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

Richard A. Miller, David E. Harrison, Gino A. Cortopassi, Ishmael Dehghan, Elizabeth Fernandez, Michael Garratt, John G. Geisler, Brett C. Ginsburg, Melissa L. Han, Catherine C. Kaczorowski, Navasuja Kumar, Scott F. Leiser, Marisa Lopez-Cruzan, Ginger Milne, James R. Mitchell, James F Nelson, Peter C. Reifsnyder, Adam B. Salmon, Ron Korstanje, Nadia RosenthalJohn R Strong

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalGeroScience
DOIs
StateAccepted/In press - 2024

Keywords

  • Alpha-ketoglutarate
  • Lifespan
  • SGLT2 inhibitor Canagliflozin

ASJC Scopus subject areas

  • Aging
  • veterinary (miscalleneous)
  • Complementary and alternative medicine
  • Geriatrics and Gerontology
  • Cardiology and Cardiovascular Medicine

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