, wherein the compound of Formula I is administered intravenously.

164. The method of any one of claims 155 to 161, wherein the compound of Formula I is administered enterally.

165. The method of claim 164, wherein the compound of Formula I is mixed with an enteral feeding formula.

166. The method of claim 164 or 165, wherein the compound of Formula I is administered by mouth (p.o.).

167. The method of claim 166, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 200-800 mg.

168. The method of claim 167, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 300-700 mg.

169. The method of claim 168, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 400-600 mg.

170. The method of claim 169, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 400-500 mg.

171. The method of claim 170, wherein the compound of Formula I is administered to a human subject at a daily oral dose of 450 mg.

172. The method of any one of claims 162 to 171, wherein the compound of Formula I is administered as a single daily dose.

173. The method of any one of claims 162 to 171, wherein the compound of Formula I is administered as a plurality of equally or unequally divided sub-doses.

174. The method of any one of claims 155 to 161, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, increases the expression level of Ppargclot (PGC-la) as compared to pre-treatment levels.

175. The method of any one of claims 155 to 174, wherein the subject is diagnosed with obesity.

176. The method of any one of claims 155 to 174, wherein the subject has an eating disorder.

177. The method of claim 176, wherein the eating disorder is binge-eating disorder.

178. The method of any one of claims 155 to 174, wherein the subject has hyperglycemia.

179. The method of any one of claims 155 to 174, wherein the subject has hyperlipidemia.

180. The method of any one of claims 155 to 174, wherein the subject has developed or is at risk of developing type 2 diabetes.

181. The method of any one of claims 155 to 174, wherein the subject has developed or is at risk of developing cardiovascular disease.

182. The method of any one of claims 155 to 174, wherein the subject has developed or is at risk of developing metabolic syndrome.

183. The method of any one of claims 155 to 182, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces the subject’s body weight by greater than 5%.

184. The method of claim 183, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces the subject’s body weight by greater than 10%.

185. The method of claim 184, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces the subject’s body weight by greater than 15%.

186. The method of any one of claims 155 to 181, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces fat mass of the subject by greater than 5%.

187. The method of claim 186, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces fat mass of the subject by greater than 10%.

188. The method of claim 187, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces fat mass of the subject by greater than 15%.

189. The method of any one of claims 155 to 181, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces visceral fat mass of the subject by greater than 5%.

190. The method of claim 189, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces visceral fat mass of the subject by greater than 10%.

191. The method of claim 190, wherein the administration of the compound of Formula I, or a salt, hydrate, deuterated analog, or fluorinated analog thereof, reduces visceral fat mass of the subject by greater than 15%.