Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate slows aging in mice

Pharmaceutical intervention of aging requires targeting multiple pathways, thus there is rationale to test combinations of drugs each targeting different but overlapping processes. In order to determine if combining drugs previously shown to improve lifespan would have greater impact than any individuyal drug, a diet containing rapamycin at 14 ppm, acarbose at 1000 ppm, and phenylbutyrate at 1000 ppm was fed to 20-month-old C57BL/6 and HET3 4-way cross mice of both sexes for three months. Mice fed the cocktail diet showed a strain and gender-dependent phenotype consistent with healthy aging including decreased body fat and blood glucose, improved cognition, and increased grip strength and walking ability compared to mice fed individual drug or control diets. A cocktail diet containing ½ dosing of each compound was overall less effective than the full dose. The composite age-related lesion score of heart, lungs, liver and kidney was decreased in mice fed the cocktail diet compared to mice fed individual drug or control diets suggesting an interactive advantage of the three drugs. Senescence and inflammatory cytokine levels in kidneys from mice fed the cocktail diet were lower than in kidneys from mice fed control diet, and consistent with low expression levels in kidneys from young untreated mice, suggesting the cocktail diet delayed aging partly by senolytic and anti-inflammatory effects.

[1]  N. LeBrasseur,et al.  Senolytics reduce coronavirus-related mortality in old mice , 2021, Science.

[2]  D. Imai,et al.  The geropathology of organ-specific aging , 2021, Journal of translational science.

[3]  M. Darvas,et al.  A Novel One‐Day Learning Procedure for Mice , 2020, Current protocols in mouse biology.

[4]  M. Ciol,et al.  Validation of a geropathology grading system for aging mouse studies , 2019, GeroScience.

[5]  D. L. Le Couteur,et al.  Anti-aging therapies, cognitive impairment and dementia. , 2019, The journals of gerontology. Series A, Biological sciences and medical sciences.

[6]  V. Galvan,et al.  mTOR in cerebrovascular disease , 2019, Aging.

[7]  Richard A. Miller,et al.  Sex differences in lifespan extension with acarbose and 17‐α estradiol: gonadal hormones underlie male‐specific improvements in glucose tolerance and mTORC2 signaling , 2017, Aging cell.

[8]  D. Liggitt,et al.  A New Preclinical Paradigm for Testing Anti-Aging Therapeutics , 2017, The journals of gerontology. Series A, Biological sciences and medical sciences.

[9]  M. Ciol,et al.  Self-motivated and stress-response performance assays in mice are age-dependent , 2017, Experimental Gerontology.

[10]  R. Kohanski,et al.  Geroscience and the trans-NIH Geroscience Interest Group, GSIG , 2017, GeroScience.

[11]  Daniel L. Smith,et al.  Targeting glucose metabolism for healthy aging , 2016, Nutrition and healthy aging.

[12]  Kathleen F. Kerr,et al.  Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice , 2016, eLife.

[13]  Dudley Lamming,et al.  Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer , 2016, Aging cell.

[14]  M. Ciol,et al.  Grip strength is potentially an early indicator of age-related decline in mice , 2016, Pathobiology of aging & age related diseases.

[15]  E. Schadt,et al.  Geroscience: Linking Aging to Chronic Disease , 2014, Cell.

[16]  Z. D. Sharp,et al.  Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction , 2014, Aging cell.

[17]  B. Ames,et al.  Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males , 2013, Aging cell.

[18]  B. Kennedy,et al.  Late‐life rapamycin treatment reverses age‐related heart dysfunction , 2013, Aging cell.

[19]  Michael P Phelps,et al.  Decline in muscle strength and running endurance in klotho deficient C57BL/6 mice , 2013, Biogerontology.

[20]  D. Liggitt,et al.  Pathology is a critical aspect of preclinical aging studies , 2013, Pathobiology of aging & age related diseases.

[21]  J. Soulillou,et al.  Mechanistic target of rapamycin inhibitors in solid organ transplantation: from benchside to clinical use , 2012, Current opinion in organ transplantation.

[22]  Maria A. Woodward,et al.  Rapamycin slows aging in mice , 2012, Aging cell.

[23]  R. Weindruch,et al.  The caloric restriction paradigm: Implications for healthy human aging , 2012, American journal of human biology : the official journal of the Human Biology Council.

[24]  W. Ladiges,et al.  Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice , 2011, Aging cell.

[25]  P. Cowan,et al.  Sirolimus: mammalian target of rapamycin inhibitor to prevent kidney rejection. , 2000, Nephrology nursing journal : journal of the American Nephrology Nurses' Association.

[26]  D. McTavish,et al.  Acarbose : An Update of its Pharmacology and Therapeutic Use in Diabetes Mellitus. , 1993, Drugs.