The association of frailty with age and lifespan in mice differs by strain and sex

Dantong Zhu; Cara L. Green; Sarah J. Mitchell; Michael R. MacArthur; Elise S. Bisset; John Mach; Judy Z. Wu; Brady A. Samuelson; Anastasia Shindyapina; Alibek Moldakozhayev; Albina Tskhay; Alexander Tyshkovskiy; Vadim N. Gladyshev; David A. Sinclair; Susan E. Howlett; Sarah N. Hilmer; Dudley W. Lamming; Alice E. Kane

doi:10.1093/gerona/glag167

The association of frailty with age and lifespan in mice differs by strain and sex

Dantong Zhu
, Cara L. Green
, Sarah J. Mitchell
, Michael R. MacArthur
, Elise S. Bisset
, John Mach
, Judy Z. Wu
, Brady A. Samuelson
, Anastasia Shindyapina
, Alibek Moldakozhayev
, Albina Tskhay
, Alexander Tyshkovskiy
, Vadim N. Gladyshev
, David A. Sinclair
, Susan E. Howlett
, Sarah N. Hilmer
, Dudley W. Lamming
, Alice E. Kane

Institute for Systems Biology
Department of Medicine
University of Wisconsin-Madison
Princeton University
Dalhousie University
North Sydney Local Health District
Harvard University
Retro Biosciences
Broad Institute of MIT and Harvard
McGill University
Research Institute of the McGill University Health Centre
Sainte-Justine Hospital
Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging
University of Washington

Research output: Contribution to journal › Article › peer-review

Abstract

Frailty indices have been assessed in mouse models for more than a decade, but the effect of sex and strain on frailty outcomes remains poorly understood. Here, we collated and harmonized item-level 31-item clinical frailty index (FI) and lifespan data from 17 independent cohorts, including 1,564 naturally aging mice (690 females, 874 males) across five commonly used mouse strains or substrains: C57BL/6JNIA, C57BL/6N, C57BL/6J, UM-HET3, and Diversity Outbred. A total of 3,665 observations were included across cross-sectional and longitudinal studies, some previously published, with 2,192 observations linked to known age at death. Across all cohorts, FI increased significantly with chronological age, but the rate of frailty accumulation differed by strain. Sex differences in age-associated frailty trajectories were evident only in C57BL/6JNIA mice. Significant strain- and sex-specific differences in both survival and health span were observed, with males generally outliving females, although sex effects varied by strain. FI was strongly associated with lifespan independent of age, although age-dependent effects emerged in specific strains with notable sex-specific patterns. At the level of individual frailty items, most health deficits showed strain-dependent associations with age and lifespan. Collectively, these findings demonstrate that the relationships between frailty, chronological age, and lifespan are strongly modulated by strain and sex. This work highlights the importance of accounting for strain and sex as factors when investigating and utilizing frailty in preclinical models.

Original language	English
Article number	glag167
Number of pages	12
Journal	The journals of gerontology. Series A, Biological sciences and medical sciences
Volume	81
Issue number	8
Early online date	26 Jun 2026
DOIs	https://doi.org/10.1093/gerona/glag167
Publication status	Published - 31 Aug 2026

Data Availability Statement

Mice frailty data and R markdown file for data analysis are available at https://github.com/Kane-Lab-ISB/Frailty-association-with-age-and-lifespan-across-mice-strains.

Funding

Alice E. Kane was supported by NIH/NIA R00AG070102 and a generous gift from Daniel T. Ling and Lee Obrzut. The Lamming lab was supported in part by the NIA (AG056771, AG062328, AG081482, AG084156, AG085898, and AG094153). Cara L. Green was supported in part by grant HF-AGE AGE-009 from the Hevolution Foundation. Sarah J. Mitchell was supported by the National Institute on Aging (P01AG055369) and by Zafgen, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NIH funds were used to support the original data collection for several studies, but not directly to support this secondary analysis. Elise S. Bisset and Susan E. Howlett at Dalhousie University were funded in part by the Canada Biomedical Research Fund, Biosciences Research Infrastructure Fund, and a transformational grant from the River Phillips Foundation (RPTMED090924-05). John Mach and the study at the Kolling Institute was funded by the Penney Aging Research Unit, Royal North Shore Hospital, Australia and the Ramsay Research and Teaching Fund, Royal North Shore Hospital, Australia. Vadim N. Gladyshev is supported by NIA and Hevolution.

Keywords

Deficit accumulation
Frailty index
Longitudinal study
Sex differences

ASJC Scopus subject areas

Ageing
Geriatrics and Gerontology

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10.1093/gerona/glag167Licence: CC BY-NC-ND

Cite this

Zhu, D., Green, C. L., Mitchell, S. J., MacArthur, M. R., Bisset, E. S., Mach, J., Wu, J. Z., Samuelson, B. A., Shindyapina, A., Moldakozhayev, A., Tskhay, A., Tyshkovskiy, A., Gladyshev, V. N., Sinclair, D. A., Howlett, S. E., Hilmer, S. N., Lamming, D. W., & Kane, A. E. (2026). The association of frailty with age and lifespan in mice differs by strain and sex. The journals of gerontology. Series A, Biological sciences and medical sciences, 81(8), Article glag167. https://doi.org/10.1093/gerona/glag167

Zhu, D, Green, CL, Mitchell, SJ, MacArthur, MR, Bisset, ES, Mach, J, Wu, JZ, Samuelson, BA, Shindyapina, A, Moldakozhayev, A, Tskhay, A, Tyshkovskiy, A, Gladyshev, VN, Sinclair, DA, Howlett, SE, Hilmer, SN, Lamming, DW & Kane, AE 2026, 'The association of frailty with age and lifespan in mice differs by strain and sex', The journals of gerontology. Series A, Biological sciences and medical sciences, vol. 81, no. 8, glag167. https://doi.org/10.1093/gerona/glag167

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abstract = "Frailty indices have been assessed in mouse models for more than a decade, but the effect of sex and strain on frailty outcomes remains poorly understood. Here, we collated and harmonized item-level 31-item clinical frailty index (FI) and lifespan data from 17 independent cohorts, including 1,564 naturally aging mice (690 females, 874 males) across five commonly used mouse strains or substrains: C57BL/6JNIA, C57BL/6N, C57BL/6J, UM-HET3, and Diversity Outbred. A total of 3,665 observations were included across cross-sectional and longitudinal studies, some previously published, with 2,192 observations linked to known age at death. Across all cohorts, FI increased significantly with chronological age, but the rate of frailty accumulation differed by strain. Sex differences in age-associated frailty trajectories were evident only in C57BL/6JNIA mice. Significant strain- and sex-specific differences in both survival and health span were observed, with males generally outliving females, although sex effects varied by strain. FI was strongly associated with lifespan independent of age, although age-dependent effects emerged in specific strains with notable sex-specific patterns. At the level of individual frailty items, most health deficits showed strain-dependent associations with age and lifespan. Collectively, these findings demonstrate that the relationships between frailty, chronological age, and lifespan are strongly modulated by strain and sex. This work highlights the importance of accounting for strain and sex as factors when investigating and utilizing frailty in preclinical models.",

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AU - Mach, John

AU - Wu, Judy Z.

AU - Samuelson, Brady A.

AU - Shindyapina, Anastasia

AU - Moldakozhayev, Alibek

AU - Tskhay, Albina

AU - Tyshkovskiy, Alexander

AU - Gladyshev, Vadim N.

AU - Sinclair, David A.

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ER -

The association of frailty with age and lifespan in mice differs by strain and sex

Abstract

Data Availability Statement

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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