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PubMed2004

Effect of caloric restriction on the 24-hour plasma DHEAS and cortisol profiles of young and old male rhesus macaques.

Although dietary caloric restriction (CR) can retard aging in laboratory rats and mice, it is unclear whether CR can exert similar effects in long-lived species, such as primates. Therefore, we tested the effect of CR on plasma levels of dehydroepiandrosterone sulfate (DHEAS), a reliable endocrine marker of aging. The study included six young (approximately 10 years) and ten old (approximately 25 years) male rhesus macaques, approximately half of the animals in each age group having undergone >4 years of 30% CR. Hourly blood samples were collected remotely for 24 hours, through a vascular catheter, and assayed for DHEAS and cortisol. Both of these adrenal steroids showed a pronounced diurnal plasma pattern, with peaks occurring in late morning, but only DHEAS showed an aging-related decline. More importantly, there was no significant difference in plasma DHEAS concentrations between the CR animals and age-matched controls. These data fail to support the hypothesis that CR can attenuate the aging-related decline in plasma DHEAS concentrations, at least not when initiated after puberty.

Aging↗

PubMed1997

Caloric restriction enhances evoked DA overflow in striatum and nucleus accumbens of aged Fischer 344 rats.

Previous studies have shown deficits in DA neuronal systems in senescence. Other studies indicate that prolonged dietary restriction can attenuate many of the detrimental effects of age. We have shown previously using in vivo electrochemistry that K+-evoked striatal DA overflow decreases as a function of age. This was a regional effect that appeared to be due to functional changes in DA neurons, rather than a decrease in the storage and synthesis of DA. In the present studies, we used in vivo electrochemistry to investigate the effects of caloric restriction on age related decreases in K+-evoked DA overflow along a dorsal to ventral axis in the striatum of aged female Fischer 344 rats. Aged (26-28-month-old) diet restricted animals (DRF) showed evoked DA overflow that was significantly greater in amplitude and duration compared to aged (26-28-month-old) ad lib fed animals (ALF). These results provide additional evidence that decreased DA neuronal function resulting from age is improved by caloric restriction.

Aging↗

PubMed2002

Endogenous oxidative stress: relationship to aging, longevity and caloric restriction.

Available studies are consistent with the possibility that oxygen radicals endogenously produced by mitochondria are causally involved in the determination of the rate of aging in homeothermic vertebrates. Oxidative damage to tissue macromolecules seems to increase during aging. The rate of mitochondrial oxygen radical generation of post-mitotic tissues is negatively correlated with animal longevity. In agreement with this, long-lived animals show lower levels of oxidative damage in their mitochondrial DNA (mtDNA) than short-lived ones, whereas this does not occur in nuclear DNA (nDNA). Caloric restriction, which decreases the rate of aging, also decreases mitochondrial oxygen radical generation and oxidative damage to mitochondrial DNA. This decrease in free radical generation occurs in complex I and is due to a decrease in the degree of electronic reduction of the complex I free radical generator, similarly to what has been described in various cases in long-lived animals. These results suggest that similar mechanisms have been used to extend longevity through decreases in oxidative stress in caloric restriction and during the evolution of species with different longevities.

Aging↗

PubMed1992

Effect of aging and caloric restriction on intestinal permeability.

Intestinal permeability is increased in several disorders such as Crohn's disease or rheumatoid arthritis. Since aging leads to alteration of many biological functions, the effect of aging on intestinal permeability was studied by measuring the intestinal permeability in aging rats gavaged with different size permeability probes--mannitol, polyethylene glycol (PEG) 400, and inulin. In rats fed with control diet, there was a significant increase in intestinal permeability to medium size probes PEG 400 (14.8 +/- 0.4 and 21.0 +/- 1.1% at 3 and 28 months respectively, p less than .01) and mannitol (3.41 +/- 0.4 and 5.3 +/- 0.5% at 3 and 28 months, respectively, p less than .01). Intestinal permeability of the large macromolecule inulin did not change (0.42 +/- 0.03 and 0.38 +/- 0.02% at 3 and 28 months, respectively) with aging. There was no correlation between weight of the rats and their intestinal permeability. Because dietary caloric restriction has been found to prolong the life span, retard deterioration of several biological functions, and affect intestinal absorptive functions, we examined the effect of lifelong calorie restriction on intestinal permeability changes. Lifelong calorie-restricted diet did not affect age-related change in intestinal permeability. We conclude that intestinal permeability of medium size probes increases with aging and that lifelong caloric restriction does not prevent this change. We speculate that age-associated deterioration in intestinal barrier functions could permit increased systemic absorption of lumenal antigens and could perhaps contribute to the genesis of antigen-related age-associated diseases.

Aging↗

PubMed2006

Synergistic effects of caloric restriction with maintained protein intake on skeletal muscle performance in 21-month-old rats: a mitochondria-mediated pathway.

Caloric restriction (CR) delays the onset of age-related mitochondrial abnormalities but does not prevent the decline in ATP production needed to sustain muscle protein fractional synthesis rate (FSR) and contractile activity. We hypothesized that improving mitochondrial activity and FSR using a CR diet with maintained protein intakes could enhance myofibrillar protein FSR and consequently improve muscle strength in aging rats. Wistar rats (21 months old) were fed either an ad libitum (AL), 40% protein-energy restricted (PER) or 40% AL-isonitrogenous energy restricted (ER) diet for 5 months. ATP production, electron transport chain activity, reactive oxygen species (ROS) generation, protein carbonyl content and FSR were determined in both tibialis anterior (TA) and soleus muscle mitochondria. Myosin and actin FSR and grip force were also investigated. The ER diet led to improved mitochondrial activity and ATP production in the TA and soleus muscles in comparison with PER. Furthermore, mitochondrial FSR in the TA was enhanced under the ER diet but diminished under the PER. Mitochondrial protein carbonyl content was decreased by both the ER and PER diets. The ER diet was able to improve myosin and actin FSR and grip force. Therefore, the synergistic effects of CR with maintained protein intake may help to limit the progression of sarcopenia by optimizing the turnover rates and functions of major proteins in skeletal muscle.

Adenosine Triphosphate↗

PubMed2004

Dietary caloric restriction may delay the development of cataract by attenuating the oxidative stress in the lenses of Brown Norway rats.

Dietary caloric restriction (CR) is the only experimental intervention that can reliably retard the development of cataract in a normal animal model. Here we have studied the possible mechanisms by which CR retards the age-related degeneration of the lens of Brown Norway rats. We have found that CR slowed protein insolubilization and blunted declines of the total soluble thiols, protein thiols, reduced glutathione and ascorbic acid levels in the lenses of old BN rats. From the lens protein point of view, the development of cataract in rat lenses has 3 stages: (1) the precipitation of gamma-crystallin, (2) the insolubilization of beta-crystallin, and (3) the final precipitation of alpha-crystallin which was saturated with other denatured lens proteins. A similar sequence is also observed when the lens proteins are subjected to oxidative stress in vitro. These data are the first to suggest that CR may retard the age-related degeneration of the lens by attenuating the oxidative stress in the lens. Since oxidative stress is likely a main cause of human cataract, CR intervention may be relevant to humans as well.

Aging↗

PubMed2004

Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice.

Age-related changes in neurogenesis and its modulation by caloric restriction (CR) were studied in C57BL/6 mice. To this end, bromodeoxyuridine (BrdU) labeling was used to assess neuronal and glial precursor proliferation and survival in the granular cell layer (GCL) and the hilus of the dentate gyrus of 2-, 12-, 18-, and 24-month-old mice. For both regions, we found an age-dependent decrease in proliferation but not in survival of newborn cells. Interestingly, the reduction in proliferation occurred between 2 and 18 months of age with no additional decline between 18- and 24-month-old mice. Phenotyping of the newborn cells revealed a decrease in the neuron fraction in the GCL between 2 and 12 months of age but not thereafter. The majority of BrdU cells in the hilus colocalized with astrocytic but none with neuronal markers. CR from 3 to 11 months of age had no effect on neurogenesis in the GCL, but had a survival-promoting effect on newly generated glial cells in the hilus of the dentate gyrus. In conclusion, C57BL/6 mice reveal a substantial reduction in neurogenesis in the dentate gyrus until late adulthood with no further decline with aging. Long-term CR does not counteract this age-related decline in neurogenesis but promotes survival of hilar glial cells.

Aging↗

PubMed2004

Caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): metabolic, physiologic, and atherosclerotic measures from a 4-year intervention trial.

Caloric restriction (CR) retards aging processes, extends maximal life span, and consistently improves insulin resistance in lower species. Insulin resistance is associated with cardiovascular disease, but data is lacking demonstrating that increased insulin sensitivity reduces atherosclerosis progression. We initiated a study in 32 adult cynomolgus monkeys to evaluate increased insulin sensitivity secondary to CR on atherosclerosis extent. Following pretrial determinations, animals were randomized to a moderately atherogenic (0.25 mg cholesterol/Cal containing 30% of calories from fat)-fed control group or CR group (30% reduction) with equivalent dietary cholesterol intake. CR significantly improved insulin sensitivity and reduced intraabdominal fat over the 4-year intervention, while no significant differences were seen for the lipid profile between groups. Despite improved insulin sensitivity with CR, atherosclerosis extent did not differ between the ad libitum-fed or CR groups. These studies demonstrate that CR significantly improves insulin sensitivity, but when elevated plasma cholesterol concentrations were held similar, there was no effect on atherosclerosis extent. However, the composition of these lesions and changes in endothelial function may have been improved but were not evaluated in this study. Thus, further studies are needed to determine if improved insulin sensitivity might decrease arterial inflammation and improve endothelial function, despite no changes in atherosclerosis extent.

Abdomen↗

PubMed2003

Effect of caloric restriction on mitochondrial reactive oxygen species production and bioenergetics: reversal by insulin.

To gain insight into the antiaging mechanisms of caloric restriction (CR), mitochondria from liver tissue of male Brown Norway rats were used to study the effects of CR and insulin on mitochondrial reactive oxygen species production and bioenergetics. As assessed by hydrogen peroxide measurement, CR resulted in a decrease in the production rate of reactive oxygen species. This decrease was attributed to a decrease in protonmotive force in mitochondria from the CR animals. The decrease in protonmotive force resulted from an increase in proton leak activity and a concomitant decrease in substrate oxidation activity. Each of these effects of CR was reversed by subjecting CR animals to 2 wk of insulin treatment. To achieve continuous and stable insulin delivery, animals were placed under temporary halothane anesthesia and miniosmotic pumps were implanted subcutaneously. To gain further insight into how CR and insulin exerted its effects on mitochondrial bioenergetics, the effects of CR and insulin were quantified using modular metabolic control analysis. This analysis revealed that the effects of CR were transmitted through different reaction branches of the bioenergetic system, and insulin reversed the effects of CR by acting through the same branches. These results provide a plausible mechanism by which mitochondrial reactive oxygen species production is lowered by CR and a complete description of the effects of CR on mitochondrial bioenergetics. They also indicate that these changes may be due to lowered insulin concentrations and altered insulin signaling in the CR animal.

Animals↗

PubMed1996

Aspects of the neuroendocrine control of somatotropic function in calorically restricted dogs and patients with eating disorders: studies with cholinergic drugs.

A series of studies was devised in both an experimental model of food deprivation, i.e., beagle dogs undergoing a progressive reduction of calorie intake and adolescent females with anorexia nervosa (AN) in the acute and recovery phase, and in patients with atypical eating disorders. The studies were aimed at ascertaining whether the alleged function of the hypothalamic system inhibitory to growth hormone (GH) secretion, i.e., the somatostatinergic, may account for at least some of the abnormalities of GH secretion present in AN patients (e.g., elevated basal GH levels, paradoxical GH rise after glucose or thyrotropin releasing hormone, etc). Caloric restricted dogs or patients with eating disorders were given an intravenous injection of the physiologic GH-releasing peptide GHRH alone or preceded by pirenzepine, a muscarinic cholinergic antagonist reportedly capable of eliciting hypothalamic release of somatostatin (SS), or pyridostigmine, a muscarinic cholinergic agonist which, conversely, would restrain hypothalamic release of SS. In addition, dogs were challenged with acute administration of glucose or thyrotropin-releasing hormone, compounds also thought to act via somatostatinergic influences. Data obtained in dogs under caloric restriction or in AN patients in the acute phase of the disease with drugs affecting cholinergic transmission suggest that the latter is increased in both conditions (only partial suppression of the GHRH-induced GH rise with pirenzepine, failure of pyridostigmine to further enhance the GH response to GHRH). Instead, in the same AN patients in the acute phase tested during recovery, in AN patients during the recovery phase, and in patients with atypical eating disorders, pirenzepine completely suppressed the GH response to GHRH, as it did in controls. Finally, data obtained on basal and GHRH-stimulated GH release in dogs given glucose or thyrotropin-releasing hormone and in AN patients given arginine, another compound thought to act via inhibition of somatostatinergic influences, do not support the view that somatostatinergic function is impaired in states of food deprivation.

Adolescent↗

PubMed1990

Immune potentiation after fractionated exposure to very low doses of ionizing radiation and/or caloric restriction in autoimmune-prone and normal C57Bl/6 mice.

Very low doses of ionizing radiation can enhance immune responsiveness and extend life span in normal mice. Total lymphoid irradiation at relatively high doses of radiation can retard autoimmune disease in genetically susceptible mice, but may impair immune function. In order to determine whether fractionated low dose exposure would enhance immune response and retard lymphadenopathy in autoimmune-prone mice, groups of C57B1/6 lpr/lpr mice were sham irradiated, exposed 5 days/week for 4 weeks to 0.04 Gy/day (0.8 Gy cumulative dose), or to 0.1 Gy/day (2.0 Gy cumulative dose). After the radiation protocol, the mice were evaluated for splenic T cell proliferative capacity, T cell subset distribution, and total spleen cell numbers. The independent and additive effect of caloric restriction was additionally assessed since this intervention has been shown to increase immune responsiveness and retard disease progression in autoimmune-prone mice. The congenic C57B1/6 +/+ immunologically normal strain was evaluated in parallel as congenic control. The results indicated that mitogen-stimulated proliferation was up-regulated in both strains of mice after exposure to 0.04 Gy/day. The proliferative capacity was additively enhanced when radiation at this dose level was combined with caloric restriction. Exposure to 0.1 Gy/day resulted in further augmentation of proliferative response in the lpr/lpr mice, but was depressive in the +/+ mice. Although the proportions of the various T cell subpopulations were altered in both strains after exposure to LDR, the specific subset alterations were different within each strain. Additional experiments were subsequently performed to assess whether the thymus is required for LDR-induced immune potentiation. Thymectomy completely abrogated the LDR effect in the +/+ mice, suggesting that thymic processing and/or trafficking is adaptively altered with LDR in this strain. In contrast, augmentation in proliferative activity after LDR in the lpr/lpr mice was maintained, although attenuated, in thymectomized mice. Taken together, these results indicate that fractionated exposure to LDR augments the proliferative response of spleen cells in both autoimmune-prone and immunologically normal mice; however, within each strain, the mechanisms appear to be different.

Animals↗

PubMed2004

Effects of caloric restriction on cell proliferation in several tissues in mice: role of intermittent feeding.

Reduced cell proliferation may mediate anticarcinogenic effects of caloric restriction (CR). Using heavy water (2H2O) labeling, we investigated the cell proliferation response to CR in detail, including time course, effect of refeeding, and role of intermittent feeding with 5% CR. In the time-course study, 8-wk-old female C57BL/6J mice were placed on a 33% CR regimen (fed 3 times/wk) for varying durations. Compared with responses in controls fed ad libitum (AL), proliferation rates of keratinocytes, mammary epithelial cells, and T cells were markedly reduced within 2 wk of CR. In mice fed 95% ad libitum (C95, fed 3 times/wk), cell proliferation was also reduced in all tissues so that differences from 33% CR were only significant at 1 mo. In the refeeding study, mice were refed a C95 diet for varying durations after 1 mo of 33% CR. Cell proliferation rebounded to a suprabasal rate in all tissues after 2 wk of refeeding and then normalized after 2 mo, although the C95 group again exhibited lower cell proliferation than the AL group. The role of intermittent feeding was studied by comparing 33% CR and C95 animals (both fed intermittently) with animals fed isocalorically either daily or continuously by pellet dispenser. Intermittent feeding had no additive effect on 33% CR but reduced cell proliferation in all tissues at the 95% caloric intake level. In summary, the CR effect on cell proliferation is potent, rapid, and reversible in several tissues, and an intermittent feeding pattern reproduces much of the effect in the absence of substantial CR.

Animals↗

PubMed2004

The effect of aging and caloric restriction on mitochondrial protein density and oxygen consumption.

It has been proposed that part of the anti-aging mechanism of caloric restriction (CR) involves changes in mitochondrial function. To investigate this hypothesis, mitochondria from various tissues of male Brown Norway rats (fully fed and CR) were isolated and respiration rates determined. In mitochondria from liver, heart, brain and kidney, there were no significant effects of CR on state 4 mitochondrial respiration rate. Further experiments using liver mitochondria under a variety of incubation conditions confirmed that CR does not alter mitochondrial respiration rate in this tissue. However, the respiration rate of mitochondria from brown adipose tissue (BAT) of CR animals was approximately three-fold higher compared to mitochondria from fully fed controls. Mitochondrial protein density was significantly higher in liver tissue of CR animals; it was significantly lower in heart and unchanged in BAT. It is concluded that whilst CR results in tissue-specific changes in mitochondrial respiration rate, these effects do not explain the CR-induced changes in free radical production reported previously for these organelles.

Aging↗

PubMed1997

Aging and caloric restriction affect mitochondrial respiration and lipid membrane status: an electron paramagnetic resonance investigation.

Previous studies have indicated that reactive oxygen species (ROS) are likely involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). ROS, generated by succinate-stimulated mitochondria, have been reported to be spin trapped and detected by electron paramagnetic resonance (EPR). Our aim in the current study was to study the impact of aging on the effect of increased metabolic stimuli on mitochondrial respiration in terms of oxy-radical generation and possible lipid peroxidative changes in brain neocortical membranes. A mixed population of brain synaptosomes and mitochondria from brown norway male rats of differing ages being fed either ad lib (AL) or a caloric-restricted diet (DR) was prepared and labeled with 5-nitroxyl stearate (5-NS), a membrane lipid-specific spin label. The changes in anisotropic motion of the intercalated 5-NS spin probe also allows one to evaluate the status of the membrane fluidity in the lipid microenvironment via the order parameter. Upon succinate stimulation of mitochondria, the ROS generated resulted in a decrease in the EPR signal amplitude of the 5-NS reporter molecule indicative of the flux of oxy-radicals produced and possible peroxidation-induced changes in the synaptosomal lipid membrane. The line width remained constant, indicating that the overall intensity was reduced. The results showed a significant overall age effect in the ability to generate oxygen-derived radicals following metabolic stimulation (p < .0001). Stimulation of state 4 mitochondrial respiration with 20 mM succinate resulted in greater oxy-radical production in 25-month-old animals as compared to younger animals, suggesting increased mitochondrial leakage with age. Free radical stress induced by metabolic stimulation also causes a concomitant increase in membrane fluidity (p < .0001). There was also a significant age effect (p < .0007) on the order parameter of the mixed population of membranes. Although caloric restriction attenuated the membrane rigidization caused by aging, it was found to play a role in limiting the oxy-radical production following metabolic stimulation of mitochondria. The overall effect of age on membrane spin-label intensities EPR signal upon succinate stimulation suggests that progressive mitochondrial dysfunction may be a key factor in the aging process and in development of age-associated diseases.

Aging↗

PubMed2005

Caloric restriction in humans: potential pitfalls and health concerns.

To date, the only intervention that has consistently been shown to slow the rate of aging, and to increase mean and maximum lifespan in short-lived species, is life-long calorie restriction. It is yet unclear whether long-term calorie restriction in longer lived species (i.e. primates and humans) will have a similar effect. In humans, several studies investigating short-term calorie restriction or "weight loss" programs suggest beneficial outcomes on parameters of cardiovascular disease. Studies on long-term calorie restriction are performed on a self-selected group of human subjects and show similar effects. However, few studies are currently investigating the quality of life and potential pitfalls of long-term calorie restriction in humans. It is likely that some of the physiological and psychological effects of caloric restriction that occur in animals may impact the human life very differently. For certain, calorie restriction has a plethora of health benefits in mammals, such as a reduction in age-related diseases such as cancer. However, despite the "magic" of CR, this intervention in humans may present itself with a number of health concerns, which may not be applicable to or impact the life of experimental animals, but may do so in humans. These potential pitfalls and "side effects" are not clearly addressed in the literature and will be a focus of this review.

Aging↗

PubMed2002

Effect of varying caloric restriction levels on female rat growth and 5-hydroxymethyl-2'-deoxyuridine in DNA.

Caloric restriction has previously been shown to decrease levels of oxidative stress in rats. In this study, we examined the effects of 5 different caloric intake levels on one type of oxidative DNA damage in rat mammary gland, blood, and liver. Animals were fed modified AIN-93G diets to accommodate 10, 20, 30, or 40% calorie restriction (CR), relative to ad libitum (AL) consumption. The intakes of fat, protein, vitamins, and minerals thus remained constant, but total carbohydrate intake decreased. Body weights of the animals at 20 weeks reflected the degree of restriction, but in the first 10 weeks, weight gain in the 10% CR group was not reduced relative to animals fed ad libitum. Levels of 5-hydroxymethyl-2'-deoxyuridine increased with time in mammary gland and nucleated blood cells regardless of CR level, indicating an effect of animal age, despite the fact that the animals were only 7 months old after the 20-week dietary study. In liver, however, there was a trend towards decreased DNA damage levels with time. The effect of diet on levels of 5-hydroxymethyl-2'-deoxyuridine was not statistically significant, indicating no protective effect of restricted dietary carbohydrate. This dietary study differed from previous work in that the modified AIN-93G dietary formulation contains relatively higher levels of fat and vitamins K, E, and B(12), and it has certain added trace minerals. This data raises the question of whether the previously reported effects of calorie restriction on preventing oxidative stress in mammary gland are dependent on the type of dietary formulation used.

Animals↗

PubMed2000

Regulation of gene expression during severe caloric restriction: lack of induction of p85 alpha phosphatidylinositol 3-kinase mRNA in skeletal muscle of patients with type II (non-insulin-dependent) diabetes mellitus.

AIMS/HYPOTHESIS: Alterations in the regulation of gene expression could be involved in the development of Type II (non-insulin-dependent) diabetes mellitus. METHODS: We compared the mRNA concentrations of eight genes encoding proteins involved in insulin action and intermediary metabolism in skeletal muscle of healthy volunteers and Type II diabetic patients. The in vivo regulation of the expression of these genes was investigated after 5 days of hypocaloric diet (1045 kJ/day). RESULTS: In the basal state, diabetic muscle showed reduced insulin receptor (-38%), hexokinase II (-73%), glycogen synthase (-45%) and lipoprotein lipase (-70%) mRNA expression. There was no difference in the mRNA abundances of IRS-1, GLUT 4, p85 alpha phosphatidylinositol-3-kinase (p85 alpha PI3K) or Rad. In both groups, caloric restriction induced weight loss, reduced glycaemia and increased plasma ketone body concentrations. The diet also increased plasma concentrations of fatty acids and decreased whole-body insulin sensitivity in control subjects. In control subjects, the diet increased p85 alpha PI3K (+146%), insulin receptor (+100%) and Rad (+40%) mRNA concentrations in muscle. In Type II diabetic patients, the diet increased insulin receptor (+41%) and Rad (+31%) mRNAs but the expression of p85 alpha PI3K was not modified. CONCLUSION/INTERPRETATION: The regulation of the expression of p85 alpha PI3K is altered during caloric restriction in skeletal muscle of Type II diabetic patients. Because we have shown in an earlier study that there is also a defective regulation of p85 alpha PI3K gene expression in response to insulin, these data support the hypothesis that alterations in the regulation of gene expression could be involved in the pathogenesis of Type II diabetes.

Adult↗

PubMed1999

Age-associated impairment in brain MAPK signal pathways and the effect of caloric restriction in Fischer 344 rats.

Mitogen-activated protein kinases (MAPKs) play important roles in cell proliferation, differentiation, and apoptosis. Important functional roles for MAPKs in postmitotic cells have recently been suggested. In the present study, we investigated the effect of aging on the brain ERK (extracellular signal-regulated kinase) and p38 MAPK signaling pathways of Fischer 344 rats. The results show that basal tyrosine-phosphorylated ERK1/ERK2 in cortex of 24-month-old rats was reduced by 36%-59%, compared to 6- and 12-month-old rats (p<.05, 24- vs. 12- or 6-month-old rats). Similarly, the phosphotransferase activities of ERK and p38 MAPK, measured by in vitro immunocomplex kinase assays using myelin basic protein (MBP) as substrate, were shown to be reduced approximately 50% and 59% respectively, in the cerebrocortex of 24-month-old rats (p<.01, 24- vs. 12- or 6-month-old rats). The reductions in basal ERK and p38 MAPK activities are not due to altered protein levels of these kinases as assessed by Western analysis. Immunohistochemically, no age-related differences in ERK expression and cellular distribution were observed However, cytosolic ERK tended to aggregate in brain neurons of aged rats. In contrast brain tyrosine-phosphorylated PLCgamma1 did not change with age. Activation of ERK in response to EGF or PMA was also reduced in cortical brain slices of 24-month-old rats. These results demonstrate an age-associated selective impairment in the MAPK signaling pathways. Moreover, lifelong caloric restriction completely prevented the age-related decrease in basal brain ERK activity and diminished the age-related reduction of p38 MAPK activity. Taken together, these data indicate that ERK and p38 MAPK signaling pathways are impaired in the aged brain and that lifelong caloric restriction modulates these defects in brain intracellular signaling pathways.

Aging↗