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Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin

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Abstract

Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana.

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Acknowledgements

We are grateful to Lindsey Burger, Micah Bush, Robert Dilg, Lori Roberts, and Jacob Sheets for animal husbandry at UM; Pamela Krason, Vicki Ingalls, Nelson Durgin, and Leonor Robidoux for expert animal care at TJL; Vanessa Calderon and Victoria DeLeon for expert assistance at UT; and technical assistance from Alexey Tomilov. We thank NIH representative Jennifer Fox for advice and collaboration.

Funding

This work was supported by NIH grants AG022308 (DEH), AG022303 (RAM), AG022307 and AG013319 (RS), and AG062817 (GAC).

Author information

Authors and Affiliations

  1. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    Richard A. Miller & Melissa L. Han

  2. Geriatrics Center, University of Michigan, Ann Arbor, MI, USA

    Richard A. Miller, Catherine C. Kaczorowski, Navasuja Kumar & Scott F. Leiser

  3. The Jackson Laboratory, Bar Harbor, ME, USA

    David E. Harrison, Peter C. Reifsnyder, Ron Korstanje & Nadia Rosenthal

  4. Molecular Biosciences, University of California, Davis, CA, USA

    Gino A. Cortopassi

  5. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Ishmael Dehghan

  6. Department of Pharmacology, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Elizabeth Fernandez & Randy Strong

  7. GRECC, South Texas Veterans Health Care Network, San Antonio, TX, USA

    Elizabeth Fernandez & Adam B. Salmon

  8. Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand

    Michael Garratt

  9. Mitochon Pharmaceuticals, Inc, Blue Bell, PA, USA

    John G. Geisler

  10. Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Brett C. Ginsburg & Marisa Lopez-Cruzan

  11. Department of Neurology, University of Michigan, Ann Arbor, MI, USA

    Catherine C. Kaczorowski

  12. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Navasuja Kumar & Scott F. Leiser

  13. Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA

    Scott F. Leiser

  14. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    Ginger Milne

  15. Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    James F. Nelson

  16. Barshop Institute for Longevity and Aging Studies and Dept of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Adam B. Salmon

  17. ETH Zurich, Switzerland

    James R. Mitchell

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  1. Richard A. Miller
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Contributions

DEH, NR, RS, and RAM are the principal investigators at the three collaborating institutions and are responsible for project design, supervision of technical personnel, interpretation of results, and preparation of manuscript drafts. BCG and MLC ran the Pharmacology Core and helped with the manuscript. ABS, JFN, RK, CK, and SL advised on experimental design and interpretation and helped with the manuscript. PR supervised laboratory procedures and data collection at The Jackson Laboratory site and organized diet preparations for all three sites. EF supervised laboratory personnel and data collection at the UTHSCSA site. GM conducted the isoprostane analyses. MH coordinated sample preparation across the three sites. NK assisted in statistical analyses. GAC, ID, MG, JGG, and JRM proposed the drugs used in the C2020 study.

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Correspondence to Richard A. Miller.

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James R. Mitchell passed away during the course of this study.

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Miller, R.A., Harrison, D.E., Cortopassi, G.A. et al. Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin. GeroScience (2024). https://doi.org/10.1007/s11357-024-01176-2

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