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

aging obesity exercise

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#1 Engadin

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Posted 31 May 2019 - 04:57 PM



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.





The number of overweight and obese older adults is steadily increasing. Of Americans age 65 or older, more than 62% have a body mass index (BMI) ≥25 and 30% have a BMI ≥ 30 (Kalish, 2016). Aging and obesity dramatically increase the risk for an array of chronic and comorbid conditions that truncate healthspan, the period of disease‐ and disability‐free life. Devising effective and safe solutions to health challenges arising from the convergence of aging and obesity is, therefore, a decisive priority. The multifaceted consequences of obesity at older ages have highlighted the need for interventions that target fundamental metabolic and aging pathways, under the hypothesis that targeting central mechanism may provide multisystem benefit. While several pharmacological approaches are being pursued (Longo et al., 2015), physical exercise and dietary interventions unequivocally improve the health of multiple organ systems, at least in young mammals.


Long‐term aerobic exercise training enhances body composition and reduces the risk of cardiovascular disease, cancer, dementia, and physical frailty, among other chronic conditions (Pedersen & Saltin, 2006). Similarly, time‐restricted feeding (TRF), which is ad libitum food access limited to an 8‐ to 12‐hr period daily, robustly reprograms metabolic physiology. In young mice, TRF beneficially impacts a range of health parameters including diurnal rhythm, body composition, glucose tolerance, insulin resistance, hepatic metabolism, and aspects of inflammation (Chaix, Zarrinpar, Miu, & Panda, 2014; Delahaye et al., 2018; Hatori et al., 2012; Sherman et al., 2012; Sundaram & Yan, 2016). Although metabolic enhancements have also been observed in middle‐aged mice (Chaix et al., 2014; Duncan et al., 2016), we are unaware of any studies that have tested whether aged, obese mice experience healthspan benefits through TRF, and to our knowledge, cardiovascular function following TRF has not been explored in young or aged mice. Similarly, while we and many others have extensively explored the effects of exercise in young and middle‐aged mice (Schafer et al., 2016), far fewer studies have comprehensively examined the health effects of a late‐life exercise intervention in obese mice. It is possible that benefits identified in youth may not unanimously translate to older ages, given that declines in systemic plasticity and metabolic flexibility accompany aging.


Here, we performed a comparative effectiveness study of voluntary running wheel exercise versus TRF on multiple parameters of healthspan in aged mice with diet‐induced obesity. We focused our healthspan profiling on phenotype domains strongly linked to obesity and aging, namely body composition, physical and cardiovascular function, ADL behavior, metabolism, and pathology. We demonstrate that exercise and TRF, even when initiated in late‐life, are distinctly able to improve multiple domains of healthspan in obese mice, including body composition, metabolism, physical function, ADL behavior, and liver pathology. Critically, TRF adversely affects both lean mass and vascular function. Consequently, our parallel assessments of healthspan in aging and obesity indicate that exercise and TRF confer overlapping, yet distinct benefits. Our findings confirm the safety of exercise, but elicit caution and warrant further study of TRF as an intervention to improve late‐life health.





2.1 TRF and exercise remodel body composition


To comparatively study the healthspan benefits conferred by aerobic exercise versus TRF in aged, obese mice, we began by administering 6‐month‐old mice a standard chow diet (normal diet [ND]) or fast‐food diet (FD), enriched with saturated fat, cholesterol, and fructose. At 20 months of age, a time point approximated to be a human equivalent age of 60 years, mice on the FD were randomized to: continue ad libitum FD with sedentary lifestyle (FD‐SD), receive ad libitum FD limited daily to an 8‐hr period of the dark cycle with sedentary lifestyle (FD‐TRF), or ad libitum FD with 24‐hr access to running wheels (FD‐EX; Figure 1a). Mice were maintained on the interventions for 4 months and were euthanized at 24 months of age, a time point approximated to be a human equivalent age of 70 years. Average daily energy intake from food and high fructose water measured over a 12‐week period during the 4‐month intervention period did not statistically differ among aged mouse groups (Figure S1A). Body weight normalized energy intake, however, was slightly lower in FD‐SD mice, compared to ND‐SD (Figure S1B), which is consistent with prior observations in young sedentary, ad libitum‐fed ND and FD mice (Hatori et al., 2012). FD‐EX mice ran 1.3 mean and 0.7 median kilometers per day. A group of 6‐month‐old sedentary mice fed ad libitum ND (ND‐Y) was also assessed at endpoint to determine aging effects that were obesity‐ and intervention‐independent. All mice were healthspan phenotyped in the month preceding necropsy. Nine mice died during the 4‐month interventional window prior to necropsy: 1/8 ND‐SD (13%), 4/11 FD‐SD (36%), and 4/10 FD‐TRF (40%). No premature mortality occurred in the FD‐EX group (n = 10) (Figure 1b), corresponding to a trend toward improved survival for exercised mice, relative to FD‐SD mice (Fischer's exact test: p = 0.0902). Healthspan data correspond only to mice euthanized at endpoint.





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. © 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)



At 20 months of age and prior to randomization, mice maintained on the FD weighed 34% more (Figure 1c) and were comprised of 56% more fat mass and 20% less lean mass, relative to ND‐SD mice. During the 4‐month intervention, aged mice in all experimental groups underwent significant changes in body composition. ND‐SD mice lost an average of 3 g or 7% of their body weight (Figure 1d), which corresponded to a significant reduction in fat mass (Figure 1e). A trend toward reduced body weight (p = 0.0562) was identified in FD‐SD mice (Figure 1d), which corresponded to a significant reduction in lean mass (Figure 1f). FD‐TRF lost an average of 10 g or 20% of their body weight, and FD‐EX lost an average of 6 g or 12% of body weight (Figure 1d). Both TRF and exercised mice lost an average of 6 g of fat mass (Figure 1e). FD‐EX mice maintained relatively stable lean mass during the 4‐month intervention window, but FD‐TRF mice lost an average of 2 g of lean mass (Figure 1f). Following intervention onset, FD‐TRF mice that died spontaneously were not able to stabilize their body mass within a week following diet introduction (Figure S2A). This outcome was not associated with anorexic behavior, since TRF mice that died prematurely consumed average energy equivalent to those that survived until necropsy (Figure S2B). Accordingly, we speculate that maladaptive catabolic processes may have occurred in aged FD‐TRF mice, which may have been dependent on impaired ability to maintain lean mass. Conversely, exercised mice maintained lean mass and had reduced total body fat.



2.2 TRF and exercise differentially alter physical function and nesting behavior


We next tested the effects of the interventions in the context of aging and obesity on physical function and nest building performance. Physical function, a key parameter of healthspan decline in humans and rodents, was measured by the duration mice ran to exhaustion on a motorized treadmill. Diet‐induced obesity significantly exacerbated the shift in age‐dependent physical decline, with FD‐SD mice running significantly shorter durations, relative to ND‐Y and ND‐SD mice (Figure 2a). Exercise improved this outcome, with FD‐EX mice running significantly greater mean durations, relative to FD‐SD mice. TRF did not improve physical function, as measured by the treadmill test.




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)



Nest building is an ADL task that models executive and personality changes often observed in older adults with cognitive decline (Deacon, 2006). We observed a non‐significant reduction in nest building performance as a function of normal aging in ND‐SD, relative to ND‐Y mice (Figure 2b). Obesity exacerbated the age‐related change, with FD‐SD mice producing nests of poorer quality than those of ND‐Y or ND‐SD mice. The obesity effect was improved by TRF, but exercise did not improve nest building performance.



2.3 TRF alters metabolic function


To assess metabolic function, we began by implementing whole‐body calorimetry. As indicated by respiratory exchange ratio (RER), ND‐fed mice displayed natural diurnal rhythms, reflective of greater metabolic activity during the dark cycle (Figure 3a,b). FD‐SD mice displayed an absence of RER cyclicity, maintaining consistently low RERs throughout both the dark and light cycle. TRF dramatically altered RER rhythm, with FD‐TRF mice exhibiting elevated RERs during the dark cycle, suggestive of higher carbohydrate utilization. RERs of FD‐TRF mice dropped precipitously following fasting onset, suggestive of a shift to higher fat utilization. Relative to TRF, exercise had a reduced effect on RER cyclicity; however, FD‐EX mice maintained RER levels that were similar to ND‐Y mice, indicative of potential benefit.






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