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

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.

SUBMITTER: Miller RA

PROVIDER: S-EPMC11336000 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature

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

Miller Richard A RA Harrison David E DE Cortopassi Gino A GA Dehghan Ishmael I Fernandez Elizabeth E Garratt Michael M Geisler John G JG Ginsburg Brett C BC Han Melissa L ML Kaczorowski Catherine C CC Kumar Navasuja N Leiser Scott F SF Lopez-Cruzan Marisa M Milne Ginger G Mitchell James R JR Nelson James F JF Reifsnyder Peter C PC Salmon Adam B AB Korstanje Ron R Rosenthal Nadia N Strong Randy R

GeroScience 20240516 5

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 ...[more]

PMID: 38753230

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Project description:BackgroundCisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival.MethodsWe randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years.ResultsA total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively.ConclusionsThe addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132 ; EudraCT number, 2007-002402-21 .).

Dataset Information

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

Publications

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

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