Age-related decline in striatal volume in rhesus monkeys: assessment of long-term calorie restriction

Using magnetic resonance imaging (MRI), we measured striatal volume in 22 male rhesus monkeys undergoing calorie restriction (CR) for 11-13 years and 38 monkeys who were fed ad libitum (CON). CR delays the onset of many age-related processes, and this study tested whether it would alter the age-related decline in striatal volume. The CON and CR groups were sub-divided into middle age (less than 24 years old) and old age groups. Contrary to expectation, volumes of the putamen (not the caudate nucleus) were larger bilaterally in the CON than in the CR group both at middle age and senescence. Regression analysis (region volume versus age) indicated bilateral age-related declines in putamen and caudate nucleus volumes in the old CON monkeys, but only for the putamen in the old CR monkeys. Because tests for slopes found no differences between the groups, the data do not establish an effect of CR. Further study, involving sequential imaging, is warranted in order to clarify the possible effects of CR on age-related changes in striatal volume.     

Age-related changes in adaptive macronutrient intake in swimming male and female Lou rats

To evaluate the age-related changes in capacity to adjust the nutrient intake to needs, self-selecting male and female Lou/C/jall rats of 4, 6, 12, 16 and 23 months of age were submitted to a swimming exercise. They were given 6 consecutive days of moderate intensity training (3 x 15 minutes per day). Exercise and postexercise periods were compared with results from the pretraining period. During swimming, a body weight loss and a decrease in both caloric intake and fat selection were observed. This effect was more marked in older groups compared to 4 month-old groups. An increase in protein intake was observed in females, specially in older groups, whereas no effect was seen in males. The ability to increase caloric ingestion and regain weight during the postexercise period decreased with advancing age and was better in females than in males. We also showed an age-related effect on the recovery of initial nutrient intake rate that was more pronounced and more precocious for males. Moreover, males tended to decrease their protein intake, whereas females significantly increased it. The present findings suggest a decrease of capacity of adjusting feeding behavior to metabolic needs in aged rats, may be due to a deterioration of the central control of food intake.     

Effect of age and caloric restriction on circadian adrenal steroid rhythms in rhesus macaques

Dietary caloric restriction (CR) slows aging, extends lifespan, and reduces the occurrence of age-related diseases in short-lived species. However, it is unclear whether CR can exert similar beneficial effects in long-lived species, like primates. Our objective was to determine if CR could attenuate purported age-related changes in the 24-h release of adrenal steroids. To this end, we examined 24-h plasma profiles of cortisol, and dehydroepiandrosterone sulfate (DHEAS) in young and old, male and female rhesus macaques (Macaca mulatta) subjected to either ad libitum (AL)-feeding or CR (70% of AL) for 2–4 years. Hormone profiles from young monkeys showed pronounced 24-h rhythms. Cortisol concentrations were higher in old males but not females, whereas DHEAS rhythms were dampened with age in both sexes. The cortisol rhythms of old CR males resembled those of young control males. However, CR failed to prevent age-related declines in DHEAS and further dampened DHEAS rhythms in both sexes. Apart from the partial attenuation of the age-related cortisol elevation in the old males, 24-h adrenal steroid rhythms did not benefit from late-onset CR.     

Effects of aging and calorie restriction on white matter in rhesus macaques

Rhesus macaques on a calorie restricted diet (CR) develop less age-related disease, have virtually no indication of diabetes, are protected against sarcopenia, and potentially live longer. Beneficial effects of caloric restriction likely include reductions in age-related inflammation and oxidative damage. Oligodendrocytes are particularly susceptible to inflammation and oxidative stress, therefore, we hypothesized that CR would have a beneficial effect on brain white matter and would attenuate age-related decline in this tissue. CR monkeys and controls underwent diffusion tensor imaging (DTI). A beneficial effect of CR indexed by DTI was observed in superior longitudinal fasciculus, fronto-occipital fasciculus, external capsule, and brainstem. Aging effects were observed in several regions, although CR appeared to attenuate age-related alterations in superior longitudinal fasciculus, frontal white matter, external capsule, right parahippocampal white matter, and dorsal occipital bundle. The results, however, were regionally specific and also suggested that CR is not salutary across all white matter. Further evaluation of this unique cohort of elderly primates to mortality will shed light on the ultimate benefits of an adult-onset, moderate CR diet for deferring brain aging.     

Can we live longer by eating less? A review of caloric restriction and longevity

Caloric restriction, decreasing caloric intake by 20-30%, was first shown to extend life in rats nearly 80 years ago. Since that time, limiting food intake for longevity has been investigated in species from yeast to humans. In yeast and lower animals, caloric restriction has repeatedly been demonstrated to lengthen the life span. Studies of caloric restriction in non-human primates and in humans are ongoing and initial results suggest prolongation of life as well as prevention of age-related disease. There is also data in rodents suggesting that short term caloric restriction has beneficial effects on fertility. Although caloric restriction has many positive effects on health and longevity, quality of life on a restricted diet as well as the ability to maintain that diet long term are concerns that must be considered in humans.     

Regulation of food intake in monkeys: Response to caloric dilution

Ability to regulate level of energy intake was studied in adult rhesus monkeys (Macaca mulatta) using calorically diluted diets. Twenty-four hour access to a complete liquid diet was provided via leakproof gravity feeders. The addition of water provided 4 caloric concentrations over the range of 0.5 to 1.35 kcal/ml. Average caloric intake per kg body weight was 84 ± 0.7 kcal/kg (mean ± SE). Seven of the eight monkeys maintained a constant caloric intake by adjusting oral intake in response to randomly ordered but sustained changes in caloric density. One monkey ingested a significantly higher caloric load while receiving the highest density diet. Rates of compensation for dilution following each diet change varied widely, occurring over periods of 3 days to 2 weeks. It was concluded that individual monkeys vary significantly in the rat of adjustment to caloric dilution, and thus long term studies must be used in studying controls of feeding in monkeys.     

Effect of treatment with dexamethasone on protein intake in adult and old Lou/c/jall rats

A deleterious decrease of protein intake had been evidenced in Lou/c/jall rats during ageing. This result could be induced by an impaired regulation of feeding behaviour. Glucocorticoids inducing specific amino-acid needs for gluconeogenesis and for the synthesis of inflammatory proteins by the liver, we investigated the age-related effect of a 4-days treatment with dexamethasone (DEX) on caloric and protein intake. Males and females aged 7, 19, 25 and 31 months received 573.6 +/- 65.6 microg/(kg day) of dexamethasone via the drinking water. Body weight (BW), caloric and macronutrients intakes were monitored during treatment and during 10 days after the treatment. A strong hypophagia was seen during treatment in all groups, which was mainly due to a decrease in fat intake. In the same time, rats maintained their protein intake so that protein became the main macronutrient of the diet in most of the groups. However, older males showed a lesser efficiency in adjusting their diet. These results are in agreement with previous data obtained in a protein deprivation study. They lead to the conclusion that the loss of appetite for protein in old age probably does not reflect a loss of ability to choose the needed amount of protein. We can hypothesise that the decrease of protein intake in old rats could be due to some inadequacy of casein to the metabolic requirement of aged animals.     

Assessment of auditory function in rhesus monkeys (Macaca mulatta): effects of age and calorie restriction

Age-related alterations in auditory function were evaluated in adult male rhesus monkeys (Macaca mulatta) involved in a long-term study evaluating the effects of caloric restriction (CR) on aging. We assessed 26 monkeys in a control group fed a low fat, high fiber diet at approximately ad libitum levels and 24 monkeys in a CR group that were fed the same diet reduced in amount by 30% compared to age- and weight-matched controls. The following measures of auditory function were obtained while monkeys were maintained under anesthesia: (1) distortion product otoacoustic emissions (DPOAEs); (2) auditory brainstem responses (ABRs); and (3) middle latency responses (MLRs). All DPOAE measures and peak II amplitude significantly decreased with age, while peak IV latency and ABR threshold significantly increased with age. We found no significant effects of CR on any auditory parameters examined.     

Age-related synapse loss in hippocampal CA3 is not reversed by caloric restriction

Caloric restriction (CR) is a reduction of total caloric intake without a decrease in micronutrients or a disproportionate reduction of any one dietary component. While CR attenuates age-related cognitive deficits in tasks of hippocampal-dependent memory, the cellular mechanisms by which CR improves this cognitive decline are poorly understood. Previously, we have reported age-related decreases in key synaptic proteins in the CA3 region of the hippocampus that are stabilized by lifelong CR. In the present study, we examined possible age-related changes in the functional microcircuitry of the synapses in the stratum lacunosum-moleculare (SL-M) of the CA3 region of the hippocampus, and whether lifelong CR might prevent these age-related alterations. We used serial electron microscopy to reconstruct and classify SL-M synapses and their postsynaptic spines. We analyzed synapse number and size as well as spine surface area and volume in young (10 months) and old (29 months) ad libitum fed rats and in old rats that were calorically restricted from 4 months of age. We limited our analysis to SL-M because previous work demonstrated age-related decreases in synaptophysin confined to this specific layer and region of the hippocampus. The results revealed an age-related decrease in macular axo-spinous synapses that was not reversed by CR that occurred in the absence of changes in the size of synapses or spines. Thus, the benefits of CR for CA3 function and synaptic plasticity may involve other biological effects including the stabilization of synaptic proteins levels in the face of age-related synapse loss.     

Food restriction as a modulator of age-related changes in serum lipids

Fischer 344 male rats were either fed ad libitum or 60% of the ad libitum intake. The restriction of food intake markedly increased the median length of life. Postabsorptive serum cholesterol and phospholipid concentrations increase in the ad libitum-fed rats with increasing age. Life-prolonging food restriction does not influence the serum levels of these lipids in young rats but delays the age-related increase in concentrations. Postabsorptive serum free fatty acid (FFA) concentrations decrease with advancing age in ad libitum-fed rats. Life-prolonging food restriction, while not affecting the serum FFA levels in young rats, delays and possibly partially prevents the age-related decrease in concentration. Food restriction lowers postabsorptive serum triglyceride levels at all ages studied. The data on serum cholesterol, phospholipids, and FFA provide further evidence that food restriction delays age-related changes in the physiological systems of rats. This delay of physiological decline may well retard the occurrence of age-related disease processes, thus prolonging life.     

Calorie restriction in nonhuman primates: assessing effects on brain and behavioral aging

Dietary caloric restriction (CR) is the only intervention repeatedly demonstrated to retard the onset and incidence of age-related diseases, maintain function, and extend both lifespan and health span in mammals, including brain and behavioral function. In 70 years of study, such beneficial effects have been demonstrated in rodents and lower animals. Recent results emerging from ongoing studies of CR in humans and nonhuman primates suggest that many of the same anti-disease and anti-aging benefits observed in rodent studies may be applicable to long-lived species. Results of studies in rhesus monkeys indicate that CR animals (30% less than controls) are healthier than fully-fed counterparts based on reduced incidence of various diseases, exhibit significantly better indices of predisposition to disease and may be aging at a slower rate based on analysis of selected indices of aging. The current review discusses approaches taken in studies of rhesus monkeys to analyze age-related changes in brain and behavioral function and the impact of CR on these changes. Approaches include analyses of gross and fine locomotor performance as well as brain imaging. In a related study it was observed that short-term CR (6 months) in adult rhesus monkeys can provide protection against a neurotoxic insult. Increasing interest in the CR paradigm will expand its role in demonstrating how nutrition can modulate the rate of aging and the mechanisms responsible for this modulation.     

Caloric restriction: impact upon pituitary function and reproduction

Reduced energy intake, or caloric restriction (CR), is known to extend life span and to retard age-related health decline in a number of different species, including worms, flies, fish, mice and rats. CR has been shown to reduce oxidative stress, improve insulin sensitivity, and alter neuroendocrine responses and central nervous system (CNS) function in animals. CR has particularly profound and complex actions upon reproductive health. At the reductionist level the most crucial physiological function of any organism is its capacity to reproduce. For a successful species to thrive, the balance between available energy (food) and the energy expenditure required for reproduction must be tightly linked. An ability to coordinate energy balance and fecundity involves complex interactions of hormones from both the periphery and the CNS and primarily centers upon the master endocrine gland, the anterior pituitary. In this review article we review the effects of CR on pituitary gonadotrope function and on the male and female reproductive axes. A better understanding of how dietary energy intake affects reproductive axis function and endocrine pulsatility could provide novel strategies for the prevention and management of reproductive dysfunction and its associated comorbidities.     

Feeding behavior during experimentally induced obesity in monkeys

In order to investigate the effects of the induction and remission of obesity on feeding behavior, male rhesus monkeys were made obese by sustained intragastric (IG) feeding of a complete liquid diet. Intragastric diet infusion levels of 100, 125, 145, and 165% of the baseline oral intake of each monkey were successively administered. During the initial overfeeding period (100% of the baseline oral intake), at least one week was required to reduce voluntary oral intake to less than 25% of the baseline levels and complete suppression of oral intake did not occur. This increased total caloric intake (IG infusion plus oral intake) resulted in a rapid rate of weight gain of at least 5 times the baseline rate. With successive increases in caloric infusion level, oral intake was eventually suppressed, and rapid weight gain was sustained. When the IG infusion was abruptly terminated after 50 to 130 days, 3 monkeys refused all food for 14 to 35 days. The monkeys' oral intakes stabilized three to ten weeks after the end of the overfeeding period. The length of this period prior to the resumption of normal oral intake was not related to length of overfeeding nor to the amount of weight gained. The monkeys' body weights dropped rapidly in the initial post-overfeeding period and then stabilized, sometimes at levels higher than their baseline body weights. In 2 monkeys, at the end of overfeeding the amounts infused were gradually reduced in order to determine the calories required to maintain their body weights at peak levels. Significantly fewer kcal/kg were required to maintain peak body weights than were ingested during the baseline periods.     

A moderate swimming exercise regularly performed throughout the life induces age and sex-related modifications in adaptive macronutrients choice

The ability of laboratory rats to adapt food intake to needs is well-known. The present study investigates changes in this adaptive behavior when animals grow old. A cohort of male and female Lou/c/jall rats was regularly submitted to an exercise throughout their life (6 consecutive days of moderate intensity training (3×15 min/day)). Caloric intake and macronutrients selection during exercise and post-exercise periods were compared to the pre-training period. During swimming, a decrease in both caloric intake and fat selection was observed and an increase in protein intake was specifically seen in female groups. However, males were unable to modify the diet composition (macronutrient rate) from 16 months of age, whereas females were able to do it until 24 months of age. The present results suggest a sex-dependant loss of capacity of adjusting feeding behavior to metabolic needs when animals grow old, may be due to a deterioration of the central control of food intake.     

Effect of dietary restriction and aging on polyploidy in rat liver

Liver polyploidy levels were compared as a function of age and diet in male Fischer 344 rats between 1 and 24 months of age. Dietary restriction was imposed on one group by reducing their food intake to 60% of ad libitum food intake. Histological sections of the livers of animals at each age and diet were examined. Diploid, tetraploid and octaploid nuclei were observed, and their size and frequency established. There were no differences in the diameter or volume of these size classes as a function of age or diet. An age-related decline in the percentage of diploid nuclei, coupled with an increase in the percentage of tetraploid and octaploid nuclei was observed in both groups. The major difference between the two groups was that the adult level of liver polyploidy was attained more slowly in the animals on dietary restriction as compared to the ad libitum fed controls. Polyploid cell formation in the liver is under the control of growth hormone, thyroid hormone and thymus, all of which might be influenced by dietary restriction.     

Effects of aging and caloric restriction on I-compounds in liver, kidney and white blood cell DNA of male Brown-Norway rats

Rodent tissues display species-, strain-, sex- and tissue-specific adduct-like DNA modifications termed I-compounds, which increase with age, are modulated by diet and are presumably derived from indigenous metabolic intermediates. We have explored whether I-compounds are affected by caloric restriction, which is known to extend life span and retard age-related degenerative and neoplastic diseases. Male Brown-Norway rats were fed NIH-31 diet ad libitum (AL). Calorically restricted (CR) rats received 60% of AL consumption, starting at 3.5 months. DNA was analyzed by 32P-postlabeling at 1, 4, 8, 12, 16 and 24 months of age in liver, kidney and white blood cells. I-compounds in AL liver and kidney exhibited complex tissue specific profiles; I-compound levels increased with age, plateaued between 8 and 18 months depending on tissue and diet and were 8.7 (liver) and 27.4 (kidney) modifications in 10(8) nucleotides at 24 months, thereby exceeding the corresponding 1-month values by 3.7- and 16.6-fold. CR resulted in similar profiles but did not diminish age-related increases, rather I-compound levels in CR liver and kidney were increased by about 70% and 30% versus age-matched AL rats. White blood cells exhibited few I-compounds and at low levels; age-related increases were small overall but more pronounced in CR rats. Higher I-compound levels in CR animals, which were presumably a consequence of metabolic effects elicited by CR, thus correlated with extended life span and, therefore, may be beneficial, in agreement with previous findings showing an association between reduced I-compound levels and hepatocarcinogenesis as well as organ susceptibility to diseases.     

Sex differences in the effects of voluntary activity on sucrose-induced obesity

Sedentary, adult rats of both sexes fed Purina chow and a 32% sucrose solution overate, gained excess weight and had higher Lee Indexes of obesity than control animals fed only Purina chow. The magnitude of these effects was similar in the males and females. Animals of both sexes fed the sucrose diet showed a slower rate of weight loss during food deprivation than the chow controls. Access to an activity wheel led to a reduction in caloric intake and the elimination of obesity in male rats. In the chow fed male rats activity led to a smaller, transient suppression in caloric intake and a slightly lower level of body weight than the sedentary chow controls. Access to activity did not affect body weight in the female rats in either dietary condition. Rather, both active groups of female rats appeared to compensate for the energy cost of voluntary activity by a small increase in food consumption. Long-term exposure to activity was associated with more rapid weight loss during food deprivation in both males and females. These data reveal that high levels of activity and obesity can co-exist when normal female rats are fed a palatable diet but that activity eliminates this form of obesity in the male rat.     

Distribution patterns of satellite associations in human lymphocytes relative to age and sex

Using ammoniacal silver for differential staining of satellites, associations from 1,668 human metaphases were studied from lymphocyte cultures of 167 normal individuals and were correlated with age and sex. There is a peak in satellite association frequency up to age 20 years in males and to 25 in females. With older ages there is a decline in association frequencies. No associations with four or more chromosomes were found in newborns. Furthermore, association in newborns, as well as in individuals older than 50 years, are significantly low compared to in-between age groups.
Females have a higher frequency of satellite associations than males between the ages of 3 and 50 years. Typically, females have greater multiple associations, while males have more single associations. Randomness or non-randomness of occurrence of associations fluctuates for different age groups within and between the two sexes.     

Physiological and psychosocial age-related changes associated with reduced food intake in older persons

Dietary intake changes during the course of aging. Normally an increase in food intake is observed around 55 years of age, which is followed by a reduction in food intake in individuals over 65 years of age. This reduction in dietary intake results in lowered levels of body fat and body weight, a phenomenon known as anorexia of aging. Anorexia of aging has a variety of consequences, including a decline in functional status, impaired muscle function, decreased bone mass, micronutrient deficiencies, reduced cognitive functions, increased hospital admission and even premature death. Several changes during lifetime have been implicated to play a role in the reduction in food intake and the development of anorexia of aging. These changes are both physiological, involving peripheral hormones, senses and central brain regulation and non-physiological, with differences in psychological and social factors. In the present review, we will focus on age-related changes in physiological and especially non-physiological factors, that play a role in the age-related changes in food intake and in the etiology of anorexia of aging. At the end we conclude with suggestions for future nutritional research to gain greater understanding of the development of anorexia of aging which could lead to earlier detection and better prevention.     

Short-term calorie restriction improves disease-related markers in older male rhesus monkeys (Macaca mulatta)

Calorie restriction (CR) is widely known for its effects on life span, physiological aging and age-related disease in laboratory rats and mice. Emerging data from CR studies in rhesus monkeys suggest that this nutritional intervention paradigm may also have beneficial effects in long-lived mammals. Studies from our laboratory and others have suggested that young- or adult-onset CR might have beneficial effects on cardiovascular disease and diabetes. For example, long-term CR reduced body fat and serum triglycerides, and increased a subfraction of HDL cholesterol associated with decreased cardiovascular disease risk. These studies suggested that long-term CR begun in young or adult animals might have important effects on markers relevant to age-related disease. Few studies have examined the effects of CR initiated in older animals (rodents or monkeys), and the temporal nature of some potentially beneficial effects of CR is unknown. The present study examined several markers related to diabetes and cardiovascular disease in thirteen older adult (> 18 year) non-obese (body fat < 22%), male rhesus monkeys during a short-term CR paradigm. Specifically, we collected these data at baseline (ad libitum feeding), 10, 20, and 30% CR, and at 6 and 12 months on 30% CR. Fasting and peak insulin were significantly reduced as were the acute and second-phase insulin responses. CR also marginally reduced triglycerides (50% reduction), but had no effect on total serum cholesterol or blood pressure. Interestingly, the observed glucoregulatory changes emerged prior to any evidence of a change in body composition suggesting that certain effects of CR may not be wholly dependent on changes in body composition in older monkeys.