Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin.
Document Type
Article
Publication Date
10-1-2024
Original Citation
Miller R,
Harrison D,
Cortopassi G,
Dehghan I,
Fernandez E,
Garratt M,
Geisler J,
Ginsburg B,
Han M,
Kaczorowski C,
Kumar N,
Leiser S,
Lopez-Cruzan M,
Milne G,
Mitchell J,
Nelson J,
Reifsnyder PC,
Salmon A,
Korstanje R,
Rosenthal N,
Strong R.
Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin. Geroscience. 2024;46(5):4657-70.
Keywords
JMG, Animals, Canagliflozin, Male, Female, Thiosulfates, Longevity, Mice, Sodium-Glucose Transporter 2 Inhibitors, Sex Factors
JAX Source
Geroscience. 2024;46(5):4657-70.
ISSN
2509-2723
PMID
38753230
DOI
https://doi.org/10.1007/s11357-024-01176-2
Grant
This work was supported by NIH grants AG022308 (DEH)
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.