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Caloric restriction has resulted in a consistent robust increase in the maximal length of life in mammalian species. This article reviews significant advances over the long history of research on calorie restriction and longevity.
The incidence of intestinal nutrient malabsorption increases with age. Therefore, an important question is whether there are age-related changes in intestinal nutrient absorption which may contribute to a decline in absorptive capacity. Sugar and amino acid transport per mg intestine generally decreases with age. The proximate mechanism underlying this age-related decrease in transport activity is a decrease in number of transporters per mg. This reduction in transporter number can be caused by age-related changes in cell proliferation rates which, in turn, can alter the ratio of absorptive to nonabsorptive cells. The age-related change in proliferation rates typically increases intestinal mass. There seems to be no age-related changes in the steady state levels of transporter mRNA. Aging also modestly impairs the ability of intestinal nutrient transport systems to adapt to changes in dietary conditions. Caloric restriction is the only procedure known to consistently increase the lifespan of mammals. Chronic caloric restriction markedly enhances intestinal nutrient transport per mg without affecting intestinal mass. Since body weight decreases with caloric restriction, there is a dramatic increase in intestinal absorptive capacity normalized to body weight. This suggests that an increase in intestinal nutrient absorption may be a critical adaptation to caloric restriction. There is a need to perform in vivo transport studies during senescence, to distinguish between acute and chronic effects of caloric restriction, and to identify hormones that may mediate aging and caloric restriction effects on intestinal nutrient transport.
Biological aging is associated with functional deficits at the cellular, organ, and system levels. The pituitary gland, the central organ of the neuroendocrine system, has been shown to play an important role in the aging process. To gain a better understanding of its functional changes with aging, we compared the gene expression profiles of the anterior pituitary of young and old Brown Norway rats, focusing on the major pituitary hormone genes. We also explored the effects of caloric restriction, an intervention shown to delay or inhibit age-associated pathologic and biologic changes in a number of systems and organisms, on the expression of these genes. Of the total of 1176 genes arrayed on each of the six membranes per group that we used, 542 (46%) were detectable in the anterior pituitary of young and old rats. Significance analysis of microarrays (SAM) of these 542 detectable genes revealed 28 genes that changed significantly with age, among which 24 decreased and 4 increased. Among the five major hormone genes on the membrane, growth hormone (GH) and prolactin decreased with age, the glycoprotein hormone common alpha subunit gene increased, and follicle-stimulating hormone-beta subunit (FSH-beta) and thyrotropin-beta (TSH-beta) subunit did not change. Among these genes, the three found to change by array analysis were confirmed to do so by Northern blot analysis. For the two genes among the five that were not selected (i.e. did not change) by array analysis, TSH-beta also showed no significant change by Northern blot; but the other, FSH-beta, showed significant increase. Thus, of the five genes checked by Northern blot analysis, the results were consistent with the array data in four cases. Short-term caloric restriction (5 weeks) of young adult animals resulted in 19 genes being significantly down-regulated, while no significantly up-regulated genes were identified. Among the genes that were down-regulated were GH, gonadotropin releasing hormone receptor (GnRH-R), three cytochrome c oxidase subunits and two heat shock proteins. With long-term (21 month) caloric restriction, about 30% of the genes that changed with aging (8/28) were prevented from doing so, and none of the age-related changes was enhanced with long-term caloric restriction. The genes that showed most significant rescue were neuropeptide Y, GnRH-R, DNA-binding protein inhibitor Id-3, and nerve growth factor-induced protein I-B. These results indicate that long-term caloric restriction can partially prevent some of the age-related changes in gene expression in the anterior pituitary of Brown Norway rats, suggesting a benefit of this regimen to be the slowing of the aging process. The fact that fewer than 30% genes derived benefit also suggests that the effect of caloric restriction is rather limit, which is consistent with the thesis that caloric restriction may slow, but not prevent, the aging process.
This study was designed to investigate the effects of aging and caloric restriction on collagen deposition in a model of wound healing. Polyvinyl alcohol sponges were implanted in Fischer 344 rats aged 6, 10, or 24 months. Sponges were removed after 7, 10, or 14 days and analyzed for hydroxyproline content and for enzymatic crosslinks. Aging was associated with a decrease in collagen accumulation as well as a delay in reaching peak rates of collagen accumulation. Levels of enzymatic crosslinks were increased in granulation tissue from old animals relative to young animals. Caloric restriction (60% of ad libitum intake) maintained only during the 2-week experimental period did not affect collagen accumulation, but did result in decreased levels of the difunctional crosslink dihydroxylysinonor-leucine (DHLNL) in sponges implanted for 10 days, but not 14 days. Caloric restriction initiated 4 months before sponges were implanted resulted in decreased collagen accumulation and decreases in DHLNL at all implantation times. These studies suggest that: (1) aging affects total collagen production as well as rate of collagen production in response to injury; (2) aging is not associated with impaired crosslinking in granulation tissue; (3) chronic caloric restriction is associated with decreased collagen production and decreased levels of DHLNL; (4) the adverse effects of chronic caloric restriction on wound healing may have a greater impact on wound healing in old animals.
Dietary caloric restriction extends life span in the Fischer 344 rat. The interaction of aging and caloric restriction was examined at the level of the plasma membrane transport-associated enzymes, Ca(2+)-adenosine triphosphatase (ATPase) and Na,K-ATPase, in the Fischer rat. Animals were in four age groups, ranging from 6.1 to 25.0 months, and were specific pathogen-free (SPF, barrier-raised). Results from male and female animals raised on an ad libitum diet were compared with those from rats that received 60% of the age-specific caloric intake of their ad lib littermates. The responses of erythrocyte membrane Ca(2+)-ATPase activity in vitro to thyroid hormone (L-thyroxine [T4]; 3,5,3'-triiodothyronine [T3]) and to purified calmodulin, a Ca(2+)-binding protein activator of Ca(2+)-ATPase, were measured. Erythrocyte membrane Na,K-ATPase was also compared in the two diet groups, as was plasma glucose. Plasma membrane Ca(2+)-ATPase activity in the absence of added thyroid hormone and calmodulin was significantly reduced in calorically restricted rats (-39%, P less than .001), compared with ad lib-fed animals, and the response was similar in the four age groups aged 6.1, 12.7, 17.0, and 25.0 months. In contrast, pooled (all ages) Ca(2+)-ATPase response in vitro to T4 and to T3 in calorically restricted animals was enhanced compared with the ad lib group (+62% and +58%, P less than .001, respectively). Calmodulin responsiveness of the enzyme was increased by 45% (P less than .001) in calorie-deprived animals, similar to the change in T4 and T3 responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)
Although the inhibitory effect of caloric restriction on tumorigenesis is substantial and well known, the pertinent mechanisms remain to be determined. We recently suggested that the risk of cancer may be directly related to the total number of dividing cells within an affected organ. This study evaluates the effects of early caloric restriction on the cellular growth of the colon. The experiment began one day postpartum and ended six weeks later with the killing of all animals. It consisted of two consecutive periods: a) three weeks of suckling and b) three weeks postweaning. Animals whose food was restricted only during the suckling period showed normal colons when killed at six weeks. Caloric restriction (40%) for three weeks postweaning resulted in colons of lower weight with fewer cells (less total DNA) and reduced total DNA synthesis [( 3H]thymidine uptake, dpm/colon) when compared with animals fed ad libitum postweaning. Conversely, only rats fed ad libitum from birth through the first three weeks after weaning demonstrated an increase (21%) in the rate of DNA synthesis (dpm/mg DNA) compared with other animals. In addition, the colonic crypts showed no differences in the number of cells or the number of dividing cells, as determined by autoradiography. By contrast, the total number of crypts (and/or the number of mucosal cells between crypts) are reduced, and hence the total number of colonic mucosal cells dividing at any given time are similarly decreased. The reduced number of dividing cells in the colons of these animals (i.e., those restricted postweaning) could explain previous data suggesting that they are resistant to the induction of colon cancer.
For the effectiveness of under-eating or caloric restriction a simple evolution-based re-adaptation hypothesis is offered. Our ancient ancestors, whose bodies we inherited, ate and weighed a good deal less in relation to their size than we do. Over hundred thousands of years their desire for food was checked by its scarcity and the effort it took to collect it daily from all over the countryside. Thereby they set the reference standard for living and eating normally and healthily, not we. We eat as much as we like. No creature has ever been adapted to that. By practicing caloric restriction and daily exercise, we simulate to some degree the essentials of the way of life of our well adapted forbears. By such re-adaptation to our generic heritage, we re-gain their health at least approximately.
Caloric restriction (CR) has been found to extend the life spans of a wide variety of species, transcending phylogenetic boundaries. The objective of this study was to test the generality of this phenomenon, using the male housefly as an insect model in which food intake can be quantified precisely. Sucrose was found to promote a longer life span than diets additionally containing proteins and lipids. Flies were fed sucrose or a more complex diet ad libitum (AL), or in amounts ranging from 50% to 100% of the average amount consumed by young flies. CR shortened rather than prolonged the life span of houseflies, particularly flies fed sucrose only. The rate of oxygen consumption was not affected by caloric restriction or by the exclusion of proteins and lipids from the diet, and the reproductive activity of male flies remained unchanged by sucrose feeding. Thus, it is unlikely that the life-shortening effects of CR can be explained either in terms of an adaptive response in metabolic rate or use of a suboptimal food source. Results of this study contradict the widely held view that CR has a life-extending effect in all species.
Paraoxonase (PON), an HDL- associated enzyme, may protect against the development of atherosclerosis. Single nucleotide polymorphisms of PON have been reported to be associated with an incidence of coronary heart diseases. We investigated the effect of PON R192Q variants on serum lipid profile after caloric restriction in nondiabetic healthy males. After caloric restriction for 12 weeks, the levels of high-density lipoprotein cholesterol (HDL-C) increased in the subjects carrying RR genotype, but not in the QR and QQ genotypes. The changes in HDL-C from the baseline values in the RR genotype were significantly different from those in the QR and QQ genotypes. Although the changes in lipoprotein lipase activity were not different among three genotypes, we observed a significant difference in the changes in hepatic lipase (HL) activity after caloric restriction, namely, a decrease in the RR genotype and an increase in the subjects carrying the Q allele. In addition, the changes in fasting insulin levels significantly correlated with those in HDL-C levels in the RR genotype, not in the QR and QQ genotypes. PON R192Q polymorphism could affect HDL-C levels after caloric restriction presumably due to decreased HL activity and altered insulin resistance.
BACKGROUND: We characterized RNA transcript levels for the whole Drosophila genome during normal aging. We compared age-dependent profiles from animals aged under full-nutrient conditions with profiles obtained from animals maintained on a low-calorie medium to determine if caloric restriction slows the aging process. Specific biological functions impacted by caloric restriction were identified using the Gene Ontology annotation. We used the global patterns of expression profiles to test if particular genomic regions contribute differentially to changes in transcript profiles with age and if global disregulation of gene expression occurs during aging. RESULTS: Whole-genome transcript profiles contained a statistically powerful genetic signature of normal aging. Nearly 23% of the genome changed in transcript representation with age. Caloric restriction was accompanied by a slowing of the progression of normal, age-related changes in transcript levels. Many genes, including those associated with stress response and oogenesis, showed age-dependent transcript representation. Caloric restriction resulted in the downregulation of genes primarily involved in cell growth, metabolism, and reproduction. We found no evidence that age-dependent changes in transcription level were confined to genes localized to specific regions of the genome and found no support for widespread disregulation of gene expression with age. CONCLUSIONS: Aging is characterized by highly dynamic changes in the expression of many genes, which provides a powerful molecular description of the normal aging process. Caloric restriction extends life span by slowing down the rate of normal aging. Transcription levels of genes from a wide variety of biological functions and processes are impacted by age and dietary conditions.
In preparation for hibernation, golden-mantled ground squirrels (Spermophilus lateralis) must deposit sufficient amounts of lipid during the summer to survive winter hibernation. We conducted an experiment from May 1998 to February 1999 to examine the effects of caloric restriction on the body composition (lipid and fat-free mass) and hibernation of golden-mantled ground squirrels. Ground squirrels were either provided with food ad lib. (controls) or with only enough food to maintain a constant body mass throughout the experiment (calorically restricted). Changes in body composition were followed using total body electrical conductivity (TOBEC). Implanted data loggers that recorded body temperature were used to determine when ground squirrels entered their first torpor bout and the lengths of torpor bouts. Body composition did not change in the calorically restricted ground squirrels between May and September, while both lipid and fat-free mass increased in the controls. However, from September to February, calorically restricted ground squirrels lost only fat-free mass, not lipid mass, but controls lost both lipid and fat-free mass. Calorically restricted ground squirrels entered their first torpor bout about 4 wk after controls, but the torpor bout duration (or length) during hibernation did not differ between the two groups. These results show that ground squirrels maintain body composition during caloric restriction, and the limited quantities of stored lipid have an effect on when hibernation begins but not on torpor bout length.
The signaling cascade mediated by Ras (p21ras) and MAPK (mitogen-activated protein kinase) and calcium/calmodulin regulating enzymes, calcineurin (CaN) and CaMK-IV, are considered to be essential for T-cell growth and function. In the present study, the effect of aging and caloric restriction (CR) on the induction of Ras and MAPK activation by concanavalin A (ConA) was studied. Splenic T cells were isolated from young (4-6 months) and old (22-24 months) rats that had free access to food (control group), and from caloric restricted old (22-24 months) rats that beginning at 6 weeks of age were fed 60%(40% caloric restriction) of the diet consumed by the control rats. We found that the induction of Ras activity in T cells isolated from control old rats was lower (P<0.001) than that in control young rats. However, the levels of Ras activity in T cells isolated from CR old rats were similar to the levels in the age-matched control rats. The induction of MAPK activity in T cells isolated from control old rats and CR old rats was significantly less than in T cells isolated from control young rats, and caloric restriction significantly (P<0.05) reduced the age-related decline in MAPK activation. We also measured the induction of CaN and CaMK-IV activities by ConA in T cells from control young and old and CR old rats. The induction of both CaN and CaMK-IV activity decreased with age. Caloric restriction significantly (P<0.05) reduced the age-related decline in CaN activity, but had no significant effect on CaMK-IV activity. The changes in Ras/MAPK activation and in CaN and CaMK-IV activity with age or with CR were not associated with alterations in their corresponding protein levels. Thus, caloric restriction has a differential effect on the activation of the upstream signaling molecules that are altered with age.
BACKGROUND: There is a strong association between oxidative stress and inflammation in the pathologies of diabetes. Recent evidence suggests that these phenomena could impair brain function. We investigated the potential role of dietary caloric restriction in ameliorating the effects of both oxidative stress and inflammation in the brain of streptozotocin-induced type 2 diabetic rats. METHODS: Forty male Wistar rats were subjected to 30% caloric restriction (20 animals) and ad libitum feeding (20 animals) for 9 weeks before the induction of diabetes in 20 animals (10 from each group) by intraperitoneal injection of 35 mg/kg body weight streptozotocin. RESULTS: Caloric restriction was able to significantly (p>0.05) reduce triglyceride, ROS, IL6, TNF-alpha and body weights in diabetic rats. However, no significant differences were obtained in the antioxidant enzyme (SOD, CAT and GPx) activities except in GPx where caloric restriction increased the levels in both non-diabetic and diabetic rats. CONCLUSION: Caloric restriction was found to ameliorate the oxidative and inflammatory effects of diabetes in the brain. Non-diabetic rats feeding ad libitum were found to have increased levels of oxidative stress and inflammatory biomarkers and these could, in part, be due to their increased body weights.
In two experiments, the effects of caloric restriction during the postinitiation phase of pancreatic carcinogenesis were evaluated. Male Lewis rats were given injections of azaserine at 14 days of age and weaned to the postinitiation test protocols at 21 days of age. In the first experiment, the caloric content of the diets was restricted by 10, 15, 20, and 30% of the intakes of the ad libitum-fed rats. A sixth group was fed diet ad libitum for only 5-6 h/day; i.e., they were "meal-fed". The development of putative preneoplastic lesions (henceforth termed foci) was evaluated by quantitative stereological (morphometric) analysis of the pancreas. Caloric restriction during the 4-month postinitiation phase resulted in a significant reduction in focal development beginning at 10% caloric restriction and increasing with more severe restriction. The caloric intake of the meal-fed group closely matched the caloric intake of the 10 or 15% caloric restriction groups and the focal response of the meal-fed rats was similar to the groups restricted in calories by 15 to 20%. In the second experiment, rats were initiated with azaserine and weaned to one of four groups: ad libitum; meal-fed; meal-fed for 2 months and ad libitum thereafter; or ad libitum for 2 months and meal-fed thereafter. Foci were evaluated at 2 and 4 months; neoplasm incidence and multiplicity were determined at 14 months postinitiation. Compared to the ad libitum group, the meal-fed group had significantly fewer foci at all times of evaluation and significantly fewer neoplasms. When rats were meal fed for 2 months and then switched to ad libitum feeding for the remainder of the experiment, the focal outcome at 4 months was similar to the group meal fed for all 4 months; and at 14 months the neoplastic outcome was intermediate between the ad libitum and the meal-fed group. Intervention in the ad libitum feeding regimen at 2 months by meal feeding for the remainder of the experiment resulted in a significant decrease in the focal and neoplastic development, as compared to the group fed ad libitum continuously. These two intervention groups were intermediate in response between the meal-fed and ad libitum-fed groups. These results indicate that the postinitiation phase of pancreatic carcinogenesis can be modulated by relatively simple dietary interventions such as moderate caloric restriction.
Caloric restriction (CR) may retard aging processes and extend lifespan in organisms by altering energy-metabolic pathways. In CR rodents, glucose influx into tissues is not reduced, as compared with control animals fed ad libitum (AL), although plasma concentrations of glucose and insulin are lower. Gene expression profiles in rodents have suggested that CR promotes gluconeogenesis and fatty acid biosynthesis in skeletal muscle. In the liver, CR promotes gluconeogenesis but decreases fatty acid synthesis and glycolysis. In lower organisms such as yeasts and nematodes, incomplete blocks in steps of insulin/insulin-like growth factor-1 (IGF-1) signal pathway extend lifespan. The life-prolonging effect of CR in yeasts requires NPT1 and SIR2 genes, both of which relate to sensing energy status and silencing genes. These findings stress the substantial role of energy metabolism on CR. Future studies on metabolic adaptation and gene silencing with regard to lower caloric intake will be warranted to understand the mechanisms of the anti-aging and life-prolonging effects of CR.
Both life-long caloric restriction (CR) and the suppression of insulin-like growth factor-1 (IGF-1) signaling reliably extend the mammalian lifespan. The neuroendocrine system, regulated by the hypothalamus, remains the most convincing site of action for both these modes of life extension. Yet, determining whether CR actions are mediated by the modulation of neuroendocrine IGF-1 signaling remains unclear. Of the hypothalamic nuclei that express the IGF-1 receptor (IGF-1R), the cells of the supraoptic nucleus (SON) display some of the most robust IGF-1R expression. Taking IGF-1R immunoreactivity as an index of sensitivity to IGF-1, we counted IGF-1R immunoreactive and non-immunoreactive cells in the SON of young-ad-libitum fed (young-Al, 6 weeks), old-ad-libitum fed (Old-Al, 22 months), and old-calorie-restricted (Old-CR, 22 months) female B6D2F1 mice. An automated imaging microscopy system (AIMS) was used to generate cell counts for each section of supraoptic hypothalamus. Results show that while the total number of cells in the SON of ad-libitum fed mice does not change significantly with aging, a significant reduction in IGF-1R immunoreactive cells does occur in ad-libitum fed mice with aging. In contrast to this, calorie restricted mice show both a decline in the total number of cells and IGF-1R immunoreactive cells in the SON with age, but with the decrease in the latter being notably attenuated when compared to the degree of loss seen in ad-libitum fed mice. Thus, while CR induces greater loss in the total number of cells in the SON with age, it reduces the degree of age-dependent loss seen in IGF-1R expressing cells. As a result, when compared to Old-AL mice, the SON of Old-CR mice displays a greater proportion of IGF-1R cells and thus possibly enhanced IGF-1 sensitivity with aging.
Enhanced production of free radicals and oxidative stress induced by hyperglycemia play a central role in the pathogenesis of diabetes and its complications. This study assessed the attenuation by dietary caloric restriction on the oxidative and lipid peroxidative effects of diabetes in the liver through reduction in body and organ weights and concomitant metabolic changes. Three-month-old male Wistar rats were subjected to ad libitum feeding and 30% caloric restriction for 9 weeks before induction of diabetes by intraperitoneal injection of 35 mg/kg body weight streptozotocin. The animals were sacrificed 2 weeks after streptozotocin treatment depicting the onset of diabetes. Caloric restriction significantly reduced the organ weights (p<0.01), malondialdehyde (p<0.01) and catalase activity (p<0.01), but significantly increased glutathione reductase activity (p<0.01), and GSH/GSSG ratios (p<0.05). Caloric restriction also non-significantly reduced reactive oxygen species, superoxide dismutase and oxidized glutathione but increased glutathione peroxidase activity and reduced glutathione levels in the diabetic rats. Our data indicate a decrease in lipid peroxidation, improvement in the antioxidant defense systems and restoration of the redox status in the liver by caloric restriction. Therefore, this could provide a non-invasive antioxidant therapy early in diabetes to prevent the development of the complications associated with the disease.
The effects of long-term caloric restriction on the hepatic phase II drug metabolizing enzymes were investigated in the male Fischer 344 rat. Rats that had been restricted to 60% of their pair-fed control consumption from 14 weeks post-partum exhibited altered conjugating enzyme activities at 22 months. Caloric restriction significantly reduced the age-related decrease in glutathione-S-transferase activity towards 1,2-dichloro-4-nitrobenzene, but did not significantly alter the age-related changes in UDP-glucuronyltransferase or sulfotransferase activities towards hydroxysteroids. Caloric restriction appeared to increase hepatic microsomal UDP-glucuronyltransferase activity toward bilirubin and gamma-glutamyltranspeptidase activities. These observations suggest that caloric restriction has multiple effects on the hepatic phase II drug metabolizing enzymes in the rat. Such effects may alter hepatic metabolism and activation or detoxification of drugs and carcinogens.