Metabolic Effects of Caloric Restriction


Caloric restriction (CR) is a dietary intervention that robustly extends lifespan in diverse species. In mammals CR extends the period in which the animal is fit and vigorous, and attenuates age‐related disease vulnerability. Benefits of CR include reduced incidence of cancer, improved cardiovascular health, increased insulin sensitivity, and resistance to neurodegenerative diseases. The fact that CR extends not only average lifespan but also maximum lifespan has led to the consensus that an optimised CR diet slows the aging process itself. Here we outline the effects of CR on physiology and metabolism and where these may fit with current theories of aging. The authors describe factors that are likely to mediate the physiological adaptations to CR, placing an emphasis on nutrient sensitive regulators of metabolism. A major incentive for research into the mechanisms of CR is the promise of novel treatments for age‐related diseases and disorders that are relevant to human aging.

Key Concepts:

  • CR has a system‐wide physiological impact.

  • Metabolic factors are responsive to CR.

  • Metabolism and aging are tightly linked.

  • Growth factor signalling impacts metabolism.

  • CR research is highly relevant for human aging.

Keywords: caloric restriction; metabolism; aging; longevity; sirtuins; AMPK; mTOR

Figure 1.

Simplified model of metabolic reprogramming by CR. Reduction in calorie intake extends lifespan suggesting an inverse relationship between energy and aging rate. This simple model predicts that a reduction in calorie intake induces differences in nutrient and energetic status (signals) that are detected by nutrient and energy sensitive factors (effectors) that regulate in the balance of energy use and energy sparing (outcomes). Regulation through systemic growth factors is superimposed on these cellular pathways, that together lead to changes in metabolism, growth, and energy sparing. How these changes translate to delayed aging and prevention of age‐related diseases is yet to be resolved.

Figure 2.

Diverse cellular functions regulated by sirtuins. The actions of the sirtuin family of posttranslational modification enzymes are coupled to metabolism due to their requirement for NAD as a cosubstrate. There are 7 mammalian sirtuins that populate distinct subcellular compartments, and mediate regulation of diverse metabolic processes including (1) metabolic enzymes – enzymes involved in multiple aspects of metabolism that are direct targets of sirtuin activity; (2) gene expression – regulation of transcription factors, coactivators, and regulatory factors; (3) structure – broad impact on the microtubule cytoskeleton and more specifically localised impact in chromatin; and (4) inflammation – direct regulation of NfκB inflammatory pathway.

Figure 3.

Integration of growth and nutrient signalling pathways through mTOR. Growth signalling and nutrient sensing are among the inputs that activate the mTOR signalling pathway. mTOR impinges on multiple key processes including protein synthesis, ribosome biogenesis, and autophagy, as part of the anabolic response. Crosstalk between the mTOR and the insulin signalling pathways is complex, with feedback inhibition of insulin signalling mediated in part by mTORC1‐dependent phosphorylation of insulin receptor interacting proteins.



Anderson R and Prolla T (2009) PGC‐1alpha in aging and anti‐aging interventions. Biochimica et Biophysica Acta 1790: 1059–1066.

Anderson RM, Bitterman KJ, Wood JG, Medvedik O and Sinclair DA (2003) Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423: 181–185.

Anderson RM and Weindruch R (2010) Metabolic reprogramming, caloric restriction and aging. Trends in Endocrinology & Metabolism 21: 134–141.

Bar‐Peled L and Sabatini DM (2014) Regulation of mTORC1 by amino acids. Trends in Cell Biology 24(7): 400–406.

Bartke A, Sun LY and Longo V (2013) Somatotropic signaling: trade‐offs between growth, reproductive development, and longevity. Physiological Reviews 93: 571–598.

Baur JA, Chen D, Chini EN et al. (2010) Dietary restriction: standing up for sirtuins. Science 329: 1012–1013.

Baur JA, Pearson KJ, Price NL et al. (2006) Resveratrol improves health and survival of mice on a high‐calorie diet. Nature 444: 337–342.

Ben‐Sahra I, Howell JJ, Asara JM and Manning BD (2013) Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339: 1323–1328.

Bjedov I, Toivonen JM, Kerr F et al. (2010) Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metabolism 11: 35–46.

Bodkin NL, Alexander TM, Ortmeyer HK, Johnson E and Hansen BC (2003) Mortality and morbidity in laboratory‐maintained Rhesus monkeys and effects of long‐term dietary restriction. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 58: 212–219.

Boily G, Seifert EL, Bevilacqua L et al. (2008) SirT1 regulates energy metabolism and response to caloric restriction in mice. PloS One 3: e1759.

Bruss MD, Khambatta CF, Ruby MA, Aggarwal I and Hellerstein MK (2010) Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates. American Journal of Physiology – Endocrinology and Metabolism 298: E108–E116.

Buler M, Aatsinki SM, Izzi V, Uusimaa J and Hakkola J (2014) SIRT5 is under the control of PGC‐1alpha and AMPK and is involved in regulation of mitochondrial energy metabolism. FASEB Journal 28: 3225–3237.

Canto C and Auwerx J (2010) AMP‐activated protein kinase and its downstream transcriptional pathways. Cellular and Molecular Life Sciences: CMLS 67: 3407–3423.

Colman RJ, Anderson RM, Johnson SC et al. (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325: 201–204.

Colman RJ, Beasley TM, Kemnitz JW et al. (2014) Caloric restriction reduces age‐related and all‐cause mortality in rhesus monkeys. Nature Communications 5: 3557.

Csibi A, Fendt SM, Li C et al. (2013) The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153: 840–854.

Dominy JE Jr, Lee Y, Jedrychowski MP et al. (2012) The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Molecular Cell 48: 900–913.

Du J, Zhou Y, Su X et al. (2011) Sirt5 is a NAD‐dependent protein lysine demalonylase and desuccinylase. Science 334: 806–807.

Edwards MG, Anderson RM, Yuan M et al. (2007) Gene expression profiling of aging reveals activation of a p53‐mediated transcriptional program. BMC Genomics 8: 80.

Feldman JL, Baeza J and Denu JM (2013) Activation of the protein deacetylase SIRT6 by long‐chain fatty acids and widespread deacylation by mammalian sirtuins. Journal of Biological Chemistry 288: 31350–31356.

Fok WC, Bokov A, Gelfond J et al. (2013) Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver. Aging Cell 13: 311–319.

Fontana L, Partridge L and Longo VD (2010) Extending healthy life span – from yeast to humans. Science 328: 321–326.

Geng YQ, Li TT, Liu XY, Li ZH and Fu YC (2011) SIRT1 and SIRT5 activity expression and behavioral responses to calorie restriction. Journal of Cellular Biochemistry 112: 3755–3761.

Hallows WC, Yu W, Smith BC et al. (2011) Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Molecular Cell 41: 139–149.

Hebert AS, Dittenhafer-Reed KE, Yu W et al. (2013) Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Molecular Cell 49: 186–199.

Hirschey MD, Shimazu T, Huang JY, Schwer B and Verdin E (2011) SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism. Cold Spring Harbor Symposia on Quantitative Biology 76: 267–277.

Hsu PP, Kang SA, Rameseder J et al. (2011) The mTOR‐regulated phosphoproteome reveals a mechanism of mTORC1‐mediated inhibition of growth factor signaling. Science 332: 1317–1322.

Iwabu M, Yamauchi T, Okada-Iwabu M et al. (2010) Adiponectin and AdipoR1 regulate PGC‐1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 464: 1313–1319.

Johnston O, Rose CL, Webster AC and Gill JS (2008) Sirolimus is associated with new‐onset diabetes in kidney transplant recipients. Journal of the American Society of Nephrology 19: 1411–1418.

Kanfi Y, Naiman S, Amir G et al. (2012) The sirtuin SIRT6 regulates lifespan in male mice. Nature 483: 218–221.

Kenyon C (2001) A conserved regulatory mechanism for aging. Cell 105: 165–168.

Lamming DW, Ye L, Katajisto P et al. (2012) Rapamycin‐induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335: 1638–1643.

Lamming DW, Ye L, Astle CM et al. (2013) Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive. Aging Cell 12: 712–718.

Lamming DW and Sabatini DM (2013) A central role for mTOR in lipid homeostasis. Cell Metabolism 18: 465–469

Larson‐Meyer DE, Heilbronn LK, Redman LM et al. (2006) Effect of calorie restriction with or without exercise on insulin sensitivity, beta‐cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care 29: 1337–1344.

Laurent G, German NJ, Saha AK et al. (2013) SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Molecular Cell 50: 686–698.

Lefevre M, Redman LM, Heilbronn LK et al. (2008) Caloric restriction alone and with exercise improves CVD risk in healthy non‐obese individuals. Atherosclerosis 203: 206–213.

Lewis KN, Andziak B, Yang T and Buffenstein R (2013) The naked mole‐rat response to oxidative stress: just deal with it. Antioxidants & Redox Signaling 19: 1388–1399.

Martin‐Montalvo A, Mercken EM, Mitchell SJ et al. (2013) Metformin improves healthspan and lifespan in mice. Nature Communications 4: 2192.

Masoro EJ (2009) Caloric restriction‐induced life extension of rats and mice: a critique of proposed mechanisms. Biochimica et Biophysica Acta 1790: 1040–1048.

Mattison JA, Roth GS, Beasley TM et al. (2012) Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489: 318–321.

McCay CM, Crowell MF and Maynard LA (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size. Journal of Nutrition 10: 63–79.

Mercken EM, Hu J, Krzysik-Walker S et al. (2014) SIRT1 but not its increased expression is essential for lifespan extension in caloric‐restricted mice. Aging Cell 13: 193–196.

Miller RA, Harrison DE, Astle CM et al. (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 66: 191–201.

Miller RA, Harper JM, Galecki A and Burke DT (2002) Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice. Aging Cell 1: 22–29.

Minor RK, Lopez M, Younts CM et al. (2011) The arcuate nucleus and neuropeptide Y contribute to the antitumorigenic effect of calorie restriction. Aging Cell 10: 483–492.

Mitchell SJ, Martin-Montalvo A, Mercken EM et al. (2014) The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Reports 6: 836–843.

Nasrin N, Wu X, Fortier E et al. (2010) SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. Journal of Biological Chemistry 285: 31995–32002.

Newman JC, He W and Verdin E (2012) Mitochondrial protein acylation and intermediary metabolism: regulation by sirtuins and implications for metabolic disease. Journal of Biological Chemistry 287: 42436–42443.

de Oliveira RM, Sarkander J, Kazantsev AG and Outeiro TF (2012) SIRT2 as a therapeutic target for age‐related disorders. Frontiers in Pharmacology 3: 82.

Pawlikowska L, Hu D, Huntsman S et al. (2009) Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8: 460–472.

Pearson KJ, Baur JA, Lewis KN et al. (2008) Resveratrol delays age‐related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metabolism 8: 157–168.

Perez VI, Bokov A, Van Remmen H et al. (2009) Is the oxidative stress theory of aging dead? Biochimica et Biophysica Acta 1790: 1005–1014.

Plank M, Wuttke D, van Dam S, Clarke SA and de Magalhaes JP (2012) A meta‐analysis of caloric restriction gene expression profiles to infer common signatures and regulatory mechanisms. Molecular Biosystems 8: 1339–1349.

Qiu X, Brown K, Hirschey MD, Verdin E and Chen D (2010) Calorie restriction reduces oxidative stress by SIRT3‐mediated SOD2 activation. Cell Metabolism 12: 662–667.

Rezzi S, Martin FP, Shanmuganayagam D et al. (2009) Metabolic shifts due to long‐term caloric restriction revealed in nonhuman primates. Experimental Gerontology 44: 356–362.

Ristow M and Zarse K (2010) How increased oxidative stress promotes longevity and metabolic health: THE concept of mitochondrial hormesis (mitohormesis). Experimental Gerontology 45: 410–418.

Rochon J, Bales CW, Ravussin E et al. (2011) Design and conduct of the CALERIE study: comprehensive assessment of the long‐term effects of reducing intake of energy. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 66: 97–108.

Selman C, McLaren JS, Collins AR, Duthie GG and Speakman JR (2013) Deleterious consequences of antioxidant supplementation on lifespan in a wild‐derived mammal. Biology Letters 9: 20130432.

Someya S, Yu W, Hallows WC et al. (2010) Sirt3 mediates reduction of oxidative damage and prevention of age‐related hearing loss under caloric restriction. Cell 143: 802–812.

Song J, Ke SF, Zhou CC et al. (2014) Nicotinamide phosphoribosyltransferase is required for the calorie restriction‐mediated improvements in oxidative stress, mitochondrial biogenesis, and metabolic adaptation. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 69: 44–57.

Swindell WR (2009) Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse. BMC Genomics 10: 585.

Tan M , Peng C, Anderson KA et al. (2014) Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metabolism 19: 605–617.

Um JH, Park SJ, Kang H et al. (2010) AMP‐activated protein kinase‐deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59: 554–563.

Uno H (1997) Age‐related pathology and biosenescent markers in captive rhesus macaques. Age 20: 1–13.

Wang YP, Zhou LS, Zhao YZ et al. (2014) Regulation of G6PD acetylation by KAT9/SIRT2 modulates NADPH homeostasis and cell survival during oxidative stress. EMBO Journal 33: 1304–1320.

Weiss EP, Racette SB, Villareal DT et al. (2006) Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial. American Journal of Clinical Nutrition 84: 1033–1042.

Xu J, Gontier G, Chaker Z et al. (2014) Longevity effect of IGF‐1R(+/−) mutation depends on genetic background‐specific receptor activation. Aging Cell 13: 19–28.

Xu Y, Li F, Lv L et al. (2014) Oxidative stress activates SIRT2 to deacetylate and stimulate phosphoglycerate mutase. Cancer Research 74: 3630–3642.

Yamada Y, Colman RJ, Kemnitz JW et al. (2013) Long‐term calorie restriction decreases metabolic cost of movement and prevents decrease of physical activity during aging in rhesus monkeys. Experimental Gerontology 48: 1226–1235.

Yilmaz OH, Katajisto P, Lamming DW et al. (2012) mTORC1 in the Paneth cell niche couples intestinal stem‐cell function to calorie intake. Nature 486: 490–495.

Yuan R, Tsaih SW, Petkova SB et al. (2009) Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 8: 277–287.

Further Reading

Anderson RM and Weindruch R (2012) The caloric restriction paradigm: implications for healthy human aging. American Journal of Human Biology 24: 101–106.

Feige JN and Auwerx J (2007) Transcriptional coregulators in the control of energy homeostasis. Trends in Cell Biology 17: 292–301.

Houtkooper RH, Pirinen E and Auwerx J (2012) Sirtuins as regulators of metabolism and healthspan. Nature Reviews Molecular Cell Biology 13: 225–238.

Kemnitz JW (2011) Calorie restriction and aging in nonhuman primates. ILAR Journal 52: 66–77.

Lamming DW, Ye L, Sabatini DM and Baur JA (2013) Rapalogs and mTOR inhibitors as anti‐aging therapeutics. Journal of Clinical Investigation 123: 980–989.

Laplante M and Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149: 274–293.

Lopez‐Otin C, Blasco MA, Partridge L, Serrano M and Kroemer G (2013) The hallmarks of aging. Cell 153: 1194–1217.

Lu C and Thompson CB (2012) Metabolic regulation of epigenetics. Cell Metabolism 16: 9–17.

Osborn O and Olefsky JM (2012) The cellular and signalling networks linking the immune system and metabolism in disease. Nature Medicine 18: 363–374.

Tseng YH, Cypess AM and Kahn CR (2010) Cellular bioenergetics as a target for obesity therapy. Nature Reviews. Drug Discovery 9: 465–482.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Lamming, Dudley W, and Anderson, Rozalyn M(Oct 2014) Metabolic Effects of Caloric Restriction. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021316.pub2]