Calorie restriction and aging

National Institute On Aging

Investigators

Linked publications & trials

Abstract

The aims of this project are to assess the effects of aging and caloric restriction (CR) at a cellular and biochemical level of analysis, to identify physiological mechanisms associated with these effects, and to evaluate interventions/molecular pathways that might alter age-related declines in function. Laboratory studies consistently demonstrate extended lifespan in animals on CR, where total caloric intake is reduced by 10-40% but adequate nutrition is otherwise maintained. CR interventions, either as a reduction of the daily caloric intake or intermittent fasting (cyclic periods of food deprivation), have been also shown to delay the onset and severity of chronic diseases associated with aging, such as cancer, and to extend health span and cognition. Less understood are the underlying mechanisms through which CR, dietary composition, and feeding patterns might act in mitigating phenotypic aging and extending maximum lifespan. In the last several years, we have carried out several studies aimed at elucidating the importance of these variables in conferring metabolic benefits, the maintenance of health, and prolonged lifespan. In brief, A. Impact of dietary composition and feeding patterns in aging. CR experiments conducted in nonhuman primates (NHPs) at the University of Wisconsin (WNPRC) and the NIA revealed that significant differences in survival and health outcomes between the two sites could have been originated from the use of different diets in the NHP CR studies. To further understand the role of macronutrients toward the differences in survival and health outcomes and investigate the underlying mechanisms between the NIA and WNPRC diets, we initiated and completed a study using mice fed the NIA or WNPRC diet under ad libitum, 30% CR, and single meal feeding (MF), which accounted for differences in energy density and calorie intake consumed by the AL mice. A pilot short-term study (3 to 4-mo) in mice has revealed that the two diets gave comparable metabolic effects in terms of bodyweight gain and fasting blood glucose as previously reported in monkeys, indicating the dietary effects are conserved across species. From these data, a longevity study was initiated in 4-mo-old male C57BL/6J mice that were single-housed to allow accurate measurements of daily energy consumption. A systematic collection of physiological, metabolic, and behavioral parameters was performed as well as tissue collection in a subset of mice that was euthanized at 2 years of age for multi-omics analysis. Lastly, a detailed histopathology assessment of the mice was carried out by a board-certified veterinary pathologist. We hypothesized that consumption of the NIA naturally sourced NHP diet would confer survival advantages over the WNPRC-purified diet and that eating patterns (MF and CR vs. AL) would have profound effects on morbidity and mortality regardless of diet composition. The results showed that MF and CR regimes enhanced longevity in either diet vs. AL controls and diet composition alone had no significant impact within feeding regimens. Like CR animals, MF mice gorged, which resulted in extended periods of daily fasting that produced significant improvements in morbidity and mortality compared with AL. Notably, CR and MF protocols were able to delay the age of onset of pathologies and subsequent death; however, the incidence and type of pathologies that mice died with was very much dependent on the diet. For example, WNPRC-fed mice had a higher incidence of fatty liver compared to mice on NIA diet. These results indicate that the health and survival benefits conferred by periods of extended daily fasting, independent of dietary composition, have major implications to human health. Using the same cohorts of mice, we performed multi-omics (transcriptomic-metabolomic) profiling in liver and serum to gain insight into pathways associated with health preservation and survival, irrespective of diet composition and feeding regimens, and then confirmed some of these findings using serum metabolomics from the two previous NHP studies (WNPRC and NIA). Distinct and shared pathways of health and lifespan were untangled following a concerted approach led by experimental design and a rigorous analytical strategy that enabled us to dissect the confounding effects of diet and feeding regimens. This integrated analysis revealed the contribution of a unique metabolic hub involving glycine-serine-threonine metabolism at the core of lifespan, and a pattern of shared pathways related to health improvement. Three papers emanated from this work B. Use of short cycles of very low caloric intake in metabolic health and anti-cancer protection in mice. Diet composition, calories, and fasting times contribute to the maintenance of health. However, the impact of very low-calorie intake (VLCI) achieved with either standard laboratory chow (SD) or a plant-based fasting mimicking diet (FMD) is not fully understood. Hence, we performed two distinct studies to assess the impact of short 4:10 VLCI cycles on metabolic health and anti-cancer protection in mice. Using middle-aged male C57Bl/6 mice, we show that 5 months of short 4:10 VLCI cycles lead to decreases in both fat and lean mass, accompanied by improved physical performance and glucoregulation, and greater metabolic flexibility independent of diet composition. A long-lasting metabolomic reprograming in serum and liver is observed in mice on VLCI cycles with SD, but not FMD. Further, when challenged with an obesogenic diet, cycles of VLCI do not prevent diet-induced obesity nor do they elicit a long-lasting metabolic memory, despite achieving modest metabolic flexibility. Our results highlight the importance of diet composition in mediating the metabolic benefits of short cycles of VLCI. To date, it is unclear whether the fasting time, level of dietary restriction, or nutrient composition is the primary driver behind cancer protection. Hence, the second study is aimed at comparing the potency of daily CR to that of short VLCI cycles of a plant-based diet (FMD) designed to mimic fasting without the chronic restriction of calories and reported to confer anti-cancer protection. Using the murine 4T1 model of triple-negative breast cancer (TBNC), we show that daily CR provides greater protection against primary tumor growth and metastatic burden to the lung, which may be in part due to the unique immune signature observed with daily CR, notably the reduced frequency of the myeloid-derived suppressor cells (MDSCs). C. TRF Study Dietary interventions are valuable strategies for promoting healthy aging. Emerging new evidence highlights the importance of prolonged daily fasting periods for the health and survival benefits of calorie restriction (CR) and time-restricted feeding (TRF). the aim of this study was to assess if limiting the access to AL food for only few hours per day (TRF) may mimic the beneficial effects of a CR diet. D. F1 project In our original study (Mitchell et al., 2016, PMID: 27304509), the role of CR in extending lifespan in laboratory mice was investigated. We found that male and female D2 mice were responsive to CR with maximum lifespan extension at 40% CR while B6 mice of both sexes responded very well to 20% CR, but there was no lifespan extension in 40% CR-fed females when compared to AL-fed controls. These results led us to hypothesize that maternal inheritance may contribute to the life extending properties of CR. E. Impact of time-restricted eating (TRE) and sleep, mood, and quality of life in adults that are overweight or obese. The optimal eating window for Time-Restricted Eating (TRE) remains unclear, particularly regarding its impact on visceral adipose tissue (VAT), which is linked to cardiometabolic morbidity and mortality. To investigate this, 197 participants with overweight or obesity were randomized into four groups: Mediterranean diet alone (UC), early TRE, late TRE, or self-selected TRE, over a 12-week period, with VAT changes measured using magnetic resonance imaging. The study found no significant differences in VAT changes between the TRE groups and the UC group, nor among the three TRE groups themselves. This suggests that adding TRE, regardless of the timing of the eating window, does not provide additional benefits over a Mediterranean diet alone in reducing VAT. A secondary analysis of the trial indicated that there were no significant changes in sleep, mood, or quality of life across the different TRE groups compared to the UC group. These findings suggest that TRE is a safe, well-tolerated, and viable nutritional weight management strategy for adults with overweight or obesity. F. This preclinical study aims to assess the impact of voluntary exercise on the anti-metastatic effects of calorie restriction (CR) in a triple-negative breast cancer (TNBC) mouse model. Our findings highlight the lack of synergy between CR and exercise in reducing tumor growth during chemotherapy in a TNBC model. Additionally, the CR-induced decrease in large metastases is diminished in mice engaged in voluntary exercise. The inconsistent results in the literature underscore the need for more standardized exercise protocols to allow for better comparisons between studies and to draw stronger conclusions about the role of exercise in cancer progression.