학술논문
Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin
Document Type
Original Paper
Author
Miller, Richard A.; Harrison, David E.; Cortopassi, Gino A.; Dehghan, Ishmael; Fernandez, Elizabeth; Garratt, Michael; Geisler, John G.; Ginsburg, Brett C.; Han, Melissa L.; Kaczorowski, Catherine C.; Kumar, Navasuja; Leiser, Scott F.; Lopez-Cruzan, Marisa; Milne, Ginger; Mitchell, James R.; Nelson, James F.; Reifsnyder, Peter C.; Salmon, Adam B.; Korstanje, Ron; Rosenthal, Nadia; Strong, Randy
Source
GeroScience: Official Journal of the American Aging Association (AGE). 46(5):4657-4670
Subject
Language
English
ISSN
2509-2723
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.