Acarbose has sex-dependent and -independent effects on age-related physical function, cardiac health, and lipid biology
Jonathan J. Herrera, … , Richard A. Miller, Michael Garratt
Jonathan J. Herrera, … , Richard A. Miller, Michael Garratt
Published September 29, 2020
Citation Information: JCI Insight. 2020;5(21):e137474. https://doi.org/10.1172/jci.insight.137474.
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Research Article Aging

Acarbose has sex-dependent and -independent effects on age-related physical function, cardiac health, and lipid biology

Abstract

With an expanding aging population burdened with comorbidities, there is considerable interest in treatments that optimize health in later life. Acarbose (ACA), a drug used clinically to treat type 2 diabetes mellitus (T2DM), can extend mouse life span with greater effect in males than in females. Using a genetically heterogeneous mouse model, we tested the ability of ACA to ameliorate functional, pathological, and biochemical changes that occur during aging, and we determined which of the effects of age and drug were sex dependent. In both sexes, ACA prevented age-dependent loss of body mass, in addition to improving balance/coordination on an accelerating rotarod, rotarod endurance, and grip strength test. Age-related cardiac hypertrophy was seen only in male mice, and this male-specific aging effect was attenuated by ACA. ACA-sensitive cardiac changes were associated with reduced activation of cardiac growth–promoting pathways and increased abundance of peroxisomal proteins involved in lipid metabolism. ACA further ameliorated age-associated changes in cardiac lipid species, particularly lysophospholipids — changes that have previously been associated with aging, cardiac dysfunction, and cardiovascular disease in humans. In the liver, ACA had pronounced effects on lipid handling in both sexes, reducing hepatic lipidosis during aging and shifting the liver lipidome in adulthood, particularly favoring reduced triglyceride (TAG) accumulation. Our results demonstrate that ACA, already in clinical use for T2DM, has broad-ranging antiaging effects in multiple tissues, and it may have the potential to increase physical function and alter lipid biology to preserve or improve health at older ages.

Authors

Jonathan J. Herrera, Sean Louzon, Kaitlyn Pifer, Danielle Leander, Gennifer E. Merrihew, Jea H. Park, Kate Szczesniak, Jeremy Whitson, John E. Wilkinson, Oliver Fiehn, Michael J. MacCoss, Sharlene M. Day, Richard A. Miller, Michael Garratt

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Figure 1

Effects of ACA on body weight dynamics, muscle mass, and body temperature.

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Effects of ACA on body weight dynamics, muscle mass, and body temperatur...
(A and B) Body weight was assessed monthly from the initiation of treatment at 4 months until 25 months of age (A), and data were used to calculate weight change across different time points (B). n = 16–19 per sex and treatment group at the start of the study, with 14–16 mice per group remaining alive at 24 months. (C) At 25 months, animals were dissected and quadriceps weight was higher in male mice treated with ACA compared with controls. (D) In a separate cohort of mice treated with ACA from 4 months, body temperature was assessed at 22 months of age and compared with untreated animals that were of the same age, in addition to younger 6 month old animals. P values in C were calculated with an ANCOVA, including body weight as a covariate. In D and E, P values are calculated from a Dunnett’s multiple comparisons test, comparing young animals and old ACA-treated animals with old controls in separate comparisons, after conducting an ANOVA. Each dot represents a data point from an individual animal.