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Beta-guanidinopropionic acid has age-specific effects on markers of health and function in mice

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Abstract

AMP-activated protein kinase (AMPK) is a central regulator of both lifespan and health across multiple model organisms. β-Guanidinopropionic acid (GPA) is an endogenous AMPK activator previously shown to improve metabolic function in young and obese mice. In this study, we tested whether age of administration significantly affects the physiological outcomes of GPA administration in mice. We report that intervention starting at 7–8 months (young) results in activation of AMPK signaling and a phenotype consisting of lower body mass, improved glucose control, enhanced exercise tolerance, and altered mitochondrial electron transport chain flux similar to previous reports. When GPA treatment is started at 18–19 months (old), the effect of GPA on AMPK signaling is blunted compared to younger mice despite similar accumulation of GPA in skeletal muscle. Even so, GPA administration in older animals delayed age-related declines in lean mass, improved measures of gait performance and circadian rhythm, and increased fat metabolism as measured by respiratory exchange ratio. These results are likely partially driven by the relative difference in basal function and metabolic plasticity between young and old mice. Our results suggest that age-related declines in AMPK sensitivity may limit potential strategies targeting AMPK signaling in older subjects and suggest that further research and development is required for AMPK activators to realize their full potential.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

Milliplex analyte panels were performed by Bioanalytics and Single-Cell Core at UT-Health San Antonio. Preparation of TEM images was performed by the Electron Microscopy Laboratory at UT-Health San Antonio. Gait, exercise tolerance, rotarod, grip, 24-h activity, and RER were performed by the Integrated Physiology of Aging Core at the San Antonio Nathan Shock Center (P30 AG013319). GPA concentrations were measured by Greg Friesenhahn of the Biological Psychiatry Analytic Laboratory at UT-Health San Antonio and the Analytical Pharmacology and Drug Evaluation Core of the San Antonio Nathan Shock Center. This material is the result of work supported with resources and the use of facilities at South Texas Veterans Health Care System, San Antonio, Texas. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

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Funding

This research was funded in part by R01 AG050797, R01 AG057431, and the Geriatric Research, Education and Clinical Center of the South Texas Veterans Health Care System and by the American Heart Association 19PRE34450033.

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Authors and Affiliations

  1. Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Jonathan D. Dorigatti, Kevin M. Thyne & Adam B. Salmon

  2. Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Brett C. Ginsburg

  3. Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Adam B. Salmon

  4. Geriatric Research Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA

    Adam B. Salmon

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  1. Jonathan D. Dorigatti
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Contributions

JDD formulated the study. JDD, KMT, and BCG collected the data. JDD analyzed the results, created the figures, and drafted the manuscript. JDD and ABS edited the manuscript. JDD, KMT, BCG, and ABS reviewed and approved the manuscript.

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Correspondence to Adam B. Salmon.

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All animal experiments were approved by the Institutional Animal Care and Use Committees at UTHSCSA.

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Dorigatti, J.D., Thyne, K.M., Ginsburg, B.C. et al. Beta-guanidinopropionic acid has age-specific effects on markers of health and function in mice. GeroScience 43, 1497–1511 (2021). https://doi.org/10.1007/s11357-021-00372-8

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