Calorie Restriction Monkeys Research Articles

Effect of dietary fat and sucrose consumption on cardiac fibrosis in mice and rhesus monkeys.

Calorie restriction (CR) improved health span in 2 longitudinal studies in nonhuman primates (NHPs), yet only the University of Wisconsin (UW) study demonstrated an increase in survival in CR monkeys relative to controls; the National Institute on Aging (NIA) study did not. Here, analysis of left ventricle samples showed that CR did not reduce cardiac fibrosis relative to controls. However, there was a 5.9-fold increase of total fibrosis in UW hearts, compared with NIA hearts. Diet composition was a prominent difference between the studies; therefore, we used the NHP diets to characterize diet-associated molecular and functional changes in the hearts of mice. Consistent with the findings from the NHP samples, mice fed a UW or a modified NIA diet with increased sucrose and fat developed greater cardiac fibrosis compared with mice fed the NIA diet, and transcriptomics analysis revealed diet-induced activation of myocardial oxidative phosphorylation and cardiac muscle contraction pathways.

Impact of dietary fat and sucrose consumption on cardiac fibrosis in rhesus monkeys and mice

Calorie restriction (CR) improved healthspan in two longitudinal studies in nonhuman primates (NHPs) aimed at investigating the effect of this nutritional intervention on markers of health and survival. However, only the University of Wisconsin (UW) study demonstrated an increase in survival in CR monkeys relative to controls; the National Institute on Aging (NIA) study did not. Using samples from these studies, we investigated the effect of chronic CR on myocardial aging. Age‐associated cardiac changes in NHPs are similar to those of humans, and as such, these samples provide a unique opportunity to further explore cardiac aging and factors that may explain some of the different outcomes between the two NHP studies. We analyzed left ventricle (LV) tissue samples from both studies to assess cardiac fibrosis. Although CR did not reduce cardiac fibrosis or hypertrophy in either study relative to controls, there was a 5.9‐fold increase in fibrosis (p<0.0001) in hearts from UW NHPs compared to NIA, irrespective of CR treatment. Differences in study design have been previously described and one important factor was the composition of the diets that were fed during these three‐decades long studies. UW fed a processed, purified diet with higher levels of sucrose and fat (28% sucrose and 10.6% fat by weight), while the NIA NHPs received a complex natural grain‐based diet containing fish oils (3.9% sucrose, 5% fat by weight). To further explore the intriguing possibility that cardiac fibrosis is affected by dietary composition, we performed rodent experiments using the NHP diets to characterize diet‐associated molecular and functional changes in the heart. Six‐month old male C57BL/6 mice were randomized into one for four diet groups: standard mouse chow, the UW diet, NIA diet, or the NIA diet modified to include increased levels of sucrose and fat equivalent to the UW diet [mNIA]) for six months. Cardiac tissue was then analyzed for fibrosis and RNA‐seq analyses of ventricular tissue. Consistent with the findings from the NHP samples, mice fed UW and mNIA diets had higher cardiac fibrosis. Furthermore, RNA‐seq analyses of hearts showed distinct gene expression signatures among the different diets. At the functional level, expression of cardiac contraction and metabolism genes were upregulated following consumption of the diets with higher sucrose and fat content. These NHP and mouse data suggest that higher dietary fat and sucrose may promote myocardial fibrosis.Support or Funding InformationWork in the Lee laboratory was supported by grants AG047131, AG059129, HL119230 from NIH. The NIA study was supported by the Intramural Research Program of the National Institute on Aging, NIH. The UW study was supported by R01AG040178 (RJC) and was made possible in part by NCRR/ORIP grants P51RR000167/P51OD011106 to the WNPRC.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract 270: Long term Caloric Restriction and Myocardial Aging in Non Human Primates

Caloric restriction (CR) has been shown to decrease aging and increase the lifespan of several model organisms. However, in two on-going independent, long-term CR studies in non-human primates (NHP) at the National Institute of Aging (NIA) and University of Wisconsin, Madison (UW) the outcome has been more complex. While CR monkeys in the UW study have experienced a significant increase in lifespan relative to their study controls, this was not the case for the NIA study. There, CR did not increase lifespan compared to the already long-lived controls. Yet, in both studies CR was associated with a decrease in the occurrence of age-related diseases. Left ventricle (LV) samples were provided from the rhesus monkeys from both studies to investigate the effect of long-term CR on myocardial pathology and aging in these two cohorts of non-human primates (NHPs). Although CR did not reduce cardiac fibrosis or hypertrophy in either study, there was a 5.9-fold increase in fibrosis (p<0.0001) in LV tissue from the UW study compared to NIA, irrespective of CR treatment. Myocardial mTOR levels were reduced with CR in the UW study, only. These findings indicate that the severity of cardiac fibrosis may not be susceptible to the mechanisms by which CR is affecting disease progression, and myocardial mTOR is apparently differently affected dependent on the study paradigm. Interestingly, the diet administered by the UW study contained a much higher sucrose content (28.5% sucrose by weight), compared to that of the NIA diet (3.9% sucrose by weight). This raises the intriguing possibility that myocardial fibrosis in NHPs may be driven by a high sucrose diet. Abbreviations: CR: Caloric Restriction NHP: Non-human primate mTOR: mechanistic Target of Rapamycin NIA: National Institute on Aging UW: University of Wisconsin, Madison

Serum Creatinine Progressively Decreases with Obesity and Type 2 Diabetes in Nonhuman Primates

Low muscle mass has been associated with insulin resistance and the development of type 2 diabetes (T2DM). Serum creatinine is a metabolite of creatine present in the skeletal muscle. The creatinine concentration is stable and directly proportional to skeletal muscle mass. Low levels of creatinine have been shown to be associated with the development of T2DM. The underlying mechanism of low creatinine and its risk for the development of diabetes is not known. Nonhuman primates (NHPs), maintained on a healthy diet, frequently develop spontaneous middle-aged obesity, metabolic syndrome (MetSyn), and T2DM similar to humans. In the present study, longitudinal evaluation of the associations between creatinine and the development of obesity, MetSyn, and T2DM in 125 male rhesus monkeys were studied. In addition, 7 male monkeys with long term calorie-restriction (CR) to maintain a healthy lean mass were used as a comparison group. Creatinine decreased as age (r=-0.39, p\0.001), body fat percent (r=-0.27, p\0.001), HbA1c% (r=-32, p\0.001) increased. Decrease in insulin sensitivity was significantly (r=0.07, p\0.001) associated with a decrease in percent fat free mass. Creatinine also declined with decreasing insulin sensitivity (r=0.23, p\0.05) and fat free mass (FFM) (r=0.26, p\001) indicating that monkeys with higher lean muscle mass exhibited better insulin sensitivity. Creatinine was significantly decreased in monkeys with T2DM compared to both MetSyn and metabolically normal monkeys (p\0.001). Longitudinal data analysis showed progressive decline of creatinine with MetSyn and the development of T2DM. CR monkeys showed no significant change in creatinine throughout the lifelong duration of calorie restriction. Also unchanged during CR were fasting plasma glucose, body fat, FFM, or body weight. This is the first longitudinal study showing the association of creatinine with the development of T2DM. Serum creatinine levels declined with decrease in fat free mass and insulin sensitivity. Disclosure U.K. Chaudhari: None. J.D. Newcomb: None. B.C. Hansen: None.

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.

Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys

Caloric restriction (CR) without malnutrition increases longevity and delays the onset of age-associated disorders in short-lived species, from unicellular organisms to laboratory mice and rats. The value of CR as a tool to understand human ageing relies on translatability of CR’s effects in primates. Here we show that CR significantly improves age-related and all-cause survival in monkeys on a long-term ~30% restricted diet since young adulthood. These data contrast with observations in the 2012 NIA intramural study report, where a difference in survival was not detected between control-fed and CR monkeys. A comparison of body weight of control animals from both studies with each other, and against data collected in a multi-centred relational database of primate ageing, suggests that the NIA control monkeys were effectively undergoing CR. Our data indicate that the benefits of CR on ageing are conserved in primates.

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Will calorie restriction work in humans?

Calorie Restriction (CR) without malnutrition slows aging and increases average and maximal lifespan in simple model organisms and rodents. In rhesus monkeys long-term CR reduces the incidence of type 2 diabetes, cardiovascular disease and cancer, and protects against age-associated sarcopenia and neurodegeneration. However, so far CR significantly increased average lifespan only in the Wisconsin, but not in the NIA monkey study. Differences in diet composition and study design between the 2 on-going trials may explain the discrepancies in survival and disease. Nevertheless, many of the metabolic and hormonal adaptations that are typical of the long-lived CR rodents did not occur in either the NIA or WNPRC CR monkeys. Whether or not CR will extend lifespan in humans is not yet known, but accumulating data indicate that moderate CR with adequate nutrition has a powerful protective effect against obesity, type 2 diabetes, inflammation, hypertension, cardiovascular disease and reduces metabolic risk factors associated with cancer. Moreover, CR in human beings improves markers of cardiovascular aging, and rejuvenates the skeletal muscle transcriptional profile. More studies are needed to understand the interactions between CR, diet composition, exercise, and other environmental and psychological factors on metabolic and molecular pathways that regulate health and longevity.

Calorie restriction attenuates astrogliosis but not amyloid plaque load in aged rhesus macaques: A preliminary quantitative imaging study

While moderate calorie restriction (CR) in the absence of malnutrition has been consistently shown to have a systemic, beneficial effect against aging in several animals models, its effect on the brain microstructure in a non-human primate model remains to be studied using post-mortem histopathologic techniques. In the present study, we investigated differences in expression levels of glial fibrillary acid protein (GFAP) and β-amyloid plaque load in the hippocampus and the adjacent cortical areas of 7 Control (ad libitum)-fed and 6 CR male rhesus macaques using immunostaining methods. CR monkeys expressed significantly lower levels (∼30% on average) of GFAP than Controls in the CA region of the hippocampus and entorhinal cortex, suggesting a protective effect of CR in limiting astrogliosis. These results recapitulate the neuroprotective effects of CR seen in shorter-lived animal models. There was a significant positive association between age and average amyloid plaque pathology in these animals, but there was no significant difference in amyloid plaque distribution between the two groups. Two of the seven Control animals (28.6%) and one of the six CR animal (16.7%) did not express any amyloid plaques, five of seven Controls (71.4%) and four of six CR animals (66.7%) expressed minimal to moderate amyloid pathology, and one of six CR animals (16.7%) expressed severe amyloid pathology. That CR affects levels of GFAP expression but not amyloid plaque load provides some insight into the means by which CR is beneficial at the microstructural level, potentially by offsetting the increased load of oxidatively damaged proteins, in this non-human primate model of aging. The present study is a preliminary post-mortem histological analysis of the effects of CR on brain health, and further studies using molecular and biochemical techniques are warranted to elucidate underlying mechanisms.

Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study

Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.

A Calorie-Restricted Diet Decreases Brain Iron Accumulation and Preserves Motor Performance in Old Rhesus Monkeys

Caloric restriction (CR) reduces the pathological effects of aging and extends the lifespan in many species, including nonhuman primates, although the effect on the brain is less well characterized. We used two common indicators of aging, motor performance speed and brain iron deposition measured in vivo using magnetic resonance imaging, to determine the potential effect of CR on elderly rhesus macaques eating restricted (n=24, 13 males, 11 females) and standard (n=17, 8 males, 9 females) diets. Both the CR and control monkeys showed age-related increases in iron concentrations in globus pallidus (GP) and substantia nigra (SN), although the CR group had significantly less iron deposition in the GP, SN, red nucleus, and temporal cortex. A Diet X Age interaction revealed that CR modified age-related brain changes, evidenced as attenuation in the rate of iron accumulation in basal ganglia and parietal, temporal, and perirhinal cortex. Additionally, control monkeys had significantly slower fine motor performance on the Movement Assessment Panel, which was negatively correlated with iron accumulation in left SN and parietal lobe, although CR animals did not show this relationship. Our observations suggest that the CR-induced benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species.

Long-term calorie restriction, but not endurance exercise, lowers core body temperature in humans

Reduction of body temperature has been proposed to contribute to the increased lifespan in calorie restricted animals and mice overexpressing the uncoupling protein-2 in hypocretin neurons. However, nothing is known regarding the long-term effects of calorie restriction (CR) with adequate nutrition on body temperature in humans. In this study, 24-hour core body temperature was measured every minute by using ingested telemetric capsules in 24 men and women (mean age 53.7 ± 9.4 yrs) consuming a CR diet for an average of 6 years, 24 age- and sex-matched sedentary (WD) and 24 body fat-matched exercise-trained (EX) volunteers, who were eating Western diets. The CR and EX groups were significantly leaner than the WD group. Energy intake was lower in the CR group (1769 ± 348 kcal/d) than in the WD (2302 ± 668 kcal/d) and EX (2798 ± 760 kcal/d) groups (P < 0.0001). Mean 24-hour, day-time and night-time core body temperatures were all significantly lower in the CR group than in the WD and EX groups (P ≤ 0.01). Long-term CR with adequate nutrition in lean and weight-stable healthy humans is associated with a sustained reduction in core body temperature, similar to that found in CR rodents and monkeys. This adaptation is likely due to CR itself, rather than to leanness, and may be involved in slowing the rate of aging.

Homocysteine, neural atrophy, and the effect of caloric restriction in rhesus monkeys

Higher serum homocysteine (Hcy) levels in humans are associated with vascular pathology and greater risk for dementia, as well as lower global and regional volumes in frontal lobe and hippocampus. Calorie restriction (CR) in rhesus monkeys (Macaca mulatta) may confer neural protection against age- or Hcy-related vascular pathology. Hcy was collected proximal to a magnetic resonance imaging (MRI) acquisition in aged rhesus monkeys and regressed against volumetric and diffusion tensor imaging indexes using voxel-wise analyses. Higher Hcy was associated with lower white matter volume in pons and corpus callosum. Hcy was correlated with lower gray matter volume and density in prefrontal cortices and striatum. CR did not influence Hcy levels. However, control monkeys exhibited a strong negative correlation between Hcy and global gray matter, whereas no relationship was evident for the CR monkeys. Similar group differences were also seen across modalities in the splenium of the corpus callosum, prefrontal cortices, hippocampus, and somatosensory areas. The data suggest that CR may ameliorate the influence of Hcy on several important age-related parameters of parenchymal health.

A Calorie-Restricted Diet Decreases Brain Iron Accumulation and Preserves Motor Performance in Old Rhesus Monkeys

Caloric restriction (CR) reduces the pathological effects of aging and extends the lifespan in many species, including nonhuman primates, although the effect on the brain is less well characterized. We used two common indicators of aging, motor performance speed and brain iron deposition measured in vivo using MRI, to determine the potential effect of CR on elderly rhesus macaques eating restricted (n = 24; 13 males, 11 females) and standard diets (n = 17; 8 males, 9 females). Both the CR and control monkeys showed age-related increases in iron concentrations in globus pallidus (GP) and substantia nigra (SN), although the CR group had significantly less iron deposition in the GP, SN, red nucleus, and temporal cortex. A diet x age interaction revealed that CR modified age-related brain changes, evidenced as attenuation in the rate of iron accumulation in basal ganglia and parietal, temporal, and perirhinal cortex. Additionally, control monkeys had significantly slower fine motor performance on the Movement Assessment Panel, which was negatively correlated with iron accumulation in left SN and parietal lobe, although CR animals did not show this relationship. Our observations suggest that the CR-induced benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species.

Age-related changes in neural volume and microstructure associated with interleukin-6 are ameliorated by a calorie-restricted diet in old rhesus monkeys

Systemic levels of proinflammatory cytokines such as interleukin-6 (IL-6) increase in old age and may contribute to neural atrophy in humans. We investigated IL-6 associations with age in T1-weighted segments and microstructural diffusion indices using MRI in aged rhesus monkeys (Macaca mulatta). Further, we determined if long-term 30% calorie restriction (CR) reduced IL-6 and attenuated its association with lower tissue volume and density. Voxel-based morphometry (VBM) and diffusion-weighted voxelwise analyses were conducted. IL-6 was associated with less global gray and white matter (GM and WM), as well as smaller parietal and temporal GM volumes. Lower fractional anisotropy (FA) was associated with higher IL-6 levels along the corpus callosum and various cortical and subcortical tracts. Higher IL-6 concentrations across subjects were also associated with increased mean diffusivity (MD) throughout many brain regions, particularly in corpus callosum, cingulum, and parietal, frontal, and prefrontal areas. CR monkeys had significantly lower IL-6 and less associated atrophy. An IL-6×CR interaction across modalities also indicated that CR mitigated IL-6 related changes in several brain regions compared to controls. Peripheral IL-6 levels were correlated with atrophy in regions sensitive to aging, and this relationship was decreased by CR.

Metabolic shifts due to long-term caloric restriction revealed in nonhuman primates

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 1H 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.

Effects of caloric restriction on inflammatory periodontal disease

Objective Dietary caloric restriction (CR) has been found to reduce systemic markers of inflammation and may attenuate the effects of chronic inflammatory conditions. The purpose of this study was to examine the effects of long-term CR on naturally occurring chronic inflammatory periodontal disease in a nonhuman primate model. Methods The effects of long-term CR on extent and severity of naturally occurring chronic periodontal disease, local inflammatory and immune responses, and periodontal microbiology, were evaluated in a cohort of 81 (35 female and 46 male; 13–40 y of age) rhesus monkeys ( Macaca mulatta) with no previous exposure to routine oral hygiene. CR monkeys had been subjected to 30% CR for 13–17 y relative to control-fed (CON) animals starting at 3–5 y of age. Results Same sex CR and CON monkeys exhibited similar levels of plaque, calculus, and bleeding on probing. Among CON animals, males showed significantly greater periodontal breakdown, as reflected by higher mean clinical attachment level and periodontal probing depth scores, than females. CR males exhibited significantly less periodontal pocketing, lower IgG antibody response, and lower IL-8 and ß-glucuronidase levels compared to CON males, whereas CR females showed a lower IgG antibody response but comparable clinical parameters and inflammatory marker levels relative to CON females. Long-term CR had no demonstrable effect on the periodontal microbiota. Conclusion Males demonstrated greater risk for naturally occurring periodontal disease than females. Long-term CR may differentially reduce the production of local inflammatory mediators and risk for inflammatory periodontal disease among males but not females.

Could Calorie Restriction Increase Longevity in Humans?

Calorie restriction (CR), a dietary intervention that is low in calories but maintains proper nutrition, is the only intervention known to date that consistently decreases the biological rate of aging and increases both average and maximal lifespan. Since the first report of prolonged lifespan in rodents more than 70 years ago [1], similar observations have been reported across a wide range of species, including yeast, worms, spiders, flies, fish, mice and rats. While the effects of CR in longer-lived species remain unknown, results reported thus far from three nonhuman primate colonies suggest that CR might have a similar effect in longer-lived species. While lifespan data remain inconclusive [2], CR monkeys display a substantially reduced age-related morbidity [3,4]. In humans, data from controlled trials are lacking and no long-term prospective trials of CR have been conducted with survival being the primary end point [5]. There is, however, a lot that can be learned from a handful of epidemiological and cross-sectional observations in longer-lived humans, centenarians and individuals who self-impose CR.

Effects of calorie restriction on chromosomal stability in rhesus monkeys (Macaca mulatta).

The basic tenet of several theories on aging is increasing genomic instability resulting from interactions with the environment. Chromosomal aberrations have been used as classic examples of increasing genomic instability since they demonstrate an increase in numerical and structural abnormalities with age in many species including humans. This accumulating damage may augment many aging processes and initiate age-related diseases, such as neoplasias. Calorie restriction (CR) is one of the most robust interventions for reducing the frequency of age-related diseases and for extending life span in many short-lived organisms. However, the mechanisms for the anti-aging effects of CR are not yet well understood. A study of rhesus monkeys was begun in 1987 to determine if CR is also effective in reducing the frequency of age-related diseases and retarding aging in a long-lived mammal. Male monkeys were begun on the diet in 1987, and females were added in 1992 to examine a possible difference in response to CR by sex. The CR monkeys have been maintained for over 10 years on a low-fat nutritional diet that provides a 30% calorie reduction compared to a control (CON) group. Because of the greater similarity of nonhuman primates to humans in life span and environmental responses to diet compared with those of rodents, the rhesus monkey provides an excellent model for the effects of CR in humans. This study examined the effects of CR on chromosomal instability with aging. Significant age effects were found in both CR and CON groups for the number of cells with aneuploidy: old animals had a higher loss and a higher gain than young animals. However, there was no effect of age on chromosomal breakage or structural aberrations in either diet group. Diet had only one significant effect: the CR group had a higher frequency of chromatid gaps than did the CON group. CR, implemented in adult rhesus monkeys, does not have a major effect on the reduction of numerical or structural aberrations related to aging.

Effect of Long-Term Calorie Restriction with Adequate Protein and Micronutrients on Thyroid Hormones

Caloric restriction (CR) retards aging in mammals. It has been hypothesized that a reduction in T(3) hormone may increase life span by conserving energy and reducing free-radical production. The objective of the study was to assess the relationship between long-term CR with adequate protein and micronutrient intake on thyroid function in healthy lean weight-stable adult men and women. In this study, serum thyroid hormones were evaluated in 28 men and women (mean age, 52 +/- 12 yr) consuming a CR diet for 3-15 yr (6 +/- 3 yr), 28 age- and sex-matched sedentary (WD), and 28 body fat-matched exercising (EX) subjects who were eating Western diets. Serum total and free T(4), total and free T(3), reverse T(3), and TSH concentrations were the main outcome measures. Energy intake was lower in the CR group (1779 +/- 355 kcal/d) than the WD (2433 +/- 502 kcal/d) and EX (2811 +/- 711 kcal/d) groups (P < 0.001). Serum T(3) concentration was lower in the CR group than the WD and EX groups (73.6 +/- 22 vs. 91.0 +/- 13 vs. 94.3 +/- 17 ng/dl, respectively) (P < or = 0.001), whereas serum total and free T(4), reverse T(3), and TSH concentrations were similar among groups. Long-term CR with adequate protein and micronutrient intake in lean and weight-stable healthy humans is associated with a sustained reduction in serum T(3) concentration, similar to that found in CR rodents and monkeys. This effect is likely due to CR itself, rather than to a decrease in body fat mass, and could be involved in slowing the rate of aging.