A study of caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): a potential model for aging research

Caloric restriction has been demonstrated to retard aging processes and extend maximal life span in rodents, and is currently being evaluated in several nonhuman primate trials. We initiated a study in 32 adult cynomolgus monkeys to evaluate the effect of caloric restriction on parameters contributing to atherosclerosis extent. Following pretrial determinations, at which time a baseline measure of ad libitum (ad lib) dietary intake was assessed, animals were randomized to an ad lib fed group (control) or a caloric restriction group (30% reduction from baseline intake). The animals are being evaluated for glycated proteins, insulin, glucose, insulin sensitivity measures, and specific measures of body fat composition by CT scans (e.g., intra-abdominal fat) over specified intervals. The results from the first year of observation demonstrate a significant diet effect on body weight, and specifically intra-abdominal fat. Further, insulin sensitivity has been significantly increased after 1 year of caloric restriction compared to the ad lib fed group. These studies indicate that caloric restriction has a marked effect on a pathologic fat depot, and this change is associated significantly with an improvement in peripheral tissue insulin sensitivity.     

Schooling, employment, and idleness in young adults with serious physical health conditions: effects of age, disability status, and parental education

Aging is associated with significant structural and functional changes in the gastrointestinal tract. Gastrin, a hormone produced by G cells in the antrum of the stomach, stimulates proliferation of gastric mucosa; its synthesis appears to decrease with age. Life-long restriction of caloric intake is the only experimental manipulation that has been shown to retard aging processes in rats. The purpose of this study was to examine the effect of short-term caloric restriction (CR) on the production and release of the hormone gastrin with aging. Aging causes a fall in both fasting plasma levels of gastrin and antral content of gastrin in Fischer 344 rats; short-term CR appears to augment this age-related decrease. Steady state levels of antral gastrin mRNA were decreased with aging, and short-term CR resulted in an augmented decrease in aged, but not in young rats. Our findings indicate that gastrin release, synthesis and gene expression decrease with age. Restriction of the caloric intake for a short period (i.e. 8 weeks) augments this age-related decrease in antral gastrin and fasting plasma levels. Short-term CR appears to decrease the production of gastrin at the level of gene expression.     

The age-associated alterations in late diastolic function in mice are improved by caloric restriction

Caloric restriction reduces the magnitude of many age-related changes in rodents. Cardiac function is altered with senescence in mice, rats, and healthy humans. We examined the effects of life-long caloric restriction on diastolic and systolic cardiac function in situ using Doppler techniques in ad libitum-fed 30- to 32-month-old (AL) and calorically restricted (CR) 32- to 35-month-old female B6D2-F1 hybrid mice. The heart weight to body weight ratio was similar in AL (5.74 +/- .24 mg/g) and CR (5.68 +/- .20 mg/g) mice. Two systolic functional parameters known to decrease with age in both humans and mice, peak aortic velocity and aortic acceleration, were unchanged by CR compared to AL. In contrast, diastolic function was altered by caloric restriction. Although left ventricular peak early filling velocity (E) was not different between CR and AL, peak atrial filling velocity (A) was 50% lower in CR compared to AL (p < .001). The ratio of early diastolic filling to atrial filling (E/A ratio) was 64% higher in the CR (2.74 +/- .31) than the AL (1.55 +/- .07; p = .004). The fraction of ventricular filling due to atrial systole, the atrial filling fraction, was also reduced in CR (.21 +/- .04) compared to AL (.36 +/- .02; p = .007). These changes occurred in CR without alteration in E deceleration time, which is consistent with improved diastolic function in CR. Through mechanisms that remain unknown, lifelong caloric restriction may prevent the age-related impairments in late diastolic function but does not alter the impairments in systolic or early diastolic cardiac function.     

The physiologic, neurologic, and behavioral effects of caloric restriction related to aging, disease, and environmental factors

Little is known about the mechanisms by which acute and chronic caloric restriction (CR) modulate disease, longevity, and toxicity. To study these endpoints, behavioral parameters such as food and water consumption and physiologic parameters such as motor activity, body temperature, metabolic output (oxygen use), and respiratory quotient (RQ) were continuously monitored in 26-month-old male B6C3F1 mice and Fischer 344 rats fed either ad libitum (AL) or a CR diet (60% of AL). Different dietary regimens were used: rodents were (1) chronically food-restricted using daily feeding starting at 14 months of age, (2) chronically food-restricted using alternate day feeding, or (3) abruptly switched from CR to AL (acute CR). The physiologic and behavioral changes seen with chronic and acute CR were consistent across strains and species. Average body temperature, the number of meals, and the ratio of food/water consumption were significantly lower in CR rodents than in AL rodents. Also, the daily range of body temperature, oxygen metabolism, RQ, average water consumption, and motor activity was significantly higher in CR rodents. CR caused the onset of altered neurobehavioral functions such as abnormal water consumption; increases in motor activity, serum corticosterone, and stress proteins (HSP); and decreases in the basal setpoint for body temperature and brain metabolism. These changes strongly suggest that many beneficial effects of CR are controlled by the hypothalamic-pituitary-adrenal axis via hormonal regulation. This study supports the assertion that nutritional status may be a primary factor of consideration in development of safety standards and assessment of risk.     

Effect of perinatal gonadal hormones on selected nonsexual behavior patterns: A critical assessment of the nonhuman and human literature.

Reviews the literature on the influence of perinatal gonadal hormones on adult nonsexual behavior patterns in rodents and primates. Perinatal androgens increase the display of adult aggressive behavior in rodents. No research on primates has investigated the effect of perinatal hormones on fighting per se. Instead, high energy expenditure, a trait associated with masculinity in monkeys, has been studied. Female monkeys treated with prenatal androgen exhibit patterns of energy expenditure similar to those of males. Human females exposed to prenatal androgen have been reported by their parents and themselves to show "tomboyish" behavior (i.e. high levels of energy expenditure in play). The effect of perinatal androgen on maternal behavior in rodents is less clear because both male and female rodents will show all aspects of maternal behavior when presented with newborn animals. Human females exposed to prenatal androgen excess have been reported by their parents and themselves to show low levels of maternalism. To explain why genetic females exposed to prenatal androgens were different from controls in regard to energy expenditure and maternalism, researchers have proposed that the behavior changes were a sequel to a masculinizing effect of androgen on the fetal brain. Alternative explanations to postnatal factors are proposed. The influence of perinatal androgen on IQ is also considered. (3 p ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of fat intake and caloric restriction on bone in aging male rats

Caloric and fat intake may have important skeletal consequences. To evaluate this possibility, skeletal effects of adult-onset caloric restriction (CR) at differing fat intakes were assessed in male Lobund-Wistar rats. At age 17 months, two groups of animals received an anti-obesity diet, restricted approximately 35% from individual ad libitum baseline calorie consumption, and two groups received a diet approximately 50% restricted. Dietary fat concentrations were 5, 15, 15, and 25% by weight, respectively. At ages 20, 24, 28, 30, and 32 months, ex vivo femoral bone densitometry and serum biochemical analyses were performed. Body weight (BW) decreased with time on CR in each group (p < .005), declining faster at the more severe restriction (p = .001). Femoral bone mineral contents (BMC) were also reduced. After adjusting for bone area and BW differences among groups, the only significant difference was a reduction in distal femur BMC in the 25% fat group subjected to more severe CR (p = .02). No differences were observed in serum parathyroid hormone, calcium, phosphorus, or creatinine. Femoral bone loss occurred with CR. This was entirely accounted for by reduction in BW. Higher dietary fat content did not affect BW in CR animals, but did result in lower distal femur BMC.     

The effects of patterned calorie-restricted diets on mammary tumor incidence and plasma endothelin levels in DMBA-treated rats

Chronic caloric restriction has been shown to inhibit mammary tumor promotion in the 7,12-dimethyl-benz[a]anthracene (DMBA) rat mammary tumor model. The objectives of this study were to determine (i) the effects of chronic caloric cycling (yo-yo dieting) on mammary tumor promotion by high fat diets and (ii) the effect of three dietary regimens +/- superimposed mammary tumor burden on plasma endothelin-1,2 (ET) levels. Female Sprague-Dawley rats were treated with DMBA (5 mg/rat) and divided into three dietary groups: ad libitum (AL) (containing 15% corn oil); 40% calorie restricted (CR) (containing 20% corn oil so consumption of fat was equivalent between AL and CR); a calorie cycled (CC) group fed alternatively AL and CR diets each 48 h period. After 10 weeks, tumor incidences were: AL, 63%; CR, 27%; CC, 57% (AL versus CR, P < 0.05; CC versus CR, P < 0.05; AL versus CC, NSD). ET levels (pg/ml plasma) were: AL, 16.0 +/- 6.54; CR, 32.31 +/- 0.34; CC, 23.44 +/- 5.04 (AL versus CR, P < 0.01; CC versus CR, P < 0.01; AL versus CC, P < 0.05). Plasma ET levels were independent of tumor incidence and tumor burden, but plasma ET levels were significantly increased in rats with a prior history of calorie restriction. As expected, maintained caloric restriction reduced mammary tumor incidence but intermittent caloric restriction (caloric cycling or yo-yo dieting) was without similar benefit.     

HER-2/Neu expression as a progression marker in pancreatic intraepithelial neoplasia

Dietary restriction is the only intervention shown to increase maximal life span, and to retard the rate of aging in rodents. As part of a long-term randomized trial of the effects of a 20-30% dietary restriction (DR) on adult rhesus macaques, female (N = 30) and male (N = 16) monkeys were assessed at baseline and 6, 12 and 18 months, following randomization to control (C) or dietary restricted (R) groups, for body composition by dual-energy x-ray absorptiometry. At baseline, there were no significant differences between C and R groups in any body composition parameters measured. Males had significantly (p < 0.05) greater values at baseline than females for body weight (BW), body mass index (BMI), total body lean tissue mass (LTM), appendicular skeletal muscle mass (ASM), and total body bone mineral content (BMC). When analyzed longitudinally through 18 months of DR, C females had significantly increased BW, total body fat tissue mass (FTM), total body percent fat tissue mass (%FTM), LTM, ASM, BMC and abdominal fat tissue mass (AbFTM) relative to R animals. Male C animals had significantly increased BW, FTM, %FTM, BMC and AbFTM relative to R males. The primary effect of DR on body composition in these animals was on FTM.     

Characterization of the oligomerization defects of two p53 mutants found in families with Li-Fraumeni and Li-Fraumeni-like syndrome

Intravenously administered nitro-imidazole radiosensitizer and alkylating anticancer compound CI-1010, designated as (R)-alpha-[[(2-bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1-ethanol monohydrobromide, causes multiorgan toxicity in rodents, including retinal degeneration. This study determined the potential of CI-1010 to induce similar effects in nonhuman primates. One male and 1 female cynomolgus monkey were given single daily doses of CI-1010 intravenously for 5 consecutive days each week for 3 wk. Doses were escalated from 5 mg per kilogram of body weight in week 1 to 40 and 60 mg/kg in week 3. Postdosing emesis occurred in both monkeys at 5 mg/kg, and clinical signs at 40 and 60 mg/kg included more pronounced emesis, reduced food consumption, pallor, weakness, and body weight loss. At study termination, both monkeys had markedly reduced peripheral blood lymphocytes and moderately lowered erythrocyte, hemoglobin, and hematocrit levels, which correlate with a decreased total nucleated bone marrow cell count. At necropsy, the monkeys had pancytic bone marrow hypocellularity, multiorgan lymphoid depletion, pancreatic acinar cell apoptosis, testicular seminiferous tubular degeneration, and bilateral multifocal retinal degeneration involving the photoreceptor and outer nuclear layers. Ultrastructurally, selected inner and outer retinal rod segments were swollen and fragmented, a state associated with cytoplasmic condensation and pyknosis of the outer nuclear cell layer. Thus, CI-1010 induced toxicity of hematopoietic/lymphoid organs, retina, testes, and pancreas in monkeys, findings similar to those of previous studies in rodents.     

Dehydroepiandrosterone sulfate: a biomarker of primate aging slowed by calorie restriction

The adrenal steroids, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), have attracted attention for their possible antiaging effects. DHEAS levels in humans decline markedly with age, suggesting the potential importance of this parameter as a biomarker of aging. Here we report that, as seen in humans, male and female rhesus monkeys exhibit a steady, age-related decline in serum DHEAS. This decline meets several criteria for a biomarker of aging, including cross-sectional and longitudinal linear decreases with age and significant stability of individual differences over time. In addition, the proportional age-related loss of DHEAS in rhesus monkeys is over twice the rate of decline observed in humans. Most important is the finding that, in rhesus monkeys, calorie restriction, which extends life span and retards aging in laboratory rodents, slows the postmaturational decline in serum DHEAS levels. This represents the first evidence that this nutritional intervention has the potential to alter aspects of postmaturational aging in a long-lived species.     

Heat acclimation, aerobic fitness, and hydration effects on tolerance during uncompensable heat stress

The purpose of the present study was to determine the separate and combined effects of aerobic fitness, short-term heat acclimation, and hypohydration on tolerance during light exercise while wearing nuclear, biological, and chemical protective clothing in the heat (40 degrees C, 30% relative humidity). Men who were moderately fit [(MF); <50 ml . kg-1 . min-1 maximal O2 consumption; n = 7] and highly fit [(HF); >55 ml . kg-1 . min-1 maximal O2 consumption; n = 8] were tested while they were euhydrated or hypohydrated by approximately 2.5% of body mass through exercise and fluid restriction the day preceding the trials. Tests were conducted before and after 2 wk of daily heat acclimation (1-h treadmill exercise at 40 degrees C, 30% relative humidity, while wearing the nuclear, biological, and chemical protective clothing). Heat acclimation increased sweat rate and decreased skin temperature and rectal temperature (Tre) in HF subjects but had no effect on tolerance time (TT). MF subjects increased sweat rate but did not alter heart rate, Tre, or TT. In both MF and HF groups, hypohydration significantly increased Tre and heart rate and decreased the respiratory exchange ratio and the TT regardless of acclimation state. Overall, the rate of rise of skin temperature was less, while DeltaTre, the rate of rise of Tre, and the TT were greater in HF than in MF subjects. It was concluded that exercise-heat tolerance in this uncompensable heat-stress environment is not influenced by short-term heat acclimation but is significantly improved by long-term aerobic fitness.     

Traversing the menopause: changes in energy expenditure and body composition

The menopause transition is associated with several physiological changes that may impact women's health outcome. Among the changes associated with the loss of ovarian function is an increased risk of metabolic and cardiovascular disease. The present review focuses on changes in energy expenditure, body composition and body fat distribution during the postmenopausal transition. Previous work indicates that the most important component of total daily expenditure, resting metabolic rate, may be reduced by the menopause, independently of the effects of the normal aging process. This effect is mainly attributable to a decrease in fat-free mass. The energy expenditure associated with physical activity is the most variable component of total daily energy expenditure. However, small changes in this component may have a substantial impact on body composition. Longitudinal data from our laboratory indicate that the menopause transition also leads to significant decreases in physical activity energy expenditure. The changes in body composition that accompany the menopause transition have been studied by several groups and, although some studies suggested increases in body mass index or total body fat mass with the menopause, currently available cross-sectional data preclude a firm conclusion. Nevertheless, results from our longitudinal study showed significant increases in fat mass with the menopause. The accumulation of abdominal fat, which may be a better correlate of the comorbidities associated with obesity, has also been shown to be accelerated by the menopause transition. In this regard, it has been shown that treatment with hormone replacement therapy prevents the increase in the rate of abdominal adipose tissue accumulation that was noted with the menopause. Thus, it appears that the loss of ovarian function induces a reduction in resting metabolic rate, physical activity energy expenditure, fat-free mass, and an increase in fat mass and abdominal adipose tissue accumulation. These modifications probably contribute to the increased risk of cardiovascular disease of postmenopausal women.     

Changes in cell-cycle kinetics during the development and evolution of primate neocortex

The evolutionary expansion of neocortical size in mammals is particularly prominent in anthropoid primates (i.e., monkeys, apes, and humans) and reflects an increased number of cortical cells, yet the developmental basis for this increase remains undefined. Cortical cell production depends on the length of the cell-division cycle of progenitor cells during neurogenesis, which previously has been measured only in smaller-brained rodents. To investigate whether cortical expansion in primates reflects modification of cell-cycle kinetics, we determined cell-cycle length during neurogenesis in the proliferative cerebral ventricular zone of fetal rhesus monkeys, by using cumulative S-phase labeling with bromodeoxyuridine. Cell-cycle durations in monkeys were as much as 5 times longer than those reported in rodents. Nonetheless, substantially more total rounds of cell division elapsed during the prolonged neurogenetic period of the monkey cortex, providing a basis for increased cell production. Moreover, unlike the progressive slowing that occurs during cortical development in rodents, cell division accelerated during neurogenesis of the enlarged cortical layers in monkeys. These findings suggest that evolutionary modification of the duration and number of progenitor cell divisions contributed to both the expansion and laminar elaboration of the primate neocortex.     

A role for sweet taste: Calorie predictive relations in energy regulation by rats.

Animals may use sweet taste to predict the caloric contents of food. Eating sweet noncaloric substances may degrade this predictive relationship, leading to positive energy balance through increased food intake and/or diminished energy expenditure. These experiments were designed to test the hypothesis that experiences that reduce the validity of sweet taste as a predictor of the caloric or nutritive consequences of eating may contribute to deficits in the regulation of energy by reducing the ability of sweet-tasting foods that contain calories to evoke physiological responses that underlie tight regulation. Adult male Sprague-Dawley rats were given differential experience with a sweet taste that either predicted increased caloric content (glucose) or did not predict increased calories (saccharin). We found that reducing the correlation between sweet taste and the caloric content of foods using artificial sweeteners in rats resulted in increased caloric intake, increased body weight, and increased adiposity, as well as diminished caloric compensation and blunted thermic responses to sweet-tasting diets. These results suggest that consumption of products containing artificial sweeteners may lead to increased body weight and obesity by interfering with fundamental homeostatic, physiological processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ethanol ingestion reduces antipneumococcal activity of rat pulmonary surfactant

Because chronic ethanol ingestion decreases pulmonary clearance of Streptococcus pneumoniae in rats, and extracellular antipneumococcal factors in rat surfactant are important in the early clearance of pneumococci from the rat alveolus, the effects of ethanol ingestion on surfactant bactericidal activity were investigated. Normal surfactant from chow-fed rats showed potent anti-pneumococcal activity, even against bacteria growing in nutrient-rich media under favorable conditions. In contrast, surfactant from ethanol-fed rats and from calorie-restricted control-fed rats had significantly reduced antipneumococcal activity compared with surfactant from chow-fed rats. The reductions in surfactant bactericidal activity produced by ethanol ingestion or caloric restriction did not appear to be mediated through changes in either the total amount or the distribution of fatty acids, the antipneumococcal factors in normal surfactant. Rather, ethanol ingestion, and to a lesser extent caloric restriction, produced a surfactant inhibitor of free fatty acids that was partially characterized as a hydrophobic protein.     

Epidemiology and treatment of otitis media with effusion in children in the first year of primary school

Children with acute lymphoblastic leukaemia (ALL) typically gain weight at excessive rates during and after therapy, and a high proportion of young adult survivors are obese. Previous studies have failed to identify the abnormalities in energy balance that predispose these children to obesity. The aim of this study was to determine the cause of excess weight gain in children treated for ALL by testing the hypothesis that energy expenditure is reduced in these patients. Twenty children [9 boys, 11 girls; mean age 10.9 (3.2) y] treated for ALL who had shown excess weight gain, but were not obese [mean body mass index SD score 0.70 (1.04)], were closely and individually matched with 20 healthy control children [9 boys, 11 girls; mean age 10.7 (3.0) y; mean body mass index SD score 0.27 (0.91)]. In each child we measured total energy expenditure by doubly-labeled water method, resting energy expenditure, energy expended on habitual physical activity, and energy intake. Total energy expenditure was significantly higher in control subjects than in patients: mean paired difference 1185 kJ/d (282 kcal/d), 95% confidence interval (CI) 218-2152. This difference was largely due to reduced energy expended on habitual physical activity in the patients. Resting energy expenditure was lower in the patients: mean paired difference 321 kJ/d (76 kcal/d), 95% CI 100-541. Energy intake was also lower in the patients: mean paired difference 1001 kJ/d (238 kcal/d), 95% CI 93-1909. Children treated for ALL are predisposed to excess weight gain, and subsequently obesity, by reduced total energy expenditure secondary to reduced habitual physical activity. Prevention of obesity in ALL should focus on modest increases in habitual physical activity, modest restriction of dietary intake, and monitoring of excess weight gain.     

Weight loss by increasing energy consumption and thermogenesis

Obesity is caused by a chronic imbalance between energy intake and energy expenditure. The increasing incidence of obesity over the last years is partly caused by the decreased physical activity following industrialization. Weight reduction can be achieved by decreasing energy intake and increasing energy expenditure. The fat loss induced by physical activity, however, is relatively small. Exercise helps to prevent the otherwise inevitable loss of muscle during caloric restriction. Due to the low success rate of conventional weight loss programs, the development of drugs to increase thermogenesis is subject to worldwide research. While in animal experiments stimulation of beta-3 adrenergic receptors leads to a significant weight loss, in humans these drugs fail to stimulate energy expenditure probably due to the lack of significant amounts of brown adipose tissue. The recently identified uncoupling proteins (UCP) 2 and 3 dissipate the protone gradient, thereby releasing stored energy as heat. These proteins might therefore act as potential targets for antiobesity drugs.     

Changes in plasma lipids and lipoproteins in humans during a 2-year period of dietary restriction in Biosphere 2

BACKGROUND: A cohort study was performed of 8 people sealed inside Biosphere 2 to evaluate the effects of dietary restriction in humans on lipid and lipoprotein levels and the relationship of these levels to energy, fat, and protein content of the diet, and body weight, weight change, and energy expenditure. METHODS: Eight healthy people aged 27 to 67 years, 4 women and 4 men, were sealed inside Biosphere 2 from September 26, 1991, to September 26, 1993, the longest sustained period in an "isolated confined environment" on record. They were studied throughout confinement and for more than 2 years after their exit and return to an ad libitum diet. Food available was severely restricted during most of the 2-year period inside Biosphere 2. High work output was maintained and food quality remained high, resulting in prolonged restriction of energy intake without malnutrition. RESULTS: Fasting plasma cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol levels; HDL subfraction distribution; dietary energy, fat, and protein content intake; and height, weight, weight change, and energy expenditure were measured. Total plasma cholesterol and triglyceride levels decreased 30% and 45%, respectively. The HDL and low-density lipoprotein levels also decreased and, in some participants, levels of HDL2 subfractions were increased. Multivariate analysis showed that the major cause of these changes was energy restriction. CONCLUSIONS: Energy restriction was the major factor leading to low lipid and lipoprotein levels. Energy restriction with adequate nutrition of young and middle-aged people may substantially reduce risk for atherosclerosis and consequent coronary artery and cerebrovascular disease.     

A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction

The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadisms. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.     

Effects of aging, diet, and sex on plasma glucose, fructosamine, and lipid concentrations in barrier-raised Fischer 344 rats

We studied the relationships of plasma glucose, fructosamine, triglycerides, and cholesterol as a function of age, gender, and diet in barrier-raised Fischer 344 rats aged 5 to 26 months, fed a diet either ad libitum or restricted to 60% of the ad libitum caloric intake. The complex relationships of these plasma levels to age, gender, and diet led to the development of a model with age, diet, and sex as covariates. Overall, fasting plasma glucose concentrations were reduced by approximately 25% in rats on the restricted diet, compared to ad libitum-fed animals. There was a significant age-dependent decline in glucose levels in male animals, whereas in females there was an increase in plasma glucose with aging. Plasma fructosamine levels in calorie-restricted animals, overall, were reduced by 7% compared to levels in animals fed ad libitum. There was a significant positive correlation between plasma glucose and fructosamine levels. Mean plasma triglyceride content was decreased by 50% in calorie-restricted rats compared to ad libitum-fed animals. A significant decrease in triglyceride levels with increasing age was seen in male animals, and an increase with aging in females. There was a significant positive correlation between plasma glucose and triglyceride levels. Plasma cholesterol levels in calorie-restricted animals were reduced by 7% compared to levels in ad libitum-fed animals. An increase of cholesterol concentration with aging was significant in both males and females. Analysis of the data showed that there were significant differences between male and female Fischer 344 rats in the response of plasma glucose and fructosamine to aging and calorie restriction. Changes of plasma triglyceride and cholesterol with aging and dietary calorie restriction were also different in males and females. Studies of the effect of aging on glycemia and blood lipid content should take into account the contributions of animal sex.