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Diabetes medications as potential calorie restriction mimetics—a focus on the alpha-glucosidase inhibitor acarbose

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Abstract

The field of aging research has grown rapidly over the last half-century, with advancement of scientific technologies to interrogate mechanisms underlying the benefit of life-extending interventions like calorie restriction (CR). Coincident with this increase in knowledge has been the rise of obesity and type 2 diabetes (T2D), both associated with increased morbidity and mortality. Given the difficulty in practicing long-term CR, a search for compounds (CR mimetics) which could recapitulate the health and longevity benefits without requiring food intake reductions was proposed. Alpha-glucosidase inhibitors (AGIs) are compounds that function predominantly within the gastrointestinal tract to inhibit α-glucosidase and α-amylase enzymatic digestion of complex carbohydrates, delaying and decreasing monosaccharide uptake from the gut in the treatment of T2D. Acarbose, an AGI, has been shown in pre-clinical models to increase lifespan (greater longevity benefits in males), with decreased body weight gain independent of calorie intake reduction. The CR mimetic benefits of acarbose are further supported by clinical findings beyond T2D including the risk for other age-related diseases (e.g., cancer, cardiovascular). Open questions remain regarding the exclusivity of acarbose relative to other AGIs, potential off-target effects, and combination with other therapies for healthy aging and longevity extension. Given the promising results in pre-clinical models (even in the absence of T2D), a unique mechanism of action and multiple age-related reduced disease risks that have been reported with acarbose, support for clinical trials with acarbose focusing on aging-related outcomes and incorporating biological sex, age at treatment initiation, and T2D-dependence within the design is warranted.

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Funding

Funding in support of this work is derived in part by NIH grant award P30AG050886.

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Authors and Affiliations

  1. Department of Nutrition Sciences, University of Alabama at Birmingham, 1720 2nd Avenue S, Webb 423, Birmingham, AL, 35294-3360, USA

    Daniel L. Smith Jr & Lyse A. Norian

  2. Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Daniel L. Smith Jr & Lyse A. Norian

  3. Integrative Center for Aging Research, University of Alabama at Birmingham, Birmingham, AL, USA

    Daniel L. Smith Jr

  4. Nathan Shock Center of Excellence in the Biology of Aging, University of Alabama at Birmingham, Birmingham, AL, USA

    Daniel L. Smith Jr

  5. Diabetes Research Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Daniel L. Smith Jr

  6. Graduate Biomedical Sciences, University of Alabama at Birmingham, Birmingham, AL, USA

    Rachael M. Orlandella

  7. School of Public Health, Indiana University – Bloomington, Bloomington, IN, USA

    David B. Allison

  8. O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Lyse A. Norian

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All authors provided input and final approval of the submitted and published version of the manuscript.

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Conflict of interest

Daniel L. Smith Jr has no conflicts relevant to the content of the review article. Dr. Smith’s institution, the University of Alabama at Birmingham, has received funds to support research from the National Institutes of Health, McCormick Science Institute and the Alliance for Potato Research and Education. Rachael M. Orlandella has no conflicts relevant to the content of this review article. Lyse A. Norian has no conflicts relevant to the content of the review article. In the last thirty-six months, Dr. Allison has received personal payments or promises for the same from the following: American Society for Nutrition; Alkermes, Inc.; American Statistical Association; Biofortis; California Walnut Commission; Columbia University; Fish & Richardson, P.C.; Frontiers Publishing; Henry Stewart Talks; IKEA; Indiana University; Laura and John Arnold Foundation; Johns Hopkins University; Law Offices of Ronald Marron; MD Anderson Cancer Center; Medical College of Wisconsin; National Institutes of Health (NIH); Sage Publishing; The Obesity Society; Soleno Therapeutics; Tomasik, Kotin & Kasserman LLC; University of Alabama at Birmingham; University of Miami; Nestle; WW (formerly Weight Watchers International, LLC). Donations to a foundation have been made on his behalf by the Northarvest Bean Growers Association. Dr. Allison has been an unpaid member of the International Life Sciences Institute North America Board of Trustees. Dr. Allison’s institution, Indiana University, has received funds to support his research or educational activities from the following: NIH; Eli Lilly, Alliance for Potato Research and Education; American Federation for Aging Research; Dairy Management Inc.; Herbalife; Laura and John Arnold Foundation; National Cattlemen’s Beef Association, Oxford University Press, the Sloan Foundation, The Gordan and Betty Moore Foundation, and numerous other for-profit and non-profit organizations to support the work of the School of Public Health and the university more broadly.

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Smith, D.L., Orlandella, R.M., Allison, D.B. et al. Diabetes medications as potential calorie restriction mimetics—a focus on the alpha-glucosidase inhibitor acarbose. GeroScience 43, 1123–1133 (2021). https://doi.org/10.1007/s11357-020-00278-x

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