Comprehensive longitudinal non-invasive quantification of healthspan and frailty in a large cohort (n=546) of geriatric C57BL/6 J mice

Frailty is an age-related condition characterized by a multisystem functional decline, increased vulnerability to stressors, and adverse health outcomes. Quantifying the degree of frailty in humans and animals is a health measure useful for translational geroscience research. Two frailty measurements, namely the frailty phenotype (FP) and the clinical frailty index (CFI), have been validated in mice and are frequently applied in preclinical research. However, these two tools are based on different concepts and do not necessarily identify the same mice as frail. In particular, the FP is based on a dichotomous classification that suffers from high sample size requirements and misclassification problems. Based on the monthly longitudinal non-invasive assessment of frailty in a large cohort of mice, here we develop an alternative scoring method, which we called physical function score (PFS), proposed as a continuous variable that resumes into a unique function, the five criteria included in the FP. This score would not only reduce misclassification of frailty but it also makes the two tools, PFS and CFI, integrable to provide an overall measurement of health, named vitality score (VS) in aging mice. VS displays a higher association with mortality than PFS or CFI and correlates with biomarkers related to the accumulation of senescent cells and the epigenetic clock. This longitudinal non-invasive assessment strategy and the VS may help to overcome the different sensitivity in frailty identification, reduce the sample size in longitudinal experiments, and establish the effectiveness of therapeutic/preventive interventions for frailty or other age-related diseases in geriatric animals.

Automated summary

Frailty is an age-related condition characterized by functional decline, vulnerability to stressors, and adverse health outcomes. Two validated measurements, frailty phenotype (FP) and clinical frailty index (CFI), have limitations in identifying frail mice. In this study, a physical function score (PFS) was developed as a continuous variable integrating the criteria of FP to reduce misclassification of frailty. The PFS, along with CFI, was used to calculate a vitality score (VS) in aging mice, which showed higher association with mortality and correlated with biomarkers linked to senescent cells and the epigenetic clock. This non-invasive assessment and the VS may improve frailty identification, reduce sample size, and evaluate interventions for age-related diseases in geriatric animals.