Calorie Restriction In Nonhuman Primates Research Articles

Calorie restriction improves brain health in aging rhesus macaques

Calorie restriction (CR) without malnutrition slows the aging and disease process, prolonging median and maximum lifespan in yeast, worms, fish, flies, and rodents. Studies of CR in non-human primates (Macaca mulatta) indicate a protective effect of CR against aging-related diseases and a salutary effect on brain health. Our group has studied the specific effects of CR on the non-human primate brain using neuroimaging, behavioral, and post-mortem histological techniques and this talk will provide an overview of these findings. Animals in this study were part of the longitudinal “Dietary Restriction and Aging Study” at the Wisconsin National Primate Research Center (WNPRC). Animals were either fed a normal diet or maintained on a moderately restricted diet (approximately 30% reduced intake from baseline), with both groups receiving comparable diet supplements. Using volumetric imaging we demonstrated that CR preserves gray matter cortex in limbic and heteromodal association areas, indicating a positive effect of CR against age-related brain atrophy. Diffusion tensor imaging showed preservation of white matter integrity in the corpus callosum and fronto-occipital fasciculus, superior longitudinal fasciculus, external capsule, and brainstem. CR also attenuated age-related iron accumulation in the basal ganglia, red nucleus, and parietal, temporal, and perirhinal cortex. Decreased iron accumulation was in turn associated with faster performance on fine motor function tests, signifying a protective effect against motor slowness that results during aging. CR moderated the effect of important plasma-based inflammatory markers (e.g. IL-6) on gray and white matter changes in several brain areas, including the parietal and temporal gray matter regions that are sensitive to aging. CR improved glucoregulatory profiles and positively influenced gray matter volume in the hippocampus. Histopathology studies reveal that CR monkeys express significantly lower (∼30%) levels of microglial activation in the hippocampus. Energy metabolism in the hippocampus as indexed by PGC1alpha and GSK3B was preserved in CR. Number of MTL amyloid plaques was however equivalent between groups. Overall, these results recapitulate the neuroprotective effects of CR from lower animal models. Taken together, these findings point to an overall beneficial effect of CR on the brain in this non-human primate model of aging.

Individual patterns in aging: monkey's lessons

Recent research on rhesus monkeys suggest that the effects of calorie restriction in nonhuman primates recapitulate many of the physiological, hematological, hormonal, immunological, and biochemical effects produced in rodents [1,2]. Measurments of markers of age-related diseases such as diabetes, cardiovascular disease, and possibly cancer suggest that restricted monkeys are healthier than ad libitum counterparts [3]. Thus, studies in monkeys are very important for identification and characterization of candidate biomarkers of aging. At least one biomarker, the rate of decrease in plasma dehydroepiandrosterone (DHEA), suggests that calorie restricted monkeys may be aging slowly [3]. The intrinsic factors, contributing to decreased stress adaptability in old animals, namely disturbances of the hypothalamic-pituitary-adrenal (HPA) axis, are likely to be responsible, at least in part, for health deterioration in the aged [4,5]. At the same time it is well known that the heterogeneity is crucial feature of the aging process. There are individual peculiarities in vulnerability and resistance to stresses and stress-related pathologies among different persons due to the heterogeneity of the ageing process. It is of great importance to elucidate the individual specificity of age-related changes of the HPA axis in the context of aging of the organism as a whole and the stress-dependent age pathologies. A paper by Goncharova and colleagues from Research Institute of Medical Primatology at Sochi, Russia [6] renders further support to this important issue and indicate a number of highly relevant points that will have to be taken into consideration for a better understanding of mechanisms involved and possible extrapolations to the situation in humans. Their aim was see in which way the differences in the HPA axis function in young (6-8 years) and old (20-27 years) female rhesus monkeys depends on various behavioral types, under basal conditions, as well as under conditions of acute psycho-emotional stress. It has been found that the monkeys with depression-like behavior demonstrate age-related changes in the HPA axis function, accompanied by maximal absolute and relative hypercortisolemia under basal conditions as well as under stress. The authors have also found that young aggressive monkeys, in comparison with young monkeys of other behavior groups, demonstrated the highest plasma levels of DHEA sulfate and the lowest molar ratios between cortisol and DHEA sulfate. No such differences were observed between old aggressive animals and other behavioral groups. The least pronounced age-related changes in the HPA axis have been revealed for the monkeys with average behavior. Goncharova and colleagues have found, for the first time, that monkeys with depression-like behavior demonstrate age-related changes in HPA axis function that are accompanied by maximal absolute and relative hypercortisolemia under basal conditions, as well as by a significantly greater increase in plasma cortisol levels under acute stress. It worthy to note that taken together these results suggest that age-related dysfunctions of the HPA axis are individual features associated with peculiarities of adaptive behavior of animals. This approach seems very fruitful for future studies. Indeed, nonhuman primates and humans are in physiology of HPA: both species have cortisol as a main glucocorticoid hormone, similar circadian rhythm of HPA activity, age-related decline in DNEA sulfate secretion [7-9]. Furthermore, unlike rodents, nonhuman primates feature the psycho-emotional reactions and adaptive behavior more similar to those in humans. Thus, Goncharova and colleagues studies focused on basic and complex issues which are important for better understanding of individual peculiarities of human aging.

Calorie restriction: what recent results suggest for the future of ageing research

Calorie Restriction (CR) research has expanded rapidly over the past few decades and CR remains the most highly reproducible, environmental intervention to improve health and extend lifespan in animal studies. Although many model organisms have consistently demonstrated positive responses to CR, it remains to be shown whether CR will extend lifespan in humans. Additionally, the current environment of excess caloric consumption and high incidence of overweight/obesity illustrate the improbable nature of the long-term adoption of a CR lifestyle by a significant proportion of the human population. Thus, the search for substances that can reproduce the beneficial physiologic responses of CR without a requisite calorie intake reduction, termed CR mimetics (CRMs), has gained momentum. Recent articles describing health and lifespan results of CR in nonhuman primates and short-term human studies are discussed. Additional consideration is given to the rapidly expanding search for CRMs. The first results from a long-term, randomized, controlled CR study in nonhuman primates showing statistically significant benefits on longevity have now been reported. Additionally, positive results from short-term, randomized, controlled CR studies in humans are suggestive of potential health and longevity gains, while test of proposed CRMs (including rapamycin, resveratrol, 2-deoxyglucose and metformin) have shown both positive and mixed results in rodents. Whether current positive results will translate into longevity gains for humans remains an open question. However, the apparent health benefits that have been observed with CR suggest that regardless of longevity gains, the promotion of healthy ageing and disease prevention may be attainable.

Endocrine alterations in response to calorie restriction in humans

This review focuses on research involving calorie restriction (CR) in humans and the resulting changes observed in endocrine and neuroendocrine systems. Special emphasis is given to the clinical science studies designed to investigate the effects of controlled, high-quality, energy-restricted diets on both biomarkers of longevity and on the development of chronic diseases of human aging. Prolonged CR has been shown to extend both the median and maximal lifespan in a variety of lower species such as yeast, worms, fish, rats and mice. The biological mechanisms of this lifespan extension via CR are not fully elucidated, but possibly involve significant alterations in energy metabolism, oxidative damage, insulin sensitivity and functional changes in both neuroendocrine and autonomic nervous systems. Most of the difficulty in characterizing the systemic endocrine and neuroendocrine changes with aging and CR is due to the limited capability to collect large and multiple blood samples from small animals, which are usually shorter lived, and hence the most studied. Ongoing studies of prolonged CR in humans are now making it possible to analyze changes in the "biomarkers of aging" to unravel some of the mechanisms of its anti-aging phenomenon. With the incremental expansion of research endeavors in the area of energy restriction, data on the effects of CR in non-human primates and human subjects are becoming more accessible. Detailed analyses from controlled human trials involving long-term CR will allow investigators to link observed alterations from body composition and endocrine systems down to changes in molecular pathways and gene expression, with their possible effects on aging.

Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus)

Recent studies from our laboratories and others suggest that calorie restriction (CR) may benefit Alzheimer's disease (AD) by preventing amyloid-beta (Abeta) neuropathology in the mouse models of AD. Moreover, we found that promotion of the NAD+-dependent SIRT1 mediated deacetylase activity, a key regulator in CR extension of life span, may be a mechanism by which CR influences AD-type neuropathology. In this study we continued to explore the role of CR in AD-type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). Monkeys were maintained on the normal and CR diets throughout the entire lifespan until they died of natural causes. We found that 30% CR resulted in reduced contents of Abeta1-40 and Abeta1-42 peptides in the temporal cortex of Squirrel monkeys, relative to control (CON) fed monkeys. The decreased contents of cortical Abeta peptide inversely correlated with SIRT1 protein concentrations in the same brain region; no detectable change in total full-length amyloid-beta protein precursor (AbetaPP) level was found. Most interestingly, we found that 30% CR resulted in a select elevation of alpha- but not beta- or gamma- secretase activity which coincided with decreased ROCK1 protein content in the same brain region, relative to CON group. Collectively, the study suggests that investigation of the role of CR in non-human primates may provide a valuable approach for further clarifying the role of CR in AD.

Calorie restriction in nonhuman primates: mechanisms of reduced morbidity and mortality

Long term chronic calorie restriction (CR) of adult nonhuman primates significantly reduces morbidity and increases median age of death. The present review is focused upon an ongoing study of sustained adult-onset calorie restriction, which has been underway for 15 years. Monkeys, initially calorie restricted at about 10 years of age, are now approximately 25 years old. The median life span of these restricted monkeys is increasing, now exceeding that of ad libitum (AL)-fed monkeys. In our laboratory, maximum life span for AL-fed monkeys appears to be about 40 years. Thus, whether CR can also increase maximal life span, as it does in rodents, cannot be determined for at least another 15 years. The earliest detectable positive benefit on morbidity in these monkeys was previously reported as the prevention of obesity. Current evidence, as reviewed here, suggests that much obesity-associated morbidity is also mitigated by sustained calorie restraint in nonhuman primates. Furthermore, probably because of the prevention of obesity, diabetes has also been prevented. Recent findings include the identification of extraordinary changes in the glycogen synthesis pathway, and on the phosphorylation of glycogen synthase in response to insulin. This calorie restriction-induced prevention of morbidity does not require excessive leanness, but is clearly present when body fat is within the normal range of 10 to 22%, and this is likely to be true in humans as well.

Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk.

The effects of calorie restriction (CR) on life span, disease, and aging in physiological systems have been documented extensively in rodent models. However, whether CR has similar effects in longer-lived species more closely related to humans remains unknown. Studies of CR and aging using nonhuman primates (rhesus monkeys) have been ongoing for several years at the National Institute on Aging and the University of Wisconsin-Madison. The majority of data published from these studies are consistent with the extensive findings reported in rodents. For example, monkeys on CR weigh less and have less body fat. Monkeys on CR also exhibit lower body temperature, fasting blood glucose and insulin, and serum lipids. In addition, insulin sensitivity is increased in monkeys on CR. Recent efforts in the NIA study have focused on the effect of this intervention on risk factors for various age-related diseases, in particular for diabetes and cardiovascular disease. We have shown that monkeys on CR have lower blood pressure, reduced body fat, and a reduced trunk:leg fat ratio. Also, monkeys on CR have reduced triglycerides and cholesterol and have increased levels of HDL2B. Low levels of this HDL subfraction have been associated with increased cardiovascular disease in humans. In short-term studies, older (> 18 years) monkeys on CR exhibit reductions in insulin and triglycerides before changes in body composition and fat distribution became evident. These and other findings have suggested that CR might have beneficial effects on certain disease risk factors independent of reductions in body weight or prevention of obesity.

Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk

The effects of calorie restriction (CR) on life span, disease, and aging in physiological systems have been documented extensively in rodent models. However, whether CR has similar effects in longer-lived species more closely related to humans remains unknown. Studies of CR and aging using nonhuman primates (rhesus monkeys) have been ongoing for several years at the National Institute on Aging and the University of Wisconsin-Madison. The majority of data published from these studies are consistent with the extensive findings reported in rodents. For example, monkeys on CR weigh less and have less body fat. Monkeys on CR also exhibit lower body temperature, fasting blood glucose and insulin, and serum lipids. In addition, insulin sensitivity is increased in monkeys on CR. Recent efforts in the NIA study have focused on the effect of this intervention on risk factors for various age-related diseases, in particular for diabetes and cardiovascular disease. We have shown that monkeys on CR have lower blood pressure, reduced body fat, and a reduced trunk:leg fat ratio. Also, monkeys on CR have reduced triglycerides and cholesterol and have increased levels of HDL2B. Low levels of this HDL subfraction have been associated with increased cardiovascular disease in humans. In short-term studies, older (> 18 years) monkeys on CR exhibit reductions in insulin and triglycerides before changes in body composition and fat distribution became evident. These and other findings have suggested that CR might have beneficial effects on certain disease risk factors independent of reductions in body weight or prevention of obesity.

Calorie restriction in nonhuman primates: mechanisms of reduced morbidity and mortality

Long term chronic calorie restriction (CR) of adult nonhuman primates significantly reduces morbidity and increases median age of death. The present review is focused upon an ongoing study of sustained adult-onset calorie restriction, which has been underway for 15 years. Monkeys, initially calorie restricted at about 10 years of age, are now approximately 25 years old. The median life span of these restricted monkeys is increasing, now exceeding that of ad libitum (AL)-fed monkeys. In our laboratory, maximum life span for AL-fed monkeys appears to be about 40 years. Thus, whether CR can also increase maximal life span, as it does in rodents, cannot be determined for at least another 15 years. The earliest detectable positive benefit on morbidity in these monkeys was previously reported as the prevention of obesity. Current evidence, as reviewed here, suggests that much obesity-associated morbidity is also mitigated by sustained calorie restraint in nonhuman primates. Furthermore, probably because of the prevention of obesity, diabetes has also been prevented. Recent findings include the identification of extraordinary changes in the glycogen synthesis pathway, and on the phosphorylation of glycogen synthase in response to insulin. This calorie restriction-induced prevention of morbidity does not require excessive leanness, but is clearly present when body fat is within the normal range of 10 to 22%, and this is likely to be true in humans as well.

Calorie Restriction in Nonhuman Primates: Implications for Age-Related Disease Risk

Calorie restriction (CR)—undernutrition without malnutrition—ranks among the most reproducible and widely used research paradigms in gerontologic research. This intervention is the only manipulation that has been shown consistently to extend the life span, delay onset and slow tumor progression, and retard physiologic aging in many systems. A large body of literature exists documenting these remarkable effects in such diverse short-lived species as rotifers, water fleas, fish, spiders, hamsters, and laboratory mice and rats. However, it is not known if CR has similar effects in longer-lived species more closely related to humans. Two major studies in rhesus monkeys, one at the National Institute on Aging and the other at the University of Wisconsin, were begun several years ago to address this question. Two similar studies focusing mostly on disease end points such as obesity, diabetes, and cardiovascular disease are also underway at the University of Maryland and Bowman-Gray School of Medicine. These studies have clearly shown that most physiologic responses assessed in monkeys on CR parallel the extensive literature on rodents. This article focuses on data related to various risk factors for age-associated diseases, in particular diabetes and cardiovascular disease. Although it will be several more years before definitive results regarding life span are available, emerging data from the monkey studies strongly suggest that CR alters several disease risk factors and may affect postmaturational aging in some systems. Therefore, it is likely that this nutritional intervention will result in at least moderate increases in the primate life span related to amelioration of certain age-related diseases and their complications.