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calorie restriction; dietary restriction; food restriction

Restriction of dietary caloric intake. Comparative biology: - calorie restriction slows the rate of aging in rodents & delays onset of diseases of old age, including malignancies [1] - disparate findings in longevity studies examining effect of calorie restriction (CR) in rhesus monkeys - NIA study found no increase in survival with CR [15] - Wisconsin study found an increase in survival with CR [16] Clinical trials: [10] - short-term study of 3 months: - 30% calorie restriction improved memory in elderly women - there are no long-term controlled studies in humans (also see weight reduction) [13] - a randomized controlled trial of calorie restriction as a treatment for cancer has been approved by the institutional review board at Duke University Laboratory: Biomarkers associated calorie restriction include: 1) diminished body temperature 2) diminished mean plasma insulin 3) decreased DNA damage* [4] * DNA damage measured by comet tail moment Inconsistent or negative effects of calorie restriction 1) increased plasma dehydroepiandrosterone sulfate (DHEA-sulfate), no change [4] 2) protein carbonyls [4] 3) fasting serum glucose [4] Biochemistry: - eNoSC complex may play a role - in mammals, calorie restriction activates Sirt1 & Sirt3 - expressed Sirt1 protein inhibits PPAR-gamma; the effect is lipolysis [6,7] - SIRT1 appears to be a component of the eNoSC complex that mediates silencing of rDNA in response to intracellular energy status - calorie restriction may inhibit Alzheimer's disease amyloid pathology via activation of SIRT1, inhibition of ROCK1 & activation of alpha-secretase [9] - nutrient/energy sensing function of mTOR & associated complexes TORC1 & TORC2 may play role - increased AMP kinase (AMPK) activity in hepatocytes [12] during calorie restriction - AMPK may sense energy status as a downstream target of the mTOR pathway - ULK1 & ULK1 interact with mTOR & AMPK as part of regulatory feedback loop in autophagy - under nutrient sufficiency, ULK1 is phosphorylated by mTOR, disrupting the interaction with AMPK & preventing activation of ULK1 (putative) - in response to nutrient limitation, ULK1 is phosphorylated & activated by AMPK, leading to autophagy activation - in response to nutrient sufficiency ULK1 is phosphorylated by mTOR, disrupting the interaction with AMPK & preventing activation of ULK1 - ULK2 acts both as a downstream effector & negative regulator of mTORC1 via interaction with RPTOR - ULK2 is activated via phosphorylation by AMPK - ULK2 also acts as a regulator of AMPK by mediating phosphorylation of AMPK subunits PRKAA1, PRKAB2 & PRKAG1, negatively regulating AMPK activity - metformin increases the activity of AMPK & extends life span of female mice [12] - SIRT2 deacetylates FOXO3a in response to calorie restriction [8] - in C elegans, the longevity of calorie restriction is linked to PHA-4.; orthologous genes in humans encode the Foxa family of transcription factors Foxa1, Foxa2 & Foxa3 [5] Notes: - according to [14], results in loss of muscle mass in obese elderly thus is less preferable to exercise alone for weight reduction - outcomes not considered

Related

very low-calorie diet (VLCD) weight reduction; intentional weight loss; excess weight reduction

General

nutritional therapy

Figures/Diagrams

Effects of Calorie Restriction on Rodents, Overview Neuroendocrine aging & CR in primates

References

  1. The Retardation of Aging and Disease by Dietary Restriction, Weindruch R & Walford RL, Charles C Thomas Publisher, Springfield, IL, 1988
  2. Journal Watch 22(18):142, 2002 Roth GS et al, Science 297:811, 2002
  3. Hursting SD et al, Calorie Restriction, Aging, and Cancer Preventrion: Mechanisms of Action and Applicability to Humans, Ann Rev Med 54:131, 2003 http://med.annualreviews.org/cgi/content/full/54/1/131
  4. Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson-Meyer DE, Rood J, Nguyen T, Martin CK, Volaufova J, Most MM, Greenway FL, Smith SR, Deutsch WA, Williamson DA, Ravussin E; Pennington CALERIE Team. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA. 2006 Apr 5;295(13):1539-48. PMID: 16595757
  5. Panowski SH, Wolff S, Aguilaniu H, Durieux J, Dillin A. PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans. Nature. 2007 May 2; [Epub ahead of print] PMID: 17476212
  6. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004 Jul 16;305(5682):390-2. Epub 2004 Jun 17. PMID: 15205477 - Wolf G Calorie restriction increases life span: a molecular mechanism. Nutr Rev 2006, 64:89 PMID: 16536186
  7. Shi T, Wang F, Stieren E, Tong Q. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J Biol Chem. 2005 Apr 8;280(14):13560-7. Epub 2005 Jan 14. PMID: 15653680
  8. Wang F, Nguyen M, Qin FX, Tong Q. SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell. 2007 Aug;6(4):505-14. Epub 2007 May 23. PMID: 17521387
  9. Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem. 2006 Aug 4;281(31):21745-54. Epub 2006 Jun 2. PMID: 16751189
  10. Witte AV et al. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A 2009 Jan 27; 106:1255. PMID: 19171901
  11. Haigis MC, Guarente LP. Mammalian sirtuins - emerging roles in physiology, aging and calorie restriction. Genes Dev 2006; 20:2913-2921 PMID: 17079682
  12. Kapahi P, Vijg J. Aging - Lost in Translation? N Engl J Med 2009; 361:2669-2670; December 31, 2009 PMID: 20042759
  13. Mulcahy M Medscope Oncology. Feb 01, 2013 Calorie Restriction to Treat Cancer: The Time Is Now http://www.medscape.com/viewarticle/778613?nlid=27803_331&src=wnl_edit_medn_honc&spon=7
  14. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  15. Mattison JA, Roth GS, Beasley TM et al Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature. 2012 Sep 13;489(7415):318-21 PMID: 22932268
  16. Colman RJ, Beasley TM, Kemnitz JW et al Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun. 2014 Apr 1;5:3557 PMID: 24691430 - Colman RJ, Anderson RM, Johnson SC et al Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009 Jul 10;325(5937):201-4. PMID: 19590001
  17. Martin CK, Bhapkar M, Pittas AG et al Effect of Calorie Restriction on Mood, Quality of Life, Sleep, and Sexual Function in Healthy Nonobese Adults. The CALERIE 2 Randomized Clinical Trial. JAMA Intern Med. Published online May 02, 2016 PMID: 27136347 http://archinte.jamanetwork.com/article.aspx?articleid=2517920