Effect of 6-mo. calorie restriction on biomarkers of longevity, metabolic adaptation and oxidative stress in overweight subjects
Abstract
Context
Prolonged calorie restriction (CR) increases lifespan in rodents. Whether prolonged CR affects biomarkers of longevity, markers of oxidative stress, and reduces metabolic rate, beyond that expected from reduced metabolic mass, has not previously been tested in humans.
Objectives
To examine the effects of 6 months of calorie restriction, with or without exercise in nonobese (25≤BMI<30) humans.
Design, Setting, and Participants
Healthy, sedentary men and women (n=48) were randomized to one of four groups for 6-mo; Control=100% of energy requirements; CR=25% diet restriction; CREX=12.5%CR+12.5% increase in energy expenditure; LCD=low calorie diet until 15% weight reduction followed by weight maintenance.
Main Outcome Measures
Body composition, dehydroepiandrosterone sulfate (DHEAS), glucose, insulin, protein carbonyls, DNA damage, 24h energy expenditure (24h-EE, metabolic chamber) and core body temperature.
Results
Weight change at M6 was -1.0(1.1)% (Control), -10.4(0.9)% (CR), -10.0(0.8)% (CREX), -13.9(0.7)% (LCD). At M6, fasting insulin was reduced from baseline in CR, CREX and LCD groups (all, p<0.01), whereas DHEAS and glucose were unchanged. Core temperature was reduced in CR by 0.2(0.05)°C and by 0.3(0.08)°C in CREX (both, p<0.05). After adjustment for changes in body composition, sedentary 24h-EE was unchanged in controls (-18(52) kcal/d; p>0.05), but decreased in CR (-135(42)kcal/d), CREX (-117(52)kcal/d) and LCD (-125(35)kcal/d, (all, p<0.008). These “metabolic adaptations” (~6% more than expected based on loss of metabolic mass) were statistically different from controls (p<0.05). DNA damage was also reduced from baseline in CR, CREX and LCD groups at M6 (p≤ 0.002).
Conclusion
These results show that two previously reported biomarkers of longevity (fasting insulin and body temperature) are reduced by prolonged CR in humans and support the theory that metabolic rate is reduced beyond the level expected for reduced metabolic body size. Studies of longer duration are now required to determine if CR attenuates the aging process in humans.
Literature Cited
References
- 1. Weindruch R, Walford RL, Fligiel S, Guthrie DThe retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986 Apr;116(4):641–654.[PubMed][Google Scholar]
- 2. Roth GS, Ingram DK, Black A, Lane MAEffects of reduced energy intake on the biology of aging: the primate model. Eur J Clin Nutr. 2000 Jun;54(Suppl 3):S15–20.[PubMed][Google Scholar]
- 3. Roth GS, Mattison JA, Ottinger MA, Chachich ME, Lane MA, Ingram DKAging in rhesus monkeys: relevance to human health interventions. Science. 2004 Sep 3;305(5689):1423–1426.[PubMed][Google Scholar]
- 4. Heilbronn LK, Ravussin ECalorie restriction and aging: review of the literature and implications for studies in humans. Am J Clin Nutr. 2003 Sep;78(3):361–369.[PubMed][Google Scholar]
- 5. Ravussin E, Bogardus CRelationship of genetics, age, and physical fitness to daily energy expenditure and fuel utilization. Am J Clin Nutr. 1989 May;49(5 Suppl):968–975.[PubMed][Google Scholar]
- 6. Leibel RL, Rosenbaum M, Hirsch JChanges in energy expenditure resulting from altered body weight. N Engl J Med. 1995 Mar 9;332(10):621–628.[PubMed][Google Scholar]
- 7. Blanc S, Schoeller D, Kemnitz J, et al Energy expenditure of rhesus monkeys subjected to 11 years of dietary restriction. J Clin Endocrinol Metab. 2003 Jan;88(1):16–23.[PubMed][Google Scholar]
- 8. DeLany JP, Hansen BC, Bodkin NL, Hannah J, Bray GALong-term calorie restriction reduces energy expenditure in aging monkeys. J Gerontol A Biol Sci Med Sci. 1999 Jan;54(1):B5–11. discussion B12-13. [[PubMed][Google Scholar]
- 9. Ballor DLEffect of dietary restriction and/or exercise on 23-h metabolic rate and body composition in female rats. J Appl Physiol. 1991 Sep;71(3):801–806.[PubMed][Google Scholar]
- 10. Dulloo AG, Girardier L24 hour energy expenditure several months after weight loss in the underfed rat: evidence for a chronic increase in whole-body metabolic efficiency. Int J Obes Relat Metab Disord. 1993 Feb;17(2):115–123.[PubMed][Google Scholar]
- 11. McCarter R, Masoro EJ, Yu BPDoes food restriction retard aging by reducing the metabolic rate? Am J Physiol. 1985 Apr;248(4 Pt 1):E488–490.[PubMed][Google Scholar]
- 12. McCarter RJ, Palmer JEnergy metabolism and aging: a lifelong study of Fischer 344 rats. Am J Physiol. 1992 Sep;263(3 Pt 1):E448–452.[PubMed][Google Scholar]
- 13. Selman C, Phillips T, Staib JL, Duncan JS, Leeuwenburgh C, Speakman JREnergy expenditure of calorically restricted rats is higher than predicted from their altered body composition. Mech Ageing Dev. 2005 Jun-Jul;126(67):783–793.[PubMed][Google Scholar]
- 14. Harman DAging: A theory based on free radical radiation chemistry. J Gerontol. 1956;11:298–300.[PubMed][Google Scholar]
- 15. Chance B, Sies H, Boveris AHydroperoxide metabolism in mammalian organs. Physiol Rev. 1979 Jul;59(3):527–605.[PubMed][Google Scholar]
- 16. St-Pierre J, Buckingham JA, Roebuck SJ, Brand MDTopology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem. 2002 Nov 22;277(47):44784–44790.[PubMed][Google Scholar]
- 17. Halliwell BaJMCG Free Radicals in Biology and Medicine. New York: Oxford University Press; 1999. [PubMed][Google Scholar]
- 18. de Oliveira SL, Diniz DB, Amaya-Farfan JCarbohydrate-energy restriction may protect the rat brain against oxidative damage and improve physical performance. Br J Nutr. 2003 Jan;89(1):89–96.[PubMed][Google Scholar]
- 19. Drew B, Phaneuf S, Dirks A, et al Effects of aging and caloric restriction on mitochondrial energy production in gastrocnemius muscle and heart. Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R474–480.[PubMed][Google Scholar]
- 20. Dubey A, Forster MJ, Lal H, Sohal RSEffect of age and caloric intake on protein oxidation in different brain regions and on behavioral functions of the mouse. Arch Biochem Biophys. 1996 Sep 1;333(1):189–197.[PubMed][Google Scholar]
- 21. Sohal RS, Agarwal S, Candas M, Forster MJ, Lal HEffect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech Ageing Dev. 1994 Oct 20;76(23):215–224.[PubMed][Google Scholar]
- 22. Zainal TA, Oberley TD, Allison DB, Szweda LI, Weindruch RCaloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle. Faseb J. 2000 Sep;14(12):1825–1836.[PubMed][Google Scholar]
- 23. Lee CK, Klopp RG, Weindruch R, Prolla TAGene expression profile of aging and its retardation by caloric restriction. Science. 1999 Aug 27;285(5432):1390–1393.[PubMed][Google Scholar]
- 24. Kayo T, Allison DB, Weindruch R, Prolla TAInfluences of aging and caloric restriction on the transcriptional profile of skeletal muscle from rhesus monkeys. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5093–5098.[Google Scholar]
- 25. Lane MA, Baer DJ, Tilmont EM, et al Energy balance in rhesus monkeys (Macaca mulatta) subjected to long-term dietary restriction. J Gerontol A Biol Sci Med Sci. 1995 Sep;50(5):B295–302.[PubMed][Google Scholar]
- 26. Roth GS, Lane MA, Ingram DK, et al Biomarkers of caloric restriction may predict longevity in humans. Science. 2002 Aug 2;297(5582):811.[PubMed][Google Scholar]
- 27. Fontana L, Meyer TE, Klein S, Holloszy JOLong-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6659–6663.[Google Scholar]
- 28. DeLany JP, Schoeller DA, Hoyt RW, Askew EW, Sharp MAField use of D2 18O to measure energy expenditure of soldiers at different energy intakes. J Appl Physiol. 1989 Nov;67(5):1922–1929.[PubMed][Google Scholar]
- 29. Schoeller DAMeasurement of energy expenditure in free-living humans by using doubly labeled water. J Nutr. 1988 Nov;118(11):1278–1289.[PubMed][Google Scholar]
- 30. Mates JM, Perez-Gomez C, Olalla L, Segura JM, Blanca MAllergy to drugs: antioxidant enzymic activities, lipid peroxidation and protein oxidative damage in human blood. Cell Biochem Funct. 2000 Jun;18(2):77–84.[PubMed][Google Scholar]
- 31. Nguyen T, de Jonge L, Smith SR, Bray GAChamber for indirect calorimetry with accurate measurement and time discrimination of metabolic plateaus of over 20 min. Med Biol Eng Comput. 2003 Sep;41(5):572–578.[PubMed][Google Scholar]
- 32. Acheson KJ, Schutz Y, Bessard T, Flatt JP, Jequier ECarbohydrate metabolism and de novo lipogenesis in human obesity. Am J Clin Nutr. 1987 Jan;45(1):78–85.[PubMed][Google Scholar]
- 33. Rising R, Fontvieille AM, Larson DE, Spraul M, Bogardus C, Ravussin ERacial difference in body core temperature between Pima Indian and Caucasian men. Int J Obes Relat Metab Disord. 1995 Jan;19(1):1–5.[PubMed][Google Scholar]
- 34. Deutsch WA, Kukreja A, Shane B, Hegde VPhenobarbital, oxazepam and Wyeth 14,643 cause DNA damage as measured by the Comet assay. Mutagenesis. 2001 Sep;16(5):439–442.[PubMed][Google Scholar]
- 35. Weyer C, Snitker S, Rising R, Bogardus C, Ravussin EDeterminants of energy expenditure and fuel utilization in man: effects of body composition, age, sex, ethnicity and glucose tolerance in 916 subjects. Int J Obes Relat Metab Disord. 1999 Jul;23(7):715–722.[PubMed][Google Scholar]
- 36. McCay CCM, Maynard LAThe effect of retarded growth upon the length of the lifespan and upon the ultimate body size. J Nutr. 1935;10:63–79.[PubMed][Google Scholar]
- 37. Gresl TA, Colman RJ, Roecker EB, et al Dietary restriction and glucose regulation in aging rhesus monkeys: a follow-up report at 8.5 yr. Am J Physiol Endocrinol Metab. 2001 Oct;281(4):E757–765.[PubMed][Google Scholar]
- 38. Ramsey JJ, Harper ME, Weindruch RRestriction of energy intake, energy expenditure, and aging. Free Radic Biol Med. 2000 Nov 15;29(10):946–968.[PubMed][Google Scholar]
- 39. Keys A, Brozek J, Henschel A, Michelson O, Taylor H The Biology of Human Starvation. Minneapolis: University of Minnesota Press; 1950. [PubMed][Google Scholar]
- 40. Rising R, Keys A, Ravussin E, Bogardus CConcomitant interindividual variation in body temperature and metabolic rate. Am J Physiol. 1992 Oct;263(4 Pt 1):E730–734.[PubMed][Google Scholar]
- 41. Weyer C, Walford RL, Harper IT, et al Energy metabolism after 2 y of energy restriction: the biosphere 2 experiment. Am J Clin Nutr. 2000 Oct;72(4):946–953.[PubMed][Google Scholar]
- 42. Weinsier RL, Hunter GR, Zuckerman PA, et al Energy expenditure and free-living physical activity in black and white women: comparison before and after weight loss. Am J Clin Nutr. 2000 May;71(5):1138–1146.[PubMed][Google Scholar]
- 43. Toubro S, Sorensen TI, Ronn B, Christensen NJ, Astrup ATwenty-four-hour energy expenditure: the role of body composition, thyroid status, sympathetic activity, and family membership. J Clin Endocrinol Metab. 1996 Jul;81(7):2670–2674.[PubMed][Google Scholar]
- 44. Tataranni PA, Larson DE, Snitker S, Ravussin EThermic effect of food in humans: methods and results from use of a respiratory chamber. Am J Clin Nutr. 1995 May;61(5):1013–1019.[PubMed][Google Scholar]
- 45. Sohal RS, Weindruch ROxidative stress, caloric restriction, and aging. Science. 1996 Jul 5;273(5271):59–63.[Google Scholar]
- 46. Sohal RS, Svensson I, Brunk UTHydrogen peroxide production by liver mitochondria in different species. Mech Ageing Dev. 1990 Apr 30;53(3):209–215.[PubMed][Google Scholar]
- 47. Dandona P, Mohanty P, Ghanim H, et al The suppressive effect of dietary restriction and weight loss in the obese on the generation of reactive oxygen species by leukocytes, lipid peroxidation, and protein carbonylation. J Clin Endocrinol Metab. 2001 Jan;86(1):355–362.[PubMed][Google Scholar]
- 48. Bevilacqua L, Ramsey JJ, Hagopian K, Weindruch R, Harper MELong-term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria. Am J Physiol Endocrinol Metab. 2005 Sep;289(3):E429–438.[PubMed][Google Scholar]