Life extension by calorie restriction (CR) has been widely reported in a variety of species and remains on the forefront of anti-aging intervention studies. We report healthspan and survival effects of CR from a 23-year study in rhesus macaques conducted at the National Institute on Aging (NIA). CR initiated at older ages did not increase survival relative to Controls; however, CR monkeys demonstrated an improved metabolic profile and may have less oxidative stress as indicated by plasma isoprostane levels. When initiated in young monkeys, there was a trend (p=0.06) for a delay in age-associated disease onset in CR monkeys; but again, survival curves were not improved, in contrast to another study reported in the literature. This suggests that the effects of CR in a long-lived animal are complex and likely dependent on a variety of environmental, nutritional, and genetic factors.

Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species but its impact in nonhuman primates has been controversial. In the late 1980s two parallel studies were initiated to determine the effect of CR in rhesus monkeys. The University of Wisconsin study reported a significant positive impact of CR on survival, but the National Institute on Aging study detected no significant survival effect. Here we present a direct comparison of longitudinal data from both studies including survival, bodyweight, food intake, fasting glucose levels and age-related morbidity. We describe differences in study design that could contribute to differences in outcomes, and we report species specificity in the impact of CR in terms of optimal onset and diet. Taken together these data confirm that health benefits of CR are conserved in monkeys and suggest that CR mechanisms are likely translatable to human health.

Summary Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time those of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15 month-old mice the exercise capacity of 3 month-old mice. This study uncovers a bone to muscle feed-forward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity.

SUMMARY Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here we show that a muscle secretory factor, Cathepsin B (CTSB) protein, is important for cognitive benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. In addition, in male wildtype (WT), but not CTSB knockout (KO) mice running enhanced adult hippocampal neurogenesis and spatial memory. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a multifunctional protein, P11, dependent mechanism. Interestingly, in Rhesus monkeys and humans treadmill exercise elevated CTSB in plasma. In humans CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition.