Acarbose has sex-dependent and -independent effects on age-related physical function, cardiac health, and lipid biology
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
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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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 3

Effect of ACA on heart structure, function, signaling, and proteomic composition.

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Effect of ACA on heart structure, function, signaling, and proteomic com...
(A–C) Echocardiography was conducted on mice at 22 months of age (n = 8 per sex for old controls; n = 12 per sex for ACA treated), and included a set of young (6-month) controls (n = 8 per sex). (D and E) Analysis of cardiac signaling pathways and ubiquitinated protein was conducted on tissue samples from 25-month-old mice by Western blot. (F) The relative presence of collagen was assessed by Picrosirius red staining. (G) Proteomics analysis was conducted on samples from 25-month-old mice and 6-month-old young controls (n = 8 per sex for each treatment group). Volcano plots for each sex are shown, highlighting the lack of proteins that have a consistent change with age in protein abundance. (H) The log2 fold change in protein abundance from old control animals is shown for old mice treated with ACA for each protein that differs between control and ACA-treated mice after correction for FDR. Each error bar is a value for a different protein, with the figure showing relative change in abundance of proteins differing significantly between young and old mice on a control diet. Proteins were split according to their association with peroxisome, as defined by Gene Ontology (GO) cellular component annotation terms.*P < 0.05, **P < 0.01. In A–C and F, the P values were computed by running an ANOVA then Dunnett’s multiple comparison test, comparing young males and old ACA-treated males with old control males in separate comparisons. In D, P values were calculated with a Student’s t test.