To investigate the translatability of CR s

To investigate the translatability of CR\'s beneficial effects from rodents to primates, three independent rhesus monkey studies were initiated in the late 1980\'s. Two of these studies are ongoing: one at the National Institute on Aging (NIA) and the other at the Wisconsin National Primate Research Center based at the University of Wisconsin (UW)-Madison. The third study, performed at the University of Maryland reported favorable effects of CR, although the study was focused on obesity and glucoregulation with only a small cohort designated to CR (Bodkin et al., 2003). At the UW, the 25% restriction intervention in a cohort of 76 adult monkeys was associated with significant improvements in morbidity and mortality (Colman et al., 2009). These findings contrasted with the report from the parallel NIA study, where a difference in survival was not observed between groups within the cohort of 121 monkeys, although a trend toward lower morbidity was reported for CR monkeys compared to controls (Mattison et al., 2012). A subsequent report from UW suggested the gap between control and CR was not as great at NIA as for UW (Colman et al., 2014), indicating that comparisons between studies might paint a different picture as to the efficacy of CR in primates. This turned out to be the case (Mattison et al., 2017). Two major differences in study design included the timing of onset of CR and in the implementation of the diet. At UW CR was introduced in adults whereas at NIA CR was initiated separately in juveniles and advanced-age animals. CR did not confer a survival advantage in young onset animals; however, the old-onset NIA cohort, although not different between control and CR within the study, were long-lived compared to UW control fed monkeys. This was reflected in lower bodyweight, lower adiposity, and lower food intake, that for both control and CR paralleled the food intake of UW CR animals. The voluntary lower food intake of old-onset controls resulted in little separation between control and CR monkeys and yielded exceptionally long-lived monkeys. Six of the NIA old-set cohort lived to 40years of age and one lived to 43years of age, a record for rhesus monkeys in captivity. A common outcome of both studies was the significant delay in the incidence of age-related morbidity among CR animals. The take home message from this joint initiative is that CR delays aging in primates, where lower food intake is associated with improvements in health and survival. The implications of this work are broader, first that aging in AN-2728 can be manipulated, supporting the concept that aging is a valuable target for intervention and eventual clinical application, and second, that the mechanisms recruited by CR to impinge on aging will likely have utility in the development of treatments to delay or abrogate age-related disease vulnerability. With evidence that CR is effective in long-lived species the next question is whether its beneficial effects and mechanistic underpinnings are conserved in humans. The hallmarks of mammalian CR include lower adiposity, increased insulin sensitivity, favorable lipid profiles, and increased levels of the adipose-derived hormone adiponectin. Short-term studies of CR in humans have been conducted as part of the multicenter study (CALERIE) in 2 phases. In the first phase of CALERIE studies (CALERIE-I), the metabolic effects of 6 or 12months of CR was evaluated in overweight individuals with a target level of restriction of 20–30%. Favorable changes in body weight, body composition, glucoregulatory function and serum risk factors for cardiovascular disease were reported in CR individuals (Most et al., 2016). These outcomes were consistent with those reported for monkeys on CR (Edwards et al., 1998; Ramsey et al., 2000a), indicating species-conservation in the CR response. The second phase longitudinal CALERIE-II studies investigated the long-term (2years) effects of 25% CR in healthy lean individuals. Results from CALERIE-II studies published so far indicate that the beneficial metabolic effects of CR observed in the 6-month CALERIE pilot studies are sustained with prolonged restriction in energy intake at 12 and 24months. CR individuals displayed metabolic adaptation with reduced total daily energy expenditure at both 12 and 24months and lowered resting metabolic rate after 12months of CR (Ravussin et al., 2015). Reduction in metabolic rate has been previously linked to weight loss in humans (Kinney, 1995), and similar outcomes were reported for the early stages of the monkey CR study (Ramsey et al., 2000b) but were resolved over a longer time frame (Raman et al., 2007; Yamada et al., 2013) indicating this is likely another point of conservation in the CR response between humans and nonhuman primates. Unlike rodents on CR, circulating levels of IGF-1, cortisol, sex hormones and GH secretion were not altered in humans in both CALERIE clinical trials. Insufficient reduction in calorie intake (~11% CR versus the planned 25% CR) could explain some of the discrepancies on CR-induced metabolic changes observed in CALERIE compared with rodent studies; however there is also the possibility that these are species-specific differences in the CR response. IGF-1 and growth stimulating hormones did not differ between control and CR monkeys on 25% CR at UW (Ramsey et al., 2000b), and an independent study at University of Oregon reported no difference in sex hormones with CR implemented at a similar level (Sitzmann et al., 2010). Overall, these studies are highly suggestive that CR\'s effect on aging is translatable to humans and confirm that nonhuman primates do indeed bridge the gap between human and rodent studies.