Dietary > Caloric Restriction



Calorie restriction, or caloric restriction, or energy restriction, is a dietary regimen that reduces calorie intake without incurring malnutrition or a reduction in essential nutrients. "Low" can be defined relative to the subject's previous intake before intentionally restricting calories, or relative to an average person of similar body type. In a number of species, including yeast, fish, rodents and dogs, calorie restriction without malnutrition has been shown to slow the biological aging process, resulting in longer maintenance of youthful health and an increase in both median and maximum lifespan.[1][2] However, the life-extending effect of calorie restriction is not shown to be universal.[3]

In humans, the long-term health effects of moderate caloric restriction with sufficient nutrients are unknown.[4]

Using rhesus monkeys, a collaboration of the United States National Institute on Aging and the University of Wisconsin found that caloric restriction without malnutrition extended lifespan and delayed the onset of age-related disorders; older age, higher diet quality, and female gender were positive factors affecting the benefits realized from lower caloric intake.[5]


  • Health effects
    • Risks of malnutrition
  • Mechanisms
    • Temperature
    • Hormesis
    • Evolution
    • Chromatin and PHA-4
    • Reduced DNA damage
    • Sirtuin-mediated mechanism
  • History
  • ResearchReferences
    • Primates
    • Rodents
    • Yeast
    • Humans
    • Research controls
  • References

Risks of malnutrition

As noted above, the term "calorie restriction" as used in biogerontology refers to dietary regimens that reduce calorie intake without incurring malnutrition.[4] If a restricted diet is not designed to include essential nutrients, malnutrition may result in serious deleterious effects, as shown in the Minnesota Starvation Experiment.[6]This study was conducted during World War II on a group of lean men, who restricted their calorie intake by 45% for 6 months, and composed roughly 90% of their diet with carbohydrates.[6] As expected, this malnutrition resulted in many positive metabolic adaptations (e.g. decreased body fat, blood pressure, improved lipid profile, low serum T3 concentration, and decreased resting heart rate and whole-body resting energy expenditure), but also caused a wide range of negative effects, such as anemia, lower extremity edema, muscle wasting, weakness, neurological deficits, dizziness, irritability, lethargy, and depression.[6]



Even though there has been research on caloric restriction for over 70 years, the mechanism by which caloric restriction works is still not well understood.[2] Some explanations include reduced core body temperature,[21] reduced cellular divisions, lower metabolic rates, reduced production of free radicals,[22] reduced DNA damage[23][24] and hormesis.[25]



Some research has pointed toward hormesis as an explanation for the benefits of caloric restriction, representing beneficial actions linked to a low-intensity biological stressor such as reduced calorie intake.[26] As a potential role for caloric restriction, the diet imposes a low-intensity biological stress on the organism, eliciting a defensive response that may help protect it against the disorders of aging.[27] In other words, caloric restriction places the organism in a defensive state so that it can survive adversity, resulting in improved health and longer life.[26] This switch to a defensive state may be controlled by longevity genes (see below).[28]

Mitochondrial hormesis

Mitochondrial hormesis was a purely hypothetical concept until late 2007, when work on a small worm named Caenorhabditis elegans suggested that the restriction of glucose metabolism extends life span primarily by increasing oxidative stress to stimulate the organism into having an ultimately increased resistance to further oxidative stress.[29] This is probably the first experimental evidence for hormesis being the reason for extended life span following caloric restriction.

Although aging can be conceptualized as the accumulation of damage, the more recent determination that free radicals participate in intracellular signaling has made the categorical equation of their effects with "damage" more problematic than was commonly appreciated in the past. It was previously proposed on a hypothetical basis that free radicals may induce an endogenous response culminating in more effective adaptations that protect against exogenous radicals (and possibly other toxic compounds).[30] Sublethal mitochondrial stress with an attendant augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction.[31][32][33]



It has been recently argued that during years of famine, it may be evolutionarily desirable for an organism to avoid reproduction and to up-regulate protective and repair enzyme mechanisms to ensure that it is fit for reproduction in future years. This argument seems to be supported by recent work studying hormones. Prolonged severe CR lowers total serum and free testosterone while increasing sex hormone binding globulin concentrations in humans; these effects are independent of adiposity.[34]

Lowering of the concentration of insulin and substances related to insulin, such as insulin-like growth factor 1 and growth hormone, has been shown to up-regulate autophagy, the repair mechanism of the cell.[35] A related hypothesis suggests that caloric restriction works by decreasing insulin levels and thereby up-regulating autophagy,[35][36] but caloric restriction affects many other health indicators, and it is still undecided whether insulin is the main concern.[37] Calorie restriction has been shown to increase DHEA in primates, but it has not been shown to increase DHEA in post-pubescent primates.[38][39] The extent to which these findings apply to humans is still under investigation.

Chromatin and PHA-4

Evidence suggests that the biological effects of caloric restriction are closely related to chromatin function.[40] One study determined that the gene PHA-4 is responsible for the longevity behind calorie restriction in roundworms, "with similar results expected in humans".[41]

Reduced DNA damage

Calorie restriction reduces production of reactive oxygen species.[22][42]

Sohal et al. observed that caloric restriction decreased 8-OHdG damages in the DNA of mice heart, skeletal muscle, brain, liver and kidney. The levels of 8-OHdG in the DNA of these organs in 15 month old mice were reduced to an average of 81% of that in the DNA of mice fed an unrestricted diet.[23] Kaneko et al. observed that, in rats, dietary restriction retarded the onset of age-related increases in 8-OHdG in nuclear DNA of brain, heart, liver and kidney. The level of 8-OHdG in these organs of the calorie restricted rats at 30 months averaged 65% of the level in rats fed an unrestricted diet.[43]

In rodents, calorie restriction slows aging, decreases ROS production and reduces the accumulation of oxidative DNA damage in multiple organs. These results link reduced oxidative DNA damage to slower aging. The consistent observation that calorie restriction reduces oxidative DNA damage lends support to the possibility that oxidative DNA damage is associated with aging.[24][44]

Sirtuin-mediated mechanism

Sirtuins, specifically Sir2 (found in yeast) has been implicated in the aging of yeast[45] and is a highly conserved, NAD+ - dependent histone deacetylase.[46] Sir2 homologs have been identified in a wide range of organisms from bacteria to humans.[47] Yeast has 3 SIR genes (SIR2, SIR3, and SIR4) that are responsible for silencing mating type loci, telomeres, and rDNA.[48] Although all three genes are required for the silencing of mating type loci and telomeres, only SIR2 has been implicated in the silencing of rDNA.[49] In addition, SIR2 related genes also regulate formation of some specialized survival forms, such as spores in yeast[50] and daher larvae in C. elegans.[51] A study done by Kaeberlein et al. (1999) in yeast found that deletions of Sir2 decreased lifespan, and additional copies increased lifespan.[47]

In many calorie restriction studies, it is believed that Sir2 mediates the longevity effects from calorie restriction for several reasons. First, it was found that in yeast without SIR2, calorie restriction did not impart longevity in yeast;[52] second, in Sir2 mutants an abundance of extra-chromosomal ribosomal DNA circles (that typically limit lifespan) has been observed, and that mitigation of these circles restore regular life span, but still are resistant to calorie restriction-mediated longevity;[53][54] third, that caloric restriction increases the activity of Sir2 in vivo.[55] Although Sir2 has been implicated in calorie restriction-mediated longevity, the method by which Sir2 is regulated under caloric restriction is still debated.

Two hypotheses of Sir2/caloric restriction -mediated longevity is the NADH mechanism and the NAD salvage pathway mechanism. In the NADH hypothesis, it is believed that caloric restriction causes an increase in respiration,[55] which in turn causes a reduction in the levels of NADH.[46] This decrease in the concentration of NADH would up regulate SIR2, since NADH functions as a competitive inhibitor of SIR2.[54] In addition, it has been shown that overexpression of NADH hydrogenase increased longevity and knocking out the electron transport chain blocked caloric restriction-mediated longevity. The NAD salvage pathway mechanism relies on a study by Anderson et al., in which they showed that caloric restriction causes an up regulation of PNC1 (an enzyme responsible for synthesizing NAD from nicotinamide and ADP-ribose) decreases the levels of nicotinamide, which in turn upregulates SIR2 and thus increases lifespan.[56] Although these models are not mutually exclusive, no experiment has been conducted linking the two.[54]


Attempts are being made to develop drugs that act as CR mimetics, and much of that work has focused on a class of proteins called sirtuins.[63] Resveratrol has been reported to activate SIRT1 and extend the lifespan of yeast,[64] nematode worms, fruit flies,[65] vertebrate fish,[66] and mice consuming a high-caloric diet.[67] However, resveratrol does not extend life span in normal mice[68] and the effect of resveratrol on lifespan in nematodes and fruit flies has been disputed.[69]

There are studies that indicate that resveratrol may not function through SIRT1[70][71] but may work through other targets.[72][73] A clinical trial of the resveratrol formulation SRT501 was suspended.[74]



The first person to promote calorie restriction as a means of prolonging life was Luigi Cornaro, a 15th-century Venetian nobleman who adopted a calorie restricted diet at age 35 to address his failing health. It is said his restricted diet cured him of all of his ailments in less than a year, and he went on to live to be 102 years old.[75] His book Discorsi della vita sobria (Discourses On the Temperate Life) described his regimen, which centered on the "quantifying principle" of restricting himself to only 350 grams of food daily (including bread, egg yolk, meat, and soup) and 414 milliliters of wine. The book was extremely successful, and "was a true reconceptualization of old age. As late as the Renaissance it was largely the negative aspects of this phase of life which were emphasized ... Cornaro’s method offered the possibility for the first time not only of a long but also a worthwhile life."[76]

The findings have since been accepted and generalized to a range of other animals. Researchers are investigating the possibility of parallel physiological links in non-human primates and humans. In response to these results, a small number of people have independently adopted the practice of calorie restriction in some form as a potential anti-aging intervention.[77]

Through 2017, the US National Institute on Aging is conducting human clinical trials on caloric restriction to determine potential for reducing the risks of age-related disorders.[78]




In a 2017 collaborative report on rhesus monkeys by scientists of the US National Institute on Aging and the University of Wisconsin, caloric restriction in the presence of adequate nutrition was effective in delaying the effects of aging.[5][79] Older age of onset, female gender, lower body weight and fat mass, reduced food intake, diet quality, and lower fasting blood glucose levels were factors associated with fewer disorders of aging and with improved survival rates.[5][79] Specifically, reduced food intake was beneficial in adult and older primates, but not in younger monkeys.[5] The study indicated that caloric restriction provided health benefits with fewer age-related disorders in elderly monkeys and, because rhesus monkeys are genetically similar to humans, the benefits and mechanisms of caloric restriction may apply to human health during aging.[5]


It has been known since the 1930s that reducing the number of calories fed to laboratory rodents increases their life spans. The life extension varies for each species, but on average there was a 30–40% increase in life span in both mice and rats.[37] In late adulthood, acute CR partially or completely reverses age-related alterations of liver, brain and heart proteins, and mice placed on CR at 19 months of age show an increases in life span.[80]


Fungi models are very easy to manipulate, and many crucial steps toward the understanding of aging have been made with them. Many studies were undertaken on budding yeast and fission yeast to analyze the cellular mechanisms behind increased longevity due to calorie restriction. First, calorie restriction is often called dietary restriction because the same effects on life span can be achieved by only changing the nutrient quality without changing the number of calories. Data from Guarente and others showed that genetic manipulations in nutrient-signaling pathways could mimic the effects of dietary restriction. In some cases, dietary restriction requires mitochondrial respiration to increase longevity (chronological aging), and in some other cases not (replicative aging). Nutrient sensing in yeast controls stress defense, mitochondrial functions, Sir2, and others. These functions are all known to regulate aging. Genes involved in these mechanisms are TOR, PKA, SCH9, MSN2/4, RIM15, and SIR2.[81][82][83][84][85] Importantly, yeast responses to CR can be modulated by genetic background. Therefore, while some strains respond to calorie restriction with increased lifespan, in others calorie restriction shortens it [86]


Studies have been conducted to examine the effects of calorie restriction with adequate intake of nutrients in humans; however, long-term effects are unknown.[4]

Biomarkers for cardiovascular risk

A review of the effects of calorie restriction on the aging heart and vasculature concluded that "Data from animal and human studies indicate that [beyond the effects of "implementation of healthier diets and regular exercise"], more drastic interventions, i.e., calorie restriction with adequate nutrition (CRAN), may have additional beneficial effects on several metabolic and molecular factors that are modulating cardiovascular aging itself (e.g., cardiac and arterial stiffness and heart rate variability)."[87] Studies of long-term practitioners of rigorous calorie restriction show that their risk factors for atherosclerosis are substantially improved in a manner consistent with experimental studies in rodent models of atherosclerosis and nonhuman primates.[87] Risk factors such as c-reactive protein; serum triglycerides, low-density lipoprotein, high-density lipoprotein; blood pressure; and fasting blood sugar, are substantially more favorable than persons consuming usual Western diets and comparable or better than long-term endurance exercisers.[87] Similar effects were also seen during a "natural experiment" in Biosphere 2,[87] and in subjects in the “Minnesota Starvation Experiment” during World War II.[6] Cardiac "diastolic function was better in subjects who practiced strict calorie restriction for 3–15 years than that in healthy age- and sex-matched control subjects ... calorie restriction subjects had less ventricular stiffness and less viscous loss of diastolic recoil, both of which would be consistent with less myocardial fibrosis.[87] "These effects, in combination with other benefits of calorie restriction, such as protection against obesity, diabetes, hypertension, and cancer, suggest that CR may have a major beneficial effect on health span, life span, and quality of life in humans."[87]

Biomarkers for cancer risk

Long-term calorie restriction in humans results in a reduction of several metabolic and hormonal factors that have been associated with increased risk of some of the most common types of cancer in developed countries, consistent with similar shifts in calorie restriction rodents and nonhuman primates, in whom calorie restriction affords substantial protection against cancer morbidity and mortality.[1][88][88] These include lower levels of total and abdominal fat, circulating insulin, testosterone, estradiol, and inflammatory cytokines linked to cancer.[1] Long-term calorie restriction can also reduce levels of serum Insulin-like growth factor 1 in humans, and increase levels of IGFBP-3; however, unlike in rodents, this effect can be blocked if dietary protein is not reduced to the Dietary Reference Intake.[1]


Activity levels

Calorie restriction preserves muscle tissue in nonhuman primates[89][90] and rodents.[91][92] Mechanisms include reduced muscle cell apoptosis and inflammation;[91]protection against[92] or adaptation to[89] age-related mitochondrial abnormalities; and preserved muscle stem cell function.[93] Muscle tissue grows when stimulated, so it has been suggested that the calorie-restricted test animals exercised more than their companions on higher calories, perhaps because animals enter a foraging state during calorie restriction. However, studies show that overall activity levels are no higher in calorie restriction than ad libitum animals in youth,[94] while calorie restriction animals are more active at middle age and beyond due to a protective effect against the decline in activity observed in middle-aged and older animals.[95]

Laboratory rodents placed on a calorie restriction diet tend to exhibit increased activity levels (particularly when provided with exercise equipment) at feeding time. Monkeys undergoing calorie restriction also appear more restless immediately before and after meals.[96] Despite this brief daily period of increased activity overall activity is no higher in calorie restriction than ad libitum animals in youth after an initial period of adaptation to the diet.[94] On the other hand, calorie restriction has been found to retard the decline in activity that occurs during normal aging: in one study, animals on a conventional diet "showed little activity" by early middle age, while those on calorie restriction "were observed to run around the cage and climb onto and hang from the wire cage tops throughout their life spans. In fact, the longest surviving calorie restriction mouse was observed hanging from the top of his cage only 3 days before he became moribund."[95]

Stereotyped behavior

Observations in some accounts of animals undergoing calorie restriction have noted an increase in stereotyped behaviors.[96] For example, monkeys on calorie restriction have demonstrated an increase in licking, sucking, and rocking behavior.[99]

A calorie restriction regimen may also lead to increased aggressive behavior in animals.[96]

Obese controls

It has sometimes been suggested that the lives of calorie-restricted animals are only extended relative to control animals whose lives are artificially shortened by weight-gain from unnatural ad libitum feeding in the laboratory.[100] However, studies designed to test this hypothesis suggest that reduced fat mass is not a major contributor to the longevity effects of calorie restriction.[4] The strongest evidence comes from a study in which ob/ob mice, which are genetically prone to overeating and obesity, were compared to lean mice of the same genetic background but lacking the ob/ob mutation. When placed on calorie restriction, the ob/ob mice still have over twice the fat mass of ad libitum-fed congenic lean mice, and yet they have double the lifespan.[4] Additionally, many modern calorie restriction studies restrict the control animals by 10–20% below their ad libitum intake in order to avoid confounding by obesity.[4]




(With special thanks to Wikipedia entry on Caloric Restriction)

1.                 ^ Jump up to:a b c d Omodei, D; Fontana, L (Jun 6, 2011). "Calorie restriction and prevention of age-associated chronic disease"


. FEBS Lett. 585 (11): 1537–42. PMC 3439843


  . PMID 21402069


. doi:10.1016/j.febslet.2011.03.015


. Retrieved 28 November 2015.

2.                 ^ Jump up to:a b Anderson, R. M.; Shanmuganayagam, D.; Weindruch, R. (2009). "Caloric Restriction and Aging: Studies in Mice and Monkeys". Toxicologic Pathology. 37 (1): 47–51. PMID 19075044


. doi:10.1177/0192623308329476



3.                 Jump up^ "Can We Prevent Aging?"


. National Institute on Aging, US National Institutes of Health, Bethesda, MD. 29 July 2016.

4.                 ^ Jump up to:a b c d e f g h i Spindler, Stephen R. (2010). "Biological Effects of Calorie Restriction: Implications for Modification of Human Aging". The Future of Aging. pp. 367–438. ISBN 978-90-481-3998-9. doi:10.1007/978-90-481-3999-6_12



5.                 ^ Jump up to:a b c d e Mattison, Julie A; Colman, Ricki J; Beasley, T Mark; Allison, David B; Kemnitz, Joseph W; Roth, George S; Ingram, Donald K; Weindruch, Richard; De Cabo, Rafael; Anderson, Rozalyn M (2017). "Caloric restriction improves health and survival of rhesus monkeys"


. Nature Communications. 8: 14063. PMC 5247583


  . PMID 28094793


. doi:10.1038/ncomms14063



6.                 ^ Jump up to:a b c d Keys A, Brozek J, Henschels A & Mickelsen O & Taylor H. The Biology of Human Starvation, 1950, Vol. 2, p. 1133. University of Minnesota Press, Minneapolis

7.                 Jump up^ Morley, John E; Chahla, Elie; Alkaade, Saad (2010). "Antiaging, longevity and calorie restriction". Current Opinion in Clinical Nutrition and Metabolic Care. 13 (1): 40–5. PMID 19851100


. doi:10.1097/MCO.0b013e3283331384



8.                 ^ Jump up to:a b c Gower BA, Casazza K (October–December 2013). "Divergent Effects of Obesity on Bone Health". Journal of Clinical Densitometry. 16 (4): 450–454. PMID 24063845


. doi:10.1016/j.jocd.2013.08.010



9.                 Jump up^ Bonewald LF, Kiel DP, Clemens TL, Esser K, Orwoll ES, O'Keefe RJ, Fielding RA (September 2013). "Forum on bone and skeletal muscle interactions: Summary of the proceedings of an ASBMR workshop"


. Journal of Bone and Mineral Research. 28 (9): 1857–1865. PMC 3749267


  . PMID 23671010


. doi:10.1002/jbmr.1980



10.              Jump up^ Fontana, L.; Klein, S. (2007). "Aging, Adiposity, and Calorie Restriction". JAMA. 297 (9): 986–94. PMID 17341713


. doi:10.1001/jama.297.9.986



11.              Jump up^ Hu, Frank (2008). "Interpreting Epidemiologic Evidence and Causal Inference in Obesity Research". In Frank B. Hu. Obesity Epidemiology


. New York, NY: Oxford University Press. pp. 38–52. ISBN 0-19-531291-0. Retrieved 2011-02-20.

12.              Jump up^ Flegal, K. M.; Graubard, B. I.; Williamson, D. F.; Gail, M. H. (2007). "Cause-Specific Excess Deaths Associated With Underweight, Overweight, and Obesity". JAMA. 298 (17): 2028–37. PMID 17986696


. doi:10.1001/jama.298.17.2028



13.              Jump up^ Holzman, Donald (2005-05-27). "Panel Suggests Methodology Flawed of Recent CDC Obesity Study"


. Medscape Medical News. Retrieved 2011-02-21.

14.              Jump up^ "Researchers weigh risks due to overweight". CA: A Cancer Journal for Clinicians. 55 (5): 268–9. 2005. doi:10.3322/canjclin.55.5.268



15.              Jump up^ St. Jeor, S. T.; Howard, B. V.; Prewitt, T. E.; Bovee, V.; Bazzarre, T.; Eckel, R. H.; Nutrition Committee Of The Council On Nutrition (2001). "Dietary Protein and Weight Reduction: A Statement for Healthcare Professionals From the Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism of the American Heart Association". Circulation. 104 (15): 1869–74. PMID 11591629


. doi:10.1161/hc4001.096152



16.              Jump up^ De Souza, RJ; Swain, JF; Appel, LJ; Sacks, FM (2008). "Alternatives for macronutrient intake and chronic disease: a comparison of the OmniHeart diets with popular diets and with dietary recommendations"


. The American Journal of Clinical Nutrition. 88 (1): 1–11. PMC 2674146


  . PMID 18614716



17.              Jump up^ Ma, Y; Pagoto, S; Griffith, J; Merriam, P; Ockene, I; Hafner, A; Olendzki, B (2007). "A Dietary Quality Comparison of Popular Weight-Loss Plans"


. Journal of the American Dietetic Association. 107 (10): 1786–91. PMC 2040023


  . PMID 17904938


. doi:10.1016/j.jada.2007.07.013



18.              Jump up^ Binge-Eating Disorder: Clinical Foundations and Treatment (1 ed.). The Guilford Press. 2007. p. 15. ISBN 978-1-59385-594-9. It can be concluded that caloric restriction does not appear to be associated with the development of binge eating in individuals who have never reported problems with binge eating.

19.              ^ Jump up to:a b "Risks"


. Retrieved 2010-07-28.

20.              Jump up^ Marzetti, E.; Wohlgemuth, S. E.; Anton, S. D.; Bernabei, R; Carter, C. S.; Leeuwenburgh, C (2012-10-19). "Cellular mechanisms of cardioprotection by calorie restriction: state of the science and future perspectives"


. Clin. Geriatr. Med. 25(4): 715–32, ix. PMC 2786899


  . PMID 19944269


. doi:10.1016/j.cger.2009.07.002



21.              ^ Jump up to:a b Conti, B; Sanchez-Alavez, M; Winsky-Sommerer, R; Morale, MC; Lucero, J; Brownell, S; Fabre, V; Huitron-Resendiz, S; Henriksen, S; Zorrilla, EP; de Lecea, L; Bartfai, T (3 November 2006). "Transgenic mice with a reduced core body temperature have an increased life span.". Science. 314 (5800): 825–8. Bibcode:2006Sci...314..825C


. PMID 17082459


. doi:10.1126/science.1132191



22.              ^ Jump up to:a b Sohal RS, Ku HH, Agarwal S, Forster MJ, Lal H (1994). "Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse". Mech Ageing Dev. 74 (1–2): 121–133. PMID 7934203


. doi:10.1016/0047-6374(94)90104-x



23.              ^ Jump up to:a b Sohal RS, Agarwal S, Candas M, Forster MJ, Lal H (1994). "Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice". Mech Ageing Dev. 76 (2–3): 215–224. PMID 7885066


. doi:10.1016/0047-6374(94)91595-4



24.              ^ Jump up to:a b Holmes GE, Bernstein C, Bernstein H (1992). "Oxidative and other DNA damages as the basis of aging: a review". Mutat Res. 275 (3–6): 305–315. PMID 1383772


. doi:10.1016/0921-8734(92)90034-m



25.              Jump up^ Hormesis: A Revolution in Biology, Toxicology and Medicine By Mark P. Mattson, Edward J. Calabrese

26.              ^ Jump up to:a b Nikolai, Sibylle; Pallauf, Kathrin; Huebbe, Patricia; Rimbach, Gerald (22 September 2015). "Energy restriction and potential energy restriction mimetics"


 (PDF). Nutrition Research Reviews. 28 (2): 1–21. PMID 26391585


. doi:10.1017/S0954422415000062


. Retrieved 8 November 2015.

27.              Jump up^ Martins, I; Galluzzi, L; Kroemer, G (2011). "Hormesis, cell death and aging"


. Aging. 3 (9): 821–8. PMC 3227447


  . PMID 21931183


. doi:10.18632/aging.100380



28.              Jump up^ Mattson, M (2008). "Dietary Factors, Hormesis and Health"


. Ageing Research Reviews. 7 (1): 43–8. PMC 2253665


  . PMID 17913594


. doi:10.1016/j.arr.2007.08.004



29.              Jump up^ Schulz, Tim J.; Zarse, Kim; Voigt, Anja; Urban, Nadine; Birringer, Marc; Ristow, Michael (2007). "Glucose Restriction Extends Caenorhabditis elegans Life Span by Inducing Mitochondrial Respiration and Increasing Oxidative Stress". Cell Metabolism. 6 (4): 280–293. PMID 17908557


. doi:10.1016/j.cmet.2007.08.011



30.              Jump up^ Tapia, P (2006). "Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: "Mitohormesis" for health and vitality". Medical Hypotheses. 66 (4): 832–43. PMID 16242247


. doi:10.1016/j.mehy.2005.09.009



31.              Jump up^ Schulz, Tim J.; Zarse, Kim; Voigt, Anja; Urban, Nadine; Birringer, Marc; Ristow, Michael (2007). "Glucose Restriction Extends Caenorhabditis elegans Life Span by Inducing Mitochondrial Respiration and Increasing Oxidative Stress". Cell Metabolism. 6 (4): 280–93. PMID 17908557


. doi:10.1016/j.cmet.2007.08.011



32.              Jump up^ Bjelakovic, G.; Nikolova, D.; Gluud, L. L.; Simonetti, R. G.; Gluud, C. (2007). "Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis". JAMA. 297 (8): 842–57. PMID 17327526


. doi:10.1001/jama.297.8.842



33.              Jump up^ Ristow, M; Zarse, K (2010). "How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis)". Experimental Gerontology. 45 (6): 410–8. PMID 20350594


. doi:10.1016/j.exger.2010.03.014



34.              Jump up^ Cangemi, Roberto; Friedmann, Alberto J.; Holloszy, John O.; Fontana, Luigi (2010). "Long-term effects of calorie restriction on serum sex-hormone concentrations in men"


. Aging Cell. 9 (2): 236–42. PMC 3569090


  . PMID 20096034


. doi:10.1111/j.1474-9726.2010.00553.x



35.              ^ Jump up to:a b Bergamini, E; Cavallini, G; Donati, A; Gori, Z (2003). "The anti-ageing effects of caloric restriction may involve stimulation of macroautophagy and lysosomal degradation, and can be intensified pharmacologically". Biomedecine & Pharmacotherapy. 57 (5–6): 203–8. doi:10.1016/S0753-3322(03)00048-9



36.              Jump up^ Cuervo, Ana Maria; Bergamini, Ettore; Brunk, Ulf T; Dröge, Wulf; Ffrench, Martine; Terman, Alexei (2005). "Autophagy and Aging: the Importance of Maintaining "Clean" Cells". Autophagy. 1 (3): 131–40. PMID 16874025


. doi:10.4161/auto.1.3.2017



37.              ^ Jump up to:a b Mattson MP (2005). "Energy intake, meal frequency, and health: a neurobiological perspective". Annu. Rev. Nutr. (Review). 25: 237–60. PMID 16011467


. doi:10.1146/annurev.nutr.25.050304.092526



38.              Jump up^ Mattison, J; Lane, MA; Roth, GS; Ingram, DK (2003). "Calorie restriction in rhesus monkeys". Experimental Gerontology. 38 (1–2): 35–46. PMID 12543259


. doi:10.1016/S0531-5565(02)00146-8



39.              Jump up^ Urbanski, H F.; Downs, J L; Garyfallou, V T; Mattison, J A; Lane, M A; Roth, G S; Ingram, D K (2004). "Effect of Caloric Restriction on the 24-Hour Plasma DHEAS and Cortisol Profiles of Young and Old Male Rhesus Macaques". Annals of the New York Academy of Sciences. 1019: 443–7. PMID 15247063


. doi:10.1196/annals.1297.081



40.              Jump up^ Vaquero, A.; Reinberg, D. (2009). "Calorie restriction and the exercise of chromatin"


. Genes & Development. 23 (16): 1849–69. PMC 2725938


  . PMID 19608767


. doi:10.1101/gad.1807009



41.              Jump up^ "The gene for longevity, if you're a worm"


. ABC News. 2007. Retrieved 2007-05-03.

42.              Jump up^ Gredilla R, Sanz A, Lopez-Torres M, Barja G (2001). "Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart". FASEB J. 15 (9): 1589–1591. PMID 11427495


. doi:10.1096/fj.00-0764fje



43.              Jump up^ Kaneko, T; Tahara, S; Matsuo, M (1997). "Retarding effect of dietary restriction on the accumulation of 8-hydroxy-2'-deoxyguanosine in organs of Fischer 344 rats during aging". Free radical biology & medicine. 23 (1): 76–81. PMID 9165299


. doi:10.1016/s0891-5849(96)00622-3



44.              Jump up^ Bernstein, H., Payne, C.M., Bernstein, C., Garewal, H., Dvorak, K. (2008). Cancer and aging as consequences of unrepaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47.

45.              Jump up^ Guarente, L. (2007). "Sirtuins in aging and disease". Cold Spring Harbor Symposia on Quantitative Biology. 72: 483–488. ISSN 0091-7451


. PMID 18419308


. doi:10.1101/sqb.2007.72.024



46.              ^ Jump up to:a b Lin, Su-Ju; Ford, Ethan; Haigis, Marcia; Liszt, Greg; Guarente, Leonard (2004-01-01). "Calorie restriction extends yeast life span by lowering the level of NADH"


. Genes & Development. 18 (1): 12–16. ISSN 0890-9369


. PMC 314267


  . PMID 14724176


. doi:10.1101/gad.1164804



47.              ^ Jump up to:a b Kaeberlein M.; McVey M.; Guarente L. (1999). "The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. '"


. Genes & Development. 13 (19): 2570–2580. PMC 317077


  . PMID 10521401


. doi:10.1101/gad.13.19.2570



48.              Jump up^ Guarente, Leonard (2000). "Sir2 links chromatin silencing, metabolism, and aging"


. Genes & Development. 14 (9): 1021–1026. ISSN 0890-9369


. PMID 10809662


. doi:10.1101/gad.14.9.1021 (inactive 2017-02-15).

49.              Jump up^ Smith, J. S.; Boeke, J. D. (1997-01-15). "An unusual form of transcriptional silencing in yeast ribosomal DNA."


. Genes & Development. 11 (2): 241–254. ISSN 0890-9369


. PMID 9009206


. doi:10.1101/gad.11.2.241



50.              Jump up^ Margolskee, Jeanne P. (1988-03-01). "The sporulation capable (sca) mutation of Saccharomyces cerevisiae is an allele of the SIR2 gene"


. Molecular and General Genetics MGG. 211 (3): 430–434. ISSN 0026-8925


. doi:10.1007/BF00425696



51.              Jump up^ Tissenbaum, Heidi A.; Guarente, Leonard (March 8, 2001). "Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans"


. Nature. 410 (6825): 227–230. ISSN 0028-0836


. PMID 11242085


. doi:10.1038/35065638



52.              Jump up^ Lin, S. J.; Defossez, P. A.; Guarente, L. (Sep 22, 2000). "Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae". Science. 289 (5487): 2126–2128. Bibcode:2000Sci...289.2126L


. ISSN 0036-8075


. PMID 11000115


. doi:10.1126/science.289.5487.2126



53.              Jump up^ Sinclair, D. A.; Guarente, L. (Dec 26, 1997). "Extrachromosomal rDNA circles--a cause of aging in yeast". Cell. 91 (7): 1033–1042. ISSN 0092-8674


. PMID 9428525


. doi:10.1016/S0092-8674(00)80493-6



54.              ^ Jump up to:a b c Guarente L, Picard F (February 2005). "Calorie Restriction— the SIR2 Connection"


. Cell. 120 (4): 473–482. PMID 15734680


. doi:10.1016/j.cell.2005.01.029


. Retrieved 2015-05-30.

55.              ^ Jump up to:a b Lin, Su-Ju; Kaeberlein, Matt; Andalis, Alex A.; Sturtz, Lori A.; Defossez, Pierre-Antoine; Culotta, Valeria C.; Fink, Gerald R.; Guarente, Leonard (July 18, 2002). "Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration"


. Nature. 418 (6895): 344–348. Bibcode:2002Natur.418..344L


. ISSN 0028-0836


. PMID 12124627


. doi:10.1038/nature00829



56.              Jump up^ Anderson, Rozalyn M.; Bitterman, Kevin J.; Wood, Jason G.; Medvedik, Oliver; Cohen, Haim; Lin, Stephen S.; Manchester, Jill K.; Gordon, Jeffrey I.; Sinclair, David A. (May 24, 2002). "Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels". The Journal of Biological Chemistry. 277(21): 18881–18890. ISSN 0021-9258


. PMID 11884393


. doi:10.1074/jbc.M111773200



57.              Jump up^ Minor, RK; Allard, JS; Younts, CM; Ward, TM; de Cabo, R (July 2010). "Dietary interventions to extend life span and health span based on calorie restriction."


. The journals of gerontology. Series A, Biological sciences and medical sciences. 65(7): 695–703. PMC 2884086


  . PMID 20371545


. doi:10.1093/gerona/glq042



58.              Jump up^ Contestabile, A (2009). "Benefits of caloric restriction on brain aging and related pathological States: understanding mechanisms to devise novel therapies.". Current medicinal chemistry. 16 (3): 350–61. PMID 19149582


. doi:10.2174/092986709787002637



59.              Jump up^ de Magalhães JP, Wuttke D, Wood SH, Plank M, Vora C (2012). "Genome-environment interactions that modulate aging: powerful targets for drug discovery"


. Pharmacol Rev. 64 (1): 88–101. PMC 3250080


  . PMID 22090473


. doi:10.1124/pr.110.004499



60.              Jump up^ Sinclair, David A; Guarente, Leonard (1997). "Extrachromosomal rDNA Circles— A Cause of Aging in Yeast". Cell. 91 (7): 1033–1042. PMID 9428525


. doi:10.1016/S0092-8674(00)80493-6



61.              Jump up^ Cohen, H. Y.; Miller, C; Bitterman, KJ; Wall, NR; Hekking, B; Kessler, B; Howitz, KT; Gorospe, M; et al. (2004). "Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase". Science. 305 (5682): 390–2. Bibcode:2004Sci...305..390C


. PMID 15205477


. doi:10.1126/science.1099196



62.              Jump up^ Picard, Frédéric; Kurtev, Martin; Chung, Namjin; Topark-Ngarm, Acharawan; Senawong, Thanaset; MacHado De Oliveira, Rita; Leid, Mark; McBurney, Michael W.; Guarente, Leonard (2004). "Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ"


. Nature. 429 (6993): 771–6. Bibcode:2004Natur.429..771P


. PMC 2820247


  . PMID 15175761


. doi:10.1038/nature02583



63.              Jump up^ Corton, J. C.; Apte, U; Anderson, SP; Limaye, P; Yoon, L; Latendresse, J; Dunn, C; Everitt, JI; et al. (2004). "Mimetics of Caloric Restriction Include Agonists of Lipid-activated Nuclear Receptors". Journal of Biological Chemistry. 279 (44): 46204–12. PMID 15302862


. doi:10.1074/jbc.M406739200



64.              Jump up^ Howitz, Konrad T.; Bitterman, Kevin J.; Cohen, Haim Y.; Lamming, Dudley W.; Lavu, Siva; Wood, Jason G.; Zipkin, Robert E.; Chung, Phuong; et al. (2003). "Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan". Nature. 425 (6954): 191–6. Bibcode:2003Natur.425..191H


. PMID 12939617


. doi:10.1038/nature01960



65.              Jump up^ Wood, Jason G.; Rogina, Blanka; Lavu, Siva; Howitz, Konrad; Helfand, Stephen L.; Tatar, Marc; Sinclair, David (2004). "Sirtuin activators mimic caloric restriction and delay ageing in metazoans". Nature. 430 (7000): 686–9. Bibcode:2004Natur.430..686W


. PMID 15254550


. doi:10.1038/nature02789



66.              Jump up^ Valenzano, Dario R.; Terzibasi, Eva; Genade, Tyrone; Cattaneo, Antonino; Domenici, Luciano; Cellerino, Alessandro (2006). "Resveratrol Prolongs Lifespan and Retards the Onset of Age-Related Markers in a Short-Lived Vertebrate". Current Biology. 16 (3): 296–300. PMID 16461283


. doi:10.1016/j.cub.2005.12.038



67.              Jump up^ Baur, Joseph A.; Pearson, Kevin J.; Price, Nathan L.; Jamieson, Hamish A.; Lerin, Carles; Kalra, Avash; Prabhu, Vinayakumar V.; Allard, Joanne S.; et al. (2006). "Resveratrol improves health and survival of mice on a high-calorie diet". Nature. 444 (7117): 337–42. Bibcode:2006Natur.444..337B


. PMID 17086191


. doi:10.1038/nature05354



68.              Jump up^ Pearson, Kevin J.; Baur, Joseph A.; Lewis, Kaitlyn N.; Peshkin, Leonid; Price, Nathan L.; Labinskyy, Nazar; Swindell, William R.; Kamara, Davida; et al. (2008). "Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan"


. Cell Metabolism. 8 (2): 157–68. PMC 2538685


  . PMID 18599363


. doi:10.1016/j.cmet.2008.06.011



69.              Jump up^ Bass, T; Weinkove, D; Houthoofd, K; Gems, D; Partridge, L (2007). "Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans". Mechanisms of Ageing and Development. 128 (10): 546–52. PMID 17875315


. doi:10.1016/j.mad.2007.07.007



70.              Jump up^ Pacholec, M.; Bleasdale, J. E.; Chrunyk, B.; Cunningham, D.; Flynn, D.; Garofalo, R. S.; Griffith, D.; Griffor, M.; et al. (2010). "SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1"


. Journal of Biological Chemistry. 285 (11): 8340–51. PMC 2832984


  . PMID 20061378


. doi:10.1074/jbc.M109.088682



71.              Jump up^ Zarse, K.; Schmeisser, S.; Birringer, M.; Falk, E.; Schmoll, D.; Ristow, M. (2010). "Differential Effects of Resveratrol and SRT1720 on Lifespan of AdultCaenorhabditis elegans". Hormone and Metabolic Research. 42 (12): 837–9. PMID 20925017


. doi:10.1055/s-0030-1265225



72.              Jump up^ Kaeberlein, Matt; Kirkland, Kathryn T.; Fields, Stanley; Kennedy, Brian K. (2004). "Sir2-Independent Life Span Extension by Calorie Restriction in Yeast"


. PLoS Biology. 2 (9): e296. PMC 514491


  . PMID 15328540


. doi:10.1371/journal.pbio.0020296



73.              Jump up^ Kaeberlein, M; Powersiii, R (2007). "Sir2 and calorie restriction in yeast: A skeptical perspective". Ageing Research Reviews. 6 (2): 128–40. PMID 17512264


. doi:10.1016/j.arr.2007.04.001



74.              Jump up^ Suspended Resveratrol Clinical Trial: More Details Emerge(May 6, 2010)


75.              Jump up^ Arthur V. Everitt; Leonie K. Heilbronn; David G. Le Couteur. "Food Intake, Life Style, Aging and Human Longevity". In Everitt, Arthur V; Rattan, Suresh IS; Le Couteur, David G; de Cabo, Rafael. Calorie Restriction, Aging and Longevity. New York: Springer. pp. 15–41. ISBN 978-90-481-8555-9.

76.              Jump up^ Schäfer, Daniel (Mar–Apr 2005). "Aging, Longevity, and Diet: Historical Remarks on Calorie Intake Reduction". Gerontology. 51 (2): 126–30. PMID 15711080


. doi:10.1159/000082198



77.              Jump up^ Cava E, Fontana L (2013). "Will calorie restriction work in humans?"


. Aging (Albany NY). 5 (7): 507–14. PMC 3765579


  . PMID 23924667


. doi:10.18632/aging.100581



78.              Jump up^ "NIH study finds calorie restriction lowers some risk factors for age-related diseases"


. National Institute on Aging, US National Institutes of Health, Bethesda, MD. September 2015.

79.              ^ Jump up to:a b "Calorie restriction lets monkeys live long and prosper"


. ScienceDirect. 17 January 2017. Retrieved 15 February 2017.

80.              Jump up^ Spindler, S (2005). "Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction". Mechanisms of Ageing and Development. 126(9): 960–6. PMID 15927235


. doi:10.1016/j.mad.2005.03.016



81.              Jump up^ Kaeberlein, Matt; Burtner, Christopher R.; Kennedy, Brian K. (2007). "Recent Developments in Yeast Aging"


. PLoS Genetics. 3 (5): e84. PMC 1877880


  . PMID 17530929


. doi:10.1371/journal.pgen.0030084



82.              Jump up^ Dilova, I.; Easlon, E.; Lin, S. -J. (2007). "Calorie restriction and the nutrient sensing signaling pathways". Cellular and Molecular Life Sciences. 64 (6): 752–67. PMID 17260088


. doi:10.1007/s00018-007-6381-y



83.              Jump up^ Chen, D; Guarente, L (2007). "SIR2: a potential target for calorie restriction mimetics". Trends in Molecular Medicine. 13 (2): 64–71. PMID 17207661


. doi:10.1016/j.molmed.2006.12.004



84.              Jump up^ Piper, Peter W. (2006). "Long-lived yeast as a model for ageing research". Yeast. 23 (3): 215–26. PMID 16498698


. doi:10.1002/yea.1354



85.              Jump up^ Longo, V (2009). "Linking sirtuins, IGF-I signaling, and starvation". Experimental Gerontology. 44 (1–2): 70–4. PMID 18638538


. doi:10.1016/j.exger.2008.06.005



86.              Jump up^ Schleit J.; Wasko B.M.; Kaeberlein M. (2012). "Yeast as a model to understand the interaction between genotype and the response to calorie restriction"


. FEBS Lett. 586 (18): 2868–2873. PMC 4016815


  . PMID 22828279


. doi:10.1016/j.febslet.2012.07.038



87.              ^ Jump up to:a b c d e f Weiss, EP; Fontana, L (Oct 2011). "Caloric restriction: powerful protection for the aging heart and vasculature"


. Am J Physiol Heart Circ Physiol. 301 (4): H1205–19. PMC 3197347


  . PMID 21841020


. doi:10.1152/ajpheart.00685.2011


. Retrieved 27 August 2014.

88.              ^ Jump up to:a b Calle EE, Kaaks R (Aug 2004). "Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms". Nat Rev Cancer. 4 (8): 579–91. PMID 15286738


. doi:10.1038/nrc1408



89.              ^ Jump up to:a b McKiernan, SH; Colman, RJ; Aiken, E; Evans, TD; Beasley, TM; Aiken, JM; Weindruch, R; Anderson, RM (Mar 2012). "Cellular adaptation contributes to calorie restriction-induced preservation of skeletal muscle in aged rhesus monkeys"


. Exp Gerontol. 47 (3): 229–36. PMC 3321729


  . PMID 22226624


. doi:10.1016/j.exger.2011.12.009



90.              Jump up^ Colman, RJ; Beasley, TM; Allison, DB; Weindruch, R (2008). "Attenuation of Sarcopenia by Dietary Restriction in Rhesus Monkeys"


. The journals of gerontology. Series A, Biological sciences and medical sciences. 63 (6): 556–9. PMC 2812805


  . PMID 18559628


. doi:10.1093/gerona/63.6.556



91.              ^ Jump up to:a b Dirks Naylor, AJ; Leeuwenburgh, C (Jan 2008). "Sarcopenia: the role of apoptosis and modulation by caloric restriction". Exerc Sport Sci Rev. 36 (1): 19–24. PMID 18156949


. doi:10.1097/jes.0b013e31815ddd9d



92.              ^ Jump up to:a b Bua, E; McKiernan, SH; Aiken, JM (Mar 2004). "Calorie restriction limits the generation but not the progression of mitochondrial abnormalities in aging skeletal muscle". FASEB J. 18 (3): 582–4. PMID 14734641


. doi:10.1096/fj.03-0668fje



93.              Jump up^ Cerletti, M; Jang, YC; Finley3=LW; Haigis 4=MC; Wagers 5=AJ (May 4, 2012). "Short-term calorie restriction enhances skeletal muscle stem cell function"


. Cell Stem Cell. 10 (5): 515–9. PMC 3561899


  . PMID 22560075


. doi:10.1016/j.stem.2012.04.002



94.              ^ Jump up to:a b Faulks, SC; Turner, N; Else, PL; Hulbert, AJ (Aug 2006). "Calorie restriction in mice: effects on body composition, daily activity, metabolic rate, mitochondrial reactive oxygen species production, and membrane fatty acid composition". J Gerontol a Biol Sci Med Sci. 61 (8): 781–94. PMID 16912094


. doi:10.1093/gerona/61.8.781



95.              ^ Jump up to:a b Means L. W.; Higgins J. L.; Fernandez T. J. (1993). "Mid-life onset of dietary restriction extends life and prolongs cognitive functioning". Physiology & Behavior. 54 (3): 503–508. doi:10.1016/0031-9384(93)90243-9



96.              ^ Jump up to:a b c Vitousek K. M.; Manke F. P.; Gray J. A.; Vitousek M. N. (2004). "Caloric Restriction for Longevity: II--The Systematic Neglect of Behavioural and Psychological Outcomes in Animal Research". European Eating Disorders Review. 12 (6): 338–360. doi:10.1002/erv.604



97.              Jump up^ Phelan, J; Rose, M (2005). "Why dietary restriction substantially increases longevity in animal models but won't in humans". Ageing Research Reviews. 4 (3): 339–50. PMID 16046282


. doi:10.1016/j.arr.2005.06.001



98.              Jump up^ "calorie restriction can increase maximum life span of all the creatures in which it's been tested, by anywhere from 40 to 60 percent on extreme versions of calorie restriction. Several studies in humans commenced in 2002, and even the short-term changes in the subjects' biomarkers already match those observed in other animal species that have been studied at length, which strongly suggests that the calorie restriction effect is truly universal in the animal kingdom." pg 23 in The Longevity Diet 2 ed. by Brian Delaney and Lisa Walford

99.              Jump up^ Weed J. L.; Lane M. A.; Roth G. S.; Speer D. L.; Ingram D. K. (1997). "Activity measures in rhesus monkeys on long-term calorie restriction". Physiology & Behavior. 62: 97–103. doi:10.1016/s0031-9384(97)00147-9



100.            Jump up^ Sohala Rajindar S.; Forster Michael J. (2014). "Caloric restriction and the aging process: a critique"


. Free Radical Biology and Medicine. 73: 366–382. doi:10.1016/j.freeradbiomed.2014.05.015