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 KaneAbstract
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 healthspan 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.