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

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

doi:10.1172/jci.insight.137474

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.

Highlights

Because the effects of aging in multiple physiological systems lead to clinically significant comorbidities and deteriorating systemic health, therapies that target the aging process may possess significant clinical value by prevention of physiological decline, concordant with their expected effects on life span.Several pharmacological interventions have been shown to extend life span in mice
Two drugs approved for human use by the Food and Drug Administration (FDA), rapamycin and acarbose (ACA), have led to significant life span extension in UM-HET3 male and female mice [2,3,4,5]
ACA increases life span in UM-HET3 mice of both sexes, life span extension is smaller in females (3%–5% change in median life span) than in males (11%–17% change in medium life span, depending on the dose) [2]

Summary

Introduction

Because the effects of aging in multiple physiological systems lead to clinically significant comorbidities and deteriorating systemic health, therapies that target the aging process may possess significant clinical value by prevention of physiological decline, concordant with their expected effects on life span.Several pharmacological interventions have been shown to extend life span in mice. The extension of life span, does not always affect both sexes in a similar manner, and a paucity of information exists about the effects of such treatments on tissue-specific indices of health [1]. Two drugs approved for human use by the Food and Drug Administration (FDA), rapamycin and acarbose (ACA), have led to significant life span extension in UM-HET3 male and female mice [2,3,4,5]. Most widely studied, can lead to an increase in life span of ~10%–20% in both sexes and can ameliorate a subset of age-related phenotypic changes in mice [6, 7]. Its side effects, which in humans can include thrombocytopenia, nephrotoxicity, and impaired wound healing [8], may limit its potential as an antiaging therapeutic

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