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 (FRailty Inferred Geriatric Health Timeline [FRIGHT] clock), predicted life expectancy (Analysis of FRAIlty and Death [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 end point. 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 = .005; male = 0.30 ± 0.02 vs 0.22 ± 0.02; p = .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 life span 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.

Keywords: Biological age; Inflammation; Life expectancy; Sex differences.

Figure 1.

Voluntary exercise had no impact on mortality but reduced frailty in aging male and female mice. Cumulative distance run for females (A, n = 11) and males (B, n = 6) illustrates heterogeneity in the total distance run over the course of the study in both sexes. Mean ± SEM exercise parameters including bouts/day (C), bout duration (D), and peak rate (E) were similar in both sexes (n = 6 female and 5 male mice; analyzed with a Student’s t test). Exercise did not affect the probability of survival assessed with a Log-rank test regardless of sex (F). Voluntary aerobic exercise attenuated the development of frailty in females (G, exercise n = 11–6, sedentary n = 11–5) and males (H, exercise n = 6–5, sedentary n = 6–5). Group differences were evaluated with a mixed-effects model. (F = female, M = male, EP = end point; * denotes significant difference between sedentary and exercise groups; # denotes significant effect of time; p < .05).

Figure 2.

Impact of voluntary exercise on FRailty Inferred Geriatric Health Timeline (FRIGHT) and Analysis of FRAIlty and Death (AFRAID) scores in aging male and female mice. FRIGHT scores (predicted biological age) declined over time in exercised compared to sedentary females, although this was not statistically significant (A). By contrast, FRIGHT scores increased with time in males and this effect was statistically significant for sedentary mice at the end point (B). AFRAID scores (estimated life expectancy) showed a significant decline with age in females (C), an effect that was not seen in males (D). Group differences were evaluated with a mixed-effects model. EP = end point. (* denotes significant difference between sedentary and exercise groups; # denotes significant effect of time; p < .05).

Figure 3.

Cytokine levels were graded by exercise volume in aging female mice. Serum cytokines (n = 14) were categorized into pro-inflammatory cytokines (A–N), chemokines (O–T), and anti-inflammatory cytokines (Q–W). Values were plotted as a function of exercise (bouts/day), using the average bouts/day for the 5 previous days before serum collection. Data were analyzed with a Pearson’s correlation and a linear regression line was drawn only if p < .05.