Aerobic Exercise Attenuates Frailty in Aging Male and Female C57Bl/6 Mice and Effects Systemic Cytokines Differentially by Sex

Abstract

Aerobic exercise is a promising intervention to attenuate frailty, but preclinical studies have used only male animals. We investigated the impact of voluntary aerobic exercise on frailty, biological age (FRIGHT clock), predicted life expectancy (AFRAID clock) and mortality in both sexes and determined whether exercise was associated with changes in inflammation. Older (21-23 months) male (n=12) and female (n=22) C57Bl/6 mice matched for baseline frailty scores were randomized into exercise (running wheel) and sedentary (no wheel) groups. Frailty index scores were measured biweekly (13 weeks), and 23 serum cytokines were measured at midpoint and endpoint. Exercise levels varied between mice but not between the sexes. Exercise had no effect on mortality, but it attenuated the development of frailty in both sexes (female=0.32±0.04 vs 0.21±0.01; p=0.005; male=0.30±0.02 vs. 0.22±0.02; p=0.042) and reduced frailty in older females after 10 weeks. FRIGHT scores were unaffected by exercise but increased with time in sedentary males indicating increased biological age. Exercise prevented the age-associated decline in AFRAID scores in older females such that exercised females had a longer life expectancy. We investigated whether aerobic exercise was associated with changes in systemic inflammation. Cytokine levels were not affected by exercise in males, but levels of pro-inflammatory cytokines were positively correlated with the frequency of exercise in females. Despite increases in systemic inflammation, exercise reduced frailty and increased lifespan in older females. Thus, voluntary aerobic exercise, even late in life, has beneficial effects on health in both sexes but may be especially helpful in older females.

“Measurements of damage and repair in aging mice and humans reveals that robustness and resilience decrease with age, operate over broad timescales, and are affected differently by interventions”

“…We first establish the trends of repair and damage rates in aging. In Figure 2, we plot the age-dependence of the repair and damage processes in mice and humans for three mouse datasets a) 1 (Keller et al, 2019); b) 2 (Bisset et al, 2021); and c) 3 (Schultz et al, 2020); and d) humans from the ELSA dataset (Phelps et al, 2020). Humans are plotted by decade of baseline age at entry to the study to separate out recruitment effects.…”

“…Terms of the curvature involving the repair rate (green) and the damage rate (pink) are separately shown. Lines represent posterior samples from our Bayesian models for b) Mouse dataset 1 (Keller et al ., 2019), c) Mouse dataset 2 (Bisset et al ., 2021), d) Mouse dataset 3 (Schultz et al ., 2020) and e) ELSA humans (Phelps et al , 2020), plotted separately by decades of baseline age. On all plots, we indicate for which ages the proportion of the posterior for the difference in these terms that is negative is below 0.05; the Bayesian analogue of a p-value testing the contributions of robustness and resilience.…”

“…For the mouse portion of this manuscript, published data on longitudinal health-related deficits in C57BL/6 mice from three papers was used (Keller et al ., 2019 [1]; Bisset et al ., 2021 [2]; Schultz et al ., 2020 [3]). A brief summary of the methods of each paper is below.…”

“…Mouse datasets 1 (Keller et al, 2019) and 2 (Bisset et al, 2021) have additional intervention groups treated with either the ACE inhibitor enalapril, or voluntary aerobic exercise, respectively.…”

“… a) Repair rates, damage rates, and Frailty Index vs age for control mice and mice treated with enalapril from Keller et al 2019. b) Repair rates, damage rates, and Frailty Index vs age for control mice and mice with voluntary exercise from Bisset et al 2021. Both enalapril and exercise impact repair and damage rates, leading to a lower Frailty Index.…”