Late-life time-restricted feeding and exercise differentially alter healthspan in obesity

Abstract

Aging and obesity increase multimorbidity and disability risk, and determining interventions for reversing healthspan decline is a critical public health priority. Exercise and time-restricted feeding (TRF) benefit multiple health parameters when initiated in early life, but their efficacy and safety when initiated at older ages are uncertain. Here, we tested the effects of exercise versus TRF in diet-induced obese, aged mice from 20 to 24 months of age. We characterized healthspan across key domains: body composition, physical, metabolic, and cardiovascular function, activity of daily living (ADL) behavior, and pathology. We demonstrate that both exercise and TRF improved aspects of body composition. Exercise uniquely benefited physical function, and TRF uniquely benefited metabolism, ADL behavior, and circulating indicators of liver pathology. No adverse outcomes were observed in exercised mice, but in contrast, lean mass and cardiovascular maladaptations were observed following TRF. Through a composite index of benefits and risks, we conclude the net healthspan benefits afforded by exercise are more favorable than those of TRF. Extrapolating to obese older adults, exercise is a safe and effective option for healthspan improvement, but additional comprehensive studies are warranted before recommending TRF.

Keywords: aging; exercise; healthspan; obesity; physical activity; time-restricted feeding.

Figure 1

Time‐restricted feeding and exercise uniquely influence survival and body composition in aged, obese mice. (a) Schematic description of experimental mouse groups. (b) Mortality of aged mice during the 4‐month intervention phase. (c) Longitudinal mean body weight throughout the entire study. Total (d) body, (e) fat, and (f) lean mass in grams (g) at intervention onset (age 20 months; open circles) and endpoint (age 24 months, filled circles) are depicted (paired t‐tests) (n = 6–10) (p < *0.05,**0.01,***0.005) (ND‐SD = old, sedentary, ad libitum (AL) normal diet; FD‐SD = old, sedentary, AL fast‐food diet; FD‐TRF = old, sedentary, 8 hr dark cycle AL access to fast‐food diet; FD‐EX = old, voluntary running wheels, AL fast‐food diet)

Figure 2

Exercise improves physical function and time‐restricted feeding improves nesting behavior in aged, obese mice. (a) Duration ran to exhaustion was assessed on a motorized treadmill test (ANOVA). (b) Nest quality was assessed at 1, 3, 5, and 24 hr in an activity of daily living behavioral test (two‐way ANOVA) (n = 5–10) (Mean ± SEM) (p < *0.05,**0.01,***0.005) (ND‐Y = young, sedentary, ad libitum normal diet; ND‐SD = old, sedentary, ad libitum normal diet; FD‐SD = old, sedentary, ad libitum fast‐food diet; FD‐TRF = old, sedentary, 8‐hr dark cycle ad libitum access to fast‐food diet; FD‐EX = old, voluntary running wheels, ad libitum fast‐food diet)

Figure 3

Time‐restricted feeding alters metabolism. (a) Average respiratory exchange ratios (RER) over one 12‐hr dark (black bar), 12‐hr light (white bar) cycle are indicated. FD‐TRF mice received food and high fructose water during the first 0.5–8.5 hr of the dark cycle (dotted line indicates food removal). All other groups received food ad libitum. (b) Quantification reflecting total mean RERs during the dark and light cycles (ANOVA per phase). (c) Insulin levels in nonfasted plasma were assessed at endpoint (ANOVA). (d) Fasted glucose levels were assessed at the beginning of a (e) GTT, in which 1.25 g/kg glucose was administered intraperitoneally, and circulating glucose levels were measured 15, 30, 60, 90, and 120 min later (two‐way ANOVA) (n = 5–10) (Mean ± SEM) (p < *0.05,**0.01,***0.005) (ND‐Y = young, sedentary, ad libitum normal diet; ND‐SD = old, sedentary, ad libitum normal diet; FD‐SD = old, sedentary, ad libitum fast‐food diet; FD‐TRF = old, sedentary, 8‐hr dark cycle ad libitum access to fast‐food diet; FD‐EX = old, voluntary running wheels, ad libitum fast‐food diet)

Figure 4

Time‐restricted feeding influences cardiovascular function. Echocardiography was used to assess (a) left ventricular mass (normalized to body weight), (b) left ventricular internal dimensions at end‐diastole, and (c) left ventricular ejection fraction (ANOVA). Isolated carotid artery segments were assessed in a pressurized organ chamber bath system to determine changes in vessel diameter in response to (d) acetylcholine, (e) DEA‐NONOate, and (f) passive pressure (two‐way ANOVA) (n = 5–10) (Mean ± SEM) (p < *0.05,**0.01,***0.005) (ND‐Y = young, sedentary, ad libitum normal diet; ND‐SD = old, sedentary, ad libitum normal diet; FD‐SD = old, sedentary, ad libitum fast‐food diet; FD‐TRF = old, sedentary, 8‐hr dark cycle ad libitum access to fast‐food diet; FD‐EX = old, voluntary running wheels, ad libitum fast‐food diet)

Figure 5

Effect of exercise and time‐restricted feeding on tumor burden and circulating biomarkers of liver health. (a) Evidence of gross pathological changes consistent with tumor burden was assessed in all experimental groups. Circulating levels of liver enzymes (b) alkaline phosphatase and (c) alanine aminotransferase were analyzed in blood collected at endpoint (ANOVA) (n = 5–10) (Mean ± SEM) (p < *0.05,**0.01,***0.005) (ND‐Y = young, sedentary, ad libitum normal diet; ND‐SD = old, sedentary, ad libitum normal diet; FD‐SD = old, sedentary, ad libitum fast‐food diet; FD‐TRF = old, sedentary, 8‐hr dark cycle ad libitum access to fast‐food diet; FD‐EX = old, voluntary running wheels, ad libitum fast‐food diet)