Caloric Restriction

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    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.

    Effects in Model Organisms

    Positive Effects

    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).

    Calorie restriction has been studied in model organisms such as Yeast (Saccharomyces Cerevisiae)[2][3], Nematodes (Caenorhabditis Elegans)[4], Fruit Flies (Drosophila Melanogaster)[5], Mice (Mus Musculus)[1], Rats (Rattus Norvegicus)[6], Domestic Dogs (Canis Familiaris)[7] and Non-Human Primates.[8][9][10]

    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.[11] 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).[8][9] 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.[12]

    Both in a study with rhesus monkeys[13] by the American National Institute on Aging, and in a study on Drosophila[5], it has been suggested that life extension depends not only on calorie restriction but also on the composition of the diet.

    General Criticism

    Various findings raise doubts about the notion that caloric restriction slows down the aging process, delays the age-related decline in physiological fitness, or extends the lifespan of organisms from different phylogenetic groups.[14] Positive effects of caloric restriction are not universal:

    In fruit flies, positive effects of caloric restriction are not reproduced with careful control of nutrient fractions.[15]

    The increase in lifespan caused by caloric restriction is not even reproducible among different strains of the same species.[14]

    Calorie restriction does not extend lifespan in all mice. In the top graph, a significant effect is observed in C57BL/6 mice ("laboratory mice"), while it is absent in DBA/2 mice ("wild type") below (AL=ad libitum, CR=Calorie Restriction).[12]

    Thus, calorie restriction does not lead to lifespan extension in all mouse strains.[12] In 19 to 27% of the mouse strains studied, a 40% caloric restriction even resulted in a shortened lifespan.[16][17]

    The frequently used C57BL/6 mice tend to become overweight with unrestricted food access (ad libitum). In these animals, the effect of caloric restriction is significant. DBA/2 mice, on the other hand, remain lean even with ad-libitum feeding. In mice from this strain, caloric restriction does not lead to lifespan extension. DBA/2 mice consume more oxygen with the same energy intake than C57BL/6 mice, meaning their metabolic rate is increased – they are poorer "feed converters."[18] It was already observed in earlier experiments that caloric restriction is most successful in mice that gain significant weight in early adulthood.[19] The results of these studies are interpreted to mean that lifespan is more influenced by the balance of energy intake and energy expenditure. Only in test animals prone to overweight or obesity can caloric restriction cause lifespan extension.[20]

    The NIA study on rhesus monkeys found no lifespan extension.[13] In a long-term study conducted at the Wisconsin National Primate Research Center over a period of 20 years on rhesus monkeys, a significantly better health status and a significantly increased lifespan were observed in the group of animals that received a reduced food supply during this period. In this group, 80% of the animals were still alive, compared to only 50% in the normally fed control group. Furthermore, in the animals with calorie restriction, a significantly delayed onset of age-associated diseases such as diabetes, cancer, and brain atrophy, as well as cardiovascular incidents, was observed. The authors of the study conclude that calorie restriction delays the aging process in this primate species.[21][22]

    Mechanism

    The reasons for the lifespan extension in model organisms through caloric restriction are not yet fully understood. The underlying mechanism of this effect remains unknown. It's possible that the extension of lifespan results from improved health status due to the absence of obesity and the delayed onset of age-related diseases of the metabolic syndrome such as Cardiovascular diseases and Type II Diabetes mellitus.

    Studies conducted with mice suggest that the lifespan extension associated with caloric restriction is not simply a result of leanness caused by calorie restriction. The maximum lifespan of male rats that maintained a low body fat mass through physical activity did not increase, but it did for mice that maintained a low body weight through caloric restriction alone, despite a sedentary lifestyle.[23]

    Caloric restriction in rats produces soluble factors in the blood serum that cause lifespan extension in human Cell cultures.[24] Various mechanisms are being discussed:

    Reduction of Oxidative Stress

    There are indications that oxidative stress is reduced by decreased food intake, thereby delaying primary aging. Primary aging is the process in cells and organs that defines the maximum lifespan in the absence of diseases (inevitable aging). Secondary aging is determined by external factors such as diseases, environmental factors, lifestyle, and physical activity (avoidable aging).[25] Oxidative stress primarily occurs in the mitochondria, the powerhouses of the cells.[26][27] In some mouse strains, the effect of calorie restriction can be partially induced by Resveratrol.[28] In yeasts, the protein Rim15, a glucose-inhibited protein kinase, acts as a sensor of nutrient concentrations as well as the initiator of Meiosis and is necessary for lifespan extension in yeasts.[29] However, a meta-analysis also reported that caloric restriction – contrary to previous results – does not lead to lifespan extension in yeasts, but the results in yeasts are partly based on methodological artifacts.[30]

    Hormesis

    According to a contrary hypothesis, oxidative stress from reactive oxygen species (ROS) is thought to positively stimulate cell metabolism (Hormesis), which may explain the health benefits of caloric restriction as well as Fasting, oxidative plant compounds in cabbage vegetables, and physical training.[31]

    In contrast to the free radical theory, it is assumed that an increased formation of reactive oxygen species in the mitochondria, associated with caloric restriction, causes an adaptive response that enhances stress resistance.[32]

    Activation of Sirtuin-1 and Reduced Expression of the mTOR Receptor

    Signal-regulating enzymes such as Sirtuin-1 (Sirt1) in mammals, or Sirtuin Sir2 in yeasts, may play a role.[33] The cells of calorically restricted test animals produce Sirt1 in larger quantities.[34] An increased production of Sirt1, in turn, reduces the expression of the mTOR receptor (mammalian Target of Rapamycin),[35] which is also associated with the aging process. The lifespan of mice can be significantly extended by administering Rapamycin, which docks to the mTOR receptor.[36][37] Melatonin is also being studied due to its activation of Sirtuin.[38]

    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.

    Todo

    • 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) [39]

    References

    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.
    2. ↑ 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.
    3. ↑ 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.
    4. ↑ 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.
    5. ↑ 5.0 5.1 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.
    6. ↑ C. M. McCay und M. F. Crowell: Prolonging the Life Span. In: The Scientific Monthly 39, 1934, S. 405–414; JSTOR 15813.
    7. ↑ Lawler DF et al.: Diet restriction and ageing in the dog: major observations over two decades. Br J Nutr 2008. (PMID 18062831) [PubMed] [DOI] This report reviews decade two of the lifetime diet restriction study of the dog. Labrador retrievers (n 48) were paired at age 6 weeks by sex and weight within each of seven litters, and assigned randomly within the pair to control-feeding (CF) or 25 % diet restriction (DR). Feeding began at age 8 weeks. The same diet was fed to all dogs; only the quantity differed. Major lifetime observations included 1.8 years longer median lifespan among diet-restricted dogs, with delayed onset of late life diseases, especially osteoarthritis. Long-term DR did not negatively affect skeletal maturation, structure or metabolism. Among all dogs, high static fat mass and declining lean body mass predicted death, most strongly at 1 year prior. Fat mass above 25 % was associated with increasing insulin resistance, which independently predicted lifespan and chronic diseases. Metabolizable energy requirement/lean body mass most accurately explained energy metabolism due to diet restriction; diet-restricted dogs required 17 % less energy to maintain each lean kilogram. Metabonomics-based urine metabolite trajectories reflected DR-related differences, suggesting that signals from gut microbiota may be involved in the DR longevity and health responses. Independent of feeding group, increased hazard of earlier death was associated with lower lymphoproliferative responses to phytohaemagglutinin, concanavalin A, and pokeweed mitogen; lower total lymphocytes, T-cells, CD4 and CD8 cells; lower CD8 percentages and higher B-cell percentages. When diet group was taken into account, PWM responses and cell counts and percentages remained predictive of earlier death.
    8. ↑ 8.0 8.1 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.
    9. ↑ 9.0 9.1 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.
    10. ↑ 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.
    11. ↑ 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.
    12. ↑ 12.0 12.1 12.2 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.
    13. ↑ 13.0 13.1 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.
    14. ↑ 14.0 14.1 Sohal RS & Forster MJ: Caloric restriction and the aging process: a critique. Free Radic Biol Med 2014. (PMID 24941891) [PubMed] [DOI] [Full text] The main objective of this review is to provide an appraisal of the current status of the relationship between energy intake and the life span of animals. The concept that a reduction in food intake, or caloric restriction (CR), retards the aging process, delays the age-associated decline in physiological fitness, and extends the life span of organisms of diverse phylogenetic groups is one of the leading paradigms in gerontology. However, emerging evidence disputes some of the primary tenets of this conception. One disparity is that the CR-related increase in longevity is not universal and may not even be shared among different strains of the same species. A further misgiving is that the control animals, fed ad libitum (AL), become overweight and prone to early onset of diseases and death, and thus may not be the ideal control animals for studies concerned with comparisons of longevity. Reexamination of body weight and longevity data from a study involving over 60,000 mice and rats, conducted by a National Institute on Aging-sponsored project, suggests that CR-related increase in life span of specific genotypes is directly related to the gain in body weight under the AL feeding regimen. Additionally, CR in mammals and "dietary restriction" in organisms such as Drosophila are dissimilar phenomena, albeit they are often presented to be the very same. The latter involves a reduction in yeast rather than caloric intake, which is inconsistent with the notion of a common, conserved mechanism of CR action in different species. Although specific mechanisms by which CR affects longevity are not well understood, existing evidence supports the view that CR increases the life span of those particular genotypes that develop energy imbalance owing to AL feeding. In such groups, CR lowers body temperature, rate of metabolism, and oxidant production and retards the age-related pro-oxidizing shift in the redox state.
    15. ↑ Lee KP et al.: Lifespan and reproduction in Drosophila: New insights from nutritional geometry. Proc Natl Acad Sci U S A 2008. (PMID 18268352) [PubMed] [DOI] [Full text] Modest dietary restriction (DR) prolongs life in a wide range of organisms, spanning single-celled yeast to mammals. Here, we report the use of recent techniques in nutrition research to quantify the detailed relationship between diet, nutrient intake, lifespan, and reproduction in Drosophila melanogaster. Caloric restriction (CR) was not responsible for extending lifespan in our experimental flies. Response surfaces for lifespan and fecundity were maximized at different protein-carbohydrate intakes, with longevity highest at a protein-to-carbohydrate ratio of 1:16 and egg-laying rate maximized at 1:2. Lifetime egg production, the measure closest to fitness, was maximized at an intermediate P:C ratio of 1:4. Flies offered a choice of complementary foods regulated intake to maximize lifetime egg production. The results indicate a role for both direct costs of reproduction and other deleterious consequences of ingesting high levels of protein. We unite a body of apparently conflicting work within a common framework and provide a platform for studying aging in all organisms.
    16. ↑ Liao CY et al.: Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging Cell 2010. (PMID 19878144) [PubMed] [DOI] [Full text] Chronic dietary restriction (DR) is considered among the most robust life-extending interventions, but several reports indicate that DR does not always extend and may even shorten lifespan in some genotypes. An unbiased genetic screen of the lifespan response to DR has been lacking. Here, we measured the effect of one commonly used level of DR (40% reduction in food intake) on mean lifespan of virgin males and females in 41 recombinant inbred strains of mice. Mean strain-specific lifespan varied two to threefold under ad libitum (AL) feeding and 6- to 10-fold under DR, in males and females respectively. Notably, DR shortened lifespan in more strains than those in which it lengthened life. Food intake and female fertility varied markedly among strains under AL feeding, but neither predicted DR survival: therefore, strains in which DR shortened lifespan did not have low food intake or poor reproductive potential. Finally, strain-specific lifespans under DR and AL feeding were not correlated, indicating that the genetic determinants of lifespan under these two conditions differ. These results demonstrate that the lifespan response to a single level of DR exhibits wide variation amenable to genetic analysis. They also show that DR can shorten lifespan in inbred mice. Although strains with shortened lifespan under 40% DR may not respond negatively under less stringent DR, the results raise the possibility that life extension by DR may not be universal.
    17. ↑ Rikke BA et al.: Genetic dissection of dietary restriction in mice supports the metabolic efficiency model of life extension. Exp Gerontol 2010. (PMID 20452416) [PubMed] [DOI] [Full text] Dietary restriction (DR) has been used for decades to retard aging in rodents, but its mechanism of action remains an enigma. A principal roadblock has been that DR affects many different processes, making it difficult to distinguish cause and effect. To address this problem, we applied a quantitative genetics approach utilizing the ILSXISS series of mouse recombinant inbred strains. Across 42 strains, mean female lifespan ranged from 380 to 1070days on DR (fed 60% of ad libitum [AL]) and from 490 to 1020days on an AL diet. Longevity under DR and AL is under genetic control, showing 34% and 36% heritability, respectively. There was no correlation between lifespans on DR and AL; thus different genes modulate longevity under the two regimens. DR lifespans are significantly correlated with female fertility after return to an AL diet after various periods of DR (R=0.44, P=0.006). We assessed fuel efficiency (FE, ability to maintain growth and body weight independent of absolute food intake) using a multivariate approach and found it to be correlated with longevity and female fertility, suggesting possible causality. We found several quantitative trait loci responsible for these traits, mapping to chromosomes 7, 9, and 15. We present a metabolic model in which the anti-aging effects of DR are consistent with the ability to efficiently utilize dietary resources.
    18. ↑ Sohal RS et al.: Life span extension in mice by food restriction depends on an energy imbalance. J Nutr 2009. (PMID 19141702) [PubMed] [DOI] [Full text] In this study, our main objective was to determine whether energy restriction (ER) affects the rate of oxygen consumption of mice transiently or lastingly and whether metabolic rate plays a role in the ER-related extension of life span. We compared rates of resting oxygen consumption between C57BL/6 mice, whose life span is prolonged by ER, and the DBA/2 mice where it is not, at 6 and 23 mo of age, following 40% ER for 2 and 19 mo, respectively. Mice of the 2 strains that consumed food ad libitum (AL) had a similar body mass at the age of 4 mo and consumed similar amounts of food throughout the experiment; however, the body weight subsequently significantly increased (20%) in the C57BL/6 mice but did not increase significantly in the DBA/2 mice. The resting rate of oxygen consumption was normalized as per g body weight, lean body mass, organ weight, and per mouse. The resting rate of oxygen consumption at 6 mo was significantly higher in AL DBA/2 mice than the AL C57BL/6 mice for all of the criteria except organ weight. A similar difference in AL mice of the 2 strains was present at 23 mo when resting oxygen consumption was normalized to body weight. Resting oxygen consumption was lowered by ER in both age groups of each strain according to all 4 criteria used for normalization, except body weight in the C57BL/6 mice. The effect of ER on resting oxygen consumption was thus neither transient nor age or strain dependent. Our results suggest that ER-induced extension of life span occurs in the mouse genotype in which there is a positive imbalance between energy intake and energy expenditure.
    19. ↑ Ross MH et al.: Dietary practices and growth responses as predictors of longevity. Nature 1976. (PMID 958413) [PubMed] [DOI]
    20. ↑ Life Extension: Myth of Caloric Restriction Refuted, https://www.aerzteblatt.de/nachrichten/35192/Lebensverlaengerung-Mythos-der-Kalorienrestriktion-widerlegt
    21. ↑ Colman RJ et al.: Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009. (PMID 19590001) [PubMed] [DOI] [Full text] Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research. In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths. At the time point reported, 50% of control fed animals survived as compared with 80% of the CR animals. Furthermore, CR delayed the onset of age-associated pathologies. Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy. These data demonstrate that CR slows aging in a primate species.
    22. ↑ rme: Template:Webarchive In: aerzteblatt.de, July 10, 2009.
    23. ↑ Fontana L & Klein S: Aging, adiposity, and calorie restriction. JAMA 2007. (PMID 17341713) [PubMed] [DOI] CONTEXT: Excessive calorie intake and subsequent obesity increases the risk of developing chronic disease and decreases life expectancy. In rodent models, calorie restriction with adequate nutrient intake decreases the risk of developing chronic disease and extends maximum life span. OBJECTIVE: To evaluate the physiological and clinical implications of calorie restriction with adequate nutrient intake. EVIDENCE ACQUISITION: Search of PubMed (1966-December 2006) using terms encompassing various aspects of calorie restriction, dietary restriction, aging, longevity, life span, adiposity, and obesity; hand search of journals that focus on obesity, geriatrics, or aging; and search of reference lists of pertinent research and review articles and books. Reviewed reports (both basic science and clinical) included epidemiologic studies, case-control studies, and randomized controlled trials, with quality of data assessed by taking into account publication in a peer-reviewed journal, number of animals or individuals studied, objectivity of measurements, and techniques used to minimize bias. EVIDENCE SYNTHESIS: It is not known whether calorie restriction extends maximum life span or life expectancy in lean humans. However, calorie restriction in adult men and women causes many of the same metabolic adaptations that occur in calorie-restricted rodents and monkeys, including decreased metabolic, hormonal, and inflammatory risk factors for diabetes, cardiovascular disease, and possibly cancer. Excessive calorie restriction causes malnutrition and has adverse clinical effects. CONCLUSIONS: Calorie restriction in adult men and women causes beneficial metabolic, hormonal, and functional changes, but the precise amount of calorie intake or body fat mass associated with optimal health and maximum longevity in humans is not known. In addition, it is possible that even moderate calorie restriction may be harmful in specific patient populations, such as lean persons who have minimal amounts of body fat.
    24. ↑ de Cabo R et al.: Serum from calorie-restricted animals delays senescence and extends the lifespan of normal human fibroblasts in vitro. Aging (Albany NY) 2015. (PMID 25855056) [PubMed] [DOI] [Full text] The cumulative effects of cellular senescence and cell loss over time in various tissues and organs are considered major contributing factors to the ageing process. In various organisms, caloric restriction (CR) slows ageing and increases lifespan, at least in part, by activating nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases of the sirtuin family. Here, we use an in vitro model of CR to study the effects of this dietary regime on replicative senescence, cellular lifespan and modulation of the SIRT1 signaling pathway in normal human diploid fibroblasts. We found that serum from calorie-restricted animals was able to delay senescence and significantly increase replicative lifespan in these cells, when compared to serum from ad libitum fed animals. These effects correlated with CR-mediated increases in SIRT1 and decreases in p53 expression levels. In addition, we show that manipulation of SIRT1 levels by either over-expression or siRNA-mediated knockdown resulted in delayed and accelerated cellular senescence, respectively. Our results demonstrate that CR can delay senescence and increase replicative lifespan of normal human diploid fibroblasts in vitro and suggest that SIRT1 plays an important role in these processes.
    25. ↑ M. Tostlebe: Disproportionalität der Aktivitäten der mitochondrialen Atmungskettenkomplexe im Myokard und in der Skelettmuskulatur im Alter. Dissertation, Martin-Luther-Universität Halle-Wittenberg, 2005.
    26. ↑ A. Csiszar et al.: Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: role of circulating factors and SIRT1. In: Mech Ageing Dev 130, 2009, pp. 518–527. PMID 19549533.
    27. ↑ J. Skrha: Effect of caloric restriction on oxidative markers. In: Adv Clin Chem 47, 2009, pp. 223–247. PMID 19634782.
    28. ↑ PMID 25824609.
    29. ↑ S. Nagarajan, A. L. Kruckeberg, K. H. Schmidt, E. Kroll, M. Hamilton, K. McInnerney, R. Summers, T. Taylor, F. Rosenzweig: Uncoupling reproduction from metabolism extends chronological lifespan in yeast. In: PNAS. Volume 111, Number 15, April 2014, Template:ISSN, pp. E1538–E1547, doi:10.1073/pnas.1323918111, PMID 24706810, Template:PMC.
    30. ↑ 25071164
    31. ↑ PMID 16242247.
    32. ↑ PMID 20350594
    33. ↑ Wang Y: Molecular Links between Caloric Restriction and Sir2/SIRT1 Activation. Diabetes Metab J 2014. (PMID 25349818) [PubMed] [DOI] [Full text] Ageing is the most significant risk factor for a range of prevalent diseases, including cancer, cardiovascular disease, and diabetes. Accordingly, interventions are needed for delaying or preventing disorders associated with the ageing process, i.e., promotion of healthy ageing. Calorie restriction is the only nongenetic and the most robust approach to slow the process of ageing in evolutionarily divergent species, ranging from yeasts, worms, and flies to mammals. Although it has been known for more than 80 years that calorie restriction increases lifespan, a mechanistic understanding of this phenomenon remains elusive. Yeast silent information regulator 2 (Sir2), the founding member of the sirtuin family of protein deacetylases, and its mammalian homologue Sir2-like protein 1 (SIRT1), have been suggested to promote survival and longevity of organisms. SIRT1 exerts protective effects against a number of age-associated disorders. Caloric restriction increases both Sir2 and SIRT1 activity. This review focuses on the mechanistic insights between caloric restriction and Sir2/SIRT1 activation. A number of molecular links, including nicotinamide adenine dinucleotide, nicotinamide, biotin, and related metabolites, are suggested to be the most important conduits mediating caloric restriction-induced Sir2/SIRT1 activation and lifespan extension.
    34. ↑ Cantó C & Auwerx J: Caloric restriction, SIRT1 and longevity. Trends Endocrinol Metab 2009. (PMID 19713122) [PubMed] [DOI] [Full text] More than 70 years after its initial report, caloric restriction stands strong as the most consistent non-pharmacological intervention increasing lifespan and protecting against metabolic disease. Among the different mechanisms by which caloric restriction might act, Sir2/SIRT1 (Silent information regulator 2/Silent information regulator T1) has been the focus of much attention because of its ability to integrate sensing of the metabolic status with adaptive transcriptional outputs. This review focuses on gathered evidence suggesting that Sir2/SIRT1 is a key mediator of the beneficial effects of caloric restriction and addresses the main questions that still need to be answered to consolidate this hypothesis.
    35. ↑ Ghosh HS et al.: SIRT1 negatively regulates the mammalian target of rapamycin. PLoS One 2010. (PMID 20169165) [PubMed] [DOI] [Full text] The IGF/mTOR pathway, which is modulated by nutrients, growth factors, energy status and cellular stress regulates aging in various organisms. SIRT1 is a NAD+ dependent deacetylase that is known to regulate caloric restriction mediated longevity in model organisms, and has also been linked to the insulin/IGF signaling pathway. Here we investigated the potential regulation of mTOR signaling by SIRT1 in response to nutrients and cellular stress. We demonstrate that SIRT1 deficiency results in elevated mTOR signaling, which is not abolished by stress conditions. The SIRT1 activator resveratrol reduces, whereas SIRT1 inhibitor nicotinamide enhances mTOR activity in a SIRT1 dependent manner. Furthermore, we demonstrate that SIRT1 interacts with TSC2, a component of the mTOR inhibitory-complex upstream to mTORC1, and regulates mTOR signaling in a TSC2 dependent manner. These results demonstrate that SIRT1 negatively regulates mTOR signaling potentially through the TSC1/2 complex.
    36. ↑ Austad S: Recent advances in vertebrate aging research 2009. Aging Cell 2010. (PMID 20331443) [PubMed] [DOI] Among the notable trends seen in this year's highlights in mammalian aging research is an awakening of interest in the assessment of age-related measures of mouse health in addition to the traditional focus on longevity. One finding of note is that overexpression of telomerase extended life and improved several indices of health in mice that had previously been genetically rendered cancer resistant. In another study, resveratrol supplementation led to amelioration of several degenerative conditions without affecting mouse lifespan. A primate dietary restriction (DR) study found that restriction led to major improvements in glucoregulatory status along with provocative but less striking effects on survival. Visceral fat removal in rats improved their survival, although not as dramatically as DR. An unexpected result showing the power of genetic background effects was that DR shortened the lifespan of long-lived mice bearing Prop1(df), whereas a previous report in a different background had found DR to extend the lifespan of Prop1(df) mice. Treatment with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, enhanced the survival of even elderly mice and improved their vaccine response. Genetic inhibition of a TOR target made female, but not male, mice live longer. This year saw the mTOR network firmly established as a major modulator of mammalian lifespan.
    37. ↑ Harrison DE et al.: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009. (PMID 19587680) [PubMed] [DOI] [Full text] Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
    38. ↑ Ramis MR et al.: Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases. Mech Ageing Dev 2015. (PMID 25824609) [PubMed] [DOI] Aging is an inevitable and multifactorial biological process. Free radicals have been implicated in aging processes; it is hypothesized that they cause cumulative oxidative damage to crucial macromolecules and are responsible for failure of multiple physiological mechanisms. However, recent investigations have also suggested that free radicals can act as modulators of several signaling pathways such as those related to sirtuins. Caloric restriction is a non-genetic manipulation that extends lifespan of several species and improves healthspan; the belief that many of these benefits are due to the induction of sirtuins has led to the search for sirtuin activators, especially sirtuin 1, the most studied. Resveratrol, a polyphenol found in red grapes, was first known for its antioxidant and antifungal properties, and subsequently has been reported several biological effects, including the activation of sirtuins. Endogenously-produced melatonin, a powerful free radical scavenger, declines with age and its loss contributes to degenerative conditions of aging. Recently, it was reported that melatonin also activates sirtuins, in addition to other functions, such as regulator of circadian rhythms or anti-inflammatory properties. The fact that melatonin and resveratrol are present in various foods, exhibiting possible synergistic effects, suggests the use of dietary ingredients to promote health and longevity.
    39. ↑ 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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