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Short-term (1 year) calorie restriction (CR) has been reported to decrease physical activity and metabolic rate in humans and non-human primate models; however, studies examining the very long-term (10 year) effect of CR on these parameters are lacking.The objective of this study was to examine metabolic and behavioral adaptations to long-term CR longitudinally in rhesus macaques.Eighteen (10 male, 8 female) control (C) and 24 (14 male, 10 female) age matched CR rhesus monkeys between 19.6 and 31.9 years old were examined after 13 and 18 years of moderate adult-onset CR. Energy expenditure (EE) was examined by doubly labeled water (DLW; TEE) and respiratory chamber (24 h EE). Physical activity was assessed both by metabolic equivalent (MET) in a respiratory chamber and by an accelerometer. Metabolic cost of movements during 24 h was also calculated. Age and fat-free mass were included as covariates.Adjusted total and 24 h EE were not different between C and CR. Sleeping metabolic rate was significantly lower, and physical activity level was higher in CR than in C independent from the CR-induced changes in body composition. The duration of physical activity above 1.6 METs was significantly higher in CR than in C, and CR had significantly higher accelerometer activity counts than C. Metabolic cost of movements during 24 h was significantly lower in CR than in C. The accelerometer activity counts were significantly decreased after seven years in C animals, but not in CR animals.The results suggest that long-term CR decreases basal metabolic rate, but maintains higher physical activity with lower metabolic cost of movements compared with C.

Dietary restriction (DR) retards aging and extends the maximum lifespan of laboratory mice and rats. To determine whether DR has similar actions in a primate species, we initiated a study in 1989 to investigate the effects of a 30% DR in 30 adult male rhesus monkeys. In 1994, an additional 30 females and 16 males were added to the study. Although the animals are still middle-aged, a few differences have developed between the control and DR animals suggesting that DR may induce physiologic changes in the rhesus monkey similar to those observed in rodents. Fasting basal insulin and glucose concentrations are lower in DR compared to control animals while insulin sensitivity is higher in the restricted animals. DR has also altered circulating LDL in a manner that may inhibit atherogenesis. These results suggest that DR may be slowing some age-related physiologic changes. In addition to measures of glucose and lipid metabolism, the animals are evaluated annually for body composition, energy expenditure, physical activity, hematologic indices, and blood or urinary hormone concentrations. In the next few years, the first animals will reach the average lifespan ( approximately 26 years) of captive rhesus monkeys and it will become possible to determine if DR retards the aging process and extends the lifespan in a primate species.

The long-term health benefits of caloric restriction (CR) are well known but the associated molecular mechanisms are poorly understood despite increasing knowledge of transcriptional and related metabolic changes. We report new metabolic insights into long-term CR in nonhuman primates revealed by the holistic inspection of plasma (1)H NMR spectroscopic metabolic and lipoprotein profiles. The results revealed attenuation of aging-dependant alterations of lipoprotein and energy metabolism by CR, noted by relative increase in HDL and reduction in VLDL levels. Metabonomic analysis also revealed animals exhibiting distinct metabolic trajectories from aging that correlated with higher insulin sensitivity. The plasma profiles of insulin-sensitive animals were marked by higher levels of gluconate and acetate suggesting a CR-modulated increase in metabolic flux through the pentose-phosphate pathway. The metabonomic findings, particularly those that parallel improved insulin sensitivity, are consistent with diminished adiposity in CR monkeys despite aging. The metabolic profile and the associated pathways are compatible with our previous findings that CR-induced gene transcriptional changes in tissue suggest the critical regulation of peroxisome proliferator-activated receptors as a key mechanism. The metabolic phenotyping provided in this study can be used to define a reference molecular profile of CR-associated health benefits and longevity in symbiotic superorganisms and man.

Sarcopenia, the decline in skeletal muscle mass and function with age, contributes to increased frailty and decreased functional performance in the aging human population. The negative health consequences of muscle mass loss emphasize the need for development of a nonhuman primate model for the prevention or attenuation of sarcopenia. The age of onset for muscle mass loss in Rhesus macaques was determined using three datasets; (i) dual-energy X-ray absorptiometry (DXA) data from a cross-sectional study of 90 adult Rhesus monkeys; (ii) lean tissue mass and estimated skeletal muscle mass (ESM) from 727 DXA scans taken in 38 monkeys in a long-term, longitudinal aging study; and, (iii) quadriceps weights taken at necropsy from 13 male and 28 female Rhesus monkeys. These data indicate that both male and female Rhesus monkeys develop sarcopenia with age. The onset of sarcopenia is 14.1±2.8 years in females and 15.8±2.5 years in males. Muscle loss reaches 20% in males by 23.2 years of age and in females by 24.5 years of age. Furthermore, our data indicate percentage declines in ESM similar to those seen in humans with advancing age. These data support the suitability of the Rhesus monkey as a primate sarcopenia model.