Extension of lifespan by epicatechin, halofuginone and mitoglitazone in male but not female genetically heterogeneous mice

Randy Strong^#¹, James F Nelson², Molly A Bogue³, Jerry R Colca⁴, Martin Denzel⁵, Vivian Diaz⁶, Brian N Finck⁷, Vadim N Gladyshev⁸, Steve Horvath^{9

10}, Nisi Jiang⁶, Tracy Keller¹¹, Rolf F Kletzien¹², Ron Korstanje³, Navasuja Kumar¹³, Christiaan Leeuwenburgh¹⁴, Elizabeth Fernandez¹, Andrzej Galecki¹⁵, Brett Ginsburg¹⁶, Melissa Han¹⁷, Catherine Kaczorowski¹⁸, Scott Leiser¹⁹, Marisa Lopez-Cruzan¹⁶, Ken Raj¹⁰, Peter C Reifsnyder³, Nadia A Rosenthal^{3

20}, Susanna Rosi²¹, Anastasia Shindyapina⁸, Peter Stacpoole²², Adam B Salmon²³, Alexander Tyshkovskiy⁸, Peter Walter²⁴, Malcolm Whitman¹¹, Richard A Miller^#¹⁷, David E Harrison^#³

Affiliations

¹ Geriatric Research, Education and Clinical Center and Research Service, Department of Pharmacology, Barshop Institute for Longevity and Aging Studies, South Texas Veterans Health Care System, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
² Department of Cellular and Integrative Physiology and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. nelsonj@uthscsa.edu.
³ The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
⁴ Cirius Therapeutics, Inc, Kalamazoo, MI, USA.
⁵ Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9B, 50931, Cologne, Germany.
⁶ Department of Cellular and Integrative Physiology and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
⁷ Division of Nutritional Sciences and Obesity Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
⁸ Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁹ Human Genetics, David Geffen School of Medicine, UCLA. Epigenetic Clock Development Foundation, Los Angeles, CA, 90095, USA.
¹⁰ Altos Labs, Cambridge Institute, Granta Park, Cambridgeshire, CB21 6GP, UK.
¹¹ Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, 02115, USA.
¹² Department of Biomedical Sciences, Metabolic Solutions Development Company (MSDC), Western Michigan University School of Medicine, KalamazooGrand Rapids, MI 49007.MI 49546 , USA.
¹³ Division of Geriatric and Palliative Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁴ Institute On Aging, Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, 32611, USA.
¹⁵ Departments of Internal Medicine and Biostatistics, School of Medicine and School of Public Health, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
¹⁶ Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
¹⁷ Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁸ Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
²⁰ National Heart and Lung Institute, Imperial College London, London, UK.
²¹ Altos Labs, Bay Area Institute, 13-Island Dr, Redwood City, CA, 94065, USA.
²² Department of Medicine. Division of Endocrinology, Diabetes and Metabolism, University of Florida. , 1600 SW Archer Road Gainesville, Florida, 32610-0226, USA.
²³ Geriatric Research, Education and Clinical Center, Department of Molecular Medicine, Barshop Institute for Longevity and Aging Studies, South Texas Veterans Health Care System, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
²⁴ Dept of Biochemistry & Biophysics, Howard Hughes Medical Institute, University of California San Francisco, MC2200. 600 16Th St, N316, San Francisco, CA, 94143, USA.

^# Contributed equally.

PMID: 40973907
DOI: 10.1007/s11357-025-01881-6

Extension of lifespan by epicatechin, halofuginone and mitoglitazone in male but not female genetically heterogeneous mice

Randy Strong et al. Geroscience. 2025.

. 2025 Sep 19.

doi: 10.1007/s11357-025-01881-6. Online ahead of print.

Authors

Affiliations

¹ Geriatric Research, Education and Clinical Center and Research Service, Department of Pharmacology, Barshop Institute for Longevity and Aging Studies, South Texas Veterans Health Care System, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
² Department of Cellular and Integrative Physiology and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. nelsonj@uthscsa.edu.
³ The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
⁴ Cirius Therapeutics, Inc, Kalamazoo, MI, USA.
⁵ Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9B, 50931, Cologne, Germany.
⁶ Department of Cellular and Integrative Physiology and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
⁷ Division of Nutritional Sciences and Obesity Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
⁸ Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁹ Human Genetics, David Geffen School of Medicine, UCLA. Epigenetic Clock Development Foundation, Los Angeles, CA, 90095, USA.
¹⁰ Altos Labs, Cambridge Institute, Granta Park, Cambridgeshire, CB21 6GP, UK.
¹¹ Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, 02115, USA.
¹² Department of Biomedical Sciences, Metabolic Solutions Development Company (MSDC), Western Michigan University School of Medicine, KalamazooGrand Rapids, MI 49007.MI 49546 , USA.
¹³ Division of Geriatric and Palliative Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁴ Institute On Aging, Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, 32611, USA.
¹⁵ Departments of Internal Medicine and Biostatistics, School of Medicine and School of Public Health, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
¹⁶ Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
¹⁷ Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁸ Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
²⁰ National Heart and Lung Institute, Imperial College London, London, UK.
²¹ Altos Labs, Bay Area Institute, 13-Island Dr, Redwood City, CA, 94065, USA.
²² Department of Medicine. Division of Endocrinology, Diabetes and Metabolism, University of Florida. , 1600 SW Archer Road Gainesville, Florida, 32610-0226, USA.
²³ Geriatric Research, Education and Clinical Center, Department of Molecular Medicine, Barshop Institute for Longevity and Aging Studies, South Texas Veterans Health Care System, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
²⁴ Dept of Biochemistry & Biophysics, Howard Hughes Medical Institute, University of California San Francisco, MC2200. 600 16Th St, N316, San Francisco, CA, 94143, USA.

^# Contributed equally.

PMID: 40973907
DOI: 10.1007/s11357-025-01881-6

Abstract

Mice bred in 2021 were tested by the Interventions Testing Program (ITP) for possible lifespan benefits of 2BAct (2BA), dichloroacetate (DCA), Epicatechin (EPI), Forskolin (FSK), Halofuginone (HAL) and Mitoglitazone (MIT). All agents were administered in the diet ad libitum beginning at 7 months of age. In male mice, EPI increased median lifespan by ~ 5%, and HAL and MIT each increased median lifespan by ~ 9%. EPI and HAL, but not MIT, increased 90% survival. In addition to adding 3 new agents to the list of interventions identified by the ITP that extend lifespan, this report continues the strong male bias in the efficacy of life-extending drugs identified so far.

Keywords: Epicatechin; Genetically heterogeneous mice; Halofuginone; Mitoglitazone; Survival.

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Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests. Note: SH has the following affiliations, but all are related to methylation data, of which there is none in this report: The Regents of the University of California are the sole owner of patents and patent applications directed at epigenetic biomarkers for which Steve Horvath is a named inventor; SH is a founder and paid consultant of the non-profit Epigenetic Clock Development Foundation that licenses these patents. SH is a Principal Investigator at the Altos Labs, Cambridge Institute of Science, a biomedical company that works on rejuvenation.

References

1. Nadon NL, Strong R, Miller RA, Nelson J, Javors M, Sharp ZD, et al. Design of aging intervention studies: the NIA interventions testing program. Age. 2008;30(4):187–99. https://doi.org/10.1007/s11357-008-9048-1 . - DOI - PubMed - PMC
1. Strong R, Miller RA, Astle CM, Floyd RA, Flurkey K, Hensley KL, et al. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell. 2008;7(5):641–50. https://doi.org/10.1111/j.1474-9726.2008.00414.x . - DOI - PubMed
1. Harrison DE, Strong R, Allison DB, Ames BN, Astle CM, Atamna H, et al. Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell. 2014;13(2):273–82. https://doi.org/10.1111/acel.12170 . - DOI - 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 α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell. 2016;15(5):872–84. https://doi.org/10.1111/acel.12496 . - DOI - PubMed - PMC
1. Harrison DE, Strong R, Reifsnyder P, Kumar N, Fernandez E, Flurkey K, et al. 17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. Aging Cell. 2021;20(5):e13328. https://doi.org/10.1111/acel.13328 . - DOI - PubMed - PMC

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Extension of lifespan by epicatechin, halofuginone and mitoglitazone in male but not female genetically heterogeneous mice

Affiliations

Extension of lifespan by epicatechin, halofuginone and mitoglitazone in male but not female genetically heterogeneous mice

Authors

Affiliations

Abstract

Conflict of interest statement

References

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