Caloric Restriction

Caloric restriction (CR), a dietary regimen that reduces calorie intake without incurring malnutrition, has been a subject of scientific study in the context of aging and longevity. This practice is thought to extend lifespan and improve health outcomes in various species, including potentially humans.

Science Behind Caloric Restriction

Mechanisms

Caloric restriction is believed to impact aging through several biological pathways. These include reduced metabolic rate, decreased oxidative stress, improved insulin sensitivity, and activation of cellular maintenance mechanisms such as autophagy.

Research Findings

Studies in model organisms, like yeast, worms, flies, and mice, have consistently shown lifespan extension with caloric restriction. Human studies, however, are more complex due to longer lifespans and ethical considerations.

Effects in Different Organisms

Effects of calorie restriction on the survival rate of laboratory mice (CR=Calorie Restriction).^[1]

Calorie restriction can significantly increase the lifespan of the fruit fly (Drosophila melanogaster).

Similar experiments to those with mice have been conducted since 1934 with a variety of species under varied experimental conditions. In many species, not only is the average lifespan of the test animals increased, but also their maximum lifespan. The frequency of age-related diseases correspondingly decreases.^[2] The effect of an increase in maximum life expectancy occurs in rodents both when starting the diet in the early life phase (1st to 3rd month), and in the middle life phase (12th month).^[3]^[4] However, if calorie restriction is started in a later life phase of the test animals, such as in the 17th or 24th month of mice, the effect reverses and the lifespan of the test animals is shortened.^[5]

Calorie restriction has been studied in organisms such as Baker's yeast (Saccharomyces cerevisiae),^[6]^[7] the nematode Caenorhabditis elegans,^[8] the fruit fly Drosophila melanogaster,^[9] Mice,^[1] Rats,PubmedParser error: Invalid PMID, please check. (PMID: McCay1) Dogs^[10] and non-human Primates.^[3]^[4]^[11]

Both in a study with rhesus monkeys^[12] by the American National Institute on Aging, and in a study on Drosophila^[9], it has been suggested that life extension depends not only on calorie restriction but also on the composition of the diet.

Benefits of Caloric Restriction

Research suggests that caloric restriction may offer several health benefits, including:

Improved metabolic health
Reduced risk of age-related diseases
Enhanced brain function and protection against neurodegenerative diseases
Possible extension of healthy lifespan

Potential Risks and Concerns

Caloric restriction, especially if not properly managed, can lead to:

Nutritional deficiencies
Loss of bone density
Reduced muscle mass and strength
Psychological challenges such as food obsession and social isolation

Guidelines for Safe Practice

Before starting caloric restriction, it is crucial to consult healthcare professionals. Some general guidelines include:

Gradual reduction in calorie intake
Emphasis on nutrient-dense foods
Regular monitoring of health parameters
Adjustment of diet based on individual health needs and lifestyle

Conclusion

While caloric restriction shows promise as a tool for extending healthspan and potentially lifespan, further research, especially in humans, is necessary. It is vital to approach this dietary regimen with caution and under medical supervision to avoid adverse effects.

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In fact, it has been shown that caloric restriction increases NAD+ bioavailability by activating the expression of NAMPT (nicotinamide phosphoribosyltransferase, which transforms nicotinamide [NAM] to NAD+ in the NAD+ salvage pathway) ^[13]

References

↑ ^1.0 ^1.1 Weindruch R et al.: The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr 1986. (PMID 3958810) [PubMed] [DOI] We sought to clarify the impact of dietary restriction (undernutrition without malnutrition) on aging. Female mice from a long-lived strain were fed after weaning in one of six ways: group 1) a nonpurified diet ad libitum; 2) 85 kcal/wk of a purified diet (approximately 25% restriction); 3) 50 kcal/wk of a restricted purified diet enriched in protein, vitamin and mineral content to provide nearly equal intakes of these essentials as in group 2 (approximately 55% restriction); 4) as per group 3, but also restricted before weaning; 5) 50 kcal/wk of a vitamin- and mineral-enriched diet but with protein intake gradually reduced over the life span; 6) 40 kcal/wk of the diet fed to groups 3 and 4 (approximately 65% restriction). Mice from groups 3-6 exhibited mean and maximal life spans 35-65% greater than for group 1 and 20-40% greater than for group 2. Mice from group 6 lived longest of all. The longest lived 10% of mice from group 6 averaged 53.0 mo which, to our knowledge, exceeds reported values for any mice of any strain. Beneficial influences on tumor patterns and on declines with age in T-lymphocyte proliferation were most striking in group 6. Significant positive correlations between adult body weight and longevity occurred in groups 3-5 suggesting that increased metabolic efficiency may be related to longevity in restricted mice. Mice from groups 3-6 ate approximately 30% more calories per gram of mouse over the life span than did mice from group 2. These findings show the profound anti-aging effects of dietary restriction and provide new information for optimizing restriction regimes.
↑ Hofer T et al.: Long-term effects of caloric restriction or exercise on DNA and RNA oxidation levels in white blood cells and urine in humans. Rejuvenation Res 2008. (PMID 18729811) [PubMed] [DOI] [Full text] Excessive adiposity is associated with increased oxidative stress and accelerated aging. Weight loss induced by negative energy balance reduces markers of oxidation in experimental animals and humans. The long-term effects of weight loss induced by calorie restriction or increased energy expenditure induced by exercise on measures of oxidative stress and damage have not been studied in humans. The objective of the present study was to compare the effects of 20% caloric restriction or 20% exercise alone over 1 year on oxidative damage to DNA and RNA, as assessed through white blood cell and urine analyses. Eighteen men and women aged 50 to 60 years with a body mass index (BMI) between 23.5 to 29.9 kg/m(2) were assigned to one of two conditions--20% CR (n = 9) or 20% EX (n = 9)--which was designed to produce an identical energy deficit through increased energy expenditure. Compared to baseline, both interventions significantly reduced oxidative damage to both DNA (48.5% and 49.6% reduction for the CR and EX groups, respectively) and RNA (35.7% and 52.1% reduction for the CR and EX groups, respectively) measured in white blood cells. However, urinary levels of DNA and RNA oxidation products did not differ from baseline values following either 12-month intervention program. Data from the present study provide evidence that negative energy balances induced through either CR or EX result in substantial and similar improvements in markers of DNA and RNA damage to white blood cells, potentially by reducing systemic oxidative stress.
↑ ^3.0 ^3.1 Lane MA et al.: Caloric restriction and aging in primates: Relevance to humans and possible CR mimetics. Microsc Res Tech 2002. (PMID 12424798) [PubMed] [DOI] For nearly 70 years it has been recognized that reduction in caloric intake by 30-40% from ad libitum levels leads to a significant extension of mean and maximal lifespan in a variety of short-lived species. This effect of caloric restriction (CR) on lifespan has been reported in nearly all species tested and has been reproduced hundreds of times under a variety of different laboratory conditions. In addition to prolonging lifespan, CR also prevents or delays the onset of age-related disease and maintains many physiological functions at more youthful levels. Studies in longer-lived species, specifically rhesus and squirrel monkeys, have been underway since the late 1980s. The studies in nonhuman primates are beginning to yield valuable information suggesting that the effect of CR on aging is universal across species and that this nutritional paradigm will have similar effects in humans. Even if CR can be shown to impact upon human aging, it is unlikely that most people will be able to maintain the strict dietary control required for this regimen. Thus, elucidation of the biological mechanisms of CR and development of alternative strategies to yield similar benefits is of primary importance. CR mimetics, or interventions that "mimic" certain protective effects of CR, may represent one such alternative strategy.
↑ ^4.0 ^4.1 Wanagat J et al.: Caloric intake and aging: mechanisms in rodents and a study in nonhuman primates. Toxicol Sci 1999. (PMID 10630588) [PubMed] [DOI] Caloric restriction (CR) increases maximum life span in rodents while attenuating the development of age-associated pathological and biological changes. Although nearly all of the rodent studies have initiated CR early in life (1-3 months of age), CR, when started at 12 months of age, also extends maximum life span in mice. Two main questions face investigators of CR. One concerns the mechanisms by which CR retards aging and diseases in rodents. There is evidence that CR may act, at least in part, by reducing oxidative stress. A CR-induced decrease in oxidative stress appears to be most profound in post-mitotic tissues and may derive from lower mitochondrial production of free radicals. The second issue is whether CR will exert similar effects in primates. Studies on CR in rhesus monkeys (maximum life span approximately 40 years) support the notion of human translatability. We describe the University of Wisconsin Study of rhesus monkeys subjected to a 30% reduction of caloric intake starting at either 1989 or 1994 when they were approximately 10 years old. The data from our study and from other trials suggest that CR can be safely carried out in monkeys and that certain physiological effects of CR that occur in rodents (e.g., decreased blood glucose and insulin levels, improved insulin sensitivity, and lowering of body temperature) also occur in monkeys. Whether oxidative stress in monkeys is reduced by CR will be known by the year 2000, while effects on longevity and diseases should be clearly seen by, appropriately, 2020.
↑ Forster MJ et al.: Genotype and age influence the effect of caloric intake on mortality in mice. FASEB J 2003. (PMID 12586746) [PubMed] [DOI] [Full text] Long-term caloric restriction (CR) has been repeatedly shown to increase life span and delay the onset of age-associated pathologies in laboratory mice and rats. The purpose of the current study was to determine whether the CR-associated increase in life span occurs in all strains of mice or only in some genotypes and whether the effects of CR and ad libitum (AL) feeding on mortality accrue gradually or are rapidly inducible and reversible. In one experiment, groups of male C57BL/6, DBA/2, and B6D2F1 mice were fed AL or CR (60% of AL) diets beginning at 4 months of age until death. In the companion study, separate groups of mice were maintained chronically on AL or CR regimens until 7, 17, or 22-24 months of age, after which, half of each AL and CR group was switched to the opposite regimen for 11 wk. This procedure yielded four experimental groups for each genotype, namely AL-->AL, AL-->CR, CR-->CR, and CR-->AL, designated according to long-term and short-term caloric regimen, respectively. Long-term CR resulted in increased median and maximum life span in C57BL/6 and B6D2F1 mice but failed to affect either parameter in the DBA/2 mice. The shift from AL-->CR increased mortality in 17- and 24-month-old mice, whereas the shift from CR-->AL did not significantly affect mortality of any age group. Such increased risk of mortality following implementation of CR at older ages was evident in all three strains but was most dramatic in DBA/2 mice. Results of this study indicate that CR does not have beneficial effects in all strains of mice, and it increases rather than decreases mortality if initiated in advanced age.
↑ Lin SJ et al.: Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 2000. (PMID 11000115) [PubMed] [DOI] Calorie restriction extends life-span in a wide variety of organisms. Although it has been suggested that calorie restriction may work by reducing the levels of reactive oxygen species produced during respiration, the mechanism by which this regimen slows aging is uncertain. Here, we mimicked calorie restriction in yeast by physiological or genetic means and showed a substantial extension in life-span. This extension was not observed in strains mutant for SIR2 (which encodes the silencing protein Sir2p) or NPT1 (a gene in a pathway in the synthesis of NAD, the oxidized form of nicotinamide adenine dinucleotide). These findings suggest that the increased longevity induced by calorie restriction requires the activation of Sir2p by NAD.
↑ Lin SJ et al.: Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 2002. (PMID 12124627) [PubMed] [DOI] Calorie restriction (CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals. We established a model of CR in budding yeast Saccharomyces cerevisiae. In this system, lifespan can be extended by limiting glucose or by reducing the activity of the glucose-sensing cyclic-AMP-dependent kinase (PKA). Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide). In this study we explore how CR activates Sir2 to extend lifespan. Here we show that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process. We discuss how this metabolic strategy may apply to CR in animals.
↑ Lakowski B & Hekimi S: The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A 1998. (PMID 9789046) [PubMed] [DOI] [Full text] Low caloric intake (caloric restriction) can lengthen the life span of a wide range of animals and possibly even of humans. To understand better how caloric restriction lengthens life span, we used genetic methods and criteria to investigate its mechanism of action in the nematode Caenorhabditis elegans. Mutations in many genes (eat genes) result in partial starvation of the worm by disrupting the function of the pharynx, the feeding organ. We found that most eat mutations significantly lengthen life span (by up to 50%). In C. elegans, mutations in a number of other genes that can extend life span have been found. Two genetically distinct mechanisms of life span extension are known: a mechanism involving genes that regulate dauer formation (age-1, daf-2, daf-16, and daf-28) and a mechanism involving genes that affect the rate of development and behavior (clk-1, clk-2, clk-3, and gro-1). We find that the long life of eat-2 mutants does not require the activity of DAF-16 and that eat-2; daf-2 double mutants live even longer than extremely long-lived daf-2 mutants. These findings demonstrate that food restriction lengthens life span by a mechanism distinct from that of dauer-formation mutants. In contrast, we find that food restriction does not further increase the life span of long-lived clk-1 mutants, suggesting that clk-1 and caloric restriction affect similar processes.
↑ ^9.0 ^9.1 Mair W et al.: Calories do not explain extension of life span by dietary restriction in Drosophila. PLoS Biol 2005. (PMID 16000018) [PubMed] [DOI] [Full text] Dietary restriction (DR) extends life span in diverse organisms, including mammals, and common mechanisms may be at work. DR is often known as calorie restriction, because it has been suggested that reduction of calories, rather than of particular nutrients in the diet, mediates extension of life span in rodents. We here demonstrate that extension of life span by DR in Drosophila is not attributable to the reduction in calorie intake. Reduction of either dietary yeast or sugar can reduce mortality and extend life span, but by an amount that is unrelated to the calorie content of the food, and with yeast having a much greater effect per calorie than does sugar. Calorie intake is therefore not the key factor in the reduction of mortality rate by DR in this species.
↑ Shimizu N et al.: Constituents of seed of Malva verticillata. VII. Structural features and reticuloendothelial system-potentiating activity of MVS-I, the major neutral polysaccharide. Chem Pharm Bull (Tokyo) 1991. (PMID 1806283) [PubMed] [DOI] The structural features of MVS-I, the major neutral polysaccharide isolated from the seeds of Malva verticillata L., were elucidated by controlled Smith degradation, methylation analysis, partial acid hydrolysis and enzymic degradation studies. It has a backbone chain composed of beta-1,3-linked D-glucose and D-galactose residues having branches composed of alpha-1,5-linked L-arabinosyl beta-1,4-linked D-galactose and of beta-1,4-linked D-galactosyl beta-1,3-linked D-glucose residues at position 6 of a part of D-galactose units as side chains. MVS-I showed remarkable reticuloendothelial system-potentiating activity in a carbon clearance test.
↑ Weindruch R: The retardation of aging by caloric restriction: studies in rodents and primates. Toxicol Pathol 1996. (PMID 8994305) [PubMed] [DOI] Caloric restriction (CR), which has been investigated by gerontologists for more than 60 yr, provides the only intervention tested to date in mammals (typically mice and rats) that repeatedly and strongly increases maximum life span while retarding the appearance of age-associated pathologic and biologic changes. Although the large majority of rodent studies have initiated CR early in life (1-3 mo of age), CR started in midadulthood (at 12 mo) also extends maximum life span in mice. Two main questions now face gerontologists investigating CR. By what mechanisms does CR retard aging and disease processes in rodents? There is evidence to suggest that age-associated increases in oxidative damage may represent a primary aging process that is attenuated by CR. Will CR exert similar actions in primates? Studies in rhesus monkeys subjected to CR and limited human epidemiological data support the notion of human translatability. However, no matter what the answers are to these questions, the prolongation of the health span and life span of rodents by CR has major implications for many disciplines, including toxicologic pathology, and raises important questions about the desirability of ad libitum feeding.
↑ Mattison JA et al.: Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 2012. (PMID 22932268) [PubMed] [DOI] [Full text] Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.
↑ Menssen A et al.: The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop. Proc Natl Acad Sci U S A 2012. (PMID 22190494) [PubMed] [DOI] [Full text] Silent information regulator 1 (SIRT1) represents an NAD(+)-dependent deacetylase that inhibits proapoptotic factors including p53. Here we determined whether SIRT1 is downstream of the prototypic c-MYC oncogene, which is activated in the majority of tumors. Elevated expression of c-MYC in human colorectal cancer correlated with increased SIRT1 protein levels. Activation of a conditional c-MYC allele induced increased levels of SIRT1 protein, NAD(+), and nicotinamide-phosphoribosyltransferase (NAMPT) mRNA in several cell types. This increase in SIRT1 required the induction of the NAMPT gene by c-MYC. NAMPT is the rate-limiting enzyme of the NAD(+) salvage pathway and enhances SIRT1 activity by increasing the amount of NAD(+). c-MYC also contributed to SIRT1 activation by sequestering the SIRT1 inhibitor deleted in breast cancer 1 (DBC1) from the SIRT1 protein. In primary human fibroblasts previously immortalized by introduction of c-MYC, down-regulation of SIRT1 induced senescence and apoptosis. In various cell lines inactivation of SIRT1 by RNA interference, chemical inhibitors, or ectopic DBC1 enhanced c-MYC-induced apoptosis. Furthermore, SIRT1 directly bound to and deacetylated c-MYC. Enforced SIRT1 expression increased and depletion/inhibition of SIRT1 reduced c-MYC stability. Depletion/inhibition of SIRT1 correlated with reduced lysine 63-linked polyubiquitination of c-Myc, which presumably destabilizes c-MYC by supporting degradative lysine 48-linked polyubiquitination. Moreover, SIRT1 enhanced the transcriptional activity of c-MYC. Taken together, these results show that c-MYC activates SIRT1, which in turn promotes c-MYC function. Furthermore, SIRT1 suppressed cellular senescence in cells with deregulated c-MYC expression and also inhibited c-MYC-induced apoptosis. Constitutive activation of this positive feedback loop may contribute to the development and maintenance of tumors in the context of deregulated c-MYC.

[pmid3958810-1] 1.0 ^1.1 Weindruch R et al.: The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr 1986. (PMID 3958810) [PubMed] [DOI] We sought to clarify the impact of dietary restriction (undernutrition without malnutrition) on aging. Female mice from a long-lived strain were fed after weaning in one of six ways: group 1) a nonpurified diet ad libitum; 2) 85 kcal/wk of a purified diet (approximately 25% restriction); 3) 50 kcal/wk of a restricted purified diet enriched in protein, vitamin and mineral content to provide nearly equal intakes of these essentials as in group 2 (approximately 55% restriction); 4) as per group 3, but also restricted before weaning; 5) 50 kcal/wk of a vitamin- and mineral-enriched diet but with protein intake gradually reduced over the life span; 6) 40 kcal/wk of the diet fed to groups 3 and 4 (approximately 65% restriction). Mice from groups 3-6 exhibited mean and maximal life spans 35-65% greater than for group 1 and 20-40% greater than for group 2. Mice from group 6 lived longest of all. The longest lived 10% of mice from group 6 averaged 53.0 mo which, to our knowledge, exceeds reported values for any mice of any strain. Beneficial influences on tumor patterns and on declines with age in T-lymphocyte proliferation were most striking in group 6. Significant positive correlations between adult body weight and longevity occurred in groups 3-5 suggesting that increased metabolic efficiency may be related to longevity in restricted mice. Mice from groups 3-6 ate approximately 30% more calories per gram of mouse over the life span than did mice from group 2. These findings show the profound anti-aging effects of dietary restriction and provide new information for optimizing restriction regimes.

[pmid18729811-2] Hofer T et al.: Long-term effects of caloric restriction or exercise on DNA and RNA oxidation levels in white blood cells and urine in humans. Rejuvenation Res 2008. (PMID 18729811) [PubMed] [DOI] [Full text] Excessive adiposity is associated with increased oxidative stress and accelerated aging. Weight loss induced by negative energy balance reduces markers of oxidation in experimental animals and humans. The long-term effects of weight loss induced by calorie restriction or increased energy expenditure induced by exercise on measures of oxidative stress and damage have not been studied in humans. The objective of the present study was to compare the effects of 20% caloric restriction or 20% exercise alone over 1 year on oxidative damage to DNA and RNA, as assessed through white blood cell and urine analyses. Eighteen men and women aged 50 to 60 years with a body mass index (BMI) between 23.5 to 29.9 kg/m(2) were assigned to one of two conditions--20% CR (n = 9) or 20% EX (n = 9)--which was designed to produce an identical energy deficit through increased energy expenditure. Compared to baseline, both interventions significantly reduced oxidative damage to both DNA (48.5% and 49.6% reduction for the CR and EX groups, respectively) and RNA (35.7% and 52.1% reduction for the CR and EX groups, respectively) measured in white blood cells. However, urinary levels of DNA and RNA oxidation products did not differ from baseline values following either 12-month intervention program. Data from the present study provide evidence that negative energy balances induced through either CR or EX result in substantial and similar improvements in markers of DNA and RNA damage to white blood cells, potentially by reducing systemic oxidative stress.

[pmid12424798-3] 3.0 ^3.1 Lane MA et al.: Caloric restriction and aging in primates: Relevance to humans and possible CR mimetics. Microsc Res Tech 2002. (PMID 12424798) [PubMed] [DOI] For nearly 70 years it has been recognized that reduction in caloric intake by 30-40% from ad libitum levels leads to a significant extension of mean and maximal lifespan in a variety of short-lived species. This effect of caloric restriction (CR) on lifespan has been reported in nearly all species tested and has been reproduced hundreds of times under a variety of different laboratory conditions. In addition to prolonging lifespan, CR also prevents or delays the onset of age-related disease and maintains many physiological functions at more youthful levels. Studies in longer-lived species, specifically rhesus and squirrel monkeys, have been underway since the late 1980s. The studies in nonhuman primates are beginning to yield valuable information suggesting that the effect of CR on aging is universal across species and that this nutritional paradigm will have similar effects in humans. Even if CR can be shown to impact upon human aging, it is unlikely that most people will be able to maintain the strict dietary control required for this regimen. Thus, elucidation of the biological mechanisms of CR and development of alternative strategies to yield similar benefits is of primary importance. CR mimetics, or interventions that "mimic" certain protective effects of CR, may represent one such alternative strategy.

[pmid10630588-4] 4.0 ^4.1 Wanagat J et al.: Caloric intake and aging: mechanisms in rodents and a study in nonhuman primates. Toxicol Sci 1999. (PMID 10630588) [PubMed] [DOI] Caloric restriction (CR) increases maximum life span in rodents while attenuating the development of age-associated pathological and biological changes. Although nearly all of the rodent studies have initiated CR early in life (1-3 months of age), CR, when started at 12 months of age, also extends maximum life span in mice. Two main questions face investigators of CR. One concerns the mechanisms by which CR retards aging and diseases in rodents. There is evidence that CR may act, at least in part, by reducing oxidative stress. A CR-induced decrease in oxidative stress appears to be most profound in post-mitotic tissues and may derive from lower mitochondrial production of free radicals. The second issue is whether CR will exert similar effects in primates. Studies on CR in rhesus monkeys (maximum life span approximately 40 years) support the notion of human translatability. We describe the University of Wisconsin Study of rhesus monkeys subjected to a 30% reduction of caloric intake starting at either 1989 or 1994 when they were approximately 10 years old. The data from our study and from other trials suggest that CR can be safely carried out in monkeys and that certain physiological effects of CR that occur in rodents (e.g., decreased blood glucose and insulin levels, improved insulin sensitivity, and lowering of body temperature) also occur in monkeys. Whether oxidative stress in monkeys is reduced by CR will be known by the year 2000, while effects on longevity and diseases should be clearly seen by, appropriately, 2020.

[pmid12586746-5] Forster MJ et al.: Genotype and age influence the effect of caloric intake on mortality in mice. FASEB J 2003. (PMID 12586746) [PubMed] [DOI] [Full text] Long-term caloric restriction (CR) has been repeatedly shown to increase life span and delay the onset of age-associated pathologies in laboratory mice and rats. The purpose of the current study was to determine whether the CR-associated increase in life span occurs in all strains of mice or only in some genotypes and whether the effects of CR and ad libitum (AL) feeding on mortality accrue gradually or are rapidly inducible and reversible. In one experiment, groups of male C57BL/6, DBA/2, and B6D2F1 mice were fed AL or CR (60% of AL) diets beginning at 4 months of age until death. In the companion study, separate groups of mice were maintained chronically on AL or CR regimens until 7, 17, or 22-24 months of age, after which, half of each AL and CR group was switched to the opposite regimen for 11 wk. This procedure yielded four experimental groups for each genotype, namely AL-->AL, AL-->CR, CR-->CR, and CR-->AL, designated according to long-term and short-term caloric regimen, respectively. Long-term CR resulted in increased median and maximum life span in C57BL/6 and B6D2F1 mice but failed to affect either parameter in the DBA/2 mice. The shift from AL-->CR increased mortality in 17- and 24-month-old mice, whereas the shift from CR-->AL did not significantly affect mortality of any age group. Such increased risk of mortality following implementation of CR at older ages was evident in all three strains but was most dramatic in DBA/2 mice. Results of this study indicate that CR does not have beneficial effects in all strains of mice, and it increases rather than decreases mortality if initiated in advanced age.

[pmid11000115-6] Lin SJ et al.: Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 2000. (PMID 11000115) [PubMed] [DOI] Calorie restriction extends life-span in a wide variety of organisms. Although it has been suggested that calorie restriction may work by reducing the levels of reactive oxygen species produced during respiration, the mechanism by which this regimen slows aging is uncertain. Here, we mimicked calorie restriction in yeast by physiological or genetic means and showed a substantial extension in life-span. This extension was not observed in strains mutant for SIR2 (which encodes the silencing protein Sir2p) or NPT1 (a gene in a pathway in the synthesis of NAD, the oxidized form of nicotinamide adenine dinucleotide). These findings suggest that the increased longevity induced by calorie restriction requires the activation of Sir2p by NAD.

[pmid12124627-7] Lin SJ et al.: Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 2002. (PMID 12124627) [PubMed] [DOI] Calorie restriction (CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals. We established a model of CR in budding yeast Saccharomyces cerevisiae. In this system, lifespan can be extended by limiting glucose or by reducing the activity of the glucose-sensing cyclic-AMP-dependent kinase (PKA). Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide). In this study we explore how CR activates Sir2 to extend lifespan. Here we show that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process. We discuss how this metabolic strategy may apply to CR in animals.

[pmid9789046-8] Lakowski B & Hekimi S: The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A 1998. (PMID 9789046) [PubMed] [DOI] [Full text] Low caloric intake (caloric restriction) can lengthen the life span of a wide range of animals and possibly even of humans. To understand better how caloric restriction lengthens life span, we used genetic methods and criteria to investigate its mechanism of action in the nematode Caenorhabditis elegans. Mutations in many genes (eat genes) result in partial starvation of the worm by disrupting the function of the pharynx, the feeding organ. We found that most eat mutations significantly lengthen life span (by up to 50%). In C. elegans, mutations in a number of other genes that can extend life span have been found. Two genetically distinct mechanisms of life span extension are known: a mechanism involving genes that regulate dauer formation (age-1, daf-2, daf-16, and daf-28) and a mechanism involving genes that affect the rate of development and behavior (clk-1, clk-2, clk-3, and gro-1). We find that the long life of eat-2 mutants does not require the activity of DAF-16 and that eat-2; daf-2 double mutants live even longer than extremely long-lived daf-2 mutants. These findings demonstrate that food restriction lengthens life span by a mechanism distinct from that of dauer-formation mutants. In contrast, we find that food restriction does not further increase the life span of long-lived clk-1 mutants, suggesting that clk-1 and caloric restriction affect similar processes.

[pmid16000018-9] 9.0 ^9.1 Mair W et al.: Calories do not explain extension of life span by dietary restriction in Drosophila. PLoS Biol 2005. (PMID 16000018) [PubMed] [DOI] [Full text] Dietary restriction (DR) extends life span in diverse organisms, including mammals, and common mechanisms may be at work. DR is often known as calorie restriction, because it has been suggested that reduction of calories, rather than of particular nutrients in the diet, mediates extension of life span in rodents. We here demonstrate that extension of life span by DR in Drosophila is not attributable to the reduction in calorie intake. Reduction of either dietary yeast or sugar can reduce mortality and extend life span, but by an amount that is unrelated to the calorie content of the food, and with yeast having a much greater effect per calorie than does sugar. Calorie intake is therefore not the key factor in the reduction of mortality rate by DR in this species.

[pmid1806283-10] Shimizu N et al.: Constituents of seed of Malva verticillata. VII. Structural features and reticuloendothelial system-potentiating activity of MVS-I, the major neutral polysaccharide. Chem Pharm Bull (Tokyo) 1991. (PMID 1806283) [PubMed] [DOI] The structural features of MVS-I, the major neutral polysaccharide isolated from the seeds of Malva verticillata L., were elucidated by controlled Smith degradation, methylation analysis, partial acid hydrolysis and enzymic degradation studies. It has a backbone chain composed of beta-1,3-linked D-glucose and D-galactose residues having branches composed of alpha-1,5-linked L-arabinosyl beta-1,4-linked D-galactose and of beta-1,4-linked D-galactosyl beta-1,3-linked D-glucose residues at position 6 of a part of D-galactose units as side chains. MVS-I showed remarkable reticuloendothelial system-potentiating activity in a carbon clearance test.

[pmid8994305-11] Weindruch R: The retardation of aging by caloric restriction: studies in rodents and primates. Toxicol Pathol 1996. (PMID 8994305) [PubMed] [DOI] Caloric restriction (CR), which has been investigated by gerontologists for more than 60 yr, provides the only intervention tested to date in mammals (typically mice and rats) that repeatedly and strongly increases maximum life span while retarding the appearance of age-associated pathologic and biologic changes. Although the large majority of rodent studies have initiated CR early in life (1-3 mo of age), CR started in midadulthood (at 12 mo) also extends maximum life span in mice. Two main questions now face gerontologists investigating CR. By what mechanisms does CR retard aging and disease processes in rodents? There is evidence to suggest that age-associated increases in oxidative damage may represent a primary aging process that is attenuated by CR. Will CR exert similar actions in primates? Studies in rhesus monkeys subjected to CR and limited human epidemiological data support the notion of human translatability. However, no matter what the answers are to these questions, the prolongation of the health span and life span of rodents by CR has major implications for many disciplines, including toxicologic pathology, and raises important questions about the desirability of ad libitum feeding.

[pmid22932268-12] Mattison JA et al.: Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 2012. (PMID 22932268) [PubMed] [DOI] [Full text] Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.

[pmid22190494-13] Menssen A et al.: The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop. Proc Natl Acad Sci U S A 2012. (PMID 22190494) [PubMed] [DOI] [Full text] Silent information regulator 1 (SIRT1) represents an NAD(+)-dependent deacetylase that inhibits proapoptotic factors including p53. Here we determined whether SIRT1 is downstream of the prototypic c-MYC oncogene, which is activated in the majority of tumors. Elevated expression of c-MYC in human colorectal cancer correlated with increased SIRT1 protein levels. Activation of a conditional c-MYC allele induced increased levels of SIRT1 protein, NAD(+), and nicotinamide-phosphoribosyltransferase (NAMPT) mRNA in several cell types. This increase in SIRT1 required the induction of the NAMPT gene by c-MYC. NAMPT is the rate-limiting enzyme of the NAD(+) salvage pathway and enhances SIRT1 activity by increasing the amount of NAD(+). c-MYC also contributed to SIRT1 activation by sequestering the SIRT1 inhibitor deleted in breast cancer 1 (DBC1) from the SIRT1 protein. In primary human fibroblasts previously immortalized by introduction of c-MYC, down-regulation of SIRT1 induced senescence and apoptosis. In various cell lines inactivation of SIRT1 by RNA interference, chemical inhibitors, or ectopic DBC1 enhanced c-MYC-induced apoptosis. Furthermore, SIRT1 directly bound to and deacetylated c-MYC. Enforced SIRT1 expression increased and depletion/inhibition of SIRT1 reduced c-MYC stability. Depletion/inhibition of SIRT1 correlated with reduced lysine 63-linked polyubiquitination of c-Myc, which presumably destabilizes c-MYC by supporting degradative lysine 48-linked polyubiquitination. Moreover, SIRT1 enhanced the transcriptional activity of c-MYC. Taken together, these results show that c-MYC activates SIRT1, which in turn promotes c-MYC function. Furthermore, SIRT1 suppressed cellular senescence in cells with deregulated c-MYC expression and also inhibited c-MYC-induced apoptosis. Constitutive activation of this positive feedback loop may contribute to the development and maintenance of tumors in the context of deregulated c-MYC.

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[8]

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