Methods to extend the lifespan of mammals

Abstract

This specification provides a method for reducing or reversing age-induced insulin resistance and / or fatty acid elevation, comprising a composition comprising a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. This specification also provides a method for extending lifespan, comprising a composition comprising a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, and its use in animal health.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 454,874, filed on 27 March 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] It is well recognized that calendar year is the greatest single risk factor for almost all major causes of death and morbidity in living organisms, including humans and companion dogs. Even before the onset of observable disease, the physiological functions of organ systems and tissues progressively decline throughout life. Throughout history, there has been a strong demand for products and methods to promote longevity and extend life. Generally, these products and methods have proven ineffective and / or unsafe. Therefore, there remains an unmet need for safe and effective products and methods to promote longevity and extend life. [Overview of the project]

[0003] In some embodiments, methods are provided herein for reducing or reversing age-induced insulin resistance in mammals that require reduction or reversal of age-induced insulin resistance, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to the mammal.

[0004] In some embodiments, methods are provided herein for reducing or reversing insulin resistance in mammals that require reduction or reversal of insulin resistance, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to the mammal.

[0005] In some embodiments herein, methods are provided for reducing or reversing age-related increases in fatty acids and other lipids in mammals where such reduction or reversal is required, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to the mammal.

[0006] In some embodiments, the Specified Provisions Provide a method for maintaining the healthy function of adipose tissue in mammals where it is necessary to maintain the healthy function of adipose tissue, comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0007] In some embodiments, the method does not decrease glucose levels in mammals. In some embodiments, the method does not increase glucose levels in mammals. In some embodiments, the method includes decreasing insulin levels in mammals. In some embodiments, the decrease in insulin levels is at least 5%. In some embodiments, the decrease in insulin levels is at least 10%, at least 15%, or at least 20%.

[0008] In some embodiments, the method improves insulin sensitivity. In some embodiments, insulin sensitivity is measured by an oral glucose tolerance test assay. In some embodiments, insulin sensitivity is measured by using fasting blood insulin levels. In some embodiments, insulin sensitivity is measured by a hyperinsulinemia-euglycemic clamp test assay.

[0009] In some embodiments, the lipids are aggregates of free fatty acids, saturated fatty acids, palmitic acid, linoleic acid, or oleic acid, or any combination thereof. In some embodiments, the fatty acids are saturated fatty acids, palmitic acid, linoleic acid, or oleic acid. In some embodiments, the fatty acids are saturated fatty acids. In some embodiments, the fatty acids are palmitic acid. In some embodiments, the method reduces triglyceride levels in mammals. In some embodiments, the method reduces cholesterol levels in mammals. In some embodiments, the method increases adiponectin levels in mammals.

[0010] In some embodiments, the mammal is a dog, cat, horse, cattle, pig, rabbit, rodent, sheep, non-human primate, or human. In some embodiments, the mammal is a dog or cat. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a cat. In some embodiments, the rodent is a mouse or rat. In some embodiments, the mammal is a human. In some embodiments, the mammal is at least 7 years old. In some embodiments, the mammal is at least 10 years old.

[0011] In some embodiments, the formulation contains about 3% to about 35% of the PPAR agonist. In some embodiments, the formulation contains about 10% to about 20% of the PPAR agonist. In some embodiments, the formulation contains about 1 mg to about 100 mg of the PPAR agonist. In some embodiments, the formulation contains about 4 mg to about 85 mg of the PPAR agonist. In some embodiments, the PPAR agonist is administered at 3 mg / kg / day. In some embodiments, the PPAR agonist is administered at 5 mg / kg / day. In some embodiments, the PPAR agonist is administered at 10 mg / kg / day. In some embodiments, the formulation is administered for at least about 4 weeks. In some embodiments, the formulation is administered for at least about 12 weeks. In some embodiments, the formulation is administered for at least about 6 months. The formulation is administered for at least about 1 year. In some embodiments, the formulation is administered daily.

[0012] In some embodiments, the PPAR agonist is pioglitazone. In some embodiments, pioglitazone is administered at 1 mg / kg / day. In some embodiments, pioglitazone is administered at 2-3 mg / kg / day. In some embodiments, the PPAR agonist is rosiglitazone.

[0013] In some embodiments, the formulation is a pharmaceutical formulation. In some embodiments, the formulation is a nutritional supplement formulation.

[0014] In some embodiments, the formulation is in the form of a tablet. In some embodiments, the tablet contains a hydrolyzed chicken product. In some embodiments, the tablet contains 18 mg, 54 mg, or 81 mg of a PPAR agonist. In some embodiments, the tablet further contains at least one filler. In some embodiments, the filler is lactose monohydrate. In some embodiments, the lactose monohydrate is present in an amount of about 10% to about 40% w / w. In some embodiments, the lactose monohydrate is present in an amount of about 22% w / w. In some embodiments, the tablet further contains sodium carboxymethylcellulose. In some embodiments, the sodium carboxymethylcellulose is present in an amount of about 2% to about 10% w / w. In some embodiments, the sodium carboxymethylcellulose is present in an amount of about 4% w / w. In some embodiments, the tablet further contains FlavorPAL X1212. In some embodiments, the FlavorPAL X1212 is present in an amount of about 10% to about 40% w / w. In some embodiments, FlavorPAL X1212 is present in an amount of about 20% w / w. In some embodiments, the tablets further contain magnesium stearate. In some embodiments, the amount of magnesium stearate is about 0.25% to about 3% w / w. In some embodiments, the amount of magnesium stearate is about 1% w / w.

[0015] In some embodiments, methods are provided herein for reducing or delaying mortality from age-related diseases in mammals where it is necessary to reduce or delay mortality from age-related diseases in mammals, comprising administering a therapeutically effective amount of a PPARg agonist, or a pharmaceutically acceptable salt or prodrug thereof, to the mammal. In some embodiments, methods are provided herein for treating age-related decline in quality of life, comprising administering a therapeutically effective amount of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, to the mammal.

[0016] In some embodiments, methods are provided herein for addressing age-related decline in quality of life, comprising administering a therapeutically effective dose of a PPAR agonist, or a pharmaceutically acceptable salt thereof, or a prodrug, to a mammal.

[0017] In some embodiments, methods are provided herein for treating age-related frailty, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to a mammal.

[0018] In some embodiments, the method further includes life extension, wherein life extension includes extending life by at least 5% relative to the expected life or median life of mammals of a similar species, strain, or variety. In some embodiments, life extension includes extending life by at least 10%, at least 15%, at least 20%, or at least 25%.

[0019] In some embodiments, the method includes reducing or reversing insulin resistance in mammals. In some embodiments, insulin resistance arises from age-related processes. In some embodiments, the method includes reducing or reversing an increase in free fatty acids (FFA). In some embodiments, the increase in free fatty acids is associated with age-related conditions. In some embodiments, age-related conditions include obesity, type 2 diabetes, cardiovascular disease, or sarcopenia. In some embodiments, the increase in free fatty acids is due to advanced aging. In some embodiments, the increase in free fatty acids with aging is associated with an increase in fasting insulin.

[0020] In some embodiments, the mammal is mature. In some embodiments, the mammal has reached old age. In some embodiments, the mammal is at least 7 years old. In some embodiments, the mammal is at least 10 years old. In some embodiments, the mammal weighs at least 14 pounds.

[0021] In some embodiments, the mammal is a dog, cat, horse, cattle, pig, rabbit, rodent, sheep, non-human primate, or human. In some embodiments, the mammal is a dog or cat. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a cat. In some embodiments, the rodent is a mouse or rat. In some embodiments, the mammal is a human.

[0022] In some embodiments, the method contains about 3% to about 35% of the PPAR agonist. In some embodiments, the method contains about 10% to about 20% of the PPAR agonist. In some embodiments, the method contains about 1 mg to about 100 mg of the PPAR agonist. In some embodiments, the method contains about 4 mg to about 85 mg of the PPAR agonist. In some embodiments, the PPAR agonist is administered at 3 mg / kg / day. In some embodiments, the PPAR agonist is administered at 5 mg / kg / day. In some embodiments, the PPAR agonist is administered at 10 mg / kg / day. In some embodiments, the PPAR agonist is administered for at least about 4 weeks. In some embodiments, the PPAR agonist is administered for at least about 12 weeks. In some embodiments, the PPAR agonist is administered for at least about 6 months. In some embodiments, the PPAR agonist is administered for at least about 1 year. In some embodiments, the PPAR agonist is administered daily.

[0023] In some embodiments, the PPAR agonist is pioglitazone. In some embodiments, pioglitazone is administered at 1 mg / kg / day. In some embodiments, pioglitazone is administered at 2-3 mg / kg / day. In some embodiments, the PPAR agonist is rosiglitazone. In some embodiments, the formulation is a pharmaceutical formulation. In some embodiments, the formulation is a nutritional supplement formulation.

[0024] In some embodiments, the formulation is in the form of a tablet. In some embodiments, the tablet comprises a hydrolyzed chicken product. In some embodiments, the tablet comprises 18 mg, 54 mg, or 81 mg of a PPAR agonist. In some embodiments, the tablet further comprises at least one filler. In some embodiments, the filler is lactose monohydrate. In some embodiments, the lactose monohydrate is in an amount of about 10% to about 40% w / w. In some embodiments, the lactose monohydrate is in an amount of about 22% w / w. In some embodiments, the tablet further comprises sodium carboxymethyl cellulose. In some embodiments, the sodium carboxymethyl cellulose is in an amount of about 2% to about 10% w / w. In some embodiments, the sodium carboxymethyl cellulose is in an amount of about 4% w / w. In some embodiments, the tablet further comprises FlavorPAL X1212. In some embodiments, the FlavorPAL X1212 is in an amount of about 10% to about 40% w / w. In some embodiments, the FlavorPAL X1212 is in an amount of about 20% w / w. In some embodiments, the tablet further comprises magnesium stearate. In some embodiments, the magnesium stearate is in an amount of about 0.25% to about 3% w / w. In some embodiments, the magnesium stearate is in an amount of about 1% w / w.

[0025] In some embodiments, provided herein is a formulation comprising pioglitazone or a pharmaceutically acceptable salt thereof for use in reducing or delaying the mortality due to age-related diseases in companion animals, the formulation being administered for at least two weeks.

[0026] In some embodiments, pioglitazone or a pharmaceutically acceptable salt thereof is pioglitazone hydrochloride. In some embodiments, pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of approximately 2–3 mg / kg / day. In some embodiments, pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of approximately 1–5 mg / kg / day. In some embodiments, pioglitazone or a pharmaceutically acceptable salt thereof is administered at a maximum dose of 10 mg / kg / day. In some embodiments, the formulation is administered once daily. In some embodiments, the formulation is administered for at least approximately 4 weeks. In some embodiments, the formulation is administered for at least approximately 12 weeks. In some embodiments, the formulation is administered for at least approximately 1 year. In some embodiments, the method includes reducing the insulin levels of a companion animal. In some embodiments, the insulin levels are reduced by at least 5%. In some embodiments, the formulation improves insulin sensitivity. In some embodiments, insulin sensitivity is measured by an oral glucose tolerance test assay or a hyperinsulinemia euglycemic clamp test assay. In some embodiments, insulin sensitivity is measured by a shortened or modified oral glucose tolerance test assay. In some embodiments, insulin sensitivity is measured by using fasting blood insulin levels. In some embodiments, the formulation reduces triglyceride levels in the companion animal. In some embodiments, the formulation reduces cholesterol levels in the companion animal. In some embodiments, use further comprises mitigating age-induced increases in fatty acids, where fatty acids are aggregates of free fatty acids, saturated fatty acids, palmitic acid, linoleic acid, or oleic acid, or any combination thereof. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is at least 7 years old. In some embodiments, the companion animal is at least 10 years old. In some embodiments, the companion animal weighs at least 14 pounds.In some embodiments, the formulation comprises from about 5% to about 15% pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 4 mg to about 85 mg pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation is in the form of a tablet. In some embodiments, the tablet comprises 18 mg, 54 mg, or 81 mg pioglitazone or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, there is provided a method of reducing or delaying mortality due to an age-related disease in a companion animal, the method comprising orally administering to the companion animal a therapeutically effective amount of a formulation comprising pioglitazone or a pharmaceutically acceptable salt thereof, the formulation being administered for at least two weeks, the method being for a companion animal that requires reducing or delaying mortality due to an age-related disease.

[0028] In some embodiments, pioglitazone or a pharmaceutically acceptable salt thereof is pioglitazone hydrochloride. In some embodiments, pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of about 2–3 mg / kg / day. In some embodiments, pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of about 1–5 mg / kg / day. In some embodiments, pioglitazone or a pharmaceutically acceptable salt thereof is administered at a maximum dose of 10 mg / kg / day. In some embodiments, the formulation is administered once daily. In some embodiments, the formulation is administered for at least about 4 weeks. In some embodiments, the formulation is administered for at least about 12 weeks. In some embodiments, the formulation is administered for at least about 1 year. In some embodiments, the method includes reducing the insulin levels of a companion animal. In some embodiments, the insulin levels are reduced by at least 5%. In some embodiments, the method improves insulin sensitivity. In some embodiments, insulin sensitivity is measured by an oral glucose tolerance test assay or a hyperinsulinemia euglycemic clamp test assay. In some embodiments, insulin sensitivity is measured by a shortened or modified oral glucose tolerance test assay. In some embodiments, insulin sensitivity is measured by using fasting blood insulin levels. In some embodiments, the method reduces the triglyceride levels of the companion animal. In some embodiments, the method reduces the cholesterol levels of the companion animal. In some embodiments, the use further comprises mitigating the age-induced increase in fatty acids, where fatty acids are aggregates of free fatty acids, saturated fatty acids, palmitic acid, linoleic acid, or oleic acid, or any combination thereof. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is at least 7 years old. In some embodiments, the companion animal is at least 10 years old. In some embodiments, the companion animal weighs at least 14 pounds.In some embodiments, the formulation contains about 5% to about 15% pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation contains about 4 mg to about 85 mg pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation is in the form of a tablet. In some embodiments, the tablet contains 18 mg, 54 mg, or 81 mg pioglitazone or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawing]

[0029] [Figure 1] Figure 1 shows blood insulin levels calculated as standardized natural logarithms (insulin) against age. Points are color-coded based on weight groups: under 50 pounds, 50-100 pounds, 100-150 pounds, and over 150 pounds. [Figure 2A] Figure 2A shows the total HRQL and frailty score index for dogs against blood insulin levels. Figure 2A shows the total HRQL score against insulin levels, calculated as a standardized natural logarithm (insulin). Points are color-coded based on age groups: under 3 years, 3-6 years, 6-9 years, 9-12 years, 12-15 years, and over 15 years. [Figure 2B] Figure 2B shows the total HRQL and canine frailty score index against blood insulin levels. Figure 2B shows the canine frailty score against insulin, in its natural scale (mIU / L), for each age: 4, 7, 10, 15, and 18 years, with the lower band line at 4 years and the upper band line at 18 years. [Figure 3A] Figure 3A shows HRQL scores over time and for different groups. Figure 3A shows estimated intermediate total HRQL scores adjusted for age in years, body weight in pounds, and BCS for groups with different insulin levels. The lowest group was classified as insulin levels 2.53 mU / L to 12 mU / L, the intermediate group as insulin levels 12 mU / L to 20.9 mU / L, and the highest group as insulin levels 20.9 mU / L to 107 mU / L. [Figure 3B] Figure 3B shows the HRQL scores over time and for various groups. Figure 3B also shows the estimated HRQL kernel density on the Davies scale as a function of age in years. [Figure 3C] Figure 3C shows HRQL scores over time and for various groups. Figure 3C shows the total HRQL score and age in years. [Figure 4A] Figure 4A shows the CFI and HRQL scores. Figure 4A shows the relationship between the CFI score and age over the years, using linear regression analysis. [Figure 4B] Figure 4B shows the CFI and HRQL scores. Figure 4B shows the relationship between the HRQL score and the CFI score using linear regression analysis. [Figure 4C] Figure 4C shows the CFI and HRQL scores. Figure 4C also shows fatty acid species and aggregates against age, using linear regression analysis. [Figure 4D] Figure 4D shows the CFI and HRQL scores. Figure 4D shows the relationship between the natural logarithm (adiponectin) and age using linear regression analysis. [Figure 4E] Figure 4E shows the CFI and HRQL scores. Figure 4E also shows the fatty acid species and aggregates for adiponectin using linear regression analysis. [Figure 4F] Figure 4F shows CFI and HRQL scores. Figure 4F shows fatty acid species and aggregates in relation to CFI scores within age groups, using linear regression analysis. [Figure 4G] Figure 4G shows CFI and HRQL scores. Figure 4G also shows the relationship between the natural logarithm (adiponectin) and CFI within age groups, using linear regression analysis. [Figure 5A] Figure 5A shows glucose and insulin levels. Group 1 refers to a normal diet + placebo, Group 2 refers to a high-fat diet + placebo, Group 3 refers to a high-fat diet + 1 mg / kg pioglitazone, and Group 4 refers to a high-fat diet + 2 mg / kg pioglitazone. In Figure 5A, Graph A shows fasting glucose levels before and after treatment, and Graph B also shows the percentage change. [Figure 5B] Figure 5B shows glucose and insulin levels. Group 1 refers to a normal diet + placebo, Group 2 refers to a high-fat diet + placebo, Group 3 refers to a high-fat diet + 1 mg / kg pioglitazone, and Group 4 refers to a high-fat diet + 2 mg / kg pioglitazone. In Figure 5B, Graph C shows fasting insulin levels, and Graph D also shows the percentage change. [Figure 5C] Figure 5C shows glucose and insulin levels. Group 1 refers to a normal diet + placebo, Group 2 refers to a high-fat diet + placebo, Group 3 refers to a high-fat diet + 1 mg / kg pioglitazone, and Group 4 refers to a high-fat diet + 2 mg / kg pioglitazone. In Figure 5C, graph A shows the AUC of glucose, and graph B shows the rate of change. [Figure 5D] Figure 5D shows glucose and insulin levels. Group 1 refers to a normal diet + placebo, Group 2 refers to a high-fat diet + placebo, Group 3 refers to a high-fat diet + 1 mg / kg pioglitazone, and Group 4 refers to a high-fat diet + 2 mg / kg pioglitazone. In Figure 5D, graph A shows the AUC of insulin, and graph B shows the rate of change. [Figure 6A] Figure 6A shows the quantification of fatty acids in various treatment groups. Group 1 refers to a normal diet + placebo, Group 2 refers to a high-fat diet + placebo, Group 3 refers to a high-fat diet + 1 mg / kg pioglitazone, and Group 4 refers to a high-fat diet + 2 mg / kg pioglitazone. Figure 6A shows the fatty acid levels of saturated fatty acids. [Figure 6B] Figure 6B shows the quantification of fatty acids in various treatment groups. Group 1 refers to a normal diet + placebo, Group 2 refers to a high-fat diet + placebo, Group 3 refers to a high-fat diet + 1 mg / kg of pioglitazone, and Group 4 refers to a high-fat diet + 2 mg / kg of pioglitazone. Figure 6B shows the fatty acid levels of palmitic acid. [Figure 6C]Figure 6C shows the quantification of fatty acids in various treatment groups. Group 1 refers to a normal diet + placebo, Group 2 refers to a high-fat diet + placebo, Group 3 refers to a high-fat diet + 1 mg / kg pioglitazone, and Group 4 refers to a high-fat diet + 2 mg / kg pioglitazone. Figure 6C shows the fatty acid levels of linoleic acid. Figure 6D shows the fatty acid levels of oleic acid. [Figure 6D] Figure 6D shows the quantification of fatty acids in various treatment groups. Group 1 refers to a normal diet + placebo, Group 2 refers to a high-fat diet + placebo, Group 3 refers to a high-fat diet + 1 mg / kg pioglitazone, and Group 4 refers to a high-fat diet + 2 mg / kg pioglitazone. Figure 6D shows the fatty acid levels of oleic acid. [Figure 6E] Figure 6E shows the quantification of fatty acids in various treatment groups. Group 1 refers to a normal diet + placebo, Group 2 refers to a high-fat diet + placebo, Group 3 refers to a high-fat diet + 1 mg / kg pioglitazone, and Group 4 refers to a high-fat diet + 2 mg / kg pioglitazone. Figure 6E shows that the clinical diagnostic assay NEFA is not sufficiently sensitive to detect physiologically relevant changes. [Figure 6F] Figure 6F shows the quantification of fatty acids in various treatment groups. Group 1 refers to a normal diet + placebo, Group 2 refers to a high-fat diet + placebo, Group 3 refers to a high-fat diet + 1 mg / kg pioglitazone, and Group 4 refers to a high-fat diet + 2 mg / kg pioglitazone. Figure 6F shows clinically measured triglyceride levels. [Figure 6G] Figure 6G shows the quantification of fatty acids in various treatment groups. Group 1 refers to a normal diet + placebo, Group 2 refers to a high-fat diet + placebo, Group 3 refers to a high-fat diet + 1 mg / kg pioglitazone, and Group 4 refers to a high-fat diet + 2 mg / kg pioglitazone. Figure 6G shows the free fatty acid and adiponectin levels of the various cohorts, with the bars for groups 1, 2, 3, and 4 progressing from left to right. [Figure 7] Figure 7 illustrates the test designs shown in Figures 8 to 10. [Figure 8A]Figure 8A shows the levels of pioglitazone (A) and adiponectin (B) in dogs over a 56-day experimental protocol, administered two weeks prior to the start of a high-fat diet, in the placebo group, the pioglitazone 1 mg / kg group, and the pioglitazone 2 mg / kg group. All data are expressed as mean ± SEM. [Figure 8B] Figure 8B shows the levels of pioglitazone (A) and adiponectin (B) in dogs over a 56-day experimental protocol, administered two weeks prior to the start of a high-fat diet, in the placebo group, the pioglitazone 1 mg / kg group, and the pioglitazone 2 mg / kg group. All data are expressed as mean ± SEM. [Figure 9A] Figure 9A shows the baseline and day 46 OGTT insulin curves (Figure 9A) and total 120-minute insulin AUC (Figure 9B). All data are expressed as mean ± SEM. [Figure 9B] Figure 9B shows the baseline and day 46 OGTT insulin curves (Figure 9A) and total 120-minute insulin AUC (Figure 9B). All data are expressed as mean ± SEM. [Figure 10A] Figure 10A shows the glucose elimination rate (Rd, Figure 10A), AUC of the glucose elimination rate (Figure 10B), and glucose infusion rate (GIR, Figure 10C) of HIEG in dogs in the placebo group, the pioglitazone 1 mg / kg group, and the pioglitazone 2 mg / kg group over the 56-day experimental protocol. All data are expressed as mean ± SEM. [Figure 10B] Figure 10B shows the glucose elimination rate (Rd, Figure 10A), AUC of the glucose elimination rate (Figure 10B), and glucose infusion rate (GIR, Figure 10C) of HIEG in dogs in the placebo group, the pioglitazone 1 mg / kg group, and the pioglitazone 2 mg / kg group over the 56-day experimental protocol. All data are expressed as mean ± SEM. [Figure 10C]Figure 10C shows the glucose elimination rate (Rd, Figure 10A), AUC of the glucose elimination rate (Figure 10B), and glucose infusion rate (GIR, Figure 10C) of HIEG in dogs in the placebo group, the pioglitazone 1 mg / kg group, and the pioglitazone 2 mg / kg group over the 56-day experimental protocol. All data are expressed as mean ± SEM. [Figure 11A] Figure 11A: (A) shows the infusion insulin levels during HIEG clamps at baseline and day 56. All data are expressed as mean ± SEM. [Figure 11B] Figure 11B: Figure 11B shows the insulin infusion rate in dogs in the pioglitazone 2 mg / kg group. All data are expressed as mean ± SEM. [Figure 11C] Figure 11C: Figure 11C shows the GIR in animals matched for insulin infusion volume within the HIEG clamp. All data are expressed as mean ± SEM. [Figure 12A] Figure 12A: Figure 12A shows free fatty acid concentrations quantified by GC-MS at baseline and on day 56. All data are expressed as mean ± SEM. [Figure 12B] Figure 12B: Figure 12B shows saturated fatty acid concentrations quantified by GC-MS at baseline and on day 56. All data are expressed as mean ± SEM. [Figure 12C] Figure 12C: Figure 12C shows linoleic acid concentrations quantified by GC-MS at baseline and on day 56. All data are expressed as mean ± SEM. [Figure 12D] Figure 12D: Figure 12D shows palmitic fatty acid concentrations quantified by GC-MS at baseline and day 56. All data are expressed as mean ± SEM. [Figure 12E] Figure 12E: Figure 12E shows the free fatty acid concentrations quantified by the clinically used NEFA assay at baseline and day 56. All data are expressed as mean ± SEM. [Modes for carrying out the invention]

[0030] Age-related changes in adipose tissue function influence many of the known mechanisms of biological aging. An increase in visceral adipose tissue and a decrease in subcutaneous fat with age are common observations in dogs, rodents, and humans. Insulin resistance increases with age in all three species. The net consequences of this age-dependent metabolic dysfunction are decreased flexibility in utilizing nutrient fuel sources, organ failure, and increased physical frailty. Increased frailty also directly leads to a decline in quality of life. As a major regulator of adipose tissue, PPARγ is uniquely positioned to influence age-dependent metabolic dysfunction. PPARγ agonists, such as pioglitazone, have been demonstrated to improve lipid metabolism, enhance insulin sensitivity, and restore adipose function in association with obesity and T2DM. Given the significant benefits observed with pioglitazone in the treatment and prevention of metabolic diseases, such benefits should also apply to age-related metabolic dysfunction. Delaying or preventing age-related metabolic dysfunction via PPAR-γ agonism reduces frailty and extends healthy lifespan and life expectancy.

[0031] definition Unless otherwise defined, all technical terms, expressions, and other technical and scientific or specialized terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art in which the claimed subject matter relates. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or for immediate reference, and the inclusion herein of such definitions is not necessarily construed as representing a substantial difference from those commonly understood in the art.

[0032] Throughout this application, various embodiments may be presented in scope form. It should be understood that scope form descriptions are merely for convenience and brevity and should not be interpreted as inflexible limitations on the scope of this disclosure. Therefore, scope descriptions should be considered to specifically disclose all possible sub-ranges and individual numbers within that range. For example, a scope description such as 1–6 should be considered to specifically disclose sub-ranges such as 1–3, 1–4, 1–5, 2–4, 2–6, 3–6, and individual numbers within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0033] As used herein and in the claims, the singular forms "a," "an," and "the" refer to multiple objects unless the context otherwise explicitly indicates. For example, the term "sample" refers to multiple samples, including mixtures thereof.

[0034] When referring to a number or numerical range, the term “approximately” means that the number or numerical range mentioned is an approximation within experimental variability (or statistical experimental error), and therefore the number or numerical range does not vary by more than 15% of the stated number or numerical range. The terms “to treat,” “to treat,” and “treatment” refer to any indication of success in treating or improving an injury, condition, state, or symptom (e.g., pain), which may include objective or subjective parameters such as: relief; remission; mitigation, reversal, or reduction of a symptom, injury, condition, or state, or making the symptom, injury, condition, or state more tolerable to the patient; a reduction in the frequency or duration of the symptom or condition; or, in some cases, prevention of the onset of the symptom or condition. Treatment or improvement of a symptom may be based on any objective or subjective parameters, including, for example, the results of a health checkup.

[0035] As used herein, the terms “formulation” and “composition” are interchangeable and refer to a mixture of two or more compounds, components, or molecules. In some embodiments, the terms “formulation” and “composition” may be used to refer to a mixture of one or more activators with a carrier or other excipient.

[0036] As used herein, the term “fat” refers to dietary fats. This includes fatty acids, esters of fatty acids, and mixtures of both fatty acids and fatty acid esters. It may also refer, but not limited to, glycerides such as diglycerides and triglycerides, lipids such as phospholipids, and sterols such as cholesterol. Fats may also refer to free fatty acids and fatty acid conjugates.

[0037] As used herein, the term “administration” refers to oral administration, administration as a suppository, topical contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intrafocal administration, intranasal or subcutaneous administration, intrathecal administration, intralymphatic administration, inhalation of microdroplets, or implantation of a sustained-release device, such as a mini osmotic pump, into the target.

[0038] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to the amount of a drug or compound administered that is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in the biological system. For example, an “effective dose” for therapeutic use is the amount of a composition containing the compound disclosed herein that is necessary to produce a clinically significant reduction in the disease. The appropriate “effective” dose in any individual case may be determined using techniques such as dose-escalation studies.

[0039] The term "pharmaceutically acceptable salt" for PPAR agonists means that it does not cause significant irritation to the mammal to which it is administered and does not substantially interfere with the biological activity and properties of the compound. A wide variety of pharmaceutically acceptable salts may be formed, and may include: - An acid addition salt formed by reacting a PPAR agonist with an organic acid, comprising aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxylalkanoates, alkanedioates, aromatic acids, aliphatic sulfonic acids and aromatic sulfonic acids, amino acids, etc., for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. - An acid addition salt formed by reacting a PPAR agonist with an inorganic acid, the acid addition salt being the acid addition salt of the form of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphoric acid, etc.

[0040] The term “metabolic dysfunction” may refer to a state of imbalance and / or reduction in metabolic function. In some embodiments, metabolic dysfunction is caused by natural aging. In some embodiments, metabolic dysfunction is caused by consuming a high-fat diet. In some embodiments, metabolic dysfunction is caused by natural aging. In some embodiments, metabolic dysfunction is caused by consuming a high-fat diet.

[0041] "Subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, as well as other apes and monkey species, domesticated animals such as cattle, horses, sheep, goats, and pigs, pet animals such as rabbits, dogs, and cats, and laboratory animals including rodents such as rats, mice, and guinea pigs. In some embodiments, the mammal is a human. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a rodent. In some embodiments, the mammal is a companion animal.

[0042] The term "reduction" refers to the reduction or elimination of one or more symptoms of a disease or condition, or risk factors associated with the disease or condition, and / or a reduction in the incidence, delay of onset, or severity of one or more symptoms of the disease or condition. In some embodiments, the term "reduction" may also refer to the prevention of the disease or condition. In some embodiments, the disease or condition is a metabolic disorder. Examples include the preventive effect against increased fasting insulin, free fatty acids, and weakness induced by metabolic disorders.

[0043] The term "reversal" refers to a return of a specific biomarker or outcome to clinically healthy levels. Examples include the reversal of the effects of increased fasting insulin, free fatty acids, and weakness induced by metabolic dysfunction. In some embodiments, metabolic dysfunction is caused by natural aging. In some embodiments, metabolic dysfunction is caused by consuming a high-fat diet.

[0044] The headings used in this specification are intended solely for structural organization and should not be interpreted as limiting the subjects described. compound

[0045] The compounds described herein may be PPAR agonists, PPARα agonists, or PPARα / PPAR agonists. The compounds described herein are PPAR agonists. In some embodiments, the PPAR agonist is a thiazolidinedione derivative. In some embodiments, the PPAR agonist is robeglitazone, troglitazone, siglitazone, riboglitazone, englitazone, paraglitazone, netoglitazone, pioglitazone, or rosiglitazone. In some embodiments, the PPAR agonist is robeglitazone, troglitazone, pioglitazone, or rosiglitazone. In some embodiments, the PPAR agonist is pioglitazone. In some embodiments, the PPAR agonist is pioglitazone or a salt thereof. In some embodiments, pioglitazone is in free base form. In some embodiments, the PPAR agonist is pioglitazone hydrochloride. In some embodiments, the PPAR agonist is pioglitazone. Pioglitazone is a PPAR agonist having the structure shown as pioglitazone HCl.

[0046] [ka]

[0047] In some embodiments, the PPAR agonist is rosiglitazone. Rosiglitazone is a PPAR agonist having the structure shown as rosiglitazone maleate.

[0048] [ka]

[0049] The compounds described herein are PPARα agonists. In some embodiments, the PPARα agonist is fenofibrate, clofibrate, pyrinixic acid, WY1, GW735, GW409544, BMS631707, KRP101, AVE8134, or pioglitazone. In some embodiments, the compound may be a bi-PPARα / PPAR agonist.

[0050] In some embodiments, pioglitazone or its salt is administered in amounts of 1 mg / kg to 20 mg / kg. In some embodiments, pioglitazone or its salt is administered in amounts of 1 mg / kg to 10 mg / kg. In some embodiments, pioglitazone or its salt is administered in amounts of 1 mg / kg to 5 mg / kg. In some embodiments, pioglitazone or its salt is administered in amounts of 1 mg / kg. In some embodiments, pioglitazone or its salt is administered in amounts of 2 mg / kg. In some embodiments, pioglitazone or its salt is administered in amounts of about 0.1 to 5 mg / kg. In some embodiments, pioglitazone or its salt is administered in amounts of about 2 to 3 mg / kg. In some embodiments, pioglitazone or its salt is administered in amounts of about 1 to 3 mg / kg. In some embodiments, pioglitazone or its salt is administered in amounts of about 2 to 5 mg / kg. In some embodiments, pioglitazone or its salt is administered in amounts of about 5 to 10 mg / kg. In some embodiments, pioglitazone or a salt thereof is administered in amounts of at least about 0.1 mg / kg, at least about 1 mg / kg, at least about 2 mg / kg, at least about 4 mg / kg, at least about 6 mg / kg, at least about 7 mg / kg, at least about 9 mg / kg, or at least about 10 mg / kg. In some embodiments, pioglitazone or a salt thereof is administered in amounts up to about 20 mg / kg, up to about 10 mg / kg, up to about 9 mg / kg, up to about 8 mg / kg, up to about 7 mg / kg, up to about 6 mg / kg, up to about 5 mg / kg, up to about 4 mg / kg, up to about 3 mg / kg, up to about 2 mg / kg, or up to about 1 mg / kg. In some embodiments, pioglitazone or a salt thereof is administered enterally. In some embodiments, pioglitazone or a salt thereof is administered orally. In some embodiments, pioglitazone or a salt thereof is administered parenterally. In some embodiments, pioglitazone or a salt thereof is administered multiple times a day, twice a day, daily, every other day, once a week, or once every two weeks.In some embodiments, pioglitazone or a salt thereof is administered daily. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 1 mg / kg / day to 20 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 1 mg / kg / day to 10 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 1 mg / kg / day to 5 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 1 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 2 mg / kg / day.

[0051] method In some embodiments, methods for reducing or reversing insulin resistance in mammals that require reduction or reversal of insulin resistance, with or without evidence of metabolic dysfunction, are described herein, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist, a pharmaceutically acceptable salt thereof, or a prodrug to the mammal.

[0052] In some embodiments, the Specified Description describes a method for delaying the onset of age-related insulin resistance in mammals that require delaying the onset of age-related insulin resistance, the method comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to the mammal.

[0053] In some embodiments, the Specified Description describes a method for maintaining the healthy function of adipose tissue in mammals where maintaining the healthy function of adipose tissue is required, comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0054] In some embodiments, the Specified Description describes a method for treating age-induced hyperinsulinemia in mammals that require treatment of age-induced hyperinsulinemia, comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0055] In some embodiments, the Specified Description describes a method for treating age-induced insulin resistance in mammals that require treatment of age-induced insulin resistance, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to the mammal.

[0056] In some embodiments, methods for treating age-related increases in fatty acids in mammals that require treatment thereof are described herein, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to the mammal.

[0057] In some embodiments, a method for reducing or reversing age-induced insulin resistance in companion animals that require reduction or reversal of age-induced insulin resistance, regardless of whether they have evidence of metabolic dysfunction or not, is described, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to a companion animal, wherein the companion animal is at least 4 years old.

[0058] In some embodiments, methods for reducing or reversing age-related increases in lipids, including fatty acids, triglycerides, and cholesterol, in companion animals that require reduction or reversal of age-related increases in lipids, including fatty acids, triglycerides, and cholesterol, with or without evidence of metabolic dysfunction, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, to a companion animal, wherein the companion animal is at least 4 years old. In some embodiments, the Specified Description describes a method for maintaining or restoring the healthy function of adipose tissue in a companion animal that requires maintenance or restoration of the healthy function of adipose tissue, comprising administering to the companion animal a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof, wherein the companion animal is at least 4 years of age.

[0059] In some embodiments, the treatment method reduces or reverses high-fat diet-induced insulin resistance in mammals. In some embodiments, the treatment method reduces or reverses high-fat diet-induced hyperinsulinemia in mammals. In some embodiments, the treatment method reduces or reverses high-fat diet-induced increases in free fatty acids. Reduction or reversal of insulin resistance includes reducing insulin resistance compared to untreated levels. Mammalian subjects may experience restored insulin sensitivity. Reduction or reversal of hyperinsulinemia includes reducing insulin resistance compared to untreated levels. Mammalian subjects may experience decreased circulating insulin levels. Reduction or reversal of high-fat diet-induced increases in free fatty acid levels includes, but is not limited to, a decrease in free fatty acid levels in subjects compared to untreated free fatty acid levels. Biomarkers for evaluating therapeutic efficacy may include, but are not limited to, measurement of glucose and free fatty acid levels in subjects.

[0060] In some embodiments, a method for reducing or reversing high-fat diet (HFD)-induced insulin resistance in mammals requiring reduction or reversal of high-fat diet (HFD)-induced insulin resistance is described, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to the mammal.

[0061] In some embodiments, methods for reducing or reversing insulin resistance in mammals where it is necessary to reduce or reverse insulin resistance, with or without evidence of metabolic dysfunction, are described, comprising administering a therapeutically effective amount of a formulation containing a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, to the mammal. In some embodiments, methods for reducing or reversing insulin resistance in mammals where it is necessary to reduce or reverse insulin resistance are described, comprising administering a therapeutically effective amount of a formulation containing a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, to the mammal. In some embodiments, methods for reducing or reversing insulin resistance in mammals where it is necessary to reduce or reverse insulin resistance are described, comprising administering a therapeutically effective amount of a formulation containing a PPAR agonist or a free base to the mammal. In some embodiments, the reversed insulin resistance also returns fasting insulin levels to normal levels.

[0062] In some embodiments, the method does not directly affect glucose levels. In some embodiments, the method does not decrease glucose levels in mammals. In some embodiments, the method does not increase glucose levels in mammals. In some embodiments, the method includes administering a PPAR agonist, or a pharmaceutically acceptable salt thereof, or a prodrug, to mammals that are susceptible to changes in glucose levels. In some embodiments, the method includes administering a PPAR agonist, or a pharmaceutically acceptable salt thereof, or a prodrug, to mammals that are susceptible to increases in glucose levels. In some embodiments, the method includes administering a PPAR agonist, or a pharmaceutically acceptable salt thereof, or a prodrug, to mammals that can benefit from stable glucose levels.

[0063] In some embodiments, the method increases adiponectin levels in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 50%, or at least 100%.

[0064] In some embodiments, the method reduces insulin levels in mammals. In some embodiments, insulin levels are reduced by at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%. In some embodiments, insulin levels are reduced by at least 5%, at least 10%, at least 15%, or at least 20%. In some embodiments, insulin levels are reduced by at least 5%. In some embodiments, insulin levels are reduced by at least 10%. In some embodiments, insulin levels are reduced by at least 15%. In some embodiments, insulin levels are reduced by at least 20%. In some embodiments, insulin levels are reduced by at least 25%.

[0065] In some embodiments, the method improves insulin sensitivity. Improving insulin sensitivity reduces insulin resistance so that insulin metabolism is reduced or reversed to pre-high-fat diet levels. Increased insulin resistance associated with pre-high-fat diets and / or pre-aging may result from decreased insulin sensitivity. Any useful insulin sensitivity assay known to those skilled in the art can be used. In some embodiments, insulin sensitivity is measured by glucose clamp, intravenous glucose tolerance test, oral glucose tolerance test assay, or using fasting blood insulin levels. In some embodiments, insulin sensitivity is measured by oral glucose tolerance test assay. In some embodiments, insulin sensitivity is measured by using fasting blood insulin levels.

[0066] Free fatty acids (FFAs) are fatty acids that circulate in the plasma of mammals. Generally, free fatty acid esters bind to transport proteins, such as albumin, rather than in their esterified form. Free fatty acids can be formed from glycers, such as triglycerides, but are not limited to free fatty acids. In some embodiments, fatty acids can form lipids such as sphingolipids, glycerolipids, and phospholipids.

[0067] In some embodiments, the fatty acid is saturated fatty acid, palmitic acid, linoleic acid, oleic acid, or a combination thereof. In some embodiments, the fatty acid is saturated fatty acid, palmitic acid, linoleic acid, or oleic acid. In some embodiments, the fatty acid is saturated fatty acid. In some embodiments, the fat is palmitic acid. In some embodiments, the fat is linoleic acid. In some embodiments, the fat is oleic acid.

[0068] Triglycerides are fats that circulate in blood cells and can be produced by mammals through food intake or de novo lipid synthesis. Triglyceride levels typically increase with age and in metabolic diseases. Administration of PPARγ agonists such as pioglitazone can lower triglyceride levels in mammals. Triglycerides can be useful biomarkers for determining insulin resistance and insulin sensitivity.

[0069] In some embodiments, the method reduces triglyceride levels in mammals. In some embodiments, the method reduces triglyceride levels by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In some embodiments, the method reduces triglyceride levels by at least 5%. In some embodiments, the method reduces triglyceride levels by at least 10%. In some embodiments, the method reduces triglyceride levels by at least 15%. In some embodiments, the method reduces triglyceride levels by at least 20%. In some embodiments, the method reduces triglyceride levels by at least 25%.

[0070] Adiponectin is an adipokine protein that enhances insulin sensitivity and can modulate glucose levels, lipid metabolism, and insulin sensitivity. Adiponectin can be upregulated by PPAR-activated pioglitazone treatment. Adiponectin can be upregulated in a dose-dependent manner to the degree of PPAR activation / pioglitazone treatment. Adiponectin may also be associated with longevity in humans and other mammals. Adiponectin may be a useful biomarker for determining insulin resistance and insulin sensitivity.

[0071] In some embodiments, the method increases adiponectin levels in mammals. In some embodiments, the method increases adiponectin levels by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In some embodiments, the method increases adiponectin levels by at least 5%. In some embodiments, the method increases adiponectin levels by at least 10%. In some embodiments, the method increases adiponectin levels by at least 20%. In some embodiments, the method increases adiponectin levels by at least 30%. In some embodiments, the method increases adiponectin levels by at least 40%. In some embodiments, the method increases adiponectin levels by at least 50%.

[0072] The subject matter of this specification is mammals. In some embodiments, the mammals are dogs, cats, horses, cattle, pigs, rabbits, rodents, sheep, non-human primates, or humans. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a cat. In some embodiments, the mammal is a rodent. In some embodiments, the rodent is a mouse or a rat. In some embodiments, the mammal is a human.

[0073] The methods described herein describe mammals as subjects. Mammals may be companion animals. In some embodiments, the mammal is a companion animal. In some embodiments, the companion animal is a dog or a cat. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is a cat.

[0074] In some embodiments, the companion animal is at least 2 years old. In some embodiments, the companion animal is at least 3 years old. In some embodiments, the companion animal is at least 4 years old. In some embodiments, the companion animal is at least 5 years old. In some embodiments, the companion animal is at least 6 years old. In some embodiments, the companion animal is at least 7 years old. In some embodiments, the companion animal is at least 8 years old. In some embodiments, the companion animal is at least 9 years old. In some embodiments, the companion animal is at least 10 years old. In some embodiments, the companion animal is at least 10 years old. In some embodiments, the companion animal is at least 11 years old. In some embodiments, the companion animal is at least 12 years old. In some embodiments, the companion animal is at least 13 years old. In some embodiments, the companion animal is at least 14 years old. In some embodiments, the companion animal is at least 15 years old.

[0075] The companion animal may have any weight suitable for the methods described herein. In some embodiments, the companion animal has a weight of at least 5 pounds. In some embodiments, the companion animal has a weight of at least 10 pounds. In some embodiments, the companion animal has a weight of at least 11 pounds. In some embodiments, the companion animal has a weight of at least 12 pounds. In some embodiments, the companion animal has a weight of at least 13 pounds. In some embodiments, the companion animal has a weight of at least 14 pounds. In some embodiments, the companion animal has a weight of at least 15 pounds. In some embodiments, the companion animal has a weight of at least 16 pounds. In some embodiments, the companion animal has a weight of at least 17 pounds. In some embodiments, the companion animal has a weight of at least 18 pounds. In some embodiments, the companion animal has a weight of at least 19 pounds. In some embodiments, the companion animal has a weight of at least 20 pounds. In some embodiments, the companion animal has a weight of at least 25 pounds. In some embodiments, the companion animal has a weight of at least 30 pounds.

[0076] In some embodiments, the companion animal is overweight. In some embodiments, the companion animal is obese.

[0077] In some embodiments, a method for extending lifespan, promoting longevity, and / or preventing, reducing the severity of, or delaying the onset of various age-related conditions in mammals where it is necessary to extend lifespan, promote longevity, and / or prevent various age-related conditions, reduce the severity of, or delay the onset of various age-related conditions, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, to the mammal. In some embodiments, the PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, is administered to the mammal before the onset of age-related metabolic dysfunction.

[0078] In some embodiments, a method for extending lifespan, promoting longevity, and / or preventing various age-related conditions, reducing the severity of various age-related conditions, or delaying the onset of various age-related conditions in mammals where it is necessary to extend lifespan, promote longevity, and / or prevent various age-related conditions, reduce the severity of various age-related conditions, or delay the onset of various age-related conditions, the method comprising administering a therapeutically effective amount of a formulation containing a PPAR agonist as described herein to the mammal.

[0079] In some embodiments, a method for treating age-related decline in quality of life is provided, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to a mammal.

[0080] In some embodiments, a method for treating age-related frailty comprises administering a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to a mammal.

[0081] In some embodiments, a method for extending life in mammals that require life extension, comprising administering a therapeutically effective amount of the formulation described herein to the mammal, wherein the life extension includes an extension of at least 5% compared to the expected life or median life of mammals of a similar species, strain, or breed. In some embodiments, a method for extending life in mammals that require life extension, comprising administering a therapeutically effective amount of the formulation described herein to the mammal, wherein the life extension includes an extension of at least 10% compared to the expected life or median life of mammals of a similar species, strain, or breed. In some embodiments, a method for extending life in mammals that require life extension, comprising administering a therapeutically effective amount of the formulation described herein to the mammal, wherein the life extension includes an extension of at least 15% compared to the expected life or median life of mammals of a similar species, strain, or breed. In some embodiments, a method for extending the lifespan of a mammal requiring life extension, comprising administering a therapeutically effective amount of the formulation described herein to the mammal, wherein the life extension includes an extension of at least 20% of the expected lifespan or median lifespan of a similar species, strain, or breed of mammal. In some embodiments, a method for extending the lifespan of a mammal requiring life extension, comprising administering a therapeutically effective amount of the formulation described herein to the mammal, wherein the life extension includes an extension of at least 25% of the expected lifespan or median lifespan of a similar species, strain, or breed of mammal.

[0082] In some embodiments, the method includes reducing or reversing insulin resistance in mammals. In some embodiments, insulin resistance arises from age-related processes. In some embodiments, the method includes reducing or reversing an increase in free fatty acids (FFA). In some embodiments, the increase in free fatty acids is associated with age-related conditions. Age-related conditions include, but are not limited to, obesity, type 2 diabetes, cardiovascular disease, sarcopenia, atherosclerosis, arthritis, and hypertension. In some embodiments, the age-related condition is obesity, type 2 diabetes, cardiovascular disease, or sarcopenia. In some embodiments, the mammals disclosed herein (e.g., companion animals) have diabetes. In some embodiments, the mammals disclosed herein (e.g., companion animals) do not have diabetes. In some embodiments, the mammals do not have alloxane-induced diabetes. In some embodiments, the mammals have not been diagnosed with diabetes.

[0083] In some embodiments, a method for promoting longevity in a mammal that requires the promotion of longevity, comprising administering a therapeutically effective amount of the formulation described herein to the mammal.

[0084] In some embodiments, the mammals had reached a level of maturity defined for their species. In some embodiments, the mammals had reached an advanced age defined for their species.

[0085] In some embodiments, the mammal is a dog, cat, horse, cattle, pig, rabbit, rodent, sheep, non-human primate, or human. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a cat. In some embodiments, the mammal is a rodent. In some embodiments, the rodent is a mouse or rat. In some embodiments, the mammal is a human.

[0086] In some embodiments, the method described herein further comprises administering a second therapeutic agent in combination with a PPARγ agonist or a salt thereof. In some embodiments, the method described herein further comprises administering a second therapeutic agent in combination with pioglitazone or a salt thereof. In some embodiments, the second therapeutic agent is a drug selected from Table 12. In some embodiments, the second therapeutic agent is selected from selegiline, levothyroxine, NSAIDs, steroids, chemotherapeutic agents, sedatives and anesthetics, opioids (excluding tramazole), tramadol, antiparasitic agents (HWpx, ectoparasitic agents, Dewarmer), supplements, prescription diets, nutritional supplements (including CBD, glucosamine, and fish oil), vaccines, antibiotics (e.g., excluding macrolides and fluoroquinolones and macrocyclic antibiotics), fluoroquinolone antibiotics (ciprofloxacin, enrofloxacin, difloxacin, orbifloxacin, marbofloxacin), ketoconazole, non-ketoconazole antifungal agents (such as miconazole and fluconazole), and cardiac drugs that are not ACE inhibitors or ACE receptor blockers.

[0087] Pharmaceutical preparations In some embodiments of the pharmaceutical formulations described herein, the PPAR agonist is in free base form. In some embodiments of the pharmaceutical formulations described herein, the PPAR agonist is a salt. In some embodiments of the pharmaceutical formulations described herein, the PPAR agonist is a hydrochloride salt. In some embodiments of the pharmaceutical formulations described herein, the PPAR agonist is a maleate salt.

[0088] In some embodiments, one or more excipients described herein are in salt form. In some embodiments, one or more excipients described herein are in free base form.

[0089] References to pharmaceutically acceptable salts should be understood to include solvated forms (solvates). Solvates are formed during the process of product formation or isolation using pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, and acetonitrile. In one embodiment, solvates are formed using Class 3 solvents, but are not limited to these. The categories of solvents are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005)". Hydrates are formed when the solvent is water, or alkolates are formed when the solvent is alcohol. In some embodiments, solvates of PPAR agonists or pharmaceutically acceptable salts thereof are conveniently prepared or formed during the processes described herein. In some embodiments, the solvates of PPAR agonists are anhydrous. In some embodiments, PPAR agonists or pharmaceutically acceptable salts thereof exist in a non-solvated form. In some embodiments, PPAR agonists or pharmaceutically acceptable salts thereof exist in a non-solvated form and are anhydrous. In some embodiments, one or more excipients described herein are solvated. In some embodiments, one or more excipients described herein are non-solvated.

[0090] In further embodiments, the PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, is prepared in a variety of forms, including but not limited to amorphous phase, crystalline form, pulverized form, and nanoparticle form. In some embodiments, the PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, is amorphous. In some embodiments, the PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, is amorphous and anhydrous. In some embodiments, the PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, is crystalline. In some embodiments, the PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, is crystalline and anhydrous.

[0091] While not intended to be bound by any particular theory, a particular solid form is characterized by physical properties (e.g., stability, solubility, and dissolution rate) suitable for pharmaceutical and therapeutic dosage forms. Furthermore, while not wishing to be bound by any particular theory, a particular solid form is characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, viscosity, solubility, water uptake, electrical properties, thermal behavior, solid reactivity, physical stability, and chemical stability) that influence specific processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, lyophilization), thereby making a particular solid form suitable for the manufacture of solid dosage forms. These properties can be determined using certain analytical chemistry techniques, including solid analysis techniques described herein and known in the art (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis).

[0092] The pharmaceutical formulations described herein comprise a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, and at least one pharmaceutically acceptable excipient, in a solid dosage form. In some embodiments, the pharmaceutical formulations described herein comprise pioglitazone and at least one pharmaceutically acceptable excipient in a solid dosage form, the solid dosage form being selected from powders, tablets, chewable tablets, caplets, capsules, gel caps, effervescent powders, rapidly disintegrating tablets, abuse-inhibiting tablets, controlled-release tablets, controlled-release caplets, controlled-release capsules, and aqueous suspensions produced from powders. In some embodiments, the pharmaceutical formulation is a liquid formulation, such as a solution or suspension. In some embodiments, the pharmaceutical formulation is a parenteral formulation, such as an injectable formulation. In some embodiments, the pharmaceutical formulation is a solid-form formulation. In some embodiments, the pharmaceutical formulation is a powder formulation added to food. In some embodiments, the pharmaceutical formulation described herein comprises a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof, and at least one pharmaceutically acceptable excipient in a solid dosage form. In some embodiments, the solid dosage form is a tablet. In some embodiments, the solid dosage form is a capsule. In some embodiments, the pharmaceutical formulation described herein comprises pioglitazone and at least one pharmaceutically acceptable excipient in a solid dosage form, and the solid dosage form is a tablet.

[0093] In some embodiments, the pharmaceutical formulation contains about 1% to about 35% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 0.5% to about 10% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 1% to about 35% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 2% to about 35% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 3% to about 35% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 5% to about 35% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 5% to about 35% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 10% to about 35% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 15% to about 35% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 10% to about 30% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 15% to about 30% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 20% to about 30% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 15% to about 25% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 20% to about 25% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 10% of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof.In some embodiments, the pharmaceutical formulation contains about 11% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 12% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 13% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 14% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 15% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 16% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 17% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 18% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 19% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 20% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 21% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 22% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 23% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 24% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 25% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 26% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof.In some embodiments, the pharmaceutical formulation contains about 27% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 28% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 29% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 30% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 31% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 32% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 33% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 34% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 35% PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof.

[0094] In some embodiments, the PPAR agonist is selected from pioglitazone and rosiglitazone.

[0095] In some embodiments, the pharmaceutical formulation contains about 3% to about 35% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 5% to about 35% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 10% to about 35% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 15% to about 35% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 10% to about 30% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 15% to about 30% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 20% to about 30% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 15% to about 25% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 20% to about 25% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 10% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 11% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 12% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 13% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 14% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 15% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 16% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 17% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 18% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 19% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 20% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 21% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 22% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 23% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 24% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 25% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 26% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 27% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 28% pioglitazone.In some embodiments, the pharmaceutical formulation contains about 29% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 30% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 31% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 32% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 33% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 34% pioglitazone. In some embodiments, the pharmaceutical formulation contains about 35% pioglitazone.

[0096] In some embodiments, the pharmaceutical formulation contains about 5% to about 35% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 10% to about 35% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 15% to about 35% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 10% to about 30% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 15% to about 30% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 20% to about 30% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 15% to about 25% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 20% to about 25% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 10% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 11% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 12% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 13% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 14% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 15% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 16% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 17% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 18% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 19% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 20% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 21% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 22% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 23% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 24% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 25% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 26% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 27% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 28% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 29% rosiglitazone.In some embodiments, the pharmaceutical formulation contains about 30% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 31% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 32% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 33% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 34% rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 35% rosiglitazone.

[0097] In some embodiments, the pharmaceutical formulation contains about 1 mg to about 120 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 100 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 120 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 120 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 4 mg to about 120 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 4 mg to about 85 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 120 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 10 mg to about 120 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 10 mg to about 110 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 10 mg to about 100 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 20 mg to about 100 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 25 mg to about 100 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 30 mg to about 100 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 30 mg to about 90 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof.In some embodiments, the pharmaceutical formulation contains about 40 mg to about 90 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 40 mg to about 80 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 45 mg to about 80 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 45 mg to about 75 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 50 mg to about 70 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 100 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 90 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 80 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 75 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 70 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 65 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 60 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 55 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 50 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 45 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof.In some embodiments, the pharmaceutical formulation contains about 40 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 30 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 20 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation contains about 10 mg of a PPAR agonist, or a pharmaceutically acceptable salt or prodrug thereof.

[0098] In some embodiments, the pharmaceutical formulation contains about 1 mg to about 120 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 100 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 120 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 120 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 4 mg to about 120 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 4 mg to about 85 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 120 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 10 mg to about 120 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 10 mg to about 110 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 10 mg to about 100 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 20 mg to about 100 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 25 mg to about 100 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 30 mg to about 100 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 30 mg to about 90 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 40 mg to about 90 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 40 mg to about 80 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 45 mg to about 80 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 45 mg to about 75 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 50 mg to about 70 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 100 mg of pioglitazone or a salt thereof, or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 90 mg of pioglitazone or a salt thereof.In some embodiments, the pharmaceutical formulation contains about 80 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 75 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 70 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 65 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 60 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 55 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 50 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 45 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 40 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 30 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 20 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 10 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation described herein contains about 18 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation described herein contains about 16 mg to about 20 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation described herein contains about 54 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 52 mg to about 56 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 81 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 79 mg to about 83 mg of pioglitazone or a salt thereof.

[0099] In some embodiments, the pharmaceutical formulation contains about 10 mg to about 120 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 10 mg to about 110 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 10 mg to about 100 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 20 mg to about 100 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 25 mg to about 100 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 30 mg to about 100 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 30 mg to about 90 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 40 mg to about 90 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 40 mg to about 80 mg of rosiglitazone or a salt thereof, or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 45 mg to about 80 mg of rosiglitazone. In some embodiments, the pharmaceutical formulation contains about 45 mg to about 75 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 50 mg to about 70 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 100 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 90 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 80 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 75 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 70 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 65 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 60 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 55 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 50 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 45 mg of rosiglitazone or a salt thereof.In some embodiments, the pharmaceutical formulation contains about 40 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 30 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 20 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical formulation contains about 10 mg of rosiglitazone or a salt thereof.

[0100] In some embodiments, the PPAR agonist (such as pioglitazone or rosiglitazone, or a salt thereof) is administered in amounts of 0.01 mg / kg to 100 mg / kg. In some embodiments, the PPAR agonist is administered in amounts of 1 mg / kg to 20 mg / kg. In some embodiments, the PPAR agonist is administered in amounts of 1 mg / kg to 10 mg / kg. In some embodiments, the PPAR agonist is administered in amounts of 1 mg / kg to 5 mg / kg. In some embodiments, the PPAR agonist is administered in amounts of 1 mg / kg. In some embodiments, the PPAR agonist is administered in amounts of 2 mg / kg.

[0101] In one embodiment, a pharmaceutical formulation in a solid dosage form comprising a PPAR agonist or a pharmaceutically acceptable salt thereof and a filler is described herein. In one embodiment, a pharmaceutical formulation in a solid dosage form comprising about 5% to about 20% by weight of a PPAR agonist or a pharmaceutically acceptable salt thereof and about 80% to about 95% by weight of a filler is described herein. In some embodiments, the pharmaceutical formulation further comprises a disintegrant, a binder, a lubricant, a flavoring agent, or a combination thereof. In some embodiments, the disintegrant is present in the formulation in an amount of about 1% to about 10% by weight. In some embodiments, the binder is present in the formulation in an amount of about 1% to about 10% by weight. In some embodiments, the lubricant is present in the formulation in an amount of about 0.3% to about 3% by weight. In some embodiments, the flavoring agent is present in the formulation in an amount of about 0.03% to about 30% by weight. In some embodiments, the flavoring agent is a meat flavoring agent. In some embodiments, the PPAR agonist or a pharmaceutically acceptable salt thereof is present in the formulation in an amount of about 1% to about 99% by weight. In some embodiments, the PPAR agonist or a pharmaceutically acceptable salt thereof is present in the formulation in an amount of about 7% to about 15% by weight. In some embodiments, the PPAR agonist or a pharmaceutically acceptable salt thereof is present in the formulation in an amount of about 10% to about 12% by weight. In some embodiments, the PPAR agonist or a pharmaceutically acceptable salt thereof is present in the formulation in an amount of about 11% by weight. In some embodiments, the PPAR agonist or a pharmaceutically acceptable salt thereof is present in the formulation in an amount of about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% by weight.

[0102] In some embodiments, the formulations described herein include one or more fillers. In some embodiments, the filler is present in the formulation in an amount of about 10% to about 80% by weight. In some embodiments, the filler is present in the formulation in an amount of about 40% to about 80% by weight. In some embodiments, the filler is present in the formulation in an amount of about 55% to about 70% by weight. In some embodiments, the filler is present in the formulation in an amount of about 20% to about 60% by weight. In some embodiments, the filler is present in the formulation in an amount of about 25% to about 50% by weight. In some embodiments, the filler is present in the formulation in an amount of about 30% to about 45% by weight. In some embodiments, the filler is present in the formulation in an amount of about 45% to about 50% by weight. In some embodiments, the filler is present in the formulation in an amount of about 45% to about 50% by weight. In some embodiments, one or more fillers include lactose monohydrate, hydroxypropyl cellulose, sodium carboxymethylcellulose, or a combination thereof.

[0103] Fillers or diluents increase the bulk in pharmaceutical formulations. Examples of such compounds include lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®, dibasic calcium phosphate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium phosphate, anhydrous lactose, spray-dried lactose, pregelled starch, compressible sugars such as Di-Pac® (Amstar); hydroxypropyl methylcellulose, sucrose-based diluents; powdered sugar for icing, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrose, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, and glycine, kaolin, sodium chloride, inositol, bentonite, etc. In some embodiments, the filler includes lactose, mannitol, dicalcium phosphate, cellulose, starch (e.g., pregelled starch), or combinations thereof. In some embodiments, the filler comprises lactose, mannitol, microcrystalline cellulose, or a combination thereof. In some embodiments, the filler comprises lactose. In some embodiments, the filler comprises lactose monohydrate. In some embodiments, the filler comprises hydroxypropyl cellulose. In some embodiments, the filler comprises sodium carboxymethylcellulose. In some embodiments, the filler comprises carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearic acid, hydroxyethylcellulose, hydroxypropyl cellulose ethylcellulose, microcrystalline cellulose, or a combination thereof. In some embodiments, the filler comprises lactose monohydrate, sodium carboxymethylcellulose, and hydroxypropyl cellulose.

[0104] Disintegrants accelerate the breakdown or disintegration of pharmaceutical formulations after administration. Examples of disintegrants include starches, such as natural starches like corn starch or potato starch, pregelled starches such as National1551 or Amijel®, or sodium glycolate starch such as Promogel® or Explotab®; cellulose from wood products, or cross-linked cellulose, such as cross-linked carboxymethylcellulose sodium (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, sodium glycolate. Examples include cross-linked starches such as starch, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, locust bean, karaya, pectin, or tragacanth, sodium glycolate starch, bentonite, natural sponge, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, and sodium lauryl sulfate in combination starches. In some embodiments, the pharmaceutical formulation includes a disintegrant. In some embodiments, the disintegrant is selected from corn starch, potato starch, microcrystalline cellulose, methylcellulose, croscarmellose sodium, sodium glycolate starch, povidone, crospovidone, hypromellose, hydroxypropylcellulose, polyvinyl alcohol, alginic acid, sodium alginate, agar, guar, locust bean, karaya, pectin, tragacanth, bentonite, citrus pulp, and sodium lauryl sulfate. In some embodiments, the disintegrant is selected from povidone, crospovidone, hypromellose, croscarmellose sodium, hydroxypropylcellulose, and polyvinyl alcohol. In some embodiments, the disintegrant is polyvinyl alcohol. In some embodiments, the disintegrant is povidone. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is croscarmellose sodium.

[0105] In some embodiments, the pharmaceutical formulation contains about 1% to about 10% of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 1% to about 9% of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 2% to about 10% of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 2% to about 9% of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 2% to about 8% of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 3% to about 8% of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 3% to about 7% of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 3% to about 6% of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 4% to about 7% of a disintegrant.

[0106] Lubricants are compounds that prevent, reduce, or inhibit adhesion or friction between materials. Examples of lubricants include hydrocarbons such as stearic acid, calcium hydroxide, talc, and mineral oil; hydrogenated vegetable oils such as hydrogenated soybean oil (Sterotex®); Lubritab®, Cutina®; high fatty acids and their alkali metal and alkaline earth metal salts; aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, glycerol, talc, wax, Stearowet®, boric acid, sodium acetate, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax®; sodium oleate, glyceryl behenate (Compitrol 888®), glyceryl palmitostearate (Precirol®); colloidal silica such as Syloid®; Carb-O-Sil®; starches such as corn starch; silicone oils; and surfactants. Examples of hydrophilic lubricants include sodium stearyl fumarate (currently marketed under the trade name PRUV®), polyethylene glycol (PEG), magnesium lauryl sulfate, sodium lauryl sulfate (SLS), sodium benzoate, and sodium chloride. In some embodiments, the pharmaceutical formulation includes a lubricant. In some embodiments, the lubricant is selected from magnesium stearate, stearic acid, and sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is stearic acid. In some embodiments, the lubricant is sodium stearyl fumarate.

[0107] In some embodiments, the pharmaceutical formulation contains about 0.1% to about 10% lubricant. In some embodiments, the pharmaceutical formulation contains about 0.3% to about 3% lubricant. In some embodiments, the pharmaceutical formulation contains about 0.3% to about 2.5% lubricant. In some embodiments, the pharmaceutical formulation contains about 0.3% to about 2% lubricant. In some embodiments, the pharmaceutical formulation contains about 0.5% to about 2% lubricant. In some embodiments, the pharmaceutical formulation contains about 0.5% to about 1.5% lubricant.

[0108] In some embodiments, the pharmaceutical formulations described herein include flavorings. In some embodiments, the pharmaceutical formulations described herein include flavorings. In some embodiments, the flavorings are natural. In some embodiments, the flavorings are artificial. In some embodiments, the pharmaceutical formulations include meat flavorings. In some embodiments, the meat flavorings are natural. In some embodiments, the meat flavorings are artificial. In some embodiments, the meat flavorings are selected from chicken, pork, and beef. In some embodiments, the flavorings are FlavorPal such as FlavorPal X1212.

[0109] In some embodiments, the pharmaceutical formulation contains about 10% to about 30% meat flavoring. In some embodiments, the pharmaceutical formulation contains about 15% to about 30% meat flavoring. In some embodiments, the pharmaceutical formulation contains about 10% to about 25% meat flavoring. In some embodiments, the pharmaceutical formulation contains about 15% to about 25% meat flavoring. In some embodiments, the pharmaceutical formulation contains about 10% to about 30% chicken flavoring. In some embodiments, the pharmaceutical formulation contains about 15% to about 30% chicken flavoring. In some embodiments, the pharmaceutical formulation contains about 10% to about 25% chicken flavoring. In some embodiments, the pharmaceutical formulation contains about 10% to about 30% flavoring. In some embodiments, the pharmaceutical formulation contains about 15% to about 30% flavoring. In some embodiments, the pharmaceutical formulation contains about 10% to about 25% flavoring. In some embodiments, the pharmaceutical formulation contains about 15% to about 25% flavoring. In some embodiments, the pharmaceutical formulation contains about 10% to about 30% flavoring. In some embodiments, the pharmaceutical formulation contains about 15% to about 30% flavoring. In some embodiments, the pharmaceutical formulation contains about 10% to about 25% flavoring.

[0110] Flow enhancers improve the flow properties of powder mixtures. Examples of such compounds include colloidal silicon dioxide such as Cab-o-sil®, tribasic calcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, kaolin, and micronized amorphous silicon dioxide (Syloid®). In some embodiments of the pharmaceutical formulations described herein, the flow enhancer is colloidal silicon dioxide or talc. In some embodiments, the flow enhancer is talc. In some embodiments, the flow enhancer is colloidal silicon dioxide.

[0111] Examples of polymer carriers include polyvinylpyrrolidone compounds such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone vinyl acetate (PVPVA 64), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetylsuccinate (HPMC AS), and methyl methacrylate polymers (Eudragit polymers).

[0112] In some embodiments, the pharmaceutical formulations described herein include one or more pH adjusters or buffers. In some embodiments, the pharmaceutical formulation includes a buffer selected from acetates, carbonates, phosphates, citrates, and glutamates. In some embodiments, the buffer is selected from potassium dihydrogen phosphate, sodium bicarbonate, magnesium carbonate, sodium citrate, sodium dihydrogen phosphate, dipotassium monohydrogen phosphate, and disodium monohydrogen phosphate. In some embodiments, the buffer is included in an amount necessary to maintain the pH of the pharmaceutical formulation within an acceptable range.

[0113] In some embodiments, a polymer coating is provided around the pharmaceutical composition to mask the taste of the formulation, providing a physical barrier to the taste buds. In some embodiments, the coating material is selected from hydrophobic or hydrophilic polymers, lipids, and sweeteners. In some embodiments, the coating material is selected from carbohydrates (cellulose), proteins, gelatin, and prolamins. In some embodiments, the coating material is selected from Eudragit E-100, ethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinyl alcohol, and polyvinyl acetate.

[0114] Examples of stabilizers include any antioxidants, such as compounds like butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol, as well as buffers and acids. In some embodiments, the pharmaceutical formulation includes a stabilizer. Examples of surfactants include sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, polaxomer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF) and d-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS). In some embodiments, the pharmaceutical formulation includes a surfactant.

[0115] In some embodiments, pharmaceutical formulations in solid dosage forms including intragranulations are described herein.

[0116] In some embodiments, pharmaceutical formulations in solid dosage forms comprising (a) pioglitazone or a salt thereof, (b) one or more fillers (e.g., lactose monohydrate, hydroxypropyl cellulose, sodium carboxymethylcellulose, or a combination thereof), (c) a lubricant (e.g., magnesium stearate), and (d) a flavoring agent are described herein. In some embodiments, as described herein, by weight, (a) Approximately 5% to 20% pioglitazone or its salts, (b) Approximately 25% to 50% lactose (e.g., lactose monohydrate), (c) Approximately 0.1% to 10% hydroxypropyl cellulose, (d) Approximately 1% to approximately 10% sodium carboxymethylcellulose, and (e) Pharmaceutical preparations in solid dosage forms containing flavorings may be described.

[0117] In some embodiments, as specified herein, by weight, (a) Approximately 5% to 30% pioglitazone or its salts, (b) Approximately 25% to 80% lactose (e.g., lactose monohydrate), (c) Approximately 0.1% to 10% hydroxypropyl cellulose, (d) Approximately 1% to approximately 25% sodium carboxymethylcellulose, and (e) Depending on the case, pharmaceutical preparations in solid dosage forms containing flavorings may be described.

[0118] In some embodiments, as described herein, (a) Approximately 10 mg to 100 mg of pioglitazone or its salt, (b) Approximately 50 mg to 400 mg of lactose (e.g., lactose monohydrate), (c) Approximately 0.5 mg to approximately 15 mg of hydroxypropyl cellulose, (d) Approximately 1 mg to approximately 50 mg of sodium carboxymethylcellulose, (e) Pharmaceutical preparations in solid dosage forms that may contain flavorings may be described.

[0119] In some embodiments, as described herein, (a) Approximately 5% to 20% pioglitazone or its salts, (b) Approximately 25% to 50% fillers (lactose, cellulose, etc.) (c) Approximately 0.1% to 10% binder, (d) Depending on the case, about 1% to about 10% of the disintegrant, and (e) Depending on the circumstances, pharmaceutical preparations in solid dosage forms containing flavorings may be described.

[0120] In some embodiments, the PPAR agonist (such as pioglitazone or rosiglitazone) is administered daily, every other day, once a week, or once every two weeks. In some embodiments, the PPAR agonist is administered for at least about two weeks. In some embodiments, the PPAR agonist is administered for at least about four weeks. In some embodiments, the PPAR agonist is administered for at least about eight weeks. In some embodiments, the PPAR agonist is administered for at least about four months. In some embodiments, the PPAR agonist is administered for at least about six months. In some embodiments, the PPAR agonist is administered for at least about eight months. In some embodiments, the PPAR agonist is administered for at least about ten months. In some embodiments, the PPAR agonist is administered for at least about one year. In some embodiments, the PPAR agonist is administered for at least about two years. In some embodiments, the PPAR agonist is administered throughout the life of the mammal.

[0121] In some embodiments, the PPAR agonist is administered daily. In some embodiments, the PPAR agonist is administered weekly. In some embodiments, the PPAR agonist is administered once a week. In some embodiments, the PPAR agonist is administered two or more times a week. In some embodiments, the PPAR agonist is administered monthly.

[0122] In some embodiments, the PPAR agonist is administered at a dose of 1 mg / kg / day to 20 mg / kg / day. In some embodiments, the PPAR agonist is administered at a dose of 1 mg / kg / day to 10 mg / kg / day. In some embodiments, the PPAR agonist is administered at a dose of 1 mg / kg / day to 5 mg / kg / day. In some embodiments, the PPAR agonist is administered at a dose of 2 mg / kg / day to 3 mg / kg / day. In some embodiments, the PPAR agonist is administered at a dose of 1 mg / kg / day. In some embodiments, the PPAR agonist is administered at a dose of 2 mg / kg / day. In some embodiments, the PPAR agonist is administered at a dose of 3 mg / kg / day. In some embodiments, the PPAR agonist is administered at a dose of 4 mg / kg / day. In some embodiments, the PPAR agonist is administered at a dose of 5 mg / kg / day. In some embodiments, the PPAR agonist is administered at a dose of 6 mg / kg / day. In some embodiments, the PPAR agonist is administered at 7 mg / kg / day. In some embodiments, the PPAR agonist is administered at 8 mg / kg / day. In some embodiments, the PPAR agonist is administered at 9 mg / kg / day. In some embodiments, the PPAR agonist is administered at 10 mg / kg / day. In some embodiments, the PPAR agonist is a salt of pioglitazone. In some embodiments, the PPAR agonist is an HCl salt of pioglitazone. In some embodiments, the PPAR agonist is pioglitazone. In some embodiments, pioglitazone or a salt thereof is administered at 1 mg / kg / day to 20 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at 1 mg / kg / day to 10 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at 1 mg / kg / day to 5 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 2 mg / kg / day to 3 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 1 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 2 mg / kg / day.In some embodiments, pioglitazone or a salt thereof is administered at a dose of 3 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 4 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 5 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 6 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 7 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 8 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 9 mg / kg / day. In some embodiments, pioglitazone or a salt thereof is administered at a dose of 10 mg / kg / day.

[0123] In some embodiments, the PPAR agonist (such as pioglitazone or rosiglitazone, or a salt thereof) is administered over a period of 1 day to 20 years. In some embodiments, the PPAR agonist is administered over a period of 1 day to 15 years. In some embodiments, the PPAR agonist is administered over a period of 1 day to 10 years. In some embodiments, the PPAR agonist is administered over a period of 1 week to 1 year. In some embodiments, the PPAR agonist is administered over a period of at least 1 day, 1 week, 1 month, 3 months, or 6 months. In some embodiments, the PPAR agonist is administered over a period of up to 1 month, 3 months, 6 months, 9 months, 1 year, or 2 years. In some embodiments, the PPAR agonist is administered chronically. In some embodiments, the PPAR agonist is administered throughout the remaining lifespan of the mammal (such as a companion animal).

[0124] The formulation and PPAR agonist may be a suitable oral formulation for oral administration to a companion animal. In some embodiments, the formulation is a solid dosage form. In some embodiments, the formulation is in the form of a tablet. In some embodiments, the PPAR agonist is in the form of a tablet. In some embodiments, the PPAR agonist is in the form of a capsule. In some embodiments, the tablet is a flavored tablet. In some embodiments, the tablet or capsule contains chicken, pork, beef, lamb, or fish flavor. In some embodiments, the tablet or capsule contains chicken, pork, beef, or lamb flavor. In some embodiments, the tablet or capsule contains a hydrolyzed chicken product or chicken flavoring.

[0125] In some embodiments, the tablets contain about 18 mg, 54 mg, or 81 mg of PPAR agonist. In some embodiments, the tablets contain about 18 mg of PPAR agonist. In some embodiments, the tablets contain about 54 mg of PPAR agonist. In some embodiments, the tablets contain about 81 mg of PPAR agonist. In some embodiments, the capsules contain about 18 mg, 54 mg, or 81 mg of PPAR agonist. In some embodiments, the capsules contain about 18 mg of PPAR agonist. In some embodiments, the capsules contain about 54 mg of PPAR agonist. In some embodiments, the capsules contain about 81 mg of PPAR agonist. In some embodiments, the PPAR agonist is pioglitazone hydrochloride.

[0126] In some embodiments, the solid dosage form (e.g., a tablet or capsule) further comprises at least one filler. In some embodiments, the solid dosage form comprises at least two fillers. In some embodiments, the solid dosage form comprises at least three fillers. In some embodiments, the filler is lactose monohydrate. In some embodiments, the lactose monohydrate is present in an amount of 10% to 40% w / w. In some embodiments, the lactose monohydrate is present in an amount of 10% to 30% w / w. In some embodiments, the lactose monohydrate is present in an amount of about 15% to 25% w / w. In some embodiments, the lactose monohydrate is present in an amount of 30% to 40% w / w. In some embodiments, the lactose monohydrate is present in an amount of 32% to 40% w / w. In some embodiments, the lactose monohydrate is present in an amount of 35% to 40% w / w. In some embodiments, the lactose monohydrate is present in an amount of about 36% to about 38% w / w. In some embodiments, the lactose monohydrate is present in an amount of approximately 37% w / w. In some embodiments, the lactose monohydrate is present in an amount of approximately 22% w / w.

[0127] In some embodiments, the solid dosage form further comprises sodium carboxymethylcellulose. In some embodiments, the amount of carboxymethylcellulose is about 1% to about 10% w / w. In some embodiments, the amount of carboxymethylcellulose is about 2% to about 10% w / w. In some embodiments, the amount of carboxymethylcellulose is about 2% to about 8% w / w. In some embodiments, the amount of carboxymethylcellulose is about 2% to about 6% w / w. In some embodiments, the amount of carboxymethylcellulose is about 3% to about 5% w / w. In some embodiments, the amount of carboxymethylcellulose is about 4% w / w.

[0128] In some embodiments, the solid dosage form (e.g., tablets or capsules) further comprises hydroxypropyl cellulose. In some embodiments, the amount of hydroxypropyl cellulose is about 0.1% to about 5% w / w. In some embodiments, the amount of hydroxypropyl cellulose is about 0.25% to about 3% w / w. In some embodiments, the amount of hydroxypropyl cellulose is about 0.5% to about 2% w / w. In some embodiments, the amount of hydroxypropyl cellulose is about 1% w / w.

[0129] The hydroxypropyl cellulose grades useful for the present invention include various viscosity grades having an average molecular weight in the range of 20 to 1500 kDa. Examples of hydroxypropyl cellulose grades useful for the present invention include, but are not limited to, EXF grades. EXF grades may have a viscosity of approximately 300 to 600 mPa·s.

[0130] In some embodiments, the solid dosage form (e.g., tablets or capsules) further comprises a flavoring agent such as FlavorPALX1212. In some embodiments, the flavoring agent is present in an amount of about 10–40% w / w. In some embodiments, the flavoring agent is present in an amount of about 10–30% w / w. In some embodiments, the flavoring agent is present in an amount of about 15–25% w / w. In some embodiments, the flavoring agent is present in an amount of about 20% w / w. In some embodiments, the flavoring agent has a meaty flavor.

[0131] In some embodiments, the solid dosage form (e.g., tablets or capsules) further comprises magnesium stearate. In some embodiments, the amount of magnesium stearate is about 0.25% to 5% w / w. In some embodiments, the amount of magnesium stearate is about 0.25% to 3% w / w. In some embodiments, the amount of magnesium stearate is about 0.25% to 2% w / w. In some embodiments, the amount of magnesium stearate is about 0.5% to 1.5% w / w. In some embodiments, the amount of magnesium stearate is about 1% w / w.

[0132] In some embodiments, the mammal described herein is a companion animal. In some embodiments, the companion animal is a dog or a cat. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is a cat. In some embodiments, the mammal described herein is a dog, a cat, a horse, a cow, a pig, a rabbit, a rodent, a sheep, a non-human primate, or a human. In some embodiments, the mammal is a dog. In some embodiments, the rodent is a mouse or a rat. In some embodiments, the mammal is a human.

[0133] In some embodiments, the mammal is a dog of any age. In some embodiments, the mammal is a dog older than 7 years. In some embodiments, the mammal is a dog between 1 and 8 years old. In some embodiments, the mammal is a dog between 1 and 3 years old. In some embodiments, the mammal is a dog between 4 and 8 years old. In some embodiments, the mammal is a dog at least 7 years old. In some embodiments, the mammal is a dog at least 9 years old. In some embodiments, the mammal is a dog at least 10 years old. In some embodiments, the mammal is a dog at least 11 years old. In some embodiments, the mammal is a dog at least 12 years old. In some embodiments, the mammal is a dog at least 13 years old. In some embodiments, the mammal is a dog at least 14 years old. In some embodiments, the mammal is a dog at least 15 years old. In some embodiments, the mammal is a dog showing signs of aging. In some embodiments, the mammal is a dog that can benefit from stable glucose levels. In some embodiments, the mammal is a dog that is susceptible to changes in glucose levels. In some embodiments, the mammal is a dog that is susceptible to increases in glucose levels. In some embodiments, the mammal is a dog showing signs of aging. In some embodiments, the mammal is a dog that can benefit from low levels of saturated fatty acids in its body. In some embodiments, the mammal is a dog with high levels of saturated fatty acids in its body. In some embodiments, the mammal is a dog with high levels of palmitic acid in its body.

[0134] Further embodiments In some embodiments, formulations comprising pioglitazone or a pharmaceutically acceptable salt thereof for use in reducing or delaying mortality from age-related diseases in companion animals are provided, the formulation being administered for at least two weeks. In some embodiments, the pharmaceutically acceptable salt thereof is pioglitazone hydrochloride. In some embodiments, the pharmaceutically acceptable salt thereof is administered at a dose of about 2-3 mg / kg / day. In some embodiments, the pharmaceutically acceptable salt thereof is administered at a dose of about 1-5 mg / kg / day. In some embodiments, the pharmaceutically acceptable salt thereof is administered at a dose of up to 10 mg / kg / day. In some embodiments, the formulation is administered once daily. In some embodiments, the formulation is administered for at least about four weeks. In some embodiments, the formulation is administered for at least about twelve weeks. In some embodiments, the formulation is administered for at least about one year. In some embodiments, the method comprises reducing the insulin levels of the companion animal. In some embodiments, insulin levels are reduced by at least 5%. In some embodiments, the formulation improves insulin sensitivity. In some embodiments, insulin sensitivity is measured by an oral glucose tolerance test assay or a hyperinsulinemia-euglycemic clamp test assay. In some embodiments, insulin sensitivity is measured by a shortened or modified oral glucose tolerance test assay. In some embodiments, insulin sensitivity is measured by using fasting blood insulin levels. In some embodiments, the formulation reduces triglyceride levels in a companion animal. In some embodiments, the formulation reduces cholesterol levels in a companion animal. In some embodiments, use further comprises mitigating age-induced increases in fatty acids, where fatty acids are aggregates of free fatty acids, saturated fatty acids, palmitic acid, linoleic acid, or oleic acid, or any combination thereof. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is at least 7 years old.In some embodiments, the companion animal is at least 10 years old. In some embodiments, the companion animal weighs at least 14 pounds. In some embodiments, the formulation contains about 5% to about 15% pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation contains about 4 mg to about 85 mg pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation is in the form of a tablet. In some embodiments, the tablet contains 18 mg, 54 mg, or 81 mg pioglitazone or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, methods are provided herein for reducing or delaying mortality from age-related diseases in companion animals where it is necessary to reduce or delay mortality from age-related diseases in companion animals, comprising orally administering a therapeutically effective dose of a formulation containing pioglitazone or a pharmaceutically acceptable salt thereof to the companion animals for at least two weeks. In some embodiments, pioglitazone or a pharmaceutically acceptable salt thereof is pioglitazone hydrochloride. In some embodiments, pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of about 2-3 mg / kg / day. In some embodiments, pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of about 1-5 mg / kg / day. In some embodiments, pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of up to 10 mg / kg / day. In some embodiments, the formulation is administered once daily. In some embodiments, the formulation is administered for at least about four weeks. In some embodiments, the formulation is administered for at least about twelve weeks. In some embodiments, the formulation is administered for at least about one year. In some embodiments, the method includes reducing the insulin levels of a companion animal. In some embodiments, the insulin levels are reduced by at least 5%. In some embodiments, the method improves insulin sensitivity. In some embodiments, insulin sensitivity is measured by an oral glucose tolerance test assay or a hyperinsulinemia euglycemic clamp test assay. In some embodiments, insulin sensitivity is measured by a shortened or modified oral glucose tolerance test assay. In some embodiments, insulin sensitivity is measured by using fasting blood insulin levels. In some embodiments, the method reduces the triglyceride levels of a companion animal. In some embodiments, the method reduces the cholesterol levels of a companion animal.In some embodiments, use further comprises mitigating the age-induced increase in fatty acids, where fatty acids are aggregates of free fatty acids, saturated fatty acids, palmitic acid, linoleic acid, or oleic acid, or any combination thereof. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is at least 7 years old. In some embodiments, the companion animal is at least 10 years old. In some embodiments, the companion animal weighs at least 14 pounds. In some embodiments, the formulation contains about 5% to about 15% pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation contains about 4 mg to about 85 mg pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation is in the form of a tablet. In some embodiments, the tablet contains 18 mg, 54 mg, or 81 mg pioglitazone or a pharmaceutically acceptable salt thereof. [Examples]

[0136] The following exemplary embodiments are representative of the embodiments of the stimuli, systems, and methods described herein and are not intended to limit them in any way.

[0137] Example 1. Metabolic aging biomarkers in HRQL studies An observational healthy life expectancy study was conducted, including health-related quality of life (HRQL) assessments. The study outcomes included owner assessments of health-related QOL (HRQL), as well as veterinary assessments of physical examination, body condition score (BCS), muscle condition score, complete blood count, biochemical tests, serum T4 measurement, urinalysis, insulin-like growth factor-1 measurement, and canine vulnerability index (CFI) score. Blood samples were collected to assess serum fasting insulin and adiponectin levels. DNA samples were also collected. Target demographic characteristics were collected from 451 eligible adult dogs, of which 43.6% were mixed breeds and 56.4% were purebreds. The target age and size of the dogs used for registration are shown in Table 1 below. Approximately 451 dogs were evaluated, and approximately 450 dogs were evaluated using HRQL. Fasting insulin levels were evaluated in approximately 409 dogs, and adiponectin levels were evaluated in approximately 352 dogs. The bivariate relationships observed between insulin and age, insulin and body weight, insulin and BCS, insulin and HRQL, and insulin and CFI are shown in Table 2 below.

[0138] [Table 1]

[0139] [Table 2]

[0140] Data from the HRQL trial were analyzed using quantile regression models to estimate the combined effects of the variables in Table 2. Multiple median regressions were performed using a full main effects model, an age-and-weight multiplicative interaction model, and an age-and-BCS interaction model, as shown in Table 3 below. Figure 1 shows graphs illustrating the relationship between age and standardized log (insulin) in dogs of various weight groups.

[0141] [Table 3]

[0142] Fasting insulin levels were examined and their relationship to HRQL scores in a healthy lifespan study was determined. To determine HRQL, owners of participating dogs were surveyed to measure their perception of their dogs' quality of life. The questionnaire included approximately 22 questions regarding the impact of aging, disease, and clinical management of disease. These questions included inquiries about the dogs' behavior in areas including active / enthusiastic (E / E), happy / satisfied (H / C), active / comfortable (A / C), and calm / relaxed (C / R). The responses to these questions were composited or combined into a single score known as the total HRQL. The scores were normalized by applying the Davies transformation (Davies 2019). A multiple median regression model was used to identify the relationship between insulin and HRQL. The standardized log (insulin) was the primary variable with age, weight, and BCS as covariates, and the results are shown in Table 4A and Figure 2A below. Multiple generalized least-squares regression models were used to identify the relationship between insulin and CFI, and its age-related acceleration. The results, with standardized logarithms (insulin) and their interaction with age as the primary factors, and body weight and BCS as covariates, are shown in Table 4B and Figure 2B.

[0143] [Table 4]

[0144] [Table 5]

[0145] Next, the total HRQL was compared to fasting insulin levels by classifying insulin levels into three groups (tertiles) of equal size. The tertiles represent the lowest, middle, and highest thirds of insulin levels in the sample. Median quantile regression was used to estimate the total HRQL based on each insulin tertile, adjusted for covariates including age, weight, and BCS. 407 insulin measurements taken along with the total HRQL score were divided into insulin tertiles, defined as follows: lowest insulin level (n=137, range=[2.53 mU / L, 12 mU / L]), highest insulin level (n=136, range=[20.9 mU / L, 107 mU / L]), and middle insulin level (n=136, range=[12 mU / L, 20.9 mU / L]). The tertiles were within the normal clinical laboratory reference ranges. Multiple quantile median regression was performed for each insulin tertile group, and the results are shown in Table 5 below. The HRQL scores for each insulin tertile group, adjusted for covariates, are shown in Figure 3A. The HRQL kernel density estimates were analyzed and are shown in Figure 3B. The total HRQL score on the Davies scale as a function of age was analyzed and is shown in Figure 3C.

[0146] [Table 6]

[0147] The Canine Frailty Index (CFI) score was based on the medical history and physical examination of participating dogs performed by a veterinarian. The CFI was calculated by summing the response scores and dividing by the total number of questions. A Frailty Index of 0 meant that the dog was not frail at all. A lower frailty score indicated fewer health defects and lower frailty, while a higher frailty score indicated more health defects or higher frailty. The CFI scores related to age were analyzed and are shown in Figure 4A. The CFI scores related to the total HRQL score were analyzed and are shown in Figure 4B.

[0148] Time-series data can be collected to further advance healthy lifespan studies, including HRQL and mortality data for participating dogs. Lipid levels can also be analyzed against HRQL scores, CFI scores, or both. Fatty acid quantification was performed using stored serum samples from the study. Only 61 dogs had sufficient volume to perform the study. Levels of free fatty acids (FFA), saturated fatty acids (SFA), palmitic acid (PA, 16:0 saturated fatty acid), oleic acid (OA, 18:1n9 monounsaturated fatty acid), and linoleic acid (LA, 18:2n6 polyunsaturated fatty acid) were measured using gas chromatography-mass spectrometry (GC-MS; Metabolon, Inc.). One of the 61 dogs lacked insulin concentration values ​​and was not included in any analysis or model involving insulin.

[0149] Age showed a significant positive correlation with all measured fatty acid species and aggregates (p<0.05, Table 6). The relationship between each fatty acid species and aggregate and age is shown in Figure 4C.

[0150] [Table 7]

[0151] After adjusting for covariates (body weight and BCS), we used multiple linear regression to estimate age-related changes in adiponectin. Adiponectin was naturally log-transformed to address non-normality issues. Adiponectin significantly decreased with age (slope and 95% CI = -0.09 (-0.11, -0.07), p-value < 0.001), adjusting for the effects of body size, body weight, and BCS. These results indicate that each year's increase in age is associated with an increase of -0.09 in ln(adiponectin). The log-transformed results can be interpreted as a change in percentage, and therefore adiponectin decreases by 100 * -0.09 = 9% for each year's increase in age. Figure 4D shows how observed and predicted adiponectin values ​​change with age.

[0152] To estimate the covariate-adjusted relationship between fatty acids and adiponectin, multiple regression models were used to estimate the relationship between fatty acids and adiponectin, taking into account the effects of age, weight, and BCS. To find the most parsimonious model, covariates with p<0.10 were retained across all models. Huber-White robust standard errors were used to address the issue of unequal variances. Fatty acids and adiponectin were standardized (mean=0, SD=1) due to the different scales among fatty acids, other covariates, and adiponectin. All fatty acid species and concentrations were significantly negatively associated with adiponectin (Table 7, all p<0.05). The coefficient estimates can be interpreted as a decrease in adiponectin standard deviation of -0.25 to -0.44 for every increase in fatty acid concentration standard deviation. Figure 4E shows the observed and covariate-adjusted predicted relationships on their natural scales.

[0153] [Table 8-1]

[0154] [Table 8-2]

[0155] Multiple linear regression was used to estimate the relationship between fatty acid species and aggregates and CFI. Both the primary effects of fatty acids and their interactions with age were examined. Fatty acid measurements were not significantly associated with CFI in a primary effects model adjusted for age. However, significant interaction effects were detected between all fatty acids (free fatty acids, saturated fatty acids, palmitic acid, oleic acid, and linoleic acid) and age (p<0.05, Table 8, Figure 4F). All coefficients for the interaction between age and fatty acid measurements were >0, suggesting that this effect appears to be stronger in older dogs.

[0156] [Table 9-1]

[0157] [Table 9-2]

[0158] Multiple regression was used to estimate the covariate-adjusted relationship between adiponectin and CFI, and to test the main effect of adiponectin as well as its interaction with age. CFI was treated as the outcome, and adiponectin was treated as the primary predictor of the subject. Adiponectin was transformed to the natural logarithm to account for nonlinearity. Covariates included age, body weight, and body center score (BCS). The covariate-adjusted relationship (i.e., slope) between adiponectin and CFI was estimated using marginal linear trends. Because the adiponectin scale and the CFI scale differ dramatically, standardized regression coefficients are reported in Table 9. After adjusting for age, weight, and BCS, the main effect of adiponectin on CFI was not statistically significant (coefficient (95% CI) = 0.01 (-0.10, 0.13), p = 0.797, Table 9). However, this is likely due to the presence of a significant interaction effect between adiponectin and age (coefficient (95% CI) for interaction terms = -0.03 (-0.06, 0.00), p = 0.026, Table 9), suggesting that the decrease in CFI associated with higher adiponectin becomes stronger with age. Estimated linear trends from the interaction model test along with the observed data are shown in Figure 4G. Panel A of Figure 4G shows all observed and predicted values ​​together, and Panel B shows these same data stratified by age group. These analyses showed that the relationship between adiponectin and CFI is relatively flat until dogs reach approximately 10 years of age, after which a decrease in CFI is observed with increasing adiponectin levels (Figure 4G, Panel B). The results of these analyses provide evidence that CFI decreases with increasing adiponectin levels, particularly in older dogs.

[0159] [Table 10]

[0160] Example 2. Effects of pioglitazone treatment on glucose and insulin. This study will investigate whether pioglitazone can reverse the development of high-fat diet (HFD)-induced insulin resistance and metabolic health decline in dogs by improving insulin sensitivity as demonstrated through oral glucose tolerance test (OGTT) results 5 weeks after HFD treatment and again 7 weeks after pioglitazone (1 mg / kg / day or 2 mg / kg / day) treatment, and by cycling the analytes.

[0161] Pioglitazone activates peroxisome proliferator-activated receptor gamma (PPARγ), stimulating the release of adiponectin from adipose tissue. The drug is hypothesized to mitigate or reverse hyperinsulinemia and impaired insulin sensitivity induced by chronic high-fever dieting (HFD). Interventions that improve glucose tolerance and reduce insulin resistance (i.e., calorie restriction, metformin) extend healthy lifespan (years spent disease-free) and lifespan in several model organisms, including rodents, dogs, and monkeys. This study aims to provide evidence that pioglitazone was metabolically protective (i.e., reduced and / or reversed the onset of clinical symptoms of insulin resistance) when used as an intervention after HFD-induced metabolic dysfunction had already occurred.

[0162] This 17-week HFD design and metabolic inversion trial was conducted on four groups of 12 Beagle dogs each. All dogs included in the trial were male, 3-7 years old, and weighed 12.05-22.95 kg. 63 days (9 weeks) after normal diet or HFD feeding, groups 1 and 2 received a placebo orally daily, while groups 3 and 4 received pioglitazone orally daily. The dogs tolerated the placebo / pioglitazone regimen well.

[0163] Throughout the trial, clinical examinations and weight measurements were performed to monitor the animals' health. Daily general health checks and fecal examinations were also conducted during the trial period.

[0164] The animals were given their daily food supply (g) in divided portions. Each feeding (AM or PM) consisted of approximately half of the animal's daily food supply and was provided with an interval of about 4 hours. Dogs were given about 2 hours to consume each prescribed portion, and the remaining food was weighed out and returned for each feeding.

[0165] All dogs were fed a "normal diet" (ND) consisting of 55% fat for all baseline measurements prior to the start of the study. Prior to the start of the study, dogs were randomly assigned to either an ND or an HFD (high-fat diet) consisting of 74% fat, and maintained for approximately 9 weeks. After 9 weeks, HFD-fed animals were further randomly assigned to treatment groups prior to administration, with fasting insulin levels as the primary factor and total body weight as the secondary factor. Dogs in the ND group continued on the ND until the end of the study.

[0166] Chemical tests, blood tests, triglycerides, cholesterol, metabolomics, and lipidomics, efficacy biomarkers (adiponectin, fasting insulin, and leptin), pioglitazone pharmacokinetics, cytokines (IL-6 and TNFα), and non-esterified fatty acids (NEFAs) were performed throughout the study to evaluate diet and drug-related effects on safety and metabolic function markers. Baseline (-56 days) and pre-treatment (day 0) readings for each parameter were compared to the readings at treatment (day 57 days).

[0167] The OGTT was performed between the pre-treatment (-14 days) and treatment (42 days) stages to evaluate glucose and insulin kinetics and insulin sensitivity. The OGTT was performed as previously described by Coate et al., 2010. Briefly, the dogs were fasted overnight before the treatment was performed. Blood samples were collected at 20 and 0 minutes before the glucose bolus, and serum and plasma were separated to establish fasting glucose and insulin values. At 0 minutes (t = 0), a glucose bolus (0.9 g / kg, oral administration) was administered. Blood was collected 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 120, 180, and 240 minutes after the glucose bolus. Subsequently, the serum was analyzed for glucose, and the plasma was analyzed for insulin levels at each time point.

[0168] Body composition and resting energy expenditure were measured using blood samples collected after the administration of intravenously administered D2O (heavy water) and 2 H2 18 O (doubly labeled water) at the pre-treatment (-21 days) and treatment (49 days) time points when the dogs had been consuming ND or HFD for 5 weeks. The dogs were fasted for at least 12 hours before the first blood draw on each sample collection day. D2O and 2 H2 18 O were prepared in autoclaved glassware and instruments, weighed separately, and drawn into separate syringes. Body weight was measured on the day of sample collection, and the prepared D2O and 2 H2 18 O were collected in separate syringes for each animal and weighed to three decimal places before administration. Two milliliters (mL) of blood were collected via an oral syringe before administering 50 mg / kg of 99% D2O and 150 mg / kg of 97% 2 H2 18 O. Subsequently, blood samples were collected 2, 24, 72, 120, and 168 hours after the first D2O + 2 H2 18 O administration. After collection, plasma was separated in K2EDTA tubes and stored at -80 o °C until analysis.

[0169] Baseline or pre-treatment readings for all parameters (blood tests, body weight, food consumption, OGTT, body composition / energy expenditure) were established for each animal and group, and these results were compared to treatment outcomes. Individual and summary statistics, arithmetic means, rates of change, and within-group and between-group comparisons were performed.

[0170] Fasting glucose and fasting insulin measurements for each group of subjects were analyzed as shown in Figure 5A (fasting glucose) and Figure 5B (fasting insulin). As shown in Figures 5C and 5D, the AUC values ​​of glucose and insulin in response to treatment were analyzed after administering pioglitazone to the subjects.

[0171] This study demonstrates that treatment with pioglitazone does not affect fasting glucose measurements or glucose exudation during glucose tolerance tests (Figures 5A and 5C). Furthermore, this study shows that pioglitazone affects fasting insulin and the insulin response to glucose, independently of any effect on glucose (Figures 5B and 5C). These findings differ from literature suggesting that PPAR activators (i.e., pioglitazone) promote metabolic health by enhancing glucose exudation and systemic insulin sensitivity, while these studies demonstrate that metabolic benefits are glucose-independent in dogs.

[0172] Example 3. Treatment with pioglitazone and its effect on harmful fatty acids. This study demonstrates that pioglitazone doses dependently modulate levels of metabolically harmful fatty acids in dogs. These fatty acids include all aggregates of saturated fatty acids (SFAs), palmitic acid, linoleic acid, and oleic acid. Infusion of these exogenous lipids in dogs (containing 20% ​​lipids, linoleic acid [44-62%], oleic acid [19-30%], palmitic acid [7-14%], linolenic acid [4-11%], and stearic acid [1.4-5.5%]) can replicate several aspects of human metabolic dysfunction and impair muscle and hepatic insulin sensitivity.

[0173] Subjects were treated with pioglitazone, and fatty acid analysis was performed on their blood samples. Fatty acids were detected, analyzed by type, and quantified. The effect of pioglitazone treatment on saturated fatty acids was analyzed as shown in Figure 6A. Furthermore, the results of the analysis of the effects of pioglitazone on various fatty acid types are shown in Figures 6B (palmitic acid), 6C (linoleic acid), and 6D (oleic acid). As shown in Figure 6E, fatty acids were measured at baseline, during pretreatment with pioglitazone, and during posttreatment with pioglitazone.

[0174] SFAs are associated with metabolic dysfunction and insulin resistance. Pioglitazone treatment has been shown to reverse the HFD-induced increase in SFAs (Figure 6A). Similarly, pioglitazone treatment reduces palmitic acid, one of the largest individual lipid species contributing to the SFA pool (Figure 6B). Palmitic acid is known to directly inhibit insulin signaling in the liver and muscle, and therefore, the specific reduction in palmitic acid induced by pioglitazone administration further supports the idea that TI improves the overall and species-specific lipid profile after HFD-induced metabolic dysfunction. These data are the first to demonstrate improvement in fatty acid levels with pioglitazone treatment in dogs.

[0175] This study also demonstrates that measuring FFA using a clinical diagnostic assay (NEFA) (1) fails to distinguish between fatty acid species, and (2) does not represent fatty acid levels when measured by a more sensitive direct measurement GC-MS-based approach. Indirect measurements from spectrophotometer-based clinical assays did not detect significant changes and did not reflect the trends observed in direct measurements. These data indicate that clinically used fatty acid quantification tools are not sufficiently sensitive to detect physiologically relevant changes (Figure 6E).

[0176] Example 4. Treatment with pioglitazone: Effects on HFD metabolic dysfunction This study leads to the following conclusions: HFD dogs showed increased food consumption and body weight (p<0.05, not shown), resulting in increased fat mass (p<0.05, not shown) and significant changes in metabolic composition. Observed changes included significant increases in cholesterol, triglycerides, FFA, SFA, leptin, and rest energy expenditure. In contrast, HFD did not have any demonstrable effect on adiponectin, cytokine, and NEFA levels.

[0177] Importantly, HFD induced a state of hyperinsulinemia, as indicated by a significant increase in fasting insulin and no change in fasting glucose. This HFD-induced hyperinsulinemia was supported by functional data from an OGTT assay showing a significant increase in insulin AUC and Cmax levels. Along with the biochemical profile (e.g., significant increases in circulating triglycerides and cholesterol), these changes indicate that HFD successfully induced a state of severe and clinically relevant metabolic dysfunction.

[0178] In dogs fed HFD and treated with pioglitazone, we observed several pieces of evidence indicating that pioglitazone, when administered as an intervention after 9 weeks of HFD feeding, mitigates or reverses HFD-related metabolic disorders over 17 weeks. First, we note the evidence that pioglitazone significantly upregulates adiponectin, a putative biomarker of target binding, and known insulin-sensitizing proteins. Second, pioglitazone treatment successfully mitigated further HFD-induced hyperinsulinemia, hyperlipidemia (e.g., a significant reduction in circulating triglycerides and cholesterol), and normalized the harmful fatty acid profile compared to the HFD-supplied placebo group. Third, dogs treated with pioglitazone and supplied with (HFD) showed markers of improved insulin sensitivity compared to the HFD-supplied placebo group, as measured by a decrease in glucose-responsive insulin secretion, assessed by evaluating insulin AUC after administration. Finally, the inventors note that treatment with pioglitazone induced changes in body composition through an increase in fat mass compared to the HFD-supplied placebo group. Histological examination of visceral and subcutaneous adipose tissue suggested that pioglitazone treatment reduced the size of visceral adipocytes and relatively increased subcutaneous fat. It is also important to note that pioglitazone exerted metabolically protective and body compositional effects without any effect on food consumption, calorie intake, or leptin levels, indicating that pioglitazone improved metabolic function through mechanisms independent of appetite or weight loss.

[0179] In summary, these data demonstrate that while the HFD canine model induces severe metabolic dysfunction, interventional pioglitazone administration can alleviate and, in some cases, reverse this condition, strongly supporting the use of pioglitazone as a therapeutic strategy for improving / maintaining metabolic function in dogs.

[0180] Example 5. Treatment with pioglitazone to prevent metabolic dysfunction. Test design The objective of this study was to evaluate the effects of pioglitazone on HFD-induced insulin resistance, hyperinsulinemia, and fatty acid regulation in beagle dogs. The inventors hypothesized that administering pioglitazone to metabolically impaired dogs fed HFD would (1) upregulate adiponectin levels, (2) protect systemic insulin sensitivity as measured by oral glucose tolerance tests (OGTT) and hyperinsulinemia-euglycemic clamps (HIEG), and (3) prevent the harmful increase in fatty acid levels associated with HFD intake. Study design: Twenty-four animals (1-2 years old) were adapted for at least two weeks, and a femoral artery catheter was surgically implanted under anesthesia. Two baseline tests were performed prior to any procedure: an oral gastrointestinal training test (OGTT) and a high-intensity gastrointestinal clamp (HIEG).

[0181] Next, the dogs were randomly assigned to one of three groups: a placebo group (n=8) that received empty capsules daily, a group that received 1 mg / kg of pioglitazone in the form of a 15 mg pill (Dose 1, n=8), and a group that received 2 mg / kg of pioglitazone in the form of two 15 mg pills (Dose 2, n=8). The pioglitazone pills (Actos, Teva Pharmaceuticals, New Jersey) were administered daily immediately before feeding with 5 mL of water.

[0182] Two weeks after the start of treatment, all animals were fed HFD (Research Diet 5SQ1, a test diet from Purina). On days 46 and 56 after the start of pioglitazone treatment, animals were given OGTT and HIEG clamps, respectively, and their baseline metabolic responses were compared. On days 46 and 56, placebo and pioglitazone were administered one hour before gastric tube feeding and one hour before somatostatin infusion. Regardless of the animals' weight gain, the same amount of glucose as in the initial OGTT trial was administered, and the rates of insulin and hormone administration were maintained at the same rate during the clamps, because it was recognized that the animals' fat gain was primarily in tissues that did not respond to insulin concentrations.

[0183] Furthermore, blood samples were taken from each animal every two weeks prior to pioglitazone administration and feeding for several chemical measurements (adiponectin, Superchem panel (performed by Antech Diagnostics)). Pioglitazone was also measured every two weeks in serum collected one hour after pill administration and feeding.

[0184] This study leads to the following conclusions: Ingestion of HFD for 5-6 weeks resulted in metabolic dysfunction in Beagle dogs. This was evident in all 8 dogs as follows: 1) Fasting insulin increased by 25%; 2) Fasting FFA (20%) was slightly elevated, suggesting mild lipid abnormalities; 3) Insulin response during OGTT increased by 39%, thus compensating for the defect caused by HFD feeding; 4) Hyperinsulinemia; Euglycemic clamp data showed a 25% decrease in GIR and a 37% decrease in Rd after 6 weeks of high-fat feeding in the presence of identical insulin, glucose, and glucagon levels; and 5) After 6 weeks of HFD feeding, fasting FFA levels increased by 25%, and the ability of insulin to inhibit lipid breakdown was significantly reduced.

[0185] In both pioglitazone treatment groups, there was a significant increase in circulating adiponectin after the start of daily pioglitazone administration (up to day 14). The placebo group showed a significant but smaller and transient increase in adiponectin on day 28. The increase in the pioglitazone groups was larger and more sustained than that in the placebo group.

[0186] 1) In both pioglitazone-treated groups, the insulin response during OGTT was reduced compared to the placebo group. Therefore, pioglitazone was able to normalize glucose metabolism without increasing insulin secretion. 2) In glucose clamp data (possibly due to enhanced insulin clearance rate – excluding 4 dogs where insulin levels were not equivalent at clamps on day 1 and day 56), both doses of pioglitazone were able to overcome the GIR and Rd deficits caused by HFD. 3) In the clamp experiment, pioglitazone reduced fasting FFA levels and improved inhibition of lipolysis.

[0187] Example 6. Treatment of aging biomarkers with pioglitazone The effect of pioglitazone on aging biomarkers can be determined in dogs owned by the client. Approximately 60 dogs will be enrolled and randomized into two groups in a 3:1 ratio (treatment group vs. control group). Dogs will be screened at visit 1, 7 days before the trial, and screening can be completed on day 0 of visit 2 of the trial. Treatment can be randomized starting from day 0. Participating dogs were enrolled for approximately 3 months and visited approximately every 30 days for biomarker measurement and safety assessment. Blood levels of HRQL, CFI, insulin, and FFA will be measured.

[0188] Commercially available pioglitazone can also be used to measure the effect of pioglitazone treatment on insulin levels and to measure FFA data in dogs for HFD.

[0189] Test Procedures and Evaluation To assess the quality of life as perceived by owners, the VetMetrica HRQL instrument is used. This is a web-based, caregiver-completed questionnaire that can be entered through the Prelude website or the ePRO application. HRQL is a validated tool that assesses four domains of canine quality of life: Active / Energetic (E / E), Happy / Satisfied (H / C), Active / Comfortable (A / C), and Calm / Relaxed (C / R). HRQL detects age-related differences in dogs and detects owner-perceived illnesses.

[0190] The initial HRQL survey is completed by the owner during the screening visit / trial visit 1 and before the principal investigator performs a physical examination (PE). For the 4th to 6th trial visits, the HRQL questionnaire must always be completed by the owner at least 7(7) days before the scheduled visit date or before the visit in which the PE is performed. The principal investigator will verify that the HRQL survey was completed before each PE in the physical examination eCRF. Owners cannot review or access previously completed HRQL surveys. Once the physical examination eCRF associated with the visit is completed, owner access to the HRQL survey associated with the examination is removed.

[0191] The Canine Frailty Index (CFI) is a veterinary assessment using 33 questions focusing on canine health and clinical data. Responses are recorded in the visit-related CFI eCRF within the eDC. It must be initiated by the investigator or examining veterinarian on the day of the PE (Patient Examination) and completed after receiving and confirming the canine clinical pathology test results.

[0192] The initial CFI (Clinical First Inspection) begins at the screening visit / trial visit 1 and is completed at or before trial visit 2. Subsequently, this evaluation begins at the 4th to 6th trial visits and is completed after confirmation of blood test results during the trial period.

[0193] At each screening visit / trial visit 1 and each trial visit (except trial visit 3), a complete medical history will be taken for all dogs, and any changes or adverse events (AEs) will be recorded. A thorough assessment of the dogs' health status is necessary to distinguish existing or ongoing medical conditions from potential adverse events (AEs) that may occur during the trial, and any changes since the last consultation and physical examination will also be noted. The report will include a brief description of each condition, the date of diagnosis (if known), the date of resolution (if resolved), or the ongoing condition (if ongoing). All medical history, including ongoing and unresolved medical conditions, will be recorded in the medical history log.

[0194] PE (Physical Examination) is performed at each trial visit (excluding trial visits 2-3), starting from screening visit / trial visit 1. PE is a subjective assessment of overall appearance, posture, ears, eyes, oral / mucosal color, respiratory system, cardiovascular system, gastrointestinal system, nervous system, musculoskeletal system, external ear system, and reproductive system. PE should include recording of temperature (°F), heart rate (beats / min), respiratory rate (breaths / min), and mucosal (MM) color. PE results are recorded for each dog at the time of the examination in the visit-related physical examination eCRF. All abnormalities are recorded in the physical examination eCRF, and all information regarding past conditions, ongoing conditions, and new conditions is recorded in the medical history log. Abnormalities discovered after the start of administration at trial visit 2 are recorded as AEs or SAEs (as per section 15) in the adverse event (AE) log or serious adverse event (SAE) form and in the medical history log.

[0195] As part of the PE (Patient Assessment), body weight is measured to one decimal place on a calibrated scale and recorded in kilograms (kg) or pounds (lbs). The dog's initial body weight is recorded in the physical examination eCRF at the first visit, which is automatically entered into the investigational drug:control log to provide the appropriate dosage of the investigational veterinary drug / control product (IVP / CP). The IVP / CP dose remains the same throughout the study, even if the dog's body weight changes.

[0196] The Body Condition Score (BCS) is measured as part of the Physical Examination (PE). The BCS is assessed using the Nestle PURINA Body Condition System. The BCS uses visualization and palpation to assess the dog's overall shape and the amount of fat covering across the ribs, spine, and hips. The BCS is on a scale of 1 to 9, with a score of 9 indicating a significantly overweight dog and a score of 1 indicating a severely underweight dog. The BCS is recorded in the Physical Examination eCRF, using supplemental BCS guides as needed.

[0197] The Muscle Condition Score (MCS) is also measured as part of the Physical Examination (PE). The MCS is assessed using equipment from the World Small Animal Veterinary Association (WSAVA). The MCS utilizes visualization and palpation of the spine, scapula, skull, and iliac wings. Muscle condition is graded as normal, mild impairment, moderate impairment, or severe impairment. The MCS is recorded in the physical examination eCRF, using supplemental MCS guides as needed.

[0198] Dogs will have blood samples taken via venous puncture for hematological and biochemical tests at all trial visits (except trial visits 2 and 3), starting with screening visit / trial visit 1. The maximum amount of blood collected from the smallest dog eligible to participate in the trial will not exceed safety standards.

[0199] All collected samples and associated sample collection information are recorded in the visit-related clinical pathology eCRF and IDEXX Lab forms. Care is taken with venous puncture techniques to limit hemolysis.

[0200] Urine for urinalysis will also be collected at all trial visits (excluding trial visits 2 and 3), starting from screening visit / trial visit 1. The method of urine collection may be at the discretion of the testing veterinarian and may be open collection, cystopuncture, or urinary catheter insertion. Owners may also collect a urine sample from their dog within two hours prior to their scheduled appointment and bring it to the clinical trial site. The collection method will be recorded on the IDEXX Lab form. Similarly, any failure to collect a urine sample will be noted and recorded as a protocol deviation on the Target Level form.

[0201] The following blood and urine tests were performed at the Central Laboratory (IDEXX): Hematology and Comprehensive Blood Count (CBC) are performed and analyzed. The following are included: absolute reticulocyte count, erythrocyte macroplasia, bands (%) and number, basophils (%) and number, eosinophils (%) and number, hematocrit (HCT), Heinz bodies, hemoglobin (HGB), lymphocytes (%) and number, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), metamyelocytes (%) and number, monocytes (%) and number, myelocytes (%) and number, neutrophils (%) and number, nucleated erythrocytes (RBC), platelet count, estimated platelet count, dysmorphic erythrocytes, pleochroism, promyelocytes (%) and number, erythrocytes (RBC), reticulocytes, unclassified, and white blood cells (WBC).

[0202] Biochemistry, general chemistry. Albumin / globulin (ALB / GLOB) ratio, albumin, alkaline phosphatase (ALP), alanine transferase (ALT), aspartate transaminase (AST), bicarbonate, bilirubin-bound, bilirubin-unbound, blood urea nitrogen (BUN), BUN / creatinine ratio, calcium, chloride, cholesterol, creatine kinase, creatinine, gamma-glutamyltransferase (GGT), globulin, glucose, hemolysis index, lactate dehydrogenase (LDH), lipemia index, Na / K ratio, phosphorus, potassium, sodium, total bilirubin, total protein, triglycerides, LDL, HDL.

[0203] Fasting insulin. Dogs must fast for 12 hours before blood collection for fasting insulin. If dogs are not fasted before blood collection, a protocol deviation: a target level eCRF must be recorded.

[0204] Evaluation by total T4 urine analysis dipstick and urine sediment microscopy. Upon receipt of clinical pathology test results for bacteria, bilirubin, blood, cast, clarity, color, crystals, epithelial cells, glucose, ketones, mucus, pH, protein, red blood cells, specific gravity, urobilinogen, urine volume, and leukocytes in the eDC system, the principal investigator or veterinary laboratory staff will promptly review and evaluate the results. The clinical significance of abnormal or out-of-reference values ​​will be assessed as clinically significant (CS) or not clinically significant (NCS). CS results will be recorded in the eDC, and any existing or ongoing CS clinical laboratory parameters or corresponding diseases / conditions should be added to the medical history log and adverse event (AE) log (if CS parameters are discovered after the start of IVP / CP administration on day 0).

[0205] Plasma collection for storage. At all trial visits (excluding trial visits 2 and 3), starting with screening visit / trial visit 1, collect a separate green top tube and submit it to IDEXX for storage.

[0206] PAXgene mRNA tube collection. PAXgene blood tubes are included in the provided laboratory supplies. They will be collected at all trial visits (except trial visits 2 and 3), starting from screening visit / trial visit 1. In this trial, these blood samples will not be used to evaluate exploratory biomarkers. These samples will be labeled and sent to IDEXX in other blood tubes.

[0207] During the screening visit / trial visit 1 only, whole blood for DNA will be collected using the same EDTA lavender-top tube used for CBC samples. These blood samples will not be used in this trial but will be stored for use in future DNA projects by the sponsor. These samples will be labeled and sent to IDEXX in separate blood tubes.

[0208] DNA Collection - Saliva Swab / Cheek Swab. Saliva or cheek swabs for DNA sampling should be collected via the PERFORMAgene PG-100 non-invasive swab kit, following manufacturer instructions, only during screening visits / test visit 1. Subjects should not have eaten or drunk any beverages at least 30 minutes prior to saliva swab collection, or at least 10 minutes prior. Care should be taken to ensure the collection sponge does not scrape teeth or get bitten by the subject.

[0209] After collection, the swabs are stored at room temperature in a safe location at the clinical trial site, away from significant temperature fluctuations. The Clinical Research Associate (CRA) assigned by the sponsor then ships the swabs to the storage facility or assists with the shipping. The saliva swabs will be used in future DNA projects by the sponsor.

[0210] Scheduled Outpatient Visits. Throughout the course of the trial, enrolled dogs may visit the principal investigator or the clinical trial site for any new clinical signs that may arise. These appointments or visits occur between trial visits and are not scheduled as part of the trial. All unscheduled visits during the trial must be recorded in the eDC system using eCRF ("Unscheduled Visits" section: physical examination eCRF, clinical pathology eCRF, IDEXX laboratory request form). Each new diagnosis or clinical sign presented by the dog must be recorded as an AE in the medical history log and, if applicable, in the adverse event (AE) log. All AEs must be handled as described in section 15.

[0211] After completion of PE and scheduled outpatient visits: Physical examination eCRF and any diagnoses performed are at the discretion of the principal investigator. All diagnoses performed must be recorded in the dog's medical records and scheduled outpatient visits. The physical examination eCRF, medical history log, and concomitant medication log must also be updated if there are any changes or new prescriptions.

[0212] Weekly medication check-in phone calls. Dog owners are not required to complete daily dosing logs for this trial. However, the first week of administration is crucial for achieving the desired effect of the IVP used in this trial. To ensure that administration is not missed during the first week, a follow-up phone call from site staff is required 5-7 days after the start of administration (trial visit 3). Site staff will record the results of the contact with the owner using a weekly medication check-in eCRF.

[0213] Owners who report missing doses during the first week must report the number of times the dose was missed, and site staff will add this information and any other comments to the weekly medication check-in eCRF. Site staff will also complete the Protocol Deviations: Target Level form.

[0214] Palatability Questionnaire: During trial visits 3-6, staff at the clinical trial site will ask pet owners to answer three "yes / no" questions regarding the palatability of the investigational drug. The answers will be recorded in the eCRF (e-Clinical Record Form) of the palatability questionnaire.

[0215] Test design This clinical trial is a multi-center, field pilot study. The design is a randomized, blinded, placebo-controlled trial in client-owned dogs. The trial includes two treatment groups randomized in a 3:1 ratio, as shown in Table 10 below.

[0216] [Table 11]

[0217] Once a subject is deemed eligible for randomization, site staff use the integrated Prelude Just-in-Time (JIT) randomization module of the randomization eCRF to assign each subject to a randomly selected treatment group. The JIT randomization module adaptively and randomly assigns subjects to treatment groups. If a subject is mistakenly given an inappropriate treatment, the randomization module can correct the treatment code assignment and update the treatment code to reflect the treatment actually administered.

[0218] The JIT randomization module assigns an IVP:CP ratio of 3:1. This results in four treatment blocks. The four blocks are stratified by site, and each site can draw from its own block at the time of randomization. Randomization is performed in the order presented within each site at trial visit 2. For example, the first dog randomized at site 1(1) is randomly assigned to a treatment group, and a unique bottle number available at the site is automatically entered (depending on their dosage based on weight at the screening visit). Then, a second dog visiting the same site is randomized based on the remaining treatment groups within the site's unique block of four, and a similar process follows.

[0219] Clinical trial procedures Table 11 below provides a description of the animals used in this study.

[0220] [Table 12]

[0221] This trial will enroll an estimated 60 dogs across all participating sites. Approximately 45 dogs will be treated with IVP and approximately 15 dogs with CP. Additional dogs may be enrolled if the initial dropout rate exceeds the expected level. Similarly, the number of enrolled dogs may decrease if the trial is terminated before the enrollment quota is reached.

[0222] Inclusion / Exclusion Criteria. Dogs screened at Trial Visit 1, completing trial enrollment, and being randomized to a treatment group must meet all eligibility requirements. The screening visit / Trial Visit 1 confirms initial eligibility regarding completion of PE, medical history, and completion of concomitant medications. Results obtained from age verification and clinicopathology collected at Trial Visit 1 will be entered as final eligibility at Trial Visit 2 or earlier. The principal investigator must verify eligibility by reviewing CBC, biochemical profile, and T4 and complete the eligibility form. Subjects ineligible for enrollment may be contacted and notified, and therefore do not need to attend Trial Visit 2. Subjects meeting the criteria for enrollment in the trial will be randomized at Trial Visit 2. Selection criteria. The following dogs may be included: Multiple dogs from the same household Dogs that meet the criteria for the animal description above A dog with a heart murmur and no other clinical signs related to heart disease. Dogs with stage B1 myxomatous mitral valve disease (MMVD) Dogs with benign neoplasms Dogs with clinical or pathological abnormalities that indicate the course of an underlying disease, which the principal investigator determines are not clinically significant or do not meet any of the following exclusion criteria. Exclusion Criteria. The following dogs will be excluded from the test. Dogs whose survival is not expected to be within six months Dogs with a confirmed diagnosis of adrenocortical insufficiency or adrenocortical hyperfunction Dogs with a confirmed or suspected diagnosis of malignant neoplasm A dog that has been diagnosed with diabetes. Definitive diagnosis of liver disease (through functional tests such as bile acid analysis) Diagnosed with dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (ARVC / boxer cardiomyopathy), or congestive heart failure (CHF). Definitive diagnosis of autoimmune diseases requiring immunosuppression Undergoing medication Dogs with anemia (hematocrit less than 30) Dogs exhibiting temperaments unsuitable for carrying out the testing procedure. Dogs that are taking prohibited drugs or drugs approved conditionally

[0223] Age verification. During Screening Visit / Study Visit 1, or before Study Visit 2, the age of the dog must be verified by checking and uploading the approved documents listed below. Breeding records or registration certificates indicating the exact date of birth Records documenting veterinary examinations or treatments of the dog that occurred when the dog was presumed to be 1 year old (1) or younger Transfer records of the protection facility for dogs that were puppies (less than six months (6 months)) at the time of transfer by foster parents Veterinary medical records at the protection facility indicating that the dog was 1 year old or younger at the time of castration

[0224] The dog's date of birth (set to the first day of the month in case of estimation) and the verification information source provided by the owner are recorded in the demographic eCRF. This original document is copied, scanned, and uploaded to the document upload form in the eDC.

[0225] Owner's consent form. Before performing any test-related procedures on the subject, the owner's consent must be obtained from each owner using the OIC form. This form is filled out at Screening Visit / Study Visit 1.

[0226] Blind trial. The owner, principal investigator, study site staff, and study sponsor are blinded to the treatment group. Staff at the study site administering IVP / CP must not speculate about the treatment group or discuss it with the owner.

[0227] Study Sites. A study site is a clinical veterinary facility where staff, facilities, equipment, record-keeping, and expected adherence to the study procedures outlined in the protocol facilitate an unbiased study evaluation. The eligibility of all study sites will be verified as outlined. The principal investigator at each study site will be a licensed veterinary physician (DVM or VMD). Additional site staff must include at least one licensed veterinary technician (LVT) or veterinary assistant. It is estimated that approximately three study sites will be recruited to conduct this study. Site recruitment may continue until three or more study sites are secured.

[0228] Test equipment. Scales used to obtain body weight at the clinical trial site must be calibrated by a certified technician within one year prior to their first use in the trial. A copy of the site's calibration record is uploaded to the Clinical Trial Management System (CTMS) and stored in the Electronic Clinical Trial Master File (eTMF). Calibration expires after one year, and the site must have a certified technician calibrate the scale annually as needed.

[0229] All registered dogs will remain in their usual living conditions with their owners. There are no special dietary requirements for participation in this trial. Owners must continue to feed their dogs their usual diet, which includes any prescription diets previously prescribed or during the trial. The diet and feeding schedule will be documented as part of the physical examination eCRF at each relevant trial visit. Prescription diets will be recorded in the concomitant medication log.

[0230] Medical administration. IVP / CP will be administered to the subjects by the owner once daily, starting from trial visit 2, throughout the trial period. The route of administration for IVP and CP is oral (PO).

[0231] Owners do not fill out administration logs. Missed doses are confirmed when owners return the investigational drug bottles, and any unadministered doses are counted when the dog receives monthly IVP / CP replenishment. Each month, returned bottles, missed doses, incorrectly administered doses, the dates of the missed or incorrectly administered doses, and replenishment are recorded in the Investigational Drug: Subject Log. If an owner administers an incorrect dose or misses a dose more than eight times on average per month, this is recorded in the Protocol Deviation: Subject Level form, but the dog is not excluded from the study. Dispensing and billing for unadministered tablets are done at the time of drug dispensing.

[0232] Owners must not miss any doses during the first week of the study, as this could prevent the drug from reaching its initial concentration and potentially affect the pharmacodynamics of the canine biomarker. Missed doses during the first week will be recorded in the weekly dose check-in eCRF and recorded as a protocol deviation in the Protocol Deviation: Constraint Level form.

[0233] Exclusion Criteria. Completion of the study for each registered dog is when the study evaluation and treatment are discontinued. Study completion may result in the removal of a subject from the study if the exclusion criteria are met. See Section 8.7. Upon study completion, the principal investigator must complete a study completion form, recording the date and, if applicable, the reason for the dog's exclusion from the study.

[0234] Exclusion of dogs. The following dogs will be excluded from the trial and must be noted on the trial completion form. Anemia with HCT levels below 30 Dog diagnosed with diabetes Dogs suspected or confirmed to have bladder cancer Dogs with sudden or unexpected edema / fluid retention or worsening of CHF Dogs diagnosed with hyperadrenocorticopathy or adrenal insufficiency A dog that was found to have been registered in error. Dogs that require prohibited medications Dogs that have developed a SAE and require open-label treatment or exclusion from treatment. Dogs whose owners did not follow the testing procedures (including dogs that did not come for testing on the regular schedule, or dogs that missed too many doses) Dogs that were withdrawn from the trial by their owners Dogs that become uncooperative with the testing procedure

[0235] Excluded dogs. In some situations, clinicopathological abnormalities, AEs, and SAEs should be followed up. This follow-up is essential to determine whether the abnormality, AE, or SAE is clinically significant and to understand its relationship to IVP.

[0236] Dogs found to have elevated liver enzymes should not necessarily be immediately excluded from the study if the principal investigator or veterinarian determines that continued participation is acceptable. Since elevated liver enzymes are nonspecific and not necessarily clinically significant, the principal investigator is permitted to exercise discretion in handling these cases. If dogs continue enrollment, their blood biochemistry profiles will be rechecked every 30 days, an appropriate recheck interval given the half-lives of the liver enzymes (including liver enzymes: AST, ALT, ALP, and bilirubin). If the rechecked liver values ​​are equal to or higher than the originally detected elevated liver enzymes, and the veterinarian determines this is appropriate, the dog may be excluded from the study, and the principal investigator will complete the trial termination form.

[0237] Concomitant medications. Concomitant medications are defined as any medications or treatments that a dog receives during the screening visit / trial visit 1 and at any point thereafter during the trial. These include, but are not limited to, flea and tick preventatives, supplements, prescription diets, and prescription medications. If a dog is administered any of the medications listed in the "Conditionally Permitted" column of Table 4, the principal investigator or laboratory veterinarian must confirm that the dog meets the criteria in the "Conditionally Permitted" column of Table 8 before proceeding with any further trial procedures. At each visit, any new or ongoing concomitant medications and associated medical history must be recorded in the medical history log and concomitant medication log.

[0238] An acceptable drug is a drug that is not restricted from being administered to dogs during the test period. There are no stops or conditions regarding the use of these drugs. In this test, since it is essential that the registered dogs represent the normal dog population, most drugs and supplements are permitted. Conditionally acceptable drugs are permitted for use during the test for some eligible subjects or with an observation period. Prohibited drugs are drugs that are not at all permitted for use in the test because they may duplicate the effects of IVP or may complicate the use due to the addition of IVP.

[0239] Table 12 below details common concomitant drugs and their relevance to the inclusion / exclusion criteria for the selection of subjects in this test.

[0240]

Table 13-1

[0241]

Table 13-2

[0242]

Table 13-3

[0243]

Table 13-4

[0244] When recording concomitant drugs during screening hospital visit / test hospital visit 1, if it is found that a dog is receiving a prohibited drug, it will be a cause for excluding the dog from the test. The drug and the reason for exclusion will be recorded in the concomitant drug log, eligibility form, and clinical trial completion form. The temperament of the dog. The dog is always under the control of the owner. Dogs that are withdrawn or excluded early from the test remain under the control of the owner. Results of dogs treated with pioglitazone

[0245] This study yielded the following conclusions: Dogs in the control group showed a mean increase in insulin levels of 3.85 (uIU / mL 95% CI=1.37, 9.06) from baseline to day 90. This increase was not statistically significant (p=0.132). Dogs treated with pioglitazone showed a mean decrease in insulin levels of 2.35 (uIU / mL 95% CI=10.07, 5.36) from baseline to day 90, but this decrease was not statistically significant (p=0.538). The mean decrease in insulin levels in dogs treated with pioglitazone tended to be lower than in dogs in the control group (p=0.171). Due to the limited power and short duration of this study, it is highly likely that even if there were statistically significant differences in insulin levels between the groups showing efficacy, these could not be detected.

[0246] However, pioglitazone-treated dogs with elevated baseline insulin levels showed a significant effect on insulin levels. This effect warrants further investigation into the individual abnormalities in these three dogs with elevated fasting insulin levels and their response to pioglitazone treatment. These case studies demonstrate not only the acute effects of pioglitazone treatment but also important safety data in dogs whose metabolic health had not peaked.

[0247] Subject 001-SAR-007 was a 9-year-old neutered male Yorkshire Terrier. At screening, his insulin level was 76.8 uIU / mL (reference range 5.2–41.5 uIU / mL). He also had elevated ALP of 177 U / L (reference range 5–160 U / L), AST of 182 U / L (reference range 16–55 U / L), ALT of 469 U / L (reference range 18–121 U / L), and TBili of 0.5 mg / dL (reference range 0.00.3 mg / dL). Prior to randomization, the study veterinarian measured pre- and post-meal bile acids, which were within the normal range. Within a month of starting pioglitazone, all of the dogs' liver function tests returned to normal (ALP 88 U / L, AST 22 U / L, ALT 48 U / L, TBili 0.2 mg / dL), and insulin levels were also within the normal range (16.2 uIU / mL).

[0248] Subject 003-BAK-016 was a 7-year-old neutered male Welsh Terrier. At the time of screening, his insulin level was 96.6 uIU / mL (reference range 5.2-41.5 uIU / mL) and his ALP level was 241 U / L (reference range 5-160 U / L). Although his ALP level remained elevated, at subsequent visits, his insulin level gradually decreased to 62.2 uIU / mL, then to 52.9 uIU / mL, and finally to 42.3 uIU / mL at 6 and 90 days after the last visit.

[0249] Subject 003-BAK-018 was an 8-year-old, spayed female Cocker Spaniel. At screening, she had an insulin level of 66.3 uIU / mL (reference range 5.2–41.5 uIU / mL) and an ALP level of 1603 U / L (reference range 5–160 U / L). The investigating veterinarian, concerned about Cushing's disease, performed a normal low-dose dexamethasone suppression trial. By the fourth visit (approximately day 30) after starting pioglitazone, the insulin level was reduced back to 15.3 uIU / mL and the ALP level was reduced to 774 U / L.

[0250] These three cases confirm the acute effects of improved metabolic function and reduced fasting insulin. These dogs also showed various additional improvements in clinical laboratory values, specifically, decreased liver enzyme levels (all three dogs), decreased or normalized triglyceride levels, and the disappearance of marked lipidemia in blood samples submitted to IDEXX (001-SAR-007 and 003-BAK-018).

[0251] Example 7. Safety of pioglitazone in dogs The safety of pioglitazone in dogs has been evaluated in numerous laboratory studies and recent clinical trials.

[0252] [Table 14-1]

[0253] [Table 14-2]

[0254] [Table 14-3]

[0255] Example 8. Formulation of pioglitazone Pioglitazone or a salt thereof can be formulated into one of the tablet forms listed in Table 13 below.

[0256] [Table 15]

[0257] Example 9. Formulation of pioglitazone Pioglitazone or a salt thereof can be formulated into one of the tablet forms listed in Table 14 below.

[0258] [Table 16]

[0259] Example 10. Formulation of pioglitazone Pioglitazone or a salt thereof can be formulated into one of the tablet forms listed in Table 15 below.

[0260] [Table 17]

[0261] Example 11. Formulation of pioglitazone Pioglitazone or a salt thereof can be formulated into one of the tablet forms listed in Table 16 below.

[0262] [Table 18]

[0263] Preferred embodiments of the present invention have been shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided merely as examples. Herein, numerous modifications, alterations, and substitutions will occur to those skilled in the art without departing from the present invention. Naturally, various substitutes for the embodiments of the present invention described herein may be used in the practice of the present invention. The following claims define the scope of the present invention, the methods and structures within these claims, and their equivalents.

Claims

1. A method for reducing or reversing age-induced insulin resistance in mammals that require reduction or reversal of age-induced insulin resistance, comprising administering a therapeutically effective amount of a formulation containing a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to a companion animal.

2. A method for reducing or reversing insulin resistance in mammals that require reduction or reversal of insulin resistance, comprising administering a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof to a companion animal.

3. A method for reducing or reversing the age-related increase in circulating lipids, including fatty acids, triglycerides, or cholesterol, in a mammal that requires reduction or reversal of the age-related increase in circulating lipids, including fatty acids, triglycerides, or cholesterol, comprising administering a therapeutically effective amount of a formulation containing a PPAR agonist, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, to the mammal.

4. A method for maintaining or restoring the healthy function of adipose tissue in a mammal that requires maintenance or restoration of the healthy function of adipose tissue, comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPAR agonist or a pharmaceutically acceptable salt or prodrug thereof.

5. The method according to any one of claims 1 to 4, wherein the method does not reduce the glucose level of the companion animal.

6. The method according to any one of claims 1 to 5, wherein the method does not increase the glucose level of the companion animal.

7. The method according to any one of claims 1 to 6, wherein the method comprises reducing the insulin level of the companion animal.

8. The method according to claim 7, wherein the decrease in insulin levels is reduced by at least 5%.

9. The method according to claim 8, wherein the reduction in insulin levels is reduced by at least 10%, at least 15%, or at least 20%.

10. The method according to any one of claims 1 to 9, wherein the method improves insulin sensitivity.

11. The method according to claim 10, wherein the insulin sensitivity is measured by an oral glucose tolerance test assay.

12. The method according to claim 10, wherein the insulin sensitivity is measured by a hyperinsulinemia-euglycemic clamp test assay.

13. The method according to claim 10, wherein the insulin sensitivity is measured by using fasting blood insulin levels.

14. The method according to claim 3 or any one of claims 5 to 13, wherein the lipid is an aggregate of free fatty acids, saturated fatty acids, palmitic acid, linoleic acid, or oleic acid, or any combination thereof.

15. The method according to claim 14, wherein the fatty acid is a saturated fatty acid.

16. The method according to claim 14, wherein the fatty acid is palmitic acid.

17. The method according to any one of claims 1 to 16, wherein the method reduces the triglyceride level in the mammal.

18. The method according to any one of claims 1 to 17, wherein the method increases the adiponectin level in the mammal.

19. The method according to any one of claims 1 to 17, wherein the method reduces cholesterol levels in the mammal.

20. The method according to any one of claims 1 to 19, wherein the mammal is a dog or a cat.

21. The method according to claim 20, wherein the mammal is a dog.

22. The method according to claim 20, wherein the mammal is a cat.

23. The method according to any one of claims 1 to 22, wherein the mammal is at least 7 years old.

24. The method according to any one of claims 1 to 23, wherein the mammal is at least 10 years old.

25. The method according to any one of claims 1 to 24, wherein the formulation comprises about 3% to about 35% of the PPAR agonist.

26. The method according to any one of claims 1 to 25, wherein the formulation comprises about 10% to about 20% of the PPAR agonist.

27. The method according to any one of claims 1 to 26, wherein the formulation comprises about 1 mg to about 100 mg of the PPAR agonist.

28. The method according to any one of claims 1 to 27, wherein the formulation comprises about 4 mg to about 85 mg of the PPAR agonist.

29. The method according to any one of claims 1 to 28, wherein the PPAR agonist is administered at approximately 3 mg / kg / day.

30. The method according to any one of claims 1 to 28, wherein the PPAR agonist is administered at approximately 5 mg / kg / day.

31. The method according to any one of claims 1 to 28, wherein the PPAR agonist is administered at approximately 10 mg / kg / day.

32. The method according to any one of claims 1 to 31, wherein the preparation is administered for at least about four weeks.

33. The method according to any one of claims 1 to 32, wherein the formulation is administered for at least about 12 weeks.

34. The method according to any one of claims 1 to 33, wherein the preparation is administered for at least about six months.

35. The method according to any one of claims 1 to 34, wherein the preparation is administered for at least about one year.

36. The method according to any one of claims 1 to 35, wherein the preparation is administered daily.

37. The method according to any one of claims 1 to 36, wherein the PPAR agonist is pioglitazone or a salt thereof or a prodrug.

38. The method according to claim 37, wherein the pioglitazone is administered at a dose of 1 mg / kg / day.

39. The method according to claim 37, wherein the pioglitazone is administered at a dose of 2 to 3 mg / kg / day.

40. The method according to any one of claims 1 to 39, wherein the PPAR agonist is rosiglitazone or a salt thereof or a prodrug.

41. The method according to any one of claims 1 to 40, wherein the preparation is a pharmaceutical preparation.

42. The method according to any one of claims 1 to 40, wherein the preparation is a nutritional preparation.

43. The method according to any one of claims 1 to 42, wherein the formulation is in solid dosage form (e.g., a tablet or a capsule).

44. The method according to claim 43, wherein the solid dosage form includes a hydrolyzed chicken product.

45. The method according to claim 43 or 44, wherein the solid dosage form comprises 18 mg, 54 mg, or 81 mg of the PPAR agonist.

46. The method according to any one of claims 43 to 45, wherein the solid dosage form further comprises at least one filler.

47. The method according to any one of claims 46, wherein the filler is lactose monohydrate.

48. The method according to claim 47, wherein the lactose monohydrate is present in an amount of about 10% to about 40% w / w.

49. The method according to claim 48, wherein the lactose monohydrate is present in an amount of about 22% w / w.

50. The method according to any one of claims 43 to 49, wherein the solid dosage form further comprises sodium carboxymethylcellulose.

51. The method according to claim 50, wherein the amount of carboxymethylcellulose sodium is about 2% to about 10% w / w.

52. The method according to claim 51, wherein the amount of carboxymethylcellulose sodium is about 4% w / w.

53. The method according to any one of claims 43 to 52, wherein the solid dosage form further comprises a flavoring agent (for example, FlavorPAL X1212).

54. The method according to claim 53, wherein the flavoring is present in an amount of about 10% to about 40% w / w.

55. The method according to claim 54, wherein the flavoring is present in an amount of approximately 20% w / w.

56. The method according to any one of claims 43 to 55, wherein the solid dosage form further comprises magnesium stearate.

57. The method according to claim 56, wherein the amount of magnesium stearate is about 0.25% to about 3% w / w.

58. The method according to any one of claims 43 to 57, wherein the solid dosage form is a tablet.

59. A method for reducing or delaying mortality from age-related diseases in a mammal where it is necessary to reduce or delay mortality from age-related diseases, comprising administering a therapeutically effective amount of a PPAR agonist, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, to the mammal.

60. A method for treating age-related decline in quality of life, comprising administering a therapeutically effective amount of a PPAR agonist, or a pharmaceutically acceptable salt thereof, or a prodrug, to the mammal.

61. A method for treating age-related frailty, comprising administering a therapeutically effective amount of a PPAR agonist, or a pharmaceutically acceptable salt thereof, or a prodrug, to the mammal.

62. The method according to claim 59, further comprising extending lifespan, wherein the extension of lifespan includes an extension of at least 5% to the expected lifespan or median lifespan of companion animals of a similar species, strain, or breed.

63. The method according to claim 62, wherein extending the lifespan includes extending the lifespan by at least 10%, at least 15%, at least 20%, or at least 25%.

64. The method according to any one of claims 59 to 63, wherein the method comprises reducing or reversing insulin resistance in the mammal.

65. The method according to claim 64, wherein the insulin resistance arises from an aging process.

66. The method according to any one of claims 59 to 65, wherein the method includes reducing or reversing the increase in fatty acids.

67. The method according to claim 66, wherein the aforementioned increase in fatty acids is related to age-related pathological conditions.

68. The method according to claim 67, wherein the age-related pathological condition is metabolic syndrome, insulin resistance, obesity, type II diabetes, cardiovascular disease, or sarcopenia.

69. The method according to any one of claims 59 to 68, wherein the mammal has reached maturity.

70. The method according to any one of claims 59 to 69, wherein the mammal is at least 7 years old.

71. The method according to any one of claims 59 to 70, wherein the mammal is at least 10 years old.

72. The method according to any one of claims 59 to 71, wherein the mammal has reached old age.

73. The method according to any one of claims 59 to 72, wherein the mammal weighs at least 14 pounds.

74. The method according to any one of claims 59 to 73, wherein the mammal is a dog or a cat.

75. The method according to claim 74, wherein the mammal is a dog.

76. The method according to claim 74, wherein the mammal is a cat.

77. The method according to any one of claims 59 to 76, wherein the method comprises about 5% to about 35% of the PPAR agonist.

78. The method according to any one of claims 59 to 77, wherein the method comprises about 10% to about 20% of the PPAR agonist.

79. The method according to any one of claims 59 to 78, wherein the method comprises about 1 mg to about 100 mg of the PPAR agonist.

80. The method according to any one of claims 59 to 79, wherein the method comprises about 4 mg to about 85 mg of the PPAR agonist.

81. The method according to any one of claims 59 to 80, wherein the PPAR agonist is administered at approximately 3 mg / kg / day.

82. The method according to any one of claims 59 to 80, wherein the PPAR agonist is administered at approximately 5 mg / kg / day.

83. The method according to any one of claims 59 to 80, wherein the PPAR agonist is administered at approximately 10 mg / kg / day.

84. The method according to any one of claims 59 to 83, wherein the PPAR agonist is administered for at least about four weeks.

85. The method according to any one of claims 59 to 84, wherein the PPAR agonist is administered for at least about 12 weeks.

86. The method according to any one of claims 59 to 85, wherein the PPAR agonist is administered for at least about six months.

87. The method according to any one of claims 59 to 86, wherein the PPAR agonist is administered for at least about one year.

88. The method according to any one of claims 59 to 87, wherein the PPAR agonist is administered daily.

89. The method according to any one of claims 59 to 88, wherein the PPAR agonist is pioglitazone or a salt thereof.

90. The method according to claim 89, wherein the pioglitazone is administered at a dose of 1 mg / kg / day.

91. The method according to claim 89, wherein the pioglitazone is administered at a dose of 2 to 3 mg / kg / day.

92. The method according to any one of claims 59 to 88, wherein the PPAR agonist is rosiglitazone or a salt thereof.

93. The method according to any one of claims 59 to 92, wherein the PPAR agonist is present in the pharmaceutical formulation.

94. The method according to any one of claims 59 to 92, wherein the PPAR agonist is present in the nutritional preparation.

95. The method according to any one of claims 59 to 94, wherein the PPAR agonist is in a solid dosage form (e.g., a tablet or a capsule).

96. The method according to claim 95, wherein the solid dosage form comprises a hydrolyzed chicken product or a chicken flavoring.

97. The method according to claim 95 or 96, wherein the solid dosage form comprises 18 mg, 54 mg, or 81 mg of the PPAR agonist.

98. The method according to any one of claims 95 to 97, wherein the solid dosage form further comprises at least one filler.

99. The method according to claim 98, wherein the filler contains lactose monohydrate, and the amount of lactose monohydrate is about 10% to about 40% w / w.

100. The method according to claim 99, wherein the lactose monohydrate is present in an amount of about 22% w / w.

101. The method according to any one of claims 95 to 100, wherein the solid dosage form further comprises sodium carboxymethylcellulose.

102. The method according to claim 101, wherein the amount of carboxymethylcellulose sodium is about 2% to about 10% w / w.

103. The method according to claim 102, wherein the amount of carboxymethylcellulose sodium is about 4% w / w.

104. The method according to any one of claims 95 to 103, wherein the solid dosage form further comprises a flavoring agent (for example, FlavorPAL X1212).

105. The method according to claim 104, wherein the flavoring is present in an amount of about 10% to about 40% w / w.

106. The method according to claim 105, wherein the flavoring is present in an amount of approximately 20% w / w.

107. The method according to any one of claims 95 to 106, wherein the solid dosage form further comprises magnesium stearate.

108. The method according to claim 107, wherein the amount of magnesium stearate is about 0.25% to about 3% w / w.

109. The method according to any one of claims 95 to 108, wherein the solid dosage form is a tablet.

110. A pharmaceutical formulation in a solid dosage form comprising (a) pioglitazone or a salt thereof, (b) one or more fillers (e.g., lactose monohydrate, hydroxypropyl cellulose, sodium carboxymethylcellulose, or a combination thereof), (c) a lubricant (e.g., magnesium stearate), and (d) a flavoring agent.

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