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

Richard A Miller^{1

2}, David E Harrison³, Gino A Cortopassi⁴, Ishmael Dehghan⁵, Elizabeth Fernandez^{6

7}, Michael Garratt⁸, John G Geisler⁹, Brett C Ginsburg¹⁰, Melissa L Han¹¹, Catherine C Kaczorowski^{12

13}, Navasuja Kumar^{12

14}, Scott F Leiser^{12

14

15}, Marisa Lopez-Cruzan¹⁰, Ginger Milne¹⁶, James R Mitchell¹⁷, James F Nelson¹⁸, Peter C Reifsnyder³, Adam B Salmon^{7

19}, Ron Korstanje³, Nadia Rosenthal³, Randy Strong⁶

Affiliations

¹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA. millerr@umich.edu.
² Geriatrics Center, University of Michigan, Ann Arbor, MI, USA. millerr@umich.edu.
³ The Jackson Laboratory, Bar Harbor, ME, USA.
⁴ Molecular Biosciences, University of California, Davis, CA, USA.
⁵ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁶ Department of Pharmacology, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁷ GRECC, South Texas Veterans Health Care Network, San Antonio, TX, USA.
⁸ Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
⁹ Mitochon Pharmaceuticals, Inc, Blue Bell, PA, USA.
¹⁰ Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
¹¹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
¹² Geriatrics Center, University of Michigan, Ann Arbor, MI, USA.
¹³ Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
¹⁴ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
¹⁶ Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
¹⁷ , ETH Zurich, Switzerland.
¹⁸ Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
¹⁹ Barshop Institute for Longevity and Aging Studies and Dept of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

PMID: 38753230
PMCID: PMC11336000
DOI: 10.1007/s11357-024-01176-2

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

Richard A Miller et al. Geroscience. 2024 Oct.

. 2024 Oct;46(5):4657-4670.

doi: 10.1007/s11357-024-01176-2. Epub 2024 May 16.

Authors

Affiliations

¹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA. millerr@umich.edu.
² Geriatrics Center, University of Michigan, Ann Arbor, MI, USA. millerr@umich.edu.
³ The Jackson Laboratory, Bar Harbor, ME, USA.
⁴ Molecular Biosciences, University of California, Davis, CA, USA.
⁵ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁶ Department of Pharmacology, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁷ GRECC, South Texas Veterans Health Care Network, San Antonio, TX, USA.
⁸ Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
⁹ Mitochon Pharmaceuticals, Inc, Blue Bell, PA, USA.
¹⁰ Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
¹¹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
¹² Geriatrics Center, University of Michigan, Ann Arbor, MI, USA.
¹³ Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
¹⁴ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
¹⁶ Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
¹⁷ , ETH Zurich, Switzerland.
¹⁸ Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
¹⁹ Barshop Institute for Longevity and Aging Studies and Dept of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

PMID: 38753230
PMCID: PMC11336000
DOI: 10.1007/s11357-024-01176-2

Erratum in

Correction to: Lifespan effects in male UM‑HET3 mice treated with sodium thiosulfate, 16‑hydroxyestriol, and late‑start canagliflozin.
Miller RA, Harrison DE, Cortopassi GA, Dehghan I, Fernandez E, Garratt M, Geisler JG, Ginsburg BC, Han ML, Jiang N, Kaczorowski CC, Kumar N, Leiser SF, Lopez-Cruzan M, Milne G, Mitchell JR, Nelson JF, Reifsnyder PC, Salmon AB, Xu Z, Korstanje R, Rosenthal N, Strong R. Miller RA, et al. Geroscience. 2025 Aug;47(4):6093-6094. doi: 10.1007/s11357-024-01283-0. Geroscience. 2025. PMID: 39004654 Free PMC article. No abstract available.
Correction to: Lifespan effects in male UM‑HET3 mice treated with sodium thiosulfate, 16-hydroxyestradiol, and late‑start canagliflozin.
Miller RA, Harrison DE, Cortopassi GA, Dehghan I, Fernandez E, Garratt M, Geisler JG, Ginsburg BC, Han ML, Kaczorowski CC, Kumar N, Leiser SF, Lopez-Cruzan M, Milne G, Mitchell JR, Nelson JF, Reifsnyder PC, Salmon AB, Korstanje R, Rosenthal N, Strong R. Miller RA, et al. Geroscience. 2025 Oct;47(5):6663-6664. doi: 10.1007/s11357-025-01752-0. Geroscience. 2025. PMID: 40536755 Free PMC article. No abstract available.

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.

Keywords: Alpha-ketoglutarate; Lifespan; SGLT2 inhibitor Canagliflozin.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
Survival plots for Cana_16, OH_Est, and THIO males (left) and females (right). Table 2 shows counts, medians, and p90 values, and p-values for log-rank and Wang-Allison statistical tests. Data are pooled across the three ITP sites, except that Cana_16 data are from UM and UT only

**Fig. 2**
Survival plots for males (left) and females (right) exposed to Cana from 6 months of age (TJL only). Table 2 shows counts, medians, and p90 values, and p-values for log-rank and Wang-Allison statistical tests

**Fig. 3**
Survival plots for males (left) and females (right) exposed to agents that did not significantly alter survival in either sex. Table 2 shows counts, medians, and p90 values, and p-values for log-rank and Wang-Allison statistical tests

**Fig. 4**
Mean body weights for treated mice in C2020. Asterisks indicate values that differed significantly from untreated control mice of the same sex at the same age by Sidak post-hoc test, following one-way ANOVA done separately for each sex. Note that the Y-axis scale differs between the two panels

**Fig. 5**
Cana levels in plasma and tissues. Each symbol represents an individual mouse. Plasma values of young and old mice are shown as µg/ml, and kidney and brain tissue values of old mice are shown as ng/mg tissue. In each case, the effect of sex is significant at p < 0.001. Numbers of mice in the 8 columns are as follows: 3, 4, 8, 5, 8, 5, 8, and 5. Minimum detectable levels were 0.1 µg/ml for plasma and 0.11 ng/ml for tissue. Note differences in the Y-axis scale among the panels. The data for 22-month-old mice were previously shown, in another format, in (3)

See this image and copyright information in PMC

References

1. Macchiarini F, Miller RA, Strong R, Rosenthal N, Harrison DE. NIA interventions testing program: a collaborative approach for investigating interventions to promote healthy aging. In: Musi N, Hornsby PJ, editors. Handbook of the Biology of Aging. 9th ed. London (UK): Academic Press; 2021.
1. Harrison DE, Strong R, Reifsnyder P, Rosenthal N, Korstanje R, Fernandez E, et al. Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used. Geroscience. 2023;46(1):795–816. - PMC - PubMed
1. Miller RA, Harrison DE, Allison DB, Bogue M, Debarba L, Diaz V, et al. Canagliflozin extends life span in genetically heterogeneous male but not female mice. JCI Insight. 2020;5(21):e140019. 10.1172/jci.insight.140019. - PMC - PubMed
1. Snyder JM, Casey KM, Galecki A, Harrison DE, Jayarathne H, Kumar N, et al. Canagliflozin retards age-related lesions in heart, kidney, liver, and adrenal gland in genetically heterogenous male mice. Geroscience. 2022;45(1):385–97. - PMC - PubMed
1. Strong R, Miller RA, Antebi A, Astle CM, Bogue M, Denzel MS, et al. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an alpha-glucosidase inhibitor or a Nrf2-inducer. Aging Cell. 2016;15(5):872–84. - PMC - PubMed

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

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

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