The effect of exercise, diet restriction, and aging on the pituitary - adrenal axis in the rat

The effects of calorie restriction, exercise, and aging on the pituitary-adrenal axis were studied in male Wistar rats from 12 to 28 months of age. There were 4 experimental groups: sedentary, ad libitum fed (A); sedentary, diet restricted by feeding on alternate days (R); exercised by swimming on alternate days, ad libitum fed (AE); exercised as AE, diet restricted as R (RE). Pituitary-adrenal function was assessed by measuring serum ACTH and corticosterone concentrations, adrenal weight, hepatic glucocorticoid receptor concentration, and hepatic tyrosine aminotransferase (TAT) activity. Serum corticosterone concentration increased with age while serum ACTH decreased from 12 to 20 months of age and then increased thereafter. TAT activity decreased and receptor concentration remained constant with age. Adrenal weights increased with age; those of AE rats increased dramatically. Analyses for relationships between variables revealed a quadratic relationship between serum ACTH and corticosterone concentrations. There tended to be an inverse relationship between TAT activity and corticosterone concentration. These observations may be indicative of a loss of feedback loop integrity with aging. Neither calorie restriction nor exercise were able to maintain the integrity of pituitary-adrenal function during aging, though dietary restriction did slow age-associated decrements of TAT activity.     

Food restriction prevents an age-associated increase in rat liver beta-adrenergic receptors

In male Wistar rats fed ad libitum (24% protein, 4.5 Kcal/gm), the [125I]iodopindolol binding capacity of the beta-adrenergic receptors in liver of 24-month-old animals is 3-4 times greater than that of 6-month-old counterparts. In rats fed the same diet, on alternate days from weaning, the receptor capacity did not increase significantly between 6 and 24 months (10.20 +/- 0.55 vs 9.20 +/- 0.72 fmol/mg) or between 24 and 30 months. This was not due to acute dietary deprivation, as rats food-restricted for only 2 weeks, at 23.5 months of age, also showed elevated receptor capacities compared to 6-month-old ad libitum fed animals. Moreover, intermittent feeding produced no significant effects among 6-month-old animals, whether restricted since weaning or for two weeks prior to sacrifice. Many biochemical parameters that decrease with aging in rats fed ad libitum are prevented by dietary restriction. Our results demonstrate that a reproducible biochemical process that increases with aging is also prevented with dietary restriction. The age-related, liver beta-receptor increase may be a potentially reliable marker for studying biochemical perturbations that modify life span.     

Aging and dietary modulation of rat skeleton and parathyroid hormone

Studies were carried out on SPF F344 male rats to evaluate the effects of aging and life-prolonging food restriction, without malnutrition, on rat skeleton and circulating PTH. Six-week-old F344 rats were divided into five groups. Group 1 rats were fed ad libitum a diet that contained 21% protein. Group 2 rats were fed 60% of the mean food intake of group 1 rats from 6 weeks of age for the rest of their lives. Group 3 rats were fed 60% of the ad libitum food intake until 6 months of age and then switched to ad libitum feeding. Group 4 rats were fed ad libitum until 6 months of age, and then switched to 60% of the ad libitum food intake. Group 5 rats were fed ad libitum a diet that contained only 12.6% protein so that these animals ingested the same amount of protein per day as the group 2 rats. In group 1 animals, bone length, weight, density, and calcium content increased rapidly with age and plateaued at about 12 months of age. There was no evidence of bone loss in these animals until about 24 months of age, but by 27 months, the animals had lost appreciable amounts of bone. The circulating immunoreactive PTH levels of the animals increased with advancing age, with a marked rise at 27 months. The age-related changes in bone and serum PTH levels of rats in groups 3 and 5 were similar to those of group 1 animals, except that a terminal increase in serum PTH did not occur in group 5 rats. In the groups 2 and 4 animals which were food restricted for the longest period, bone growth and maturation were slowed down, but the animals did not experience senile bone loss or marked terminal increase in circulating PTH. The salutary effects of food restriction were, therefore, not due specifically to the restriction of protein intake or to restricting food intake only during the period of rapid growth.     

Lifelong dietary modulation of calcitonin levels in rats

Studies were carried out on specific pathogen-free rats to evaluate the effects of aging and dietary manipulation on serum and thyroid calcitonin (CT) levels. Male Fischer 344 rats were randomized at 6 weeks of age to six dietary groups and subsequently maintained on the following dietary regimens. Group 1 rats were fed ad libitum throughout life; group 2 rats were fed 60% of the ad libitum food uptake, but received the same amounts of calcium, phosphorus, and vitamin D; group 3 rats were fed as the group 2 animals until 6 months of age and from then on were fed ad libitum; group 4 rats were fed ad libitum until 6 months of age and then switched to 60% food restriction; group 5 rats were fed ad libitum on food isocaloric with that of group 1 rats, but containing only 60% of the protein. Group 6 rats were killed at 6 weeks of age to serve as baseline controls. Ten rats were killed in each of the remaining five groups 15 h postprandial at 6-month intervals. The following observations were made. Serum CT increased with age similarly in the ad libitum fed group 1 and 5 rats. Food restriction markedly inhibited the increase in serum CT, and the effect was more profound in animals whose food intake was restricted after 6 months of age (group 4) than in animals on lifelong food restriction (group 2). In rats switched from food restriction to ad libitum feeding (group 3) at 6 months of age, serum CT increased with age to levels identical with those of lifelong ad libitum fed group 1 animals. Thyroid CT showed a similar pattern of age-dependent and dietary modulated changes. In contrast, aging and dietary modulation had no appreciable effect on serum calcium levels, except at 27 months of age when the serum calcium level of group 1 animals increased dramatically from the level for 24-month-old animals. There was a weak positive correlation between serum calcium and serum CT (r = 0.627; P = 0.02) and a highly significant positive correlation between serum CT and thyroid CT (r = 0.917; P = 0.001). These findings indicate that elective and therapeutic restriction of food intake might also attenulate CT levels in humans, with potentially adverse implications for skeletal homeostasis.     

Modulation of age-related hyperparathyroidism and senile bone loss in Fischer rats by soy protein and food restriction

Studies were carried out to explore the influence of soy protein and food restriction on age-related changes in serum PTH and bone. Three groups of male Fischer 344 rats were studied from 6 weeks of age. Group A rats were fed ad libitum diet A, which has casein as the protein source. Group B rats were fed diet B (with casein as protein source) at 60% of the mean ad libitum food intake. Group C rats were fed ad libitum diet C, which has soy protein as the protein source. The animals were killed at periodic intervals beginning at 6 months of age after an overnight fast. Serum PTH, measured with an intact N-terminal-specific RIA, and immunoreactive calcitonin increased progressively with aging. The increase was markedly suppressed by food restriction, and in the case of PTH by the soy protein diet as well. Serum creatinine started to increase after 18 months of age, and both dietary regimens of groups 2 and 3 retarded the increase. Aging was associated with a fall in serum 25-hydroxyvitamin D, and loss of bone occurred during the terminal part of life in the ad libitum-fed animals. These were prevented by food restriction, while the soy protein diet delayed the onset of bone loss. We conclude from these findings and other data from this study that in the male F344 rats 1) an age-related increase in serum PTH precedes an age-related increase in serum creatinine concentration; 2) an age-related decline in renal function probably contributes to age-related hyperparathyroidism, which, in turn, contributes to senile bone loss; 3) food restriction inhibits age-related hyperparathyroidism and senile bone loss; 4) on the basis of the data from rats fed a soy protein-containing diet, a decline in renal function and progressive hyperparathyroidism are not inevitable consequences of aging in the ad libitum fed rats.     

Dietary restriction alters characteristics of glucose fuel use.

A longitudinal study of plasma glucose and insulin concentrations in ad libitum fed and dietary restricted male F344 rats was carried out. The life span diurnal pattern of plasma glucose concentration was such that through most of the day dietary restricted rats have significantly lower plasma glucose levels than ad libitum fed rats. Throughout the life span, dietary restricted rats maintain mean 24-hour plasma glucose concentrations about 15% below those of ad libitum fed rats. Plasma insulin levels are maintained in dietary restricted rats at about 50% of the levels in ad libitum fed rats. Although plasma glucose and insulin levels are lower, dietary restricted rats use glucose fuel at the same rate per unit of metabolic mass per day as rats fed ad libitum. While these findings are consistent with the glycation hypothesis of aging and with our hypothesis that dietary restriction retards the aging processes by altering the characteristics of fuel use, they do not establish the validity of either. It is possible that this effect of dietary restriction on carbohydrate metabolism plays no role in its antiaging action. Further studies are required to define the role of these altered characteristics of carbohydrate metabolism in the aging processes.     

Influence of age and long-term dietary restriction on plasma insulin-like growth factor-1 (IGF-1), IGF-1 gene expression, and IGF-1 binding proteins.

The purpose of these studies was to determine more accurately the relationship between IGF-1 and life span, and to determine whether moderate dietary caloric restriction alters the age-related changes in IGF-1. Studies included an assessment of plasma IGF-1, hepatic IGF-1 mRNA, and plasma IGF-1 binding proteins (IGF-1-BP). Rats (6, 12, 22, and 28 months of age) were fed ad libitum or maintained on a diet 60% of ad libitum. In ad libitum fed animals, plasma IGF-1 decreased by 20% between 6 and 28 months of age. Similar age-related declines were observed in dietary restricted animals but levels were generally 14-25% lower at each age group. IGF-1 mRNA levels demonstrated similar decreases with age in ad libitum fed animals, but in dietary restricted animals, levels plateaued at 22 and 28 months. IGF-1 binding protein analysis revealed 3 bands at approximate molecular weights of 40k, 30k, and 24k. All bands demonstrated a decrease in relative IGF-1-BP concentration with age, as well as a decrease in the 40k and 30k binding proteins after dietary restriction. These results indicate that (a) aging in ad libitum fed animals is associated with decreases in plasma IGF-1, IGF-1-BP, and IGF-1 mRNA levels; and (b) long-term dietary restriction decreases plasma IGF-1 and IGF-1-BP levels in each age group although the age-associated decreases in IGF-1 mRNA levels are prevented by dietary restriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

The age-related accumulation of protein carbonyl in rat liver correlates with the age-related decline in liver proteolytic activities.

Increases of protein carbonyl in animal tissues have been associated with the aging process. So far, the accumulation of oxidized proteins, highly susceptible to proteolysis, has been attributed to age-related changes in proteasomal alkaline proteases. Carbonyl in protein was monitored in six different tissues of male Sprague-Dawley rats fed ad libitum up to the age of 27 months, and of 24 and 27-month-old rats subjected to anti-aging diet restriction (every-other-day feeding ad libitum). Alkaline protease activities and liver lysosomal proteolysis were studied. The levels of protein carbonyl were significantly different in different tissues, and quite stable throughout life; accumulation was restricted to liver tissue very late in life, between ages 24 and 27 months; was fully prevented by diet restriction; was not accompanied by any diet-restriction-sensitive decline of alkaline protease activity; and was accompanied by a dramatic age-related decline in lysosomal proteolysis that was partially prevented by anti-aging diet restriction. No correlation was found between levels of alkaline protease activity and levels of protein carbonyl in the different tissues from younger animals. It is concluded that the process of autophagy, a well-known mechanism for cell maintenance, may deserve more interest in aging studies.     

Life span, morphology, and pathology of diet-restricted germ-free and conventional Lobund-Wistar rats

The effect of germ-free life and dietary restriction (DR) on life span and pathology was investigated in isolator housed germ-free (GF) and conventional (CV) Lobund-Wistar rats fed either ad libitum or restricted to 12 grams per day (70% of adult ad libitum intake) of a natural ingredient diet from weaning. The median length of life of ad libitum CV and GF rats was 31.0 and 33.6 months respectively, while DR increased the median length of life of CV and GF rats to 38.6 and 37.8 months respectively. DR reduced the frequency or postponed the occurrence of diseases which eventually lead to death in the Lobund-Wistar rat. This was especially true of prostate adenocarcinoma, prostatitis, and mammary fibroma. The reduced early food intake and smaller body weight of adult GF rats may be the reason ad libitum fed GF rats live slightly longer than their CV counterparts, but GF life was without additional effect on life span when food intake was restricted.     

The effects of acute and life-long food restriction on basal and stress-induced serum corticosterone levels in young and aged rats

The effects of short term (1-month) and life-long 60% ad libitum food restriction on the adrenocortical response to restraint stress were compared in young and aged Fischer 344 rats. In rats restricted for 1 month (study 1), the adrenocortical response differed as a function of age. In 8-month-old animals, the initial steep rise in corticosterone in response to stress was of similar magnitude in ad libitum and restricted animals. In 23-month-old animals the corticosterone response was severely blunted in restricted animals. In life-long restricted animals (study 2), the corticosterone response to restraint stress was tested at 8, 16, and 24 months of age. The general pattern of response to stress in these animals was similar to that in study 1. The 16- and 24-month-old animals showed the same blunted response to stress found in the 23-month-old animals restricted for only 1 month, suggesting that the severe restriction per se and not life-long food restriction blunted the response to stress in aged animals. The similarity between the response to stress in study 1 and study 2 was evident even though animals were tested in one case before feeding when corticosterone levels were high, and in the other 4-5 h after feeding when corticosterone levels were lower. In study 3 it was found that in food-restricted young rats, the mean corticosterone level over a 24-h period was significantly elevated above that in ad libitum fed young rats. In aged rats, however, except before daily feeding, corticosterone levels of food-restricted rats remained significantly below those of ad libitum fed animals, whose levels were, in turn, significantly elevated compared to those of ad libitum fed young rats. These findings suggest that in aged animals severe food restriction reduces basal corticosterone levels, adrenal responsiveness to stress, and adrenal size and has the potential to protect against the consequences of high corticosterone levels in aging.     

Auerbach plexus structure with NADH histochemistry in a line of obese rats: effects of dietary restriction

This report aims to study architectural Auerbach plexus structure with NADH histochemistry (nicotinamide adenine dinucleotide, reduced form), along ages and their modifications with restricted diet in obese beta line rats. Experimental groups were: 1) After weaning, male rats were fed ad libitum (ALD) with standard rat chow. Autopsies were done at 2, 4, 8, 12, and 18 months old. 2) After weaning, one group was fed ad libitum, another group of rats were maintained on a restricted diet (RD). Autopsy was performed at 8 months of age. 3) After weaning, male rats were fed ad libitum (ALD) with standard rat chow. At 60 days old one group was continued with standard rat chow. Another group was fed with a restricted diet (RD). Autopsy was performed at 120 days old. After autopsy, segments of small intestine, proximal and distal colon were processed for NADH histochemistry. 1) At 2 months of age some empty spaces ("neuronal ghosts") were seen between neurons. Later on partial to total disruption of reticular structures was seen along ages. 2) In RD rats of 8 months of age, a mesh-like structure similar to normal control rats was observed. In ALD rats, partial to total disruption of mesh-like structures was seen. 3) In RD rats of 4 months of age, disruption intermingled with normal mesh-like zones was seen, more severe in ALD rats. Changes in Auerbach plexus structure (disruption of mesh-like appearance) in this line of rats were quite different from normal control rats suggesting dismetabolism effects. Dietary restriction delayed alterations in Auerbach plexus structures in obese rats.     

Effects of wheat bran and energy restriction on onset of puberty, cell proliferation and development of mammary tissue in female rats.

Delayed onset of puberty and mammary development is assumed to reduce the risk of mammary cancer. An animal experiment was performed to investigate the influence of dietary fiber, which is known to affect hormonal balance, on these characteristics. Forty-five immature female rats were randomized into three groups, which were fed ad libitum a low-fiber diet (less than 0.5% dietary fiber based on white wheat flour), a high-fiber diet (9.2% dietary fiber based on wheat bran), or an energy-restricted low-fiber diet providing 90% of the energy of the ad libitum low-fiber diet. Energy intake in the second and third groups was similar. Wheat bran slightly delayed onset of puberty, whereas restricted energy intake delayed onset of puberty by about six days. At 48-58 days of age, 14 rats of the low-fiber group, 10 of the high-fiber group and 7 of the restricted group were in cycle. Development of mammary tissue was rudimentary in rats of the energy-restricted low-fiber group, stronger in the high-fiber group and strongest in the ad libitum low-fiber group. Cell proliferation in mammary tissue was similar for both groups fed ad libitum, but significantly lower in the restricted group. Peroxidase activity, a biomarker for estrogenicity, was lower in the high-fiber group than in the two low-fiber groups. It is concluded that wheat bran and, even more effectively, an imposed restricted energy intake delays onset of puberty and mammary development. This shortens the time for mammary cells to be initiated to tumor cells and hence reduces the risk of mammary cancer development.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma protein's glycation is decreased in Sprague Dawley rats under caloric restriction

Different dietary regimens were applied to three cohorts of rats. The first was fed ad libitum every day (AL), the second was fed ad libitum every other day (EOD) and the third was fed a diet equivalent to 60% of the caloric intake (60% CI) of the AL cohort. Levels of stable early glycation products in plasma proteins were then measured according to two different methods. Glycation of plasma proteins progressively increased in AL animals belonging to the 2-12 month age interval, while it showed a less pronounced age-dependent increase in EOD and 60% CI animals. The lowest degree of glycation was detected 2-3 months after the beginning of caloric restriction. After 12 months of age a lower level of glycation was detected in 60% CI rats than in EOD animals. Body weight was lower in restricted animals than in AL animals and was lowest in 60% CI rats. During the life span, glycemia was lower in fasting 60% CI than in EOD or AL rats.     

Modulation of free radicals and superoxide dismutases by age and dietary restriction

Reducing dietary intake has been shown to be the most effective means for modulating aging processes in laboratory rodents. Dietary restriction has also been shown to be a modulator of membrane lipid peroxidation and cytosolic antioxidant status. In the present study, anti-radical action of dietary restriction was investigated further by quantitating the formation of the superoxide radical, hydroxyl radical and hydrogen peroxide by liver microsomes from rats of various ages. The results show that the ad libitum fed group maintained a higher production of superoxide and hydroxyl radicals when compared to the food restricted group of the same age. Hydrogen peroxide formation followed the same trend but was statistically greater only at 3 and 6 months of age. The food restricted group tended to show a higher superoxide dismutase (SOD) activity in both cytosolic and mitochondrial fractions than ad libitum fed controls. These data indicate that the free radical activity observed in the liver microsomes of ad libitum fed rats can be attenuated by dietary restriction, thereby providing a possible biochemical mechanism for its anti-lipoxidative action on membrane lipid peroxidation as reported in an earlier study. This action may in part underlie the life span-prolonging action of food restriction.     

Dietary restriction reduces age-related degeneration of stria vascularis in the inner ear of the rat

We report here beneficial effects of life-long dietary restriction on the progression of age-associated cochlear degeneration in female Sprague–Dawley rats. Thirty-month old rats on a 70% dietary restriction were compared to ad libitum fed age-matched rats, and three-month old adult rats. As expected, aged dietary restricted rats displayed about 20% higher survival rate than age-matched rats fed ad libitum. This difference was reflected also in the auditory system. In the dietary restricted group, 73% of the subjects had preserved auditory reflexes (Preyer), and only modest degeneration of the stria vascularis of the inner ear was observed. In contrast, aged ad libitum fed animals, of which only 15% had detectable Preyer reflexes, showed a marked thinning, cellular degeneration and loss of cell processes in the stria vascularis. The extent of loss of sensory hair cells (~ 24%) was similar in both the aged groups, and neither group showed a significant reduction in the number of spiral ganglion neurons across adult life-span. The observations thus demonstrate that dietary restriction delays age-related degradation of the auditory system. The results provide further insights into the mechanisms of strial presbycusis.     

Dietary restriction maintains the basal rate of somatotrope renewal in later life in male rats

We investigated the impact of dietary restriction on the basal rate of somatotrope renewal in the pituitary gland. Bromodeoxyuridine (BrdU), a thymidine analog, was administered continuously for 1 week in male F344 rats at 3, 8 and 20 months of age (mo), fed ad libitum (AL) or diet restricted from 1.5 mo (DR). Combined immunostainings for BrdU and GH visualized newly formed somatotropes as well as pituitary cells in tissue sections. The rate of incorporation of BrdU by anterior pituitary cells (BrdU-labeled nuclei/100 nuclei) was not influenced by the dietary regimen or age. The fraction of BrdU-labeled somatotropes relative to all labeled cells precipitously decreased to the same level in both dietary groups between 3 and 8 mo, although the fraction was greater in DR rats at 3 mo. In AL rats, the fraction decreased further between 8 and 20 mo, while it stabilized in DR rats. Our results suggested that dietary restriction maintains the basal rate of somatotrope renewal in later life in male rats. Although one must also estimate the effects of dietary restriction on apoptotic cell death in pituitary cells, the present study provides evidence that dietary restriction modulates somatotropes cell turnover and preserves the cell population for GH secretion during aging.     

Assessment of the role of the glucocorticoid system in aging processes and in the action of food restriction

The Glucocorticoid Cascade Hypothesis of Aging and the hypothesis that food restriction retards the aging processes by preventing the development with age of hyperadrenocorticism were investigated. A longitudinal life span study of the daily concentration pattern of plasma corticosterone was conducted in male Fischer 344 rats fed ad libitum or restricted to 60% of the mean food intake of ad libitum fed rats. In another group of ad libitum fed and food-restricted rats, the influence of age on the response of plasma corticosterone levels to restraint stress was measured as was the time course of the return of plasma corticosterone to basal levels following the stress. The findings do not support the hypothesis that food restriction retards the aging processes by preventing the development of hyperadrenocorticism with advancing age. They also indicate that the Glucocorticoid Cascade Hypothesis does not describe a major aspect of the aging processes. Rather, the results suggest the possibility that a lifetime of daily periods of mild hyperadrenocorticism may, if anything, retard the aging processes.     

In vivo DNA synthesis in the dietary restricted long-lived rat

Male CFY Sprague-Dawley rats maintained at 50% growth rate of ad libitum fed, age-matched control animals showed a 42% extension in maximum lifespan and an increase in the overall doubling time of the rate of mortality from 102 days to 203 days. The slower growth rate of animals on the restricted diet was reflected in lower DNA, RNA, and protein content of liver, kidney and heart with age. DNA synthesis in vivo measured by the incorporation of 3H-thymidine was severely inhibited in liver, kidney, heart, and abdominal skin, particularly during the first six months of life. The developmental peak in DNA synthesis observed in liver and kidney of ad libitum fed animals before 100 days of age was completely inhibited. No effect of restricted feeding on DNA synthesis in the small intestine was observed; however, DNA synthesis was higher in thymic tissue from the experimental animals. A decrease in RNA content of liver, kidney, and heart preceded any change in protein or DNA in animals subjected to restricted feeding. The capacity for protein synthesis (RNA/DNA ratio) was decreased by restricted feeding and was associated with a reduced protein/DNA ratio indicative of reduced cell size during the first six months of life. The translational activity per ribosome (protein/RNA ratio) was not disturbed by undernutrition in any of the tissues studied.     

The effect of food restriction and germ-free environment on age-related changes in bone matrix

Studies were performed to determine the effects of food restriction or a germ-free environment on age-related changes in bone. Four groups of male Lobund-Wistar rats were examined at 6 months, 18 months, and 30 months of age. Conventional-free-fed rats were housed in routine laboratory cages and fed ad libitum. Conventional-restricted diet rats were fed 12 grams a day, which becomes restrictive at 8 weeks of age. Germ-free rats were maintained using gnotobiotic procedures and were free of pathogens. The germ-free rats were maintained on either the full-fed or restricted diet regimens. Serum bone Gla protein and matrix concentrations of calcium, magnesium, and hydroxyproline (reflecting collagen content) and bone Gla protein were not significantly different between the four treatment groups. All of these parameters except hydroxyproline, however, showed age-related declines in all four treatment groups. We conclude that prolongation of rat life span by dietary restriction and/or a germ-free environment did not alter the measured parameters in each age group, and did not alter or slow the age-related changes in the bone matrix.     

Impact of moderate physical exercise--in comparison with dietary restrictions--on age-associated decline in cell-mediated immunity of Sprague-Dawley rats

BACKGROUND AND AIMS: Moderate physical exercise and dietary restriction have both been demonstrated to delay some of the adverse effects of aging. In order to elucidate similarities or dissimilarities in their mode of action on the aging immune system in a comparative setting, we examined significant parameters of cell-mediated immunity in Sprague- Dawley rats. METHODS: Male Sprague-Dawley rats, housed individually, were divided into four groups, living from 5 months (baseline group BL) up to 15, 19 and 23 months of age as follows: voluntary running in wheels (RW), food restricted by feeding to pair weight with RW animals (PW), forced running on treadmills (TM), and sedentary controls with ad libitum access to food (S1). White blood cell counts, capacity for lymphocyte proliferation in response to Concanavalin A, and interleukin-2 (IL-2) plasma concentrations were determined. RESULTS: White blood cell counts and the cell numbers of lymphocytes, neutrophil and eosinophil granulocytes were significantly lower in the older RW and PW groups. We observed influences of forced exercise on lymphocyte proliferation: blastogenic reactivity was higher in TM animals compared with RW and PW animals at 23 months of age. Exclusively for RW animals, we found lower plasma concentrations of IL-2 at 23 months. CONCLUSIONS: Our data support the idea that moderate physical exercise modulates age-associated decline in the cell-mediated immunity of old Sprague-Dawley rats significantly more than corresponding dietary restrictions.