Global Food Restriction

  • Michelle E. Matzko
  • Roger J. McCarter
  • Edward J. Masoro
Part of the Aging Medicine book series (AGME)


The use of restricted feeding paradigms to understand mechanisms of aging in rodent models is discussed. The phrase global food restriction is defined so as to avoid ambiguities that have arisen with the use of the phrase dietary restriction. Evidence is evaluated regarding the claim that such procedures not only extend longevity but also retard aging processes. Several hypotheses that have been advanced to explain this action (such as growth retardation, reduction of body fat, decreased metabolic rate, decreased plasma levels of various metabolites, and decreased levels of oxidative damage) are assessed and found wanting. Evidence is described in support of an overall mechanism in which hormesis plays an important role. It is suggested that moderate reduction of energy intake constitutes a low-intensity stressor that results in the mobilization of cellular defense mechanisms. These defense mechanisms decrease the accumulation of the cellular molecular damage that underlies senescence. It seems likely that the energy-restricted animal now exists in a new metabolic state in which many, rather than few, metabolic characteristics are altered. Many or all of these altered metabolic characteristics may play a role in the beneficial effects of caloric restriction.


Caloric restriction dietary restriction extended longevity mechanisms of aging rodent models hormesis 



Advanced glycosylation end product


Ad libitum


Caloric restriction


Dietary restriction




Growth hormone


Insulin-like growth factor I


Mononuclear cell leukemia


Metabolic rate


Mitochondrial DNA




Peroxisome proliferator-activated receptor coactivator 1


Peroxisome proliferator-activated receptor alpha


Receptor for advanced glycosylation end product


Reactive oxygen species




Target of rapamycin


  1. 1.
    McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life and upon the ultimate body size. J Nutr 1935;10:63–79.Google Scholar
  2. 2.
    Masoro, EJ. Caloric restriction: A key to understanding and modulating aging. Amsterdam: Elsevier, 2002.Google Scholar
  3. 3.
    Weindruch R, Walford RL. The retardation of aging and disease by dietary restriction. Springfield, IL: Charles C. Thomas, 1998.Google Scholar
  4. 4.
    Holehan AM, Merry BJ. The experimental manipulation of ageing by diet. Biol Rev 1986;61:329–69.PubMedGoogle Scholar
  5. 5.
    Pletcher SD, Khazaeli AA, Curtsinger JA. Why do life spans differ? Partitioning mean longevity differences in terms of age-specific mortality parameters. J Gerontol 2000;55A:B381–9.Google Scholar
  6. 6.
    Pugh TD, Oberly TD, Weindruch R. Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice. Cancer Res 1999;59:1642–8.PubMedGoogle Scholar
  7. 7.
    Finch CE. Longevity, senescence, and the genome. Chicago, IL: University of Chicago Press, 1990.Google Scholar
  8. 8.
    Driver C. A further comment on why the Gompertz plot does not measure aging. Biogerontology 2003;4:325–7.PubMedGoogle Scholar
  9. 9.
    Dhahbi JM, Kim HJ, Mote PL, Beaver RJ, Spindler SR. Temporal linkage between phenotype and genomic responses to caloric restriction. Proc Natl Acad Sci U S A 2004;101:5524–9.PubMedGoogle Scholar
  10. 10.
    Lipman RD, Smith DE, Blumberg J, Bronson RT. Effects of caloric restriction or augmentation in adult rats: Longevity and lesion biomarkers. Aging Clin Exp Res 1998;10:463–70.Google Scholar
  11. 11.
    Masoro EJ. Dietary restriction: An experimental approach to the study of the biology of aging. In: Masoro EJ, Austad SN, eds. Handbook of the biology of aging, 5th ed. San Diego, CA: Academic, 2001, pp. 396–420.Google Scholar
  12. 12.
    Liepa GU, Masoro EJ, Bertrand HA, Yu BP. Food restriction as a modulator of age-related changes in serum lipids. Am J Physiol 1980;238:E253–7.PubMedGoogle Scholar
  13. 13.
    Ward WF. Food restriction enhancement of the proteolytic capacity of aging rat liver. J Gerontol 1988;43:B121–4.PubMedGoogle Scholar
  14. 14.
    McClearn GE. Markers of aging. In: Birren JE, ed. Encyclopedia of gerontology, 2nd ed., vol. 2. San Diego, CA: Elsevier, 2007, pp. 117–24.Google Scholar
  15. 15.
    Maeda H, Gleiser CA, Masoro EJ, Murata I, McMahan CA, Yu BP. Nutritional influences on aging of Fischer 344 rats: II. Pathology. J Gerontol 1985;40:671–88.PubMedGoogle Scholar
  16. 16.
    Bronson RT, Lipman RD. Reduction in the rate of occurrence of age-related lesions in dietary restricted laboratory mice. Growth Dev Aging 1991;55:169–84.PubMedGoogle Scholar
  17. 17.
    Weindruch R. Dietary restriction, tumors, and aging in rodents. J Gerontol 1989;44(special issue):67–71.PubMedGoogle Scholar
  18. 18.
    Shimokawa I, Higami Y, Hubbard GB, McMahan CA, Masoro EJ, Yu BP. Diet and the suitability of the male Fischer 344 rat as a model for aging research. J Gerontol 1993;48:B27–32.PubMedGoogle Scholar
  19. 19.
    Mattson MP, Duan W, Lee J, Guo Z. Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanisms. Mech Ageing Dev 2001;122:757–78.PubMedGoogle Scholar
  20. 20.
    Fernandes G, Yunis EJ, Miranda M, Smith J, Good RA. Nutritional inhibition of genetically determined renal disease and autoimmunity with prolongation of life in kdkd mice. Proc Natl Acad Sci U S A 1978;75:2888–92.PubMedGoogle Scholar
  21. 21.
    Wolf NS, Li Y, Pendergras W, Schmeider C, Turturro A. Normal mouse and rat strains as models for age-related cataract and the effect of caloric restriction on its development. Exp Eye Res 2000;70:683–92.PubMedGoogle Scholar
  22. 22.
    Sheldon WG, Warbritton AR, Bucci TJ, Tutturro A. Glaucoma in food restricted and ad libitum-fed DBA/2NNIA mice. Lab Anim Sci 1995;45:508–18.PubMedGoogle Scholar
  23. 23.
    Sheldon WG, Bucci TJ, Tuturro A. Thoracic apohyseal osteoarthritis in feed-restricted and ad libitum-fed B6C3F1mice. In: Mohr U, Dungworth D, Capen C, Carlton W, Sundberg J, Ward J, eds. Pathobiology of the aging mouse, vol 1. Washington, DC: ILSI, 1996, pp. 445–53.Google Scholar
  24. 24.
    Masoro EJ. Are age-associated diseases an integral part of aging? In Masoro EJ, Austad SM, eds. Handbook of the biology of aging, 6th ed. San Diego, CA: Elsevier, 2006, pp. 43–62.Google Scholar
  25. 25.
    McCay CM, Maynard LA, Sperling G, Barenes LL. Retarded growth, lifespan, ultimate body size, and age change in the albino rat after feeding diets restricted in calories. J Nutr 1939;18:1–13.Google Scholar
  26. 26.
    Masoro EJ, Iwaski K, Gleiser CA, McMahan CA, Seo E, Yu BP. Dietary modulation of the progression of nephropathy in aging rats: an evaluation of the importance of protein. Am J Clin Nutr 1989;49:1217–27.PubMedGoogle Scholar
  27. 27.
    Iwasaki K, Gleiser CA, Masoro EJ, McMahan CA, Seo E, Yu BP. Influence of restricting individual dietary components on longevity and age-related disease of Fischer rats: the fat component and the mineral component. J Gerontol 1998;43:B13–21.Google Scholar
  28. 28.
    Yu BP, Masoro EJ, Murata I, Bertrand HA, Lynd FT. Life span study of SPF Fischer 344 rats fed ad libitum or restricted diets: longevity, growth, lean body mass, and disease. J Gerontol 1982;37:130–41.PubMedGoogle Scholar
  29. 29.
    Zimmerman JA, Malloy V, Krojjcik R, Orentreich N. Nutritional control of aging. Exp Gerontol 2003;38:47–52.PubMedGoogle Scholar
  30. 30.
    Miller RA, Buehner G, Chang Y, Harper JM, Sigler R, Smith-Wheelock M. Methionine deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-1 and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 2005;4:119–25.PubMedGoogle Scholar
  31. 31.
    Weindruch R, Walford RL. Dietary restriction in mice beginning at 1 year of age: effects on lifespan and spontaneous cancer incidence. Science 1982;215:1415–8.PubMedGoogle Scholar
  32. 32.
    Yu BP, Masoro EJ, McMahan CA. Life span study of SPF Fischer 344 male rats: I. Physical, metabolic, and longevity characteristics. J Gerontol 1985;40:657–70.PubMedGoogle Scholar
  33. 33.
    Bonkowski MS, Rocha JS, Masternak MM, Al Regaiey KA, Bartke A. Targeted disruption of growth hormone receptor interferes with the beneficial actions of caloric restriction. Proc Natl Acad Sci U S A 2006;103:7901–5.PubMedGoogle Scholar
  34. 34.
    Sonntag WE, Lenham JE, Ingram RL. Effects of aging and dietary restriction on tissue protein synthesis: Relationship to plasma insulin-like growth factor-1. J Gerontol 1992;47:B159–62.PubMedGoogle Scholar
  35. 35.
    Miller RA, Harper JM, Galecki A, Burke DT. Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice. Aging Cell 2002;1:22–9.PubMedGoogle Scholar
  36. 36.
    Berg BN, Simms HS. Nutrition and longevity in the rat. II. Longevity and onset of disease with different levels of intake. J Nutr 1960;71:255–63.PubMedGoogle Scholar
  37. 37.
    Peeters A, Barendregt JJ, Willekins F, Mackenbach JP, Mamun AAI, Bonneux L. Obesity in adulthood and its consequences for life expectancy: A life-table analysis. Ann Intern Med 2003;138:E24–33.Google Scholar
  38. 38.
    Westman S. Development of the obese-hyperglycaemic syndrome in mice. Diabetologia 1968;4:141–9.PubMedGoogle Scholar
  39. 39.
    Garthwaite TL, Martinson DR, Tseng LF, Hagen TC, Menahan LA. A longitudinal hormonal profile of the genetically obese mouse. Endocrinology 1980;107:671–6.PubMedGoogle Scholar
  40. 40.
    Bertrand HA, Lynd FT, Masoro EJ, Yu BP. Changes in adipose mass and cellularity through the adult life of rats fed ad libitum or a life-prolonging restricted diet. J Gerontology 1980;35:827–35.Google Scholar
  41. 41.
    Harrison DE, Archer JR, Astle CM. Effects of food restriction on aging: separation of food intake and adiposity. Proc Natl Acad Sci U S A 1984;81:1835–8.PubMedGoogle Scholar
  42. 42.
    Barzilai N, Gupta GG. Revisiting the role of fat mass in life extension induced by caloric restriction. J Gerontol 1999;54A:B89–96.Google Scholar
  43. 43.
    Blüher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 2003;299:572–4.PubMedGoogle Scholar
  44. 44.
    Blüher M, Michael MD, Peroni OD, et al. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell 2002;3:25–38.PubMedGoogle Scholar
  45. 45.
    Moitra J, Mason MM, Olive M, et al. Life without white fat: a transgenic mouse. Genes Dev 1998;12:3168–81.PubMedGoogle Scholar
  46. 46.
    Ross SR, Graves RA, Spiegelman BM. Targeted expression of a toxin gene to adipose tissue: transgenic mice resistant to obesity. Genes Dev 1993;7:1318–24.PubMedGoogle Scholar
  47. 47.
    Shimomura I, Hammer RE, Richardson JA, et al. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 1998;12:3182–94.PubMedGoogle Scholar
  48. 48.
    Benedict FG. Vital energetics. A study in comparative basal metabolism. Publication 503. Washington, DC: Carnegie Institute of Washington, 1938, pp. 1–215.Google Scholar
  49. 49.
    Garrow JS. Energy balance and obesity in man. Oxford: Elsevier/North Holland, 1978, p. 195.Google Scholar
  50. 50.
    Sacher GA. Life table modification and life prolongation. In: Finch C, Hayflick L, eds. Handbook of the biology of aging. New York: Van Nootrand Reinhold, 1977, pp. 582–638.Google Scholar
  51. 51.
    Pearl R. The rate of living. New York, NY: Alfred Knopf, 1928, p. 185.Google Scholar
  52. 52.
    Harman D. Ageing: a theory based on free radical and radiation chemistry. J Gerontol 1956;11:298–300.PubMedGoogle Scholar
  53. 53.
    Cutler R. Antioxidants, aging and longevity. In: Pryor WA, ed. Free radicals in biology, vol. 6. Orlando, FL: Academic Press, 1984, p. 381.Google Scholar
  54. 54.
    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;88:16–23.PubMedGoogle Scholar
  55. 55.
    Dulloo AG, Giradier L. 24 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;17:115–23.PubMedGoogle Scholar
  56. 56.
    Lane MA, Baer DJ, Rumpler WV, et al. Calorie restriction lowers body temperature in rhesus monkey, consistent with a postulated anti-aging mechanism in rodents. Proc Natl Acad Sci U S A 1996;93:4159–64.PubMedGoogle Scholar
  57. 57.
    Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev 1998;78:547–81.PubMedGoogle Scholar
  58. 58.
    Barja G. Rate of generation of oxidative stress-related damage and animal longevity. Free Radic Biol Med 2002;33:1167–72.PubMedGoogle Scholar
  59. 59.
    Bevilacqua L, Ramsey JJ, Hagopian K, Weindruch R, Harper ME. Long-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;280:E429–38.Google Scholar
  60. 60.
    McCarter R, Shimokawa A, Ikeno Y, et al. Physical activity as a factor in the action of dietary restriction on aging: Effects in Fischer 344 rats. Aging (Milano) 1997;9:73–9.Google Scholar
  61. 61.
    Masoro EJ, Yu BP, Bertrand H. Action of food restriction in delaying the aging processes. Proc Natl Acad Sci U S A 1982;79:4239–41.PubMedGoogle Scholar
  62. 62.
    McCarter RJ, Palmer J. Energy metabolism and aging: a lifelong study in Fischer 344 rats. Am J Physiol 1992;263:E448–52.PubMedGoogle Scholar
  63. 63.
    Speakman JR, Talbot DA, Selman C, et al. Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell 2004;3:87–95.PubMedGoogle Scholar
  64. 64.
    Selman C, Phillips T, Staib JL, Duncan JS, Leeuwenburgh C, Speakman JR. Energy expenditure of calorically restricted rats is higher than predicted from their altered body composition. Mech Ageing Dev 2005;126:783–93.PubMedGoogle Scholar
  65. 65.
    Lambert AJ, Merry BJ. Lack of effect of caloric restriction on bioenergetics and reactive oxygen species production in intact rat hepatocytes. J Gerontol A Biol Sci Med Sci 2005;60A:175–80.Google Scholar
  66. 66.
    McCarter RJ, Masoro EJ, Yu BP. Rat muscle structure and metabolism in relation to age and food intake. Am J Physiol 1982;242:R89–93.PubMedGoogle Scholar
  67. 67.
    Gonzalez-Pacheco DM, Buss WC, Koehler KM, Woodside WF, Alpert SS. Energy restriction reduces metabolic rate in adult male Fisher-344 rats. J Nutr 1993;123:90–7.Google Scholar
  68. 68.
    Austad SN, Fischer KE. Mammalian aging, metabolism and ecology: evidence from the bats and marsupials. J Gerontol 1991;46:B47–53.PubMedGoogle Scholar
  69. 69.
    Gerschman R, Gilbert DL, Nye SW, Dwyer P, Fenn WO. Oxygen poisoning and X-irrradiation: a mechanism in common. Science 1954;119:623–26.PubMedGoogle Scholar
  70. 70.
    Commoner B, Townsend J, Pake GE. Free radicals in biological materials. Nature 1954;174:689–91.PubMedGoogle Scholar
  71. 71.
    Wallace DC. Mitochondrial defects in neurodegenerative disease. Ment Retard Dev Disabil Res Rev 2001;7:158–66.PubMedGoogle Scholar
  72. 72.
    Austad SN. Vertebrate aging research. Aging Cell 2007;6:135–8.PubMedGoogle Scholar
  73. 73.
    VanRemmen H, Ikeno Y, Hamilton M, et al. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics 2003;16:29–37.Google Scholar
  74. 74.
    Huang TT, Carlson EJ, Gillespie AM, Shi Y, Epstein CJ. 2000. Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice. J Gerontol A Biol Sci Med Sci 2000;55:85–9.Google Scholar
  75. 75.
    Schriner SE, Linford NJ, Martin GM, et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 2005;308:1909–11.PubMedGoogle Scholar
  76. 76.
    Andziak B, O’Connor TP, Qi W, et al. High oxidative damage levels in the longest-living rodent, the naked mole-rat. Aging Cell 2006;5:463–71.PubMedGoogle Scholar
  77. 77.
    Shigenaga MK, Hagen TM, Ames BN. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci U S A 1994;91:10771–8.PubMedGoogle Scholar
  78. 78.
    De AK, Chipalkatti S, Aiyar AS. Some biochemical parameters of ageing in relation to dietary protein. Mech Ageing Dev 1983;21:37–48.PubMedGoogle Scholar
  79. 79.
    Chipalkatti S, De AK, Aiyar AS. Effect of diet restriction on some biochemical parameters related to aging in mice. J Nutr 1983;113:944–50.PubMedGoogle Scholar
  80. 80.
    Laganiere S, Yu BP. Effect of chronic food restriction in aging rats I. Liver subcellular membranes. Mech Ageing Dev 1989;48:207–19.PubMedGoogle Scholar
  81. 81.
    Laganiere S, Yu BP. Anti-lipoperoxidation action of food restriction. Biochem Biophys Res Commun 1987;145:1185–91.PubMedGoogle Scholar
  82. 82.
    Merry BJ. Calorie restriction and age-related stress. In: Toussaint O, Osiewacz HD, Lithgow G, Brack C, eds. Molecular and cellular gerontology. New York, NY: New York Academy of Sciences, 2002, pp. 180–98.Google Scholar
  83. 83.
    Dubey A, Forster M, Harbans L, Sohal RS. Effect of age and caloric intake on protein oxidation in different brain regions and on behavioral functions of the mouse. Arch Biochem Biophys 1996;333:189–97.PubMedGoogle Scholar
  84. 84.
    Lass A, Sohal BH, Weindruch R, Forster MJ, Sohal RS. Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria. Free Radic Biol Med 1998;25:1089–97.PubMedGoogle Scholar
  85. 85.
    Kaneko T, Tahara S, Matsuo M. Retarding effect of dietary restriction on the accumulation of 8-hydroxy-2’-deoxyguanosine in organs of Fischer 344 rats during aging. Free Radic Biol Med 1997;23:76–81.PubMedGoogle Scholar
  86. 86.
    Kang CM, Krystal BS, Yu BP. Age-related mitochondrial DNA deletions: effect of dietary restriction. Free Radic Biol Med 1998;24:148–54.PubMedGoogle Scholar
  87. 87.
    Muller FJ, Lustgarten MS, Jang Y, Richardson A, VanRemmen H. Trends in oxidative aging theories. Free Radic Biol Med 2007;43:477–503.PubMedGoogle Scholar
  88. 88.
    Merry BJ. Oxidative stress and mitochondrial function with aging – the effects of calorie restriction. Aging Cell 2004;3:7–12.PubMedGoogle Scholar
  89. 89.
    Cerami A. Hypothesis: glucose as a mediator of aging. J Am Geriatr Soc 1985;33:626–34.PubMedGoogle Scholar
  90. 90.
    Kassi E, Papavassiliou AG. Could glucose be a proaging factor? J Cell Mol Med 2008;12:1194–8.PubMedGoogle Scholar
  91. 91.
    Masoro EJ, Katz MS, McMahan CA. Evidence for the glycation hypothesis of aging from the food restricted rodent model. J Gerontol 1989;44:B20–2.PubMedGoogle Scholar
  92. 92.
    Monnier VM. Nonenzymatic glycosylation, the Maillard Reaction and the aging process. J Gerontol 1990;45:B105–11.PubMedGoogle Scholar
  93. 93.
    Sell DR, Monnier VM. Long-lived proteins: extracellular matrix and lens crystallins. In: Masoro EJ, ed. Handbook of physiology: section II, aging. New York, NY: Oxford University Press, 1995, pp. 235–308.Google Scholar
  94. 94.
    Cai W, He JC, Zhu L, Chen X, Striker GE, Vlassara H. AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66shc-dependent FKHRL1 phosphorylation. Am J Physiol Cell Physiol 2008;294:C145–52.PubMedGoogle Scholar
  95. 95.
    Yan SF, D’Agati V, Schmidt AM, Ramasamy R. Receptor for advanced glycation endproducts (RAGE): a formidable force in the pathogenesis of the cardiovascular complications of diabetes and aging. Curr Mol Med 2007;7:699–710.PubMedGoogle Scholar
  96. 96.
    McCarter RJ, Mejia W, Ikeno Y, et al Plasma glucose and the action of calorie restriction on aging. J Gerontol A Biol Sci Med Sci 2007;62A:1059–70.Google Scholar
  97. 97.
    Masoro EJ, McCarter RJ, Katz MS, McMahan CA. Dietary restriction alters characteristics of glucose fuel use. J Gerontol 1992;47:B202–8.PubMedGoogle Scholar
  98. 98.
    Bergman RN. Toward physiological understanding of glucose tolerance. Minimal model approach. Diabetes 1989;38:1512–27.PubMedGoogle Scholar
  99. 99.
    Kenyon C, Chang J, Gensch A, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as the wild type. Nature 1993;366:461–4.PubMedGoogle Scholar
  100. 100.
    Clancy DJ, Gems D, Harshman LG, et al. Extension of life span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 2001;292:104–6.PubMedGoogle Scholar
  101. 101.
    Tatar M, Kopelman A, Epstein D, et al. A mutant Drosophila insulin receptor homolog that extends life span and impairs neuroendocrine function. Science 2001;292:107–10.PubMedGoogle Scholar
  102. 102.
    Gupta G, Li S, Ma X-H, et al. Aging does not contribute to the decline in insulin action on storage of muscle glycogen in rats. Am J Physiol 2000;278:111–7.Google Scholar
  103. 103.
    Iida KT, Shimano H, Kawakami Y, et al. Insulin up-regulates tumor necrosis factor-alpha in macrophages through extracellular-regulated kinase-dependent pathway. J Biol Chem 2001;276:32531–7.PubMedGoogle Scholar
  104. 104.
    Biddinger SB, Kahn CR. From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol 2000;68:123–58.Google Scholar
  105. 105.
    Taguchi A, Wartschow LM, White MF. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 2007;317:369–72.PubMedGoogle Scholar
  106. 106.
    Dean DJ, Brozinick JT Jr, Cushman SW, Cartee GD. Calorie restriction increases cell surface GLUT-4 in insulin-stimulated skeletal muscle. Am J Physiol 1998;275:E957–64.PubMedGoogle Scholar
  107. 107.
    Swanson DR. Somatomedin C and arginine: implicit connections between mutually isolated literatures. Perspect Biol Med 1990;33:157–86.PubMedGoogle Scholar
  108. 108.
    Kelijman M. Age-related alterations of the growth hormone/insulin-like-growth-factor I axis. J Am Geriatr Soc 1991;39:295–307.PubMedGoogle Scholar
  109. 109.
    Laron Z, Doron M, Arnikan B. Plasma growth hormone in men and women over 70 years of age. Med Sport Phys Activity Aging 1970;4:126–9.Google Scholar
  110. 110.
    Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev 1993;14:20–39.PubMedGoogle Scholar
  111. 111.
    Sonntag WE, Steger RW, Forman LJ, Meites J. Decreased pulsatile release of growth hormone in old male rats. Endocrinology 1980;107:1875–9.PubMedGoogle Scholar
  112. 112.
    Florini JR, Harned JA, Richman RA, Weiss JP. Effect of rat age on serum levels of growth hormone and somatomedins. Mech Ageing Dev 1981;15:165–76.PubMedGoogle Scholar
  113. 113.
    Holzenberger M, Dupont J, Ducos B, et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 2003;21:182–7.Google Scholar
  114. 114.
    Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ. Assessment of growth parameters and lifespan of GHR/BP gene-disrupted mice. Endocrinology 2000;141:2608–13.PubMedGoogle Scholar
  115. 115.
    Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A 2001;98:6736–41.PubMedGoogle Scholar
  116. 116.
    Brown-Borg HM, Borg KE, Meliska CJ, Bartke A. Dwarf mice and the aging process. Nature 1996;384:33.PubMedGoogle Scholar
  117. 117.
    Hursting SD, Switzer BR, French JE, Kari FW. The growth hormone: insulin-like growth factor-1 axis is a mediator of diet restriction-induced inhibition of mononuclear cell leukemia in Fischer rats. Cancer Res 1993;53:2750–7.PubMedGoogle Scholar
  118. 118.
    Breese CR, Ingram RL, Sonntag WE. Influence of age and long-term dietary restriction on plasma insulin-like growth factor-1 (IGF-1), IGF-1 gene expression, and IGF-1 binding proteins. J Gerontol 1991;46:B180–7.PubMedGoogle Scholar
  119. 119.
    D’Costa AP, Lenham JE, Ingram RL, Sonntag WE. Moderate caloric restriction increases type 1 IGF-1 receptors and protein synthesis in aging rats. Mech Aging Dev 1993;71:59–71.PubMedGoogle Scholar
  120. 120.
    Sonntag WE, Lynch CD, Cefalu WT, et al Pleiotropic effects of growth hormone and insulin-like growth factor (IGF-1) on biological aging: inferences from moderate caloric-restricted animals. J Gerontol 1999;54A:B521–38.Google Scholar
  121. 121.
    Masoro EJ. Hormesis and the antiaging action of dietary restriction. Exp Gerontol 1998;33:61–6.PubMedGoogle Scholar
  122. 122.
    Turturro A, Hass B, Hart RW. Hormesis: implications for risk assessment caloric intake (body weight) as an exemplar. Hum Exp Toxicol 1998;17:454–9.PubMedGoogle Scholar
  123. 123.
    Calebrese EJ, Baldwin LA. Hormesis as a biological hypothesis. Environ Health Perspect 1998;106(suppl 1):357–62.Google Scholar
  124. 124.
    Caratero A, Courtade M, Bonnet L, Planel H, Caratero C. Effect of continuous gamma irradiation at very low dose on the life span of mice. Gerontology 1998;44:272–6.PubMedGoogle Scholar
  125. 125.
    Mattson MP. Hormesis defined. Ageing Res Rev 2008;7:1–7.PubMedGoogle Scholar
  126. 126.
    Rattan SIS. Applying hormesis in aging research and therapy. Hum Exp Toxicol 2001;20:281–5.PubMedGoogle Scholar
  127. 127.
    Munck CV, Guyre PM, Holbrook NJ. Physiologic functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 1984;5:25–44.PubMedGoogle Scholar
  128. 128.
    Sabatino F, Masoro EJ, McMahan CA, Kuhn RW. An assessment of the role of the glucocorticoid system in aging processes and in the action of food restriction. J Gerontol 1991;46:B171–9.PubMedGoogle Scholar
  129. 129.
    Klebanov S, Shehab D, Stavinoha WB, Yongman S, Nelson JF. Hyperadrenocorticism attenuated inflammation and the life-prolonging action of food restriction in mice. J Gerontol 1995;50A:B78–82.Google Scholar
  130. 130.
    Heydari AR, Wu B, Takahashi R, Strong R, Richardson A. Expression of heat shock protein 70 is altered by age and diet at the level of transcription. Mol Cell Biol 1993;13:2900–18.Google Scholar
  131. 131.
    Duffy PH, Feuers FJ, Pipkin JL, et al The effect of dietary restriction and aging on physiological response to drugs. In: Hart RW, Neuman DA, Robertson RT, eds. Dietary restriction: implications for the design and interpretation of toxicity and carcinogenicity studies. Washington, DC: ILSI, 1995, pp. 125–40.Google Scholar
  132. 132.
    Keenan KP, Ballam GC, Dixit R, et al The effect of diet, overfeeding and moderate dietary restriction on Sprague–Dawley rat survival, disease, and toxicology. J Nutr 1997;127(suppl):851S–6S.PubMedGoogle Scholar
  133. 133.
    Rattan SIS. Aging, anti-aging, and hormesis. Mech Ageing Dev 2004;125:285–9.PubMedGoogle Scholar
  134. 134.
    Crypser JR, Johnson TE. Multiple stressors in Caenorhabditis elegans induced stress hormesis and extended longevity. J Gerontol 2002;57:B109–14.Google Scholar
  135. 135.
    Martin GM, Austad SN, Johnson TE. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nat Genet 1996;13:25–34.PubMedGoogle Scholar
  136. 136.
    Oster MH, Fiedler PJ, Levin N, Cronin MJ. Adaptation of growth hormone and insulin-like growth factor-1 axis to chronic and severe calorie or protein malnutrition. J Clin Invest 1995;95:2258–65.PubMedGoogle Scholar
  137. 137.
    Dillmann WH, Berry S, Alexander N, A physiological dose of triiodothyronine normalizes cardiac myosin adenosine triphosphatase activity and changes myosin isoenzyme distribution in semistarved rats. Endocrinology 1983;112:2081–7.PubMedGoogle Scholar
  138. 138.
    Sabatino F, Masoro EJ, McMahan CA, Kuhn RW. An assessment of the role of the glucocorticoid system in aging processes and in the action of food restriction. J Gerontol 1991;46:B171–9.PubMedGoogle Scholar
  139. 139.
    Tomita M, Shimokawa I, Higami Y, et al. Modulation by dietary restriction in gene expression related to insulin-like growth factor-1 in rat muscle. Aging Clin Exp Res 2001;13:273–81.Google Scholar
  140. 140.
    Herlihy JT, Stacy C, Bertrand HA. Long-term food restriction depresses serum thyroid concentration in the rat. Mech Ageing Dev 1990;53:9–16.PubMedGoogle Scholar
  141. 141.
    Richardson A, McCarter RJM. Mechanism of food restriction: Change of rate or change of set point. In: Ingram DK, Baker GT III, Shock NW, eds. Nutritional modulation of aging processes. Trumbull, CT: Food and Nutrition Press, 1991, pp. 193–204.Google Scholar
  142. 142.
    Sinclair DA, Horwitz KT. Dietary restriction, hormesis, and small molecule mimetics. In: Masoro EJ, Austad DN, eds. Handbook of the biology of aging, 6th ed. San Diego, CA: Elsevier, 2006, pp. 63–104.Google Scholar
  143. 143.
    Kennedy BK, Steffen KK, Kaeberlein M. Ruminations on dietary restriction and aging. Cell Mol Life Sci 2007;64:1323–8.PubMedGoogle Scholar
  144. 144.
    Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004;305:390–2.PubMedGoogle Scholar
  145. 145.
    Corton JF, Brown-Borg HM. Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction. J Gerontol 2005;60A:1494–509.Google Scholar
  146. 146.
    Nemoto S, Fergusson MM, Finkel T. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 2004;306:2105–8.PubMedGoogle Scholar
  147. 147.
    Mori K, Yahata K, Mukoyama M, et al. Disruption of klotho gene causes an abnormal energy homeostasis response in mice. Biochem Biophys Res Commun 2000;278:665–70.PubMedGoogle Scholar
  148. 148.
    Wang F, Nguyen M, Qin FX, Tong Q. SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell 2007;6:505–14.PubMedGoogle Scholar
  149. 149.
    Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A. Opposing activities protect against age-onset proteotoxicity. Science 2006;313:1604–10.PubMedGoogle Scholar
  150. 150.
    Corton JC, Apte U, Anderson SP, et al. Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors. J Biol Chem 2004;279:46204–12.PubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Michelle E. Matzko
    • 1
  • Roger J. McCarter
    • 1
  • Edward J. Masoro
    • 2
  1. 1.Center for Developmental and Health GeneticsThe Pennsylvania State UniversityUniversity ParkUSA
  2. 2.Barshop Institute for Longevity and Aging StudiesUniversity of Texas Health Science CenterSan AntonioUSA

Personalised recommendations