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

Abstract

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

Effects of Human LAV-BPIFB4 Gene Therapy on the Epigenetic Clock and Health of Aged Mice

“…coeff. = −0.329; p < 0.001) ( Figure 2 A–C), as previously demonstrated [ 2 ]. The regression analysis estimated that the epigenetic age increases by 7 weeks for each 0.1 increase in CFI, by 2.9 weeks for each 0.1 decrease in PFS and by 6.8 weeks for each 0.1 decrease in VS ( Figure 2 A–C).…”

“…Moreover, we demonstrated that the relationship between epigenetic and functional changes is independent of the treatment, consistent with an effect of the treatment on both parameters. We further explained that the LAV therapy positively affects the Vitality Score, corroborating this tool as a reliable predictor of global health status [ 2 ]. The delayed effect on the Vitality Score, highlighted two months after the impact on DNA methylation, supports the concept of a non-synchronicity between molecular and functional outcomes [ 3 ].…”

“…Since we previously demonstrated (i) a delay in the progression of frailty in LAV-BPIFB4-AAV-injected old mice [ 18 ] and (ii) a correlation between the 3 CpG epigenetic age and the frailty scores in C57BL6/J mice [ 2 ], we investigated whether and at what extent the LAV-BPIFB4 gene therapy may affect the relationship between epigenetic age and frailty. Therefore, the frailty scores (CFI, PFS and VS) were recorded at t0 and post-treatment, with monthly frequency from t1 to t3 ( Figure 1 A).…”

“…The C57BL/6J strain is the most used of all inbred mouse strains. With an average lifespan of about 28 months, exceptionally reaching 36 months [ 1 , 2 ], C57BL/6J mice allow the development of longitudinal studies on longevity, which are harder to perform in humans. Moreover, several biomarkers of aging, measurable parameters associated with age-related changes, have been identified and validated in mice, like those used for humans.…”

“…The Clinical Frailty Index, a measure of frailty based on a clinical evaluation of health deficits, tightly correlates with the risk of disease and death, and is used to predict biological age and survival, in humans as well as in mice [ 16 , 17 ]. A recent longitudinal study on a large cohort of mice developed a novel frailty assessment tool, named the Vitality Score (VS), which combines the Clinical Frailty Index (CFI) with a new Physical Function Score (PFS), a continuous measure of the overall physical performance summarizing the five Fried’s areas of frailty (shrinkness, weakness, endurance, slowness and activity) [ 2 ]. The combined VS inversely correlates with chronological age, declines as death approaches, predicts mortality and shows a negative correlation with biomarkers of aging, including the epigenetic clock, thus providing an overall evaluation of the health status [ 2 ].…”