The Immune System, a Marker and Modulator of the Rate of Aging

  • Monica De la FuenteEmail author


The ageing process shows heterogeneity in the changes suffered by each physiological system in the diverse members of a population of the same chronological age. This phenomenon led to the concept of “biological ageing,” which determines the rate of ageing experienced by each individual and therefore his/her life quality and expectancy. Since the biological age of a subject is difficult to measure, it is necessary to find markers, which will make it possible. The functional capacity of immune cells has been proposed as a marker of health, and using mice with premature senescence, long-lived mice, and human centenarians, it has been confirmed that several immune functions are good markers of biological age and predictors of longevity. Moreover, we have proposed the oxidation-inflammation theory of ageing, in which the immune system is involved in the rate of oxi-inflamm-ageing of the organism and in the biological age. This has been confirmed that applying several lifestyle strategies improves the immune cell functions, decreases oxidative stress, improves the general health, and consequently increases longevity in elderly.


Immune Cell Immune Function Aging Process Caloric Restriction Environmental Enrichment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author thanks Mr. D. Potter for his help with the English language revision of the manuscript and also expresses her gratitude to Dr. Ortega, Dr. Vallejo, Dr. Medina, Dr. Victor, Dr. Alvarado, Dr. Alvarez, Dr. Alonso, Dr. Arranz, Dr. Baeza, Dr, Gimenez-Llort, Ms De Castro, Ms Vida, Ms Hernandez, Ms Cruces, and Ms Maté for their invaluable help in performing several of the experiments which have allowed us to arrive at the ideas expressed in this chapter. This work was supported by grants of the MINECO (BFU2011-03336), Research Group of UCM (910379ENEROINN), and RETICEF (RD06/0013/0003) (RD12/0043/0018)(ISCIII-FEDER of the European Union).


  1. Ahmed T, Das SK, Golden JK et al (2009) Caloric restriction enhances T-cell-mediated immune response in adult overweight men and women. J Gerontol A Biol Sci Med Sci 64:1107–1113PubMedGoogle Scholar
  2. Alonso-Fernandez P, De la Fuente M (2011) Role of the immune system in aging and longevity. Curr Aging Sci 4:78–100PubMedGoogle Scholar
  3. Alonso-Fernandez P, Maté I, De la Fuente M (2010) Neutrophils: markers of biological age and predictors of longevity. In: DeFranco JE (ed) Neutrophils: lifespan, functions and role in disease. Nova Science Publisher Inc, New YorkGoogle Scholar
  4. Anderson RM, Weindruch R (2012) The caloric restriction paradigm: implications for healthy human aging. Am J Hum Biol 24:101–106PubMedGoogle Scholar
  5. Arranz L, Guayerbas N, De la Fuente M (2007) Impairment of several immune functions in anxious women. J Psychosom Res 62:1–8PubMedGoogle Scholar
  6. Arranz L, De Vicente A, Muñoz M et al (2009) Impairment of immune function in the social excluded homeless population. Neuroimmunomodulation 16:251–260PubMedGoogle Scholar
  7. Arranz L, Caamaño J, Lord JM, De la Fuente M (2010a) Preserved immune functions and controlled leukocyte oxidative stress in naturally long-lived mice: possible role of nuclear factor-kappa B. J Gerontol A Biol Sci Med Sci 65A:941–950Google Scholar
  8. Arranz L, De Castro NM, Baeza I et al (2010b) Differential expression of Toll-like receptor 2 and 4 on peritoneal leukocyte populations from long-lived and non-selected old female mice. Biogerontology 11:475–482PubMedGoogle Scholar
  9. Arranz L, De Castro NM, Baeza I et al (2010c) Environmental enrichment improves age-related immune system impairment. Long-term exposure since adulthood increases life span in mice. Rejuvenation Res 13:415–428PubMedGoogle Scholar
  10. Arranz L, Lord JM, De la Fuente M (2010d) Preserved ex vivo inflammatory status and cytokine responses in naturally long-lived mice. Age (Dordr) 32:451–466Google Scholar
  11. Arranz L, De Castro NM, Baeza I (2011) Effect of environmental enrichment on the immunoendocrineageing of male and female triple-transgenic 3xTg-AD mice for Alzheimer’s disease. J Alzheimers Dis 25:727–737PubMedGoogle Scholar
  12. Arranz L, Naudi A, De la Fuente M, Pamplona R (2013) Exceptionally old mice are highly resistant to lipoxidation-derived molecular damage. Age (Dordr) 35(3):621–635Google Scholar
  13. Atzmon G, Cho M, Cawthon RM et al (2010) Evolution in health and medicine Sackler colloquium: genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci U S A 107:1710–1717PubMedGoogle Scholar
  14. Bae CY, Kang YG, Kim S et al (2008) Development of models for predicting biological age (BA) with physical, biochemical, and hormonal parameters. Arch Gerontol Geriatr 47:253–265PubMedGoogle Scholar
  15. Bandeen-Roche K, Walston JD, Huang Y et al (2009) Measuring systemic inflammatory regulation in older adults: evidence and utility. Rejuvenation Res 12:403–410PubMedGoogle Scholar
  16. Barak Y (2006) The immune system and happiness. Autoimmun Rev 5:523–527PubMedGoogle Scholar
  17. Barja G (2004) Free radicals and aging. Trends Neurosci 27:595–600PubMedGoogle Scholar
  18. Bauer ME (2008) Chronic stress and immunosenescence. A review. Neuroimmunomodulation 15:244–253Google Scholar
  19. Benfante R, Reed R, Brody J (1985) Biological and social predictors of health in an aging cohort. J Chronic Dis 38:175–181Google Scholar
  20. Benjamin H (1947) Biologic versus chronologic age. J Gerontol 2:217–227PubMedGoogle Scholar
  21. Besedovsky HO, Del Rey A (2007) Physiology of psychoneuroimmunology: a personal view. Brain Behav Immun 21:34–44PubMedGoogle Scholar
  22. Besedovsky HO, Del Rey A (2011) Central and peripheral cytokines mediate immune-brain connectivity. Neurochem Res 36:1–6PubMedGoogle Scholar
  23. Borkan A, Norris AH (1980) Assessment of biological age using a profile of physical parameters. J Gerontol 35:177–184PubMedGoogle Scholar
  24. Bulpitt CJ, Antikainen RL, Markowe HL et al (2009) Mortality according to a prior assessment of biological age. Curr Aging Sci 2:193–199PubMedGoogle Scholar
  25. Calabrese EJ, Blain R (2005) The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview. Toxicol Appl Pharmacol 202:289–301PubMedGoogle Scholar
  26. Calabrese V, Cornelius C, Trovato A, Cavallaro M, Mancuso C, Di Rienzo L, Condorelli D, De Lorenzo A, Calabrese EJ (2010) The hormetic role of dietary antioxidants in free radical-related diseases. Curr Pharm Des 16:877–883PubMedGoogle Scholar
  27. Calabrese EJ, Iavicoli I, Calabrese V (2012) Hormesis: why it is important to biogerontologists. Biogeron-tology 13:215–235Google Scholar
  28. Carnes BA, Staats DO, Sonntag WE (2008) Does senescence give rise to disease? Mech Ageing Dev 129:693–699PubMedGoogle Scholar
  29. Cavallini G, Donati A, Gori Z et al (2008) Towards an understanding of the anti-aging mechanism of caloric restriction. Curr Aging Sci 1:4–9PubMedGoogle Scholar
  30. Corona AW, Fenn AM, Godbout JP (2012) Cognitive and behavioral consequences of impaired immunoregulation in aging. J Neuroimmune Pharmacol 7:7–23PubMedGoogle Scholar
  31. Couillard-Depres S, Iglseder B, Aigner L (2011) Neurogenesis, cellular plasticity and cognition: the impact of stem cells in the adult and aging brain. Gerontology 57:559–564Google Scholar
  32. De la Fuente M (1985) Changes in the macrophage function with aging. Comp Biochem Physiol 81:935–938Google Scholar
  33. De la Fuente M (2004) The immune system as a marker of health and longevity. Antiaging Med 1:31–41Google Scholar
  34. De la Fuente M (2010) Murine models of premature ageing for the study of diet-induced immune changes. Improvement of leukocyte functions in two strains of old prematurely ageing mice by dietary supplementation with sulphur-containing antioxidants. Proc Nutr Soc 69:651–659PubMedGoogle Scholar
  35. De la Fuente M, Arranz L (2012) The importance of the environment in brain aging: be happy, live longer! In: Thakur MK, Rattan SI (eds) Brain aging, therapeutic interventions. Springer, New YorkGoogle Scholar
  36. De la Fuente M, De Castro NM (2012) Obesity as a model of premature immunosenescence. Curr Immunol Rev 8:63–75Google Scholar
  37. De la Fuente M, Miquel J (2009) An update of the oxidation-inflammation theory of aging the involvement of the immune system in oxi-inflamm-aging. Curr Pharm Des 15:3003–3026PubMedGoogle Scholar
  38. De la Fuente M, Hernanz A, Vallejo MC (2005) The immune system in the oxidation stress conditions of aging and hypertension favorable effects of antioxidants and physical exercise. Antioxid Redox Signal 7:1356–1366PubMedGoogle Scholar
  39. De la Fuente M, Hernandez O, Cruces J et al (2011) Strategies to improve the functions and redox state of the immune system in aged subjects. Curr Pharm Des 17:3966–3993Google Scholar
  40. Dewan SK, Zheng SB, Xia SJ (2012) Senescent remodeling of the immune system and its contribution to the predisposition of the elderly to infections. Chin Med J 125:3325–3331PubMedGoogle Scholar
  41. Dietert RR, Piepenbrink MS (2008) The managed immune system: protecting the womb to delay the tomb. Hum Exp Toxicol 27:129–134PubMedGoogle Scholar
  42. Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95PubMedGoogle Scholar
  43. Ferguson FG, Wikby A, Maxson P et al (1995) Immune parameters in a longitudinal study of a very old population of Swedish people: a comparison between survivors and nonsurvivors. J Gerontol A Biol Sci Med Sci 50:B378–B382PubMedGoogle Scholar
  44. Franceschi C, Bonafe M, Valensin S et al (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254PubMedGoogle Scholar
  45. Frasca D, Blomberg BB (2009) Effects of aging on B cell function. Curr Opin Immunol 21:425–430PubMedGoogle Scholar
  46. Fulop T, Larbi A, Kotb R et al (2011) Aging, immunity, and cancer. Discov Med 11:537–550PubMedGoogle Scholar
  47. Gaman L, Stoian I, Atanasiu V (2011) Can ageing be slowed?: hormetic and redox perspectives. J Med Life 4:346–351PubMedGoogle Scholar
  48. Garrido P (2011) Aging and stress: past hypothesis, present approaches and perspectives. Aging Dis 2:80–99PubMedGoogle Scholar
  49. Gayoso I, Sanchez-Correa B, Campos C et al (2011) Immunosenescence of human natural killer cells. J Innate Immun 3:337–343PubMedGoogle Scholar
  50. Gimenez-Llort L, Mate I, Masnassra R et al (2012) Peripheral immune system and neuroimmune communication impairment in a mouse model of Alzheimer’s disease. Ann N Y Acad Sci 1262:74–84PubMedGoogle Scholar
  51. Gouin JP, Hantsoo L, Kiecolt. Glaser JK (2008) Immune dysregulation and chronic stress among older adults: a review. Neuroimmunomodulation 15:254–262Google Scholar
  52. Goyns MH (2002) Genes, telomeres and mammalian ageing. Mech Ageing Dev 123:791–799PubMedGoogle Scholar
  53. Guayerbas N, De la Fuente M (2003) An impairment of phagocytic function is linked to a shorter life span in two strains of prematurely aging mice. Dev Comp Immunol 27:339–350PubMedGoogle Scholar
  54. Guayerbas N, Puerto M, Víctor VM et al (2002) Leukocyte function and life span in a murine model of premature immunosenescence. Exp Gerontol 37:249–256PubMedGoogle Scholar
  55. Haman D (2006) Free radical theory of aging: an update: increasing the functional life span. Ann N Y Acad Sci 1067:10–21Google Scholar
  56. Harman D (1956) Ageing: a theory based on free radical and radiation chemistry. J Gerontol 2:298–300Google Scholar
  57. Hayflick L (2007) Biological aging is no longer an unsolved problem. Ann N Y Acad Sci 1100:1–13PubMedGoogle Scholar
  58. Haynes L, Maue AC (2009) Effects of aging on T cell function. Curr Opin Immunol 21:414–417PubMedGoogle Scholar
  59. Hernanz A, Bayon J, Bisbal E et al (2008) Leukocyte functions are altered in patients with depressive disorder. J Neuroimmunol 197:167–168Google Scholar
  60. Jenny NS (2012) Inflammation in aging: cause, effect, or both? Discov Med 13:451–460PubMedGoogle Scholar
  61. Kirkwood TBL (2008) Gerontology: healthy old age. Nature 455:739–740PubMedGoogle Scholar
  62. Kokkinos P (2012) Physical activity, health benefits, and mortality risk. ISRN Cardiol. doi: 10.5402/2012/718789 PubMedGoogle Scholar
  63. Kouda K, Iki M (2010) Beneficial effects of mild stress (hormetic effects): dietary restriction and health. J Physiol Anthropol 29:127–132PubMedGoogle Scholar
  64. Lang PO, Govin S, Aspinall R (2013) Reversing T cell immunosenescence: why, who and how. Age 35(3):609–620PubMedGoogle Scholar
  65. Lupien SJ, McEwen BS, Gunnar MR (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434–445PubMedGoogle Scholar
  66. Makrantonaki E, Schonknecht P, Hossini AM (2010) Skin and brain age together: the role of hormones in the ageing process. Exp Gerontol 45:801–813PubMedGoogle Scholar
  67. Masoro EJ (2009) Caloric restriction induced life extension of rats and mice: a critique of proposed mechanisms. Biochim Biophys Acta 1790:1040–1048PubMedGoogle Scholar
  68. Mattson MP (2008) Hormesis defined. Ageing Res Rev 7:1–7PubMedGoogle Scholar
  69. Medvedev ZA (1990) An attempt at a rational classification of theories of aging. Biol Rev 65:375–398PubMedGoogle Scholar
  70. Messaoudi I, Fischer M, Warner J et al (2008) Optimal window of caloric restriction onset limits its beneficial impact on T-cell senescence in primates. Aging Cell 7:908–919PubMedGoogle Scholar
  71. Miquel J (1998) An update on the oxygen stress-mitochondrial mutation theory of aging: genetic and evolutionary implications. Exp Gerontol 33:113–126PubMedGoogle Scholar
  72. Miquel J, Economos AC, Fleming J et al (1980) Mitochondrial role in cell aging. Exp Gerontol 15:575–591PubMedGoogle Scholar
  73. Moncek F, Duncko R, Johansson BB et al (2004) Effect of environmental enrichment on stress related systems in rats. J Neuroendocrinol 16:423–431PubMedGoogle Scholar
  74. Nakamura E, Miyao K (2007) A method for identifying biomarkers of aging and constructing and index of biological age in humans. J Gerontol A Biol Sci Med Sci 62:1096–1105PubMedGoogle Scholar
  75. Ogata K, Yokose N, Tamura H et al (1997) Natural killer cells in the late decades of human life. Clin Immunol Immunopathol 84:269–275PubMedGoogle Scholar
  76. Pae M, Meydani SN, Wu D (2012) The role of nutrition in enhancing immunity in aging. Aging Dis 3:91–129PubMedGoogle Scholar
  77. Pandey KB, Rizvi SI (2010) Markers of oxidative stress in erythrocytes and plasma during aging in humans. Oxidative Med Cel Longevity 3:2–12Google Scholar
  78. Park J, Cho B, Kwon H (2009) Developing a biological age assessment equation using principal component analysis and clinical biomarkers of aging in Korean men. Arch Gerontol Geriatr 49:7–12PubMedGoogle Scholar
  79. Pauwels EK (2011) The protective effect of the Mediterranean diet: focus on cancer and cardiovascular risk. Med Princ Pract 20:103–111PubMedGoogle Scholar
  80. Pawelec G (2006) Immunity and ageing in man. Exp Gerontol 41:1239–1242PubMedGoogle Scholar
  81. Pawelec G, Larbi A, Derhovanesian E (2010) Senescence of the human immune system. J Comp Pathol. doi: 10.1016/j.jcpa.2009.09.005 PubMedGoogle Scholar
  82. Puerto M, Guayerbas N, Alvarez P, De la Fuente M (2005) Modulation of neuropeptide Y and norepinephrine on several leucocyte functions in adult, old and very old mice. J Neuroimmunol 165:33–40PubMedGoogle Scholar
  83. Radak Z, Chung HY, Koltai E et al (2008) Exercise, oxidative stress and hormesis. Ageing Res Rev 7:34–42PubMedGoogle Scholar
  84. Rattan SI (2008) Hormesis in aging. Ageing Res Rev 7:63–78PubMedGoogle Scholar
  85. Rattan SI, Demirovic D (2009) Hormesis can and does work in humans. Dose Response 8:58–63PubMedGoogle Scholar
  86. Ristow M, Schmeisser S (2011) Extending life span by increasing oxidative stress. Free Radic Biol Med 51:327–336PubMedGoogle Scholar
  87. Ristow M, Zarse K (2010) How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp Gerontol 45:410–418PubMedGoogle Scholar
  88. Ruiz Torres A (1991) Basic results for assessment of human ageing. Arch Gerontol Geriatr 12:261–272PubMedGoogle Scholar
  89. Salim S, Chugh G, Asghar M (2012) Inflammation and anxiety. Adv Protein Chem Struct Biol 88:1–25PubMedGoogle Scholar
  90. Salminen A, Huuskonen J, Ojala J (2008a) Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res Rev 7:83–105PubMedGoogle Scholar
  91. Salminen A, Kauppinen A, Suuronen T et al (2008b) SIRT 1 longevity factor suppresses NF-kappaB-driven immune responses: regulation of aging via NF-kappa B acetylation? Bioessays 30:939–942PubMedGoogle Scholar
  92. Schloesser RJ, Lehmann M, Martinowich K et al (2010) Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Mol Psychiatry 15:1152–1163PubMedGoogle Scholar
  93. Shaw AC, Joshi S, Greenwood H et al (2010) Aging of the innate immune system. Curr Opin Immunol 22:507–513PubMedGoogle Scholar
  94. Simpson RJ, Lowder TW, Spielmann G et al (2012) Exercise and the aging immune system. Ageing Res Rev 11:404–420PubMedGoogle Scholar
  95. Strehler BL (1977) Time, cells and aging, 2nd edn. Academic, New YorkGoogle Scholar
  96. Vaiserman AM (2010) Hormesis, adaptive epigenetic reorganization, and implications for human health and longevity. Dose Response 8:16–21PubMedGoogle Scholar
  97. Vallejo AN (2011) Is immune aging a cause of disease among the elderly, or is it a passive indicator of general decline of physiologic function? Aging Dis 2:444–448PubMedGoogle Scholar
  98. Vasto S, Scapagnini G, Bulati M et al (2010) Biomarkers of aging. Front Biosci 2:392–402Google Scholar
  99. Viveros MP, Arranz L, Hernanz A et al (2007) A model of premature ageing in mice based on altered stress-related behavioural response and immunosenescence. Neuroimmunomodulation 14:157–162PubMedGoogle Scholar
  100. Walford L (1969) The immunologic theory of aging. Williams & Wilkins, BaltimoreGoogle Scholar
  101. Walsh NP, Gleeson M, Shepard RJ et al (2011) Positive statement. Part one: immune function and exercise. Exerc Immunol Rev 17:6–63PubMedGoogle Scholar
  102. Wang L, Xie Y, Zhu LJ et al (2010) An association between immunosenescence and CD4(+) CD25(+) regulatory T cells: a systematic review. Biomed Environ Sci 23:327–332PubMedGoogle Scholar
  103. Wayne SJ, Rhyne RL, Garry PJ et al (1990) Cell-mediated immunity as a predictor of morbidity and mortality in subjects over 60. J Gerontol 114:80–88Google Scholar
  104. Williams GC (1957) Pleiotropy, natural selection and the evolution of senescence. Evolution 2:397–411Google Scholar
  105. Yirmiya R, Goshen I (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25:181–213PubMedGoogle Scholar
  106. Yoon SO, Yun CH, Cheng AS (2002) Dose effect of oxidative stress on signal transduction in aging. Mech Ageing Dev 50:1–8Google Scholar

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Authors and Affiliations

  1. 1.Department of Physiology, Faculty of BiologyComplutense University of MadridMadridSpain

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