Physical Resilience as a Predictor of Lifespan and Late-Life Health in Genetically Heterogeneous Mice

Abstract

Dynamic measures of resilience-the ability to resist and recover from a challenge-may be informative of the rate of aging before overt manifestations such as chronic disease, disability, and frailty. From this perspective mid-life resilience may predict longevity and late-life health. To test this hypothesis, we developed simple, reproducible, clinically relevant challenges, and outcome measures of physical resilience that revealed differences between and within age groups of genetically heterogeneous mice, and then examined associations between mid-life resilience and both lifespan and late-life measures of physiological function. We demonstrate that time to recovery from isoflurane anesthesia and weight change following a regimen of chemotherapy significantly differed among young, middle-aged, and older mice, and were more variable in older mice. Females that recovered faster than the median time from anesthesia (more resilient) at 12 months of age lived 8% longer than their counterparts, while more resilient males in mid-life exhibited better cardiac (fractional shortening and left ventricular volumes) and metabolic (glucose tolerance) function at 24 months of age. Moreover, female mice with less than the median weight loss at Day 3 of the cisplatin challenge lived 8% longer than those that lost more weight. In contrast, females who had more weight loss between Days 15 and 20 were relatively protected against early death. These data suggest that measures of physical resilience in mid-life may provide information about individual differences in aging, lifespan, and key parameters of late-life health.

Keywords: Anesthesia; Chemotherapy; Frailty; Healthspan; Stress.

Figure 1.

Older mice exhibit reduced and more variable resilience to anesthesia than younger mice. (A) Transition time in younger (n = 10), middle-aged (n = 12), and older (n = 12) female mice. Analysis by Kruskal–Wallis ANOVA and Dunn’s multiple comparison test. (B) Transition time in (A) younger (n = 10), middle-aged (n = 12), and older (n = 8) male mice. Analysis by one-way ANOVA and Tukey’s multiple comparison test. (C) Walk time in younger, middle-aged, and older female mice. Analysis by one-way ANOVA and Tukey’s multiple comparison test. (D) Walk time in younger, middle-aged, and older male mice. Analysis by ANOVA and Dunnett’s T3 multiple comparisons test. Graphs illustrate individual data points, mean, and standard error of the mean for each group. *, **, and *** denote p < .05, .01, and .001, respectively.

Figure 2.

Older mice exhibit reduced and more variable resilience to chemotherapy than younger mice. (A) Changes in body weight in younger (n = 10), middle-aged (n = 12), and older (n = 11) female mice and (B) younger (n = 10), middle-aged (n = 12), and older (n = 8) male mice administered 2 mg/kg cisplatin for 5 consecutive days. Analysis by repeated-measures 2-way ANOVA and Tukey’s multiple comparison test. Area above the curve (AAC) for changes in body weight between baseline and Day 36 in younger, middle-aged, and older (C) female mice and (D) male mice. Maximal body weight loss in each age group of (E) female mice and (F) male mice. Analysis of AAC and maximal body weight loss within each sex by ANOVA and Dunnett’s T3 multiple comparisons test. Graphs illustrate mean, standard error of the mean, and, in C-F, individual data points for each group. * and ** denote p < .05 and .01, respectively.

Figure 3.

Female mice more resilient to anesthesia in mid-life live longer. (A) Walk times for female mice that had slower (less resilient, n = 25) and faster recovery (more resilient, n = 25) following an anesthesia challenge at 12 months of age. (B) Lifespan curves for less resilient and more resilient female mice based on recovery from anesthesia in mid-life. Comparison of curves by log-rank test, with p-value in upper right quadrant of graph. (C) Walk times and (D) lifespan curves for male mice that had slower (less resilient, n = 25) and faster recovery (more resilient, n = 25) following an anesthesia challenge at 12 months of age. Graphs A and C illustrate individual data points, mean, and standard error of the mean for each group, and data were analyzed by Welch’s unpaired t test *** denotes p < .001.

Figure 4.

Mid-life resilience to anesthesia is positively associated with late-life cardiac and metabolic health in male mice. The associations between walk time following anesthesia at 12 months of age and echocardiography-derived measures of (A) fractional shortening (FS), (B) left ventricular end systolic volume (LVESV), and (C) left ventricular end diastolic volume (LVEDV) at 24 months of age in male mice (n = 13). (D) Association between walk time at 12 months of age following anesthesia in male mice and glucose tolerance, defined by area under the glucose concentration curve (AUC) in male mice (n = 11). The associations between walk time following anesthesia at 12 months of age in female mice and echocardiography-derived measures of (E) FS, (F) LVESV, and (C) LVEDV at 24 months of age in female mice (n = 14). (D) Association between walk time at 12 months of age following anesthesia and glucose tolerance, defined by AUC in female mice (n = 14). Analysis of associations by simple linear regression.

Figure 5.

Female mice more resilient to chemotherapy in mid-life live longer. (A) Female mice that experienced the most (Tertile 1 (T1), n = 15), intermediate (T2, n = 16), and least (T3, n = 16) body weight loss on Day 3 consequent to cisplatin administration at 12 months of age. (B) Comparison of weight change trajectories and (D) lifespan curves for T1, T2, and T3 female mice. (D) Female mice that experienced the most (T1), intermediate (T2), and least (T3) body weight loss on Day 17 and their (E) weight change trajectories and (F) lifespan curves. (G) Male mice that experienced the most (Tertile 1 (T1), n = 13), intermediate (T2, n = 13), and least (T3, n = 12) body weight loss on Day 3 consequent to cisplatin administration at 12 months of age. (H) Comparison of weight change trajectories and (I) lifespan curves for T1, T2, and T3 male mice. (J) Male mice that experienced the most (T1), intermediate (T2), and least (T3) body weight loss on Day 17 and their (K) weight change trajectories and (L) lifespan curves. Graphs A, B, D, and E, and G, H, J, and K illustrate individual data points and/or mean and standard error of the mean for each group. Data in graphs A, D, G, and J analyzed by Kruskal–Wallis ANOVA and Dunn’s multiple comparison test. **, and *** denote p < .01 and .001, respectively.