TY - JOUR
T1 - Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin
AU - Miller, Richard A.
AU - Harrison, David E.
AU - Cortopassi, Gino A.
AU - Dehghan, Ishmael
AU - Fernandez, Elizabeth
AU - Garratt, Michael
AU - Geisler, John G.
AU - Ginsburg, Brett C.
AU - Han, Melissa L.
AU - Kaczorowski, Catherine C.
AU - Kumar, Navasuja
AU - Leiser, Scott F.
AU - Lopez-Cruzan, Marisa
AU - Milne, Ginger
AU - Mitchell, James R.
AU - Nelson, James F.
AU - Reifsnyder, Peter C.
AU - Salmon, Adam B.
AU - Korstanje, Ron
AU - Rosenthal, Nadia
AU - Strong, Randy
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to American Aging Association 2024.
PY - 2024/10
Y1 - 2024/10
N2 - 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.
AB - 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.
KW - Alpha-ketoglutarate
KW - Lifespan
KW - SGLT2 inhibitor Canagliflozin
UR - http://www.scopus.com/inward/record.url?scp=85193302581&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85193302581&partnerID=8YFLogxK
U2 - 10.1007/s11357-024-01176-2
DO - 10.1007/s11357-024-01176-2
M3 - Article
C2 - 38753230
AN - SCOPUS:85193302581
SN - 2509-2715
VL - 46
SP - 4657
EP - 4670
JO - GeroScience
JF - GeroScience
IS - 5
ER -