Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Normal aging

George E Taffet, MD
Section Editor
Kenneth E Schmader, MD
Deputy Editor
H Nancy Sokol, MD


Time modifies many biologic processes. Aging is characterized by progressive and broadly predictable changes that are associated with increased susceptibility to many diseases. Aging is not a homogenous process. Rather, organs in the same person age at different rates influenced by multiple factors, including genetic make-up, lifestyle choices, and environmental exposures. A Danish twin study found that genetics accounted for about 25 percent of the variation in longevity among twins, and environmental factors accounted for about 50 percent [1]. However, with greater longevity (to age 90 or 100), genetic influences became more important.

This topic will present an overview of normal aging. Effects of aging on the endocrine and immune systems, and abnormal aging, are discussed in more detail separately. (See "Endocrine changes with aging" and "Immune function in older adults".)


Physiologic rhythms — The organization of rhythmic physiologic processes is altered by aging. Age impacts the circadian pattern of body temperature, plasma cortisol, and sleep and can cause desynchronization or "internal phase drift." Phase advances can lead to the occurrence of some rhythmic functions (eg, the 24-hour body temperature trough and sleep onset) one to two hours earlier in older adults. The pulsatile secretion of gonadotropins, growth hormone, thyrotropin, melatonin, and adrenocorticotropic hormone (ACTH) are attenuated with age [2]. One source of this dysfunction appears to be neuronal loss in the suprachiasmatic nucleus in the hypothalamus [3]. In addition, age may delay the ability to reset physiologic rhythms to a new photoperiod.

Loss of complexity — Loss of complexity, a concept derived from the field of nonlinear dynamics, may be a general principle of all aging systems [4]. This loss of complexity may result in decreased heart-rate variability, blood-pressure variability, electroencephalographic frequencies, response to auditory frequencies, and response to stress. Age-related loss of complexity may not be immutable, however; as an example, senior athletes show greater heart rate variability than sedentary age-matched controls [5].

Homeostenosis — Homeostenosis refers to the concept that, from maturity to senescence, diminishing physiologic reserves are available to meet challenges to homeostasis. This concept was first recognized by Walter Cannon in the 1940s [6]. Homeostenosis leads to the increased vulnerability to disease that occurs with aging.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Dec 2016. | This topic last updated: Mon Jan 09 00:00:00 GMT+00:00 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. vB Hjelmborg J, Iachine I, Skytthe A, et al. Genetic influence on human lifespan and longevity. Hum Genet 2006; 119:312.
  2. Veldhuis JD. Altered pulsatile and coordinate secretion of pituitary hormones in aging: evidence of feedback disruption. Aging (Milano) 1997; 9:19.
  3. Hofman MA, Swaab DF. Living by the clock: the circadian pacemaker in older people. Ageing Res Rev 2006; 5:33.
  4. Lipsitz LA, Goldberger AL. Loss of 'complexity' and aging. Potential applications of fractals and chaos theory to senescence. JAMA 1992; 267:1806.
  5. Galetta F, Franzoni F, Femia FR, et al. Lifelong physical training prevents the age-related impairment of heart rate variability and exercise capacity in elderly people. J Sports Med Phys Fitness 2005; 45:217.
  6. Cowdry EV. Problems of ageing: biological and medical aspects, 2nd ed, Williams & Wilkins, Baltimore 1942.
  7. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13:818.
  8. Knaus WA, Wagner DP, Draper EA, et al. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest 1991; 100:1619.
  9. Beer RJ, Teasdale TA, Ghusn HF, Taffet GE. Estimation of severity of illness with APACHE II: age-related implications in cardiac arrest outcomes. Resuscitation 1994; 27:189.
  10. Romero-Ortuno R, Wallis S, Biram R, Keevil V. Clinical frailty adds to acute illness severity in predicting mortality in hospitalized older adults: An observational study. Eur J Intern Med 2016; 35:24.
  11. Sansoni P, Cossarizza A, Brianti V, et al. Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood 1993; 82:2767.
  12. Kirkland JL, Tchkonia T, Pirtskhalava T, et al. Adipogenesis and aging: does aging make fat go MAD? Exp Gerontol 2002; 37:757.
  13. French RA, Broussard SR, Meier WA, et al. Age-associated loss of bone marrow hematopoietic cells is reversed by GH and accompanies thymic reconstitution. Endocrinology 2002; 143:690.
  14. Artz AS. From biology to clinical practice: aging and hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 18:S40.
  15. Boggs DR, Patrene KD. Hematopoiesis and aging III: Anemia and a blunted erythropoietic response to hemorrhage in aged mice. Am J Hematol 1985; 19:327.
  16. Harrison DE. Long-term erythropoietic repopulating ability of old, young, and fetal stem cells. J Exp Med 1983; 157:1496.
  17. Lipschitz DA, Udupa KB, Milton KY, Thompson CO. Effect of age on hematopoiesis in man. Blood 1984; 63:502.
  18. Bagnara GP, Bonsi L, Strippoli P, et al. Hemopoiesis in healthy old people and centenarians: well-maintained responsiveness of CD34+ cells to hemopoietic growth factors and remodeling of cytokine network. J Gerontol A Biol Sci Med Sci 2000; 55:B61.
  19. Albright JW, Makinodan T. Decline in the growth potential of spleen-colonizing bone marrow stem cells of long-lived aging mice. J Exp Med 1976; 144:1204.
  20. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371:2488.
  21. Pinto A, De Filippi R, Frigeri F, et al. Aging and the hemopoietic system. Crit Rev Oncol Hematol 2003; 48:S3.
  22. Fuentes E, Palomo I. Role of oxidative stress on platelet hyperreactivity during aging. Life Sci 2016; 148:17.
  23. Franchini M. Hemostasis and aging. Crit Rev Oncol Hematol 2006; 60:144.
  24. Isaia G, Greppi F, Ausiello L, et al. D-dimer plasma concentrations in an older hospitalized population. J Am Geriatr Soc 2011; 59:2385.
  25. Mehta J, Mehta P, Lawson D, Saldeen T. Plasma tissue plasminogen activator inhibitor levels in coronary artery disease: correlation with age and serum triglyceride concentrations. J Am Coll Cardiol 1987; 9:263.
  26. Yamamoto K, Takeshita K, Kojima T, et al. Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly. Cardiovasc Res 2005; 66:276.
  27. Yamamoto K, Takeshita K, Shimokawa T, et al. Plasminogen activator inhibitor-1 is a major stress-regulated gene: implications for stress-induced thrombosis in aged individuals. Proc Natl Acad Sci U S A 2002; 99:890.
  28. Hall KE, Proctor DD, Fisher L, Rose S. American gastroenterological association future trends committee report: effects of aging of the population on gastroenterology practice, education, and research. Gastroenterology 2005; 129:1305.
  29. Dunn-Walters DK, Howard WA, Bible JM. The Aeging Gut. Mech Ageing Dev 2004; 125:851.
  30. Smith CH, Boland B, Daureeawoo Y, et al. Effect of aging on stimulated salivary flow in adults. J Am Geriatr Soc 2013; 61:805.
  31. Nagler RM, Hershkovich O. Age-related changes in unstimulated salivary function and composition and its relations to medications and oral sensorial complaints. Aging Clin Exp Res 2005; 17:358.
  32. Fulp SR, Dalton CB, Castell JA, Castell DO. Aging-related alterations in human upper esophageal sphincter function. Am J Gastroenterol 1990; 85:1569.
  33. Frederick MG, Ott DJ, Grishaw EK, et al. Functional abnormalities of the pharynx: a prospective analysis of radiographic abnormalities relative to age and symptoms. AJR Am J Roentgenol 1996; 166:353.
  34. Lasch H, Castell DO, Castell JA. Evidence for diminished visceral pain with aging: studies using graded intraesophageal balloon distension. Am J Physiol 1997; 272:G1.
  35. Kekki M, Samloff IM, Ihamäki T, et al. Age- and sex-related behaviour of gastric acid secretion at the population level. Scand J Gastroenterol 1982; 17:737.
  36. Feldman M, Cryer B, McArthur KE, et al. Effects of aging and gastritis on gastric acid and pepsin secretion in humans: a prospective study. Gastroenterology 1996; 110:1043.
  37. Hurwitz A, Brady DA, Schaal SE, et al. Gastric acidity in older adults. JAMA 1997; 278:659.
  38. Haruma K, Kamada T, Kawaguchi H, et al. Effect of age and Helicobacter pylori infection on gastric acid secretion. J Gastroenterol Hepatol 2000; 15:277.
  39. Marshall BJ. Helicobacter pylori. Am J Gastroenterol 1994; 89:S116.
  40. Guslandi M, Pellegrini A, Sorghi M. Gastric mucosal defences in the elderly. Gerontology 1999; 45:206.
  41. Tarnawski AS, Ahluwalia A, Jones MK. Increased susceptibility of aging gastric mucosa to injury: the mechanisms and clinical implications. World J Gastroenterol 2014; 20:4467.
  42. Gomez-Pinilla PJ, Gibbons SJ, Sarr MG, et al. Changes in interstitial cells of cajal with age in the human stomach and colon. Neurogastroenterol Motil 2011; 23:36.
  43. Saltzman JR, Russell RM. The aging gut. Nutritional issues. Gastroenterol Clin North Am 1998; 27:309.
  44. Salles N. Basic mechanisms of the aging gastrointestinal tract. Dig Dis 2007; 25:112.
  45. Drozdowski L, Thomson AB. Aging and the intestine. World J Gastroenterol 2006; 12:7578.
  46. Parlesak A, Klein B, Schecher K, et al. Prevalence of small bowel bacterial overgrowth and its association with nutrition intake in nonhospitalized older adults. J Am Geriatr Soc 2003; 51:768.
  47. Man AL, Bertelli E, Rentini S, et al. Age-associated modifications of intestinal permeability and innate immunity in human small intestine. Clin Sci (Lond) 2015; 129:515.
  48. Hilton D, Iman N, Burke GJ, et al. Absence of abdominal pain in older persons with endoscopic ulcers: a prospective study. Am J Gastroenterol 2001; 96:380.
  49. Cowen T, Johnson RJ, Soubeyre V, Santer RM. Restricted diet rescues rat enteric motor neurones from age related cell death. Gut 2000; 47:653.
  50. Wade PR, Hornby PJ. Age-related neurodegenerative changes and how they affect the gut. Sci Aging Knowledge Environ 2005; 2005:pe8.
  51. Lyon C, Clark DC. Diagnosis of acute abdominal pain in older patients. Am Fam Physician 2006; 74:1537.
  52. Gundling F, Seidl H, Scalercio N, et al. Influence of gender and age on anorectal function: normal values from anorectal manometry in a large caucasian population. Digestion 2010; 81:207.
  53. Bitar KN, Patil SB. Aging and gastrointestinal smooth muscle. Mech Ageing Dev 2004; 125:907.
  54. Lewicky-Gaupp C, Hamilton Q, Ashton-Miller J, et al. Anal sphincter structure and function relationships in aging and fecal incontinence. Am J Obstet Gynecol 2009; 200:559.e1.
  55. Comparato G, Pilotto A, Franzè A, et al. Diverticular disease in the elderly. Dig Dis 2007; 25:151.
  56. Commane DM, Arasaradnam RP, Mills S, et al. Diet, ageing and genetic factors in the pathogenesis of diverticular disease. World J Gastroenterol 2009; 15:2479.
  57. Xiao ZQ, Moragoda L, Jaszewski R, et al. Aging is associated with increased proliferation and decreased apoptosis in the colonic mucosa. Mech Ageing Dev 2001; 122:1849.
  58. Tran L, Greenwood-Van Meerveld B. Age-associated remodeling of the intestinal epithelial barrier. J Gerontol A Biol Sci Med Sci 2013; 68:1045.
  59. McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004; 56:163.
  60. Schmucker DL. Aging and the liver: an update. J Gerontol A Biol Sci Med Sci 1998; 53:B315.
  61. Rahmioglu N, Andrew T, Cherkas L, et al. Epidemiology and genetic epidemiology of the liver function test proteins. PLoS One 2009; 4:e4435.
  62. Anantharaju A, Feller A, Chedid A. Aging Liver. A review. Gerontology 2002; 48:343.
  63. Fu A, Nair KS. Age effect on fibrinogen and albumin synthesis in humans. Am J Physiol 1998; 275:E1023.
  64. Tietz NW, Shuey DF, Wekstein DR. Laboratory values in fit aging individuals--sexagenarians through centenarians. Clin Chem 1992; 38:1167.
  65. Rudman D, Feller AG, Nagraj HS, et al. Relation of serum albumin concentration to death rate in nursing home men. JPEN J Parenter Enteral Nutr 1987; 11:360.
  66. Schmucker DL. Age-related changes in liver structure and function: Implications for disease ? Exp Gerontol 2005; 40:650.
  67. Sotaniemi EA, Arranto AJ, Pelkonen O, Pasanen M. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther 1997; 61:331.
  68. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol 2003; 38:843.
  69. Froom P, Miron E, Barak M. Oral anticoagulants in the elderly. Br J Haematol 2003; 120:526.
  70. Valdivieso V, Palma R, Wünkhaus R, et al. Effect of aging on biliary lipid composition and bile acid metabolism in normal Chilean women. Gastroenterology 1978; 74:871.
  71. Bülow R, Simon P, Thiel R, et al. Anatomic variants of the pancreatic duct and their clinical relevance: an MR-guided study in the general population. Eur Radiol 2014; 24:3142.
  72. Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec 1992; 232:194.
  73. Tracy RE, Velez-Duran M, Heigle T, Oalmann MC. Two variants of nephrosclerosis separately related to age and blood pressure. Am J Pathol 1988; 131:270.
  74. Long DA, Mu W, Price KL, Johnson RJ. Blood vessels and the aging kidney. Nephron Exp Nephrol 2005; 101:e95.
  75. Rule AD, Amer H, Cornell LD, et al. The association between age and nephrosclerosis on renal biopsy among healthy adults. Ann Intern Med 2010; 152:561.
  76. Fuiano G, Sund S, Mazza G, et al. Renal hemodynamic response to maximal vasodilating stimulus in healthy older subjects. Kidney Int 2001; 59:1052.
  77. Esposito C, Plati A, Mazzullo T, et al. Renal function and functional reserve in healthy elderly individuals. J Nephrol 2007; 20:617.
  78. Ungar A, Cristofari C, Torrini M, et al. Changes in renal autacoids in aged human hypertensives. J Physiol Pharmacol 2000; 51:619.
  79. Field TS, Gurwitz JH, Glynn RJ, et al. The renal effects of nonsteroidal anti-inflammatory drugs in older people: findings from the Established Populations for Epidemiologic Studies of the Elderly. J Am Geriatr Soc 1999; 47:507.
  80. Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med 1999; 106:13S.
  81. Lindeman RD. Overview: renal physiology and pathophysiology of aging. Am J Kidney Dis 1990; 16:275.
  82. Giannelli SV, Patel KV, Windham BG, et al. Magnitude of underascertainment of impaired kidney function in older adults with normal serum creatinine. J Am Geriatr Soc 2007; 55:816.
  83. Fliser D. Assessment of renal function in elderly patients. Curr Opin Nephrol Hypertens 2008; 17:604.
  84. Lopes MB, Araújo LQ, Passos MT, et al. Estimation of glomerular filtration rate from serum creatinine and cystatin C in octogenarians and nonagenarians. BMC Nephrol 2013; 14:265.
  85. Christensson A, Elmståhl S. Estimation of the age-dependent decline of glomerular filtration rate from formulas based on creatinine and cystatin C in the general elderly population. Nephron Clin Pract 2011; 117:c40.
  86. Odden MC, Tager IB, Gansevoort RT, et al. Age and cystatin C in healthy adults: a collaborative study. Nephrol Dial Transplant 2010; 25:463.
  87. Sands JM. Urine concentrating and diluting ability during aging. J Gerontol A Biol Sci Med Sci 2012; 67:1352.
  88. Pucelikova T, Dangas G, Mehran R. Contrast-induced nephropathy. Catheter Cardiovasc Interv 2008; 71:62.
  89. Toprak O. Risk markers for contrast-induced nephropathy. Am J Med Sci 2007; 334:283.
  90. Schmitt R, Cantley LG. The impact of aging on kidney repair. Am J Physiol Renal Physiol 2008; 294:F1265.
  91. Ishida M, Bulos B, Takamoto S, Sacktor B. Hydroxylation of 25-hydroxyvitamin D3 by renal mitochondria from rats of different ages. Endocrinology 1987; 121:443.
  92. Diz DI. Lewis K. Dahl memorial lecture: the renin-angiotensin system and aging. Hypertension 2008; 52:37.
  93. Powers JS, Krantz SB, Collins JC, et al. Erythropoietin response to anemia as a function of age. J Am Geriatr Soc 1991; 39:30.
  94. White N. The relationship of the degree of coronary atherosclerosis with age in men. Circulation 1950; 1:645.
  95. Fleg JL, O'Connor F, Gerstenblith G, et al. Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol (1985) 1995; 78:890.
  96. Taffet GE, Lakatta EG. Aging of the Cardiovascular System. In: Principles of Geriatric Medicine and Gerontology, 5th ed, Hazzard WR, Blass JP, Halter JB, et al. (Eds), McGraw-Hill, New York 2003. p.403.
  97. Van de Veire NR, De Backer J, Ascoop AK, et al. Echocardiographically estimated left ventricular end-diastolic and right ventricular systolic pressure in normotensive healthy individuals. Int J Cardiovasc Imaging 2006; 22:633.
  98. Gates PE, Tanaka H, Graves J, Seals DR. Left ventricular structure and diastolic function with human ageing. Relation to habitual exercise and arterial stiffness. Eur Heart J 2003; 24:2213.
  99. Kitzman DW, Scholz DG, Hagen PT, et al. Age-related changes in normal human hearts during the first 10 decades of life. Part II (Maturity): A quantitative anatomic study of 765 specimens from subjects 20 to 99 years old. Mayo Clin Proc 1988; 63:137.
  100. Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal in humans. Science 2009; 324:98.
  101. Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res 1991; 68:1560.
  102. Zhang XP, Vatner SF, Shen YT, et al. Increased apoptosis and myocyte enlargement with decreased cardiac mass; distinctive features of the aging male, but not female, monkey heart. J Mol Cell Cardiol 2007; 43:487.
  103. Kajstura J, Cheng W, Sarangarajan R, et al. Necrotic and apoptotic myocyte cell death in the aging heart of Fischer 344 rats. Am J Physiol 1996; 271:H1215.
  104. Jones SA, Boyett MR, Lancaster MK. Declining into failure: the age-dependent loss of the L-type calcium channel within the sinoatrial node. Circulation 2007; 115:1183.
  105. Stratton JR, Cerqueira MD, Schwartz RS, et al. Differences in cardiovascular responses to isoproterenol in relation to age and exercise training in healthy men. Circulation 1992; 86:504.
  106. Parati G, Di Rienzo M. Determinants of heart rate and heart rate variability. J Hypertens 2003; 21:477.
  107. Fleg JL, Kennedy HL. Long-term prognostic significance of ambulatory electrocardiographic findings in apparently healthy subjects greater than or equal to 60 years of age. Am J Cardiol 1992; 70:748.
  108. Busby MJ, Shefrin EA, Fleg JL. Prevalence and long-term significance of exercise-induced frequent or repetitive ventricular ectopic beats in apparently healthy volunteers. J Am Coll Cardiol 1989; 14:1659.
  109. Stratton JR, Levy WC, Cerqueira MD, et al. Cardiovascular responses to exercise. Effects of aging and exercise training in healthy men. Circulation 1994; 89:1648.
  110. Swinne CJ, Shapiro EP, Lima SD, Fleg JL. Age-associated changes in left ventricular diastolic performance during isometric exercise in normal subjects. Am J Cardiol 1992; 69:823.
  111. Gillooly M, Lamb D. Airspace size in lungs of lifelong non-smokers: effect of age and sex. Thorax 1993; 48:39.
  112. Janssens JP. Aging of the respiratory system: impact on pulmonary function tests and adaptation to exertion. Clin Chest Med 2005; 26:469.
  113. Taylor BJ, Johnson BD. The pulmonary circulation and exercise responses in the elderly. Semin Respir Crit Care Med 2010; 31:528.
  114. Tagaram HR, Wang G, Umstead TM, et al. Characterization of a human surfactant protein A1 (SP-A1) gene-specific antibody; SP-A1 content variation among individuals of varying age and pulmonary health. Am J Physiol Lung Cell Mol Physiol 2007; 292:L1052.
  115. Moliva JI, Rajaram MV, Sidiki S, et al. Molecular composition of the alveolar lining fluid in the aging lung. Age (Dordr) 2014; 36:933.
  116. Stam H, Hrachovina V, Stijnen T, Versprille A. Diffusing capacity dependent on lung volume and age in normal subjects. J Appl Physiol (1985) 1994; 76:2356.
  117. Hardie JA, Mørkve O, Ellingsen I. Effect of body position on arterial oxygen tension in the elderly. Respiration 2002; 69:123.
  118. Crapo RO, Jensen RL, Hegewald M, Tashkin DP. Arterial blood gas reference values for sea level and an altitude of 1,400 meters. Am J Respir Crit Care Med 1999; 160:1525.
  119. Cerveri I, Zoia MC, Fanfulla F, et al. Reference values of arterial oxygen tension in the middle-aged and elderly. Am J Respir Crit Care Med 1995; 152:934.
  120. Hardie JA, Vollmer WM, Buist AS, et al. Reference values for arterial blood gases in the elderly. Chest 2004; 125:2053.
  121. Estenne M, Yernault JC, De Troyer A. Rib cage and diaphragm-abdomen compliance in humans: effects of age and posture. J Appl Physiol (1985) 1985; 59:1842.
  122. Polkey MI, Harris ML, Hughes PD, et al. The contractile properties of the elderly human diaphragm. Am J Respir Crit Care Med 1997; 155:1560.
  123. Kuster SP, Kuster D, Schindler C, et al. Reference equations for lung function screening of healthy never-smoking adults aged 18-80 years. Eur Respir J 2008; 31:860.
  124. Xu X, Laird N, Dockery DW, et al. Age, period, and cohort effects on pulmonary function in a 24-year longitudinal study. Am J Epidemiol 1995; 141:554.
  125. Taffet GE, Donohue JF, Altman PR. Considerations for managing chronic obstructive pulmonary disease in the elderly. Clin Interv Aging 2014; 9:23.
  126. Enright PL, Kronmal RA, Manolio TA, et al. Respiratory muscle strength in the elderly. Correlates and reference values. Cardiovascular Health Study Research Group. Am J Respir Crit Care Med 1994; 149:430.
  127. Summerhill EM, Angov N, Garber C, McCool FD. Respiratory muscle strength in the physically active elderly. Lung 2007; 185:315.
  128. Kronenberg RS, Drage CW. Attenuation of the ventilatory and heart rate responses to hypoxia and hypercapnia with aging in normal men. J Clin Invest 1973; 52:1812.
  129. Pack AI, Millman RP. Changes in control of ventilation, awake and asleep, in the elderly. J Am Geriatr Soc 1986; 34:533.
  130. Svartengren M, Falk R, Philipson K. Long-term clearance from small airways decreases with age. Eur Respir J 2005; 26:609.
  131. Fleg JL, Morrell CH, Bos AG, et al. Accelerated longitudinal decline of aerobic capacity in healthy older adults. Circulation 2005; 112:674.
  132. Hollenberg M, Yang J, Haight TJ, Tager IB. Longitudinal changes in aerobic capacity: implications for concepts of aging. J Gerontol A Biol Sci Med Sci 2006; 61:851.
  133. Hu TW, Wagner TH, Bentkover JD, et al. Costs of urinary incontinence and overactive bladder in the United States: a comparative study. Urology 2004; 63:461.
  134. Elbadawi A, Diokno AC, Millard RJ. The aging bladder: morphology and urodynamics. World J Urol 1998; 16 Suppl 1:S10.
  135. Gilpin SA, Gilpin CJ, Dixon JS, et al. The effect of age on the autonomic innervation of the urinary bladder. Br J Urol 1986; 58:378.
  136. Tadic SD, Griffiths D, Schaefer W, et al. Brain activity underlying impaired continence control in older women with overactive bladder. Neurourol Urodyn 2012; 31:652.
  137. Dubeau CE. The aging lower urinary tract. J Urol 2006; 175:S11.
  138. Capobianco G, Donolo E, Borghero G, et al. Effects of intravaginal estriol and pelvic floor rehabilitation on urogenital aging in postmenopausal women. Arch Gynecol Obstet 2012; 285:397.
  139. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol 2003; 44:637.
  140. Lindau ST, Gavrilova N. Sex, health, and years of sexually active life gained due to good health: evidence from two US population based cross sectional surveys of ageing. BMJ 2010; 340:c810.
  141. Seftel AD. From aspiration to achievement: assessment and noninvasive treatment of erectile dysfunction in aging men. J Am Geriatr Soc 2005; 53:119.
  142. Harris ID, Fronczak C, Roth L, Meacham RB. Fertility and the aging male. Rev Urol 2011; 13:e184.
  143. Hermann M, Untergasser G, Rumpold H, Berger P. Aging of the male reproductive system. Exp Gerontol 2000; 35:1267.
  144. Tarlatzis BC, Zepiridis L. Perimenopausal conception. Ann N Y Acad Sci 2003; 997:93.
  145. Kingsberg SA. The impact of aging on sexual function in women and their partners. Arch Sex Behav 2002; 31:431.
  146. Baumgartner RN, Waters DL, Gallagher D, et al. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 1999; 107:123.
  147. Pasco JA, Mohebbi M, Holloway KL, et al. Musculoskeletal decline and mortality: prospective data from the Geelong Osteoporosis Study. J Cachexia Sarcopenia Muscle 2016.
  148. Ryall JG, Schertzer JD, Lynch GS. Cellular and molecular mechanisms underlying age-related skeletal muscle wasting and weakness. Biogerontology 2008; 9:213.
  149. Reinders I, Murphy RA, Brouwer IA, et al. Muscle Quality and Myosteatosis: Novel Associations With Mortality Risk: The Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. Am J Epidemiol 2016; 183:53.
  150. Reinders I, Murphy RA, Koster A, et al. Muscle Quality and Muscle Fat Infiltration in Relation to Incident Mobility Disability and Gait Speed Decline: the Age, Gene/Environment Susceptibility-Reykjavik Study. J Gerontol A Biol Sci Med Sci 2015; 70:1030.
  151. Cesari M, Pahor M, Lauretani F, et al. Skeletal muscle and mortality results from the InCHIANTI Study. J Gerontol A Biol Sci Med Sci 2009; 64:377.
  152. Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 2001; 86:5755.
  153. Pruchnic R, Katsiaras A, He J, et al. Exercise training increases intramyocellular lipid and oxidative capacity in older adults. Am J Physiol Endocrinol Metab 2004; 287:E857.
  154. Faulkner JA, Larkin LM, Claflin DR, Brooks SV. Age-related changes in the structure and function of skeletal muscles. Clin Exp Pharmacol Physiol 2007; 34:1091.
  155. Delbono O. Neural control of aging skeletal muscle. Aging Cell 2003; 2:21.
  156. Brooks SV, Faulkner JA. Contractile properties of skeletal muscles from young, adult and aged mice. J Physiol 1988; 404:71.
  157. Degens H. Age-related skeletal muscle dysfunction: causes and mechanisms. J Musculoskelet Neuronal Interact 2007; 7:246.
  158. Carlson BM, Faulkner JA. Muscle transplantation between young and old rats: age of host determines recovery. Am J Physiol 1989; 256:C1262.
  159. Musch TI, Eklund KE, Hageman KS, Poole DC. Altered regional blood flow responses to submaximal exercise in older rats. J Appl Physiol (1985) 2004; 96:81.
  160. Sinha M, Jang YC, Oh J, et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 2014; 344:649.
  161. Brun CE, Rudnicki MA. GDF11 and the Mythical Fountain of Youth. Cell Metab 2015; 22:54.
  162. Chan GK, Duque G. Age-related bone loss: old bone, new facts. Gerontology 2002; 48:62.
  163. Giangregorio L, Blimkie CJ. Skeletal adaptations to alterations in weight-bearing activity: a comparison of models of disuse osteoporosis. Sports Med 2002; 32:459.
  164. Schwab P, Klein RF. Nonpharmacological approaches to improve bone health and reduce osteoporosis. Curr Opin Rheumatol 2008; 20:213.
  165. Meyer RA Jr, Desai BR, Heiner DE, et al. Young, adult, and old rats have similar changes in mRNA expression of many skeletal genes after fracture despite delayed healing with age. J Orthop Res 2006; 24:1933.
  166. Gruber R, Koch H, Doll BA, et al. Fracture healing in the elderly patient. Exp Gerontol 2006; 41:1080.
  167. Driscoll I, Davatzikos C, An Y, et al. Longitudinal pattern of regional brain volume change differentiates normal aging from MCI. Neurology 2009; 72:1906.
  168. Salat DH, Kaye JA, Janowsky JS. Prefrontal gray and white matter volumes in healthy aging and Alzheimer disease. Arch Neurol 1999; 56:338.
  169. Wagner M, Jurcoane A, Volz S, et al. Age-related changes of cerebral autoregulation: new insights with quantitative T2'-mapping and pulsed arterial spin-labeling MR imaging. AJNR Am J Neuroradiol 2012; 33:2081.
  170. Moreno-Torres A, Pujol J, Soriano-Mas C, et al. Age-related metabolic changes in the upper brainstem tegmentum by MR spectroscopy. Neurobiol Aging 2005; 26:1051.
  171. Walhovd KB, Westlye LT, Amlien I, et al. Consistent neuroanatomical age-related volume differences across multiple samples. Neurobiol Aging 2011; 32:916.
  172. Lee NJ, Park IS, Koh I, et al. No volume difference of medulla oblongata between young and old Korean people. Brain Res 2009; 1276:77.
  173. Sastry PS, Rao KS. Apoptosis and the nervous system. J Neurochem 2000; 74:1.
  174. Dorszewska J. Cell biology of normal brain aging: synaptic plasticity-cell death. Aging Clin Exp Res 2013; 25:25.
  175. van der Zee EA. Synapses, spines and kinases in mammalian learning and memory, and the impact of aging. Neurosci Biobehav Rev 2015; 50:77.
  176. Terman A, Brunk UT. Lipofuscin: mechanisms of formation and increase with age. APMIS 1998; 106:265.
  177. Mountz JM, Laymon CM, Cohen AD, et al. Comparison of qualitative and quantitative imaging characteristics of [11C]PiB and [18F]flutemetamol in normal control and Alzheimer's subjects. Neuroimage Clin 2015; 9:592.
  178. Schöll M, Lockhart SN, Schonhaut DR, et al. PET Imaging of Tau Deposition in the Aging Human Brain. Neuron 2016; 89:971.
  179. Schliebs R, Arendt T. The cholinergic system in aging and neuronal degeneration. Behav Brain Res 2011; 221:555.
  180. Anglade P, Vyas S, Javoy-Agid F, et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol Histopathol 1997; 12:25.
  181. Klostermann EC, Braskie MN, Landau SM, et al. Dopamine and frontostriatal networks in cognitive aging. Neurobiol Aging 2012; 33:623.e15.
  182. Chowdhury R, Guitart-Masip M, Lambert C, et al. Dopamine restores reward prediction errors in old age. Nat Neurosci 2013; 16:648.
  183. Fjell AM, McEvoy L, Holland D, et al. What is normal in normal aging? Effects of aging, amyloid and Alzheimer's disease on the cerebral cortex and the hippocampus. Prog Neurobiol 2014; 117:20.
  184. Reuter-Lorenz PA, Jonides J, Smith EE, et al. Age differences in the frontal lateralization of verbal and spatial working memory revealed by PET. J Cogn Neurosci 2000; 12:174.
  185. Wilson RS, Beckett LA, Barnes LL, et al. Individual differences in rates of change in cognitive abilities of older persons. Psychol Aging 2002; 17:179.
  186. Salthouse T. Consequences of age-related cognitive declines. Annu Rev Psychol 2012; 63:201.
  187. Cognitive Neuroscience of Aging: Linking Cognitive and Cerebral Aging, Cabeza R, Nyberg L, Park D. (Eds), Oxford University Press, New York 2004.
  188. Draganski B, Lutti A, Kherif F. Impact of brain aging and neurodegeneration on cognition: evidence from MRI. Curr Opin Neurol 2013; 26:640.
  189. Tam HM, Lam CL, Huang H, et al. Age-related difference in relationships between cognitive processing speed and general cognitive status. Appl Neuropsychol Adult 2015; 22:94.
  190. Harada CN, Natelson Love MC, Triebel KL. Normal cognitive aging. Clin Geriatr Med 2013; 29:737.
  191. Yang AC, Huang CC, Yeh HL, et al. Complexity of spontaneous BOLD activity in default mode network is correlated with cognitive function in normal male elderly: a multiscale entropy analysis. Neurobiol Aging 2013; 34:428.
  192. Petersen SE, van Mier H, Fiez JA, Raichle ME. The effects of practice on the functional anatomy of task performance. Proc Natl Acad Sci U S A 1998; 95:853.
  193. Reuter-Lorenz PA, Lustig C. Brain aging: reorganizing discoveries about the aging mind. Curr Opin Neurobiol 2005; 15:245.
  194. Reuter-Lorenz PA, Cappell KA. Neurocognitive aging and the compensation hypothesis. Curr Dir Psychol Sci 2008; 17:177.
  195. Reuter-Lorenz PA, Park DC. How does it STAC up? Revisiting the scaffolding theory of aging and cognition. Neuropsychol Rev 2014; 24:355.
  196. Amieva H, Stoykova R, Matharan F, et al. What aspects of social network are protective for dementia? Not the quantity but the quality of social interactions is protective up to 15 years later. Psychosom Med 2010; 72:905.
  197. Middleton LE, Yaffe K. Promising strategies for the prevention of dementia. Arch Neurol 2009; 66:1210.
  198. Ball K, Edwards JD, Ross LA. The impact of speed of processing training on cognitive and everyday functions. J Gerontol B Psychol Sci Soc Sci 2007; 62 Spec No 1:19.
  199. Engvig A, Fjell AM, Westlye LT, et al. Effects of cognitive training on gray matter volumes in memory clinic patients with subjective memory impairment. J Alzheimers Dis 2014; 41:779.
  200. Moragas A, Castells C, Sans M. Mathematical morphologic analysis of aging-related epidermal changes. Anal Quant Cytol Histol 1993; 15:75.
  201. Montagna W, Carlisle K. Structural changes in ageing skin. Br J Dermatol 1990; 122 Suppl 35:61.
  202. Ashcroft GS, Mills SJ, Ashworth JJ. Ageing and wound healing. Biogerontology 2002; 3:337.
  203. Yaar M, Gilchrest BA. Skin aging: postulated mechanisms and consequent changes in structure and function. Clin Geriatr Med 2001; 17:617.
  204. Varani J, Dame MK, Rittie L, et al. Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am J Pathol 2006; 168:1861.
  205. Uitto J. The role of elastin and collagen in cutaneous aging: intrinsic aging versus photoexposure. J Drugs Dermatol 2008; 7:s12.
  206. Anderson RK, Kenney WL. Effect of age on heat-activated sweat gland density and flow during exercise in dry heat. J Appl Physiol (1985) 1987; 63:1089.
  207. Inbar O, Morris N, Epstein Y, Gass G. Comparison of thermoregulatory responses to exercise in dry heat among prepubertal boys, young adults and older males. Exp Physiol 2004; 89:691.
  208. Perry SD. Evaluation of age-related plantar-surface insensitivity and onset age of advanced insensitivity in older adults using vibratory and touch sensation tests. Neurosci Lett 2006; 392:62.
  209. Matsuoka S, Suzuki H, Morioka S, et al. Quantitative and qualitative studies of Meissner's corpuscles in human skin, with special reference to alterations caused by aging. J Dermatol 1983; 10:205.
  210. Gescheider GA, Bolanowski SJ, Hall KL, et al. The effects of aging on information-processing channels in the sense of touch: I. Absolute sensitivity. Somatosens Mot Res 1994; 11:345.
  211. Holick MF, Matsuoka LY, Wortsman J. Age, vitamin D, and solar ultraviolet. Lancet 1989; 2:1104.
  212. McCullough JL, Kelly KM. Prevention and treatment of skin aging. Ann N Y Acad Sci 2006; 1067:323.
  213. Griffiths CE. The role of retinoids in the prevention and repair of aged and photoaged skin. Clin Exp Dermatol 2001; 26:613.
  214. Van Haeringen NJ. Aging and the lacrimal system. Br J Ophthalmol 1997; 81:824.
  215. Schnohr P, Nyboe J, Lange P, Jensen G. Longevity and gray hair, baldness, facial wrinkles, and arcus senilis in 13,000 men and women: the Copenhagen City Heart Study. J Gerontol A Biol Sci Med Sci 1998; 53:M347.
  216. Salvi SM, Akhtar S, Currie Z. Ageing changes in the eye. Postgrad Med J 2006; 82:581.
  217. Bishop PN, Holmes DF, Kadler KE, et al. Age-related changes on the surface of vitreous collagen fibrils. Invest Ophthalmol Vis Sci 2004; 45:1041.
  218. Strenk SA, Strenk LM, Koretz JF. The mechanism of presbyopia. Prog Retin Eye Res 2005; 24:379.
  219. Liem AT, Keunen JE, van Norren D, van de Kraats J. Rod densitometry in the aging human eye. Invest Ophthalmol Vis Sci 1991; 32:2676.
  220. Gates GA, Mills JH. Presbycusis. Lancet 2005; 366:1111.
  221. Howarth A, Shone GR. Ageing and the auditory system. Postgrad Med J 2006; 82:166.
  222. Mojet J, Christ-Hazelhof E, Heidema J. Taste perception with age: generic or specific losses in threshold sensitivity to the five basic tastes? Chem Senses 2001; 26:845.
  223. Gudziol H, Hummel T. Normative values for the assessment of gustatory function using liquid tastants. Acta Otolaryngol 2007; 127:658.
  224. Boyce JM, Shone GR. Effects of ageing on smell and taste. Postgrad Med J 2006; 82:239.
  225. Franceschi C. Inflammaging as a major characteristic of old people: can it be prevented or cured? Nutr Rev 2007; 65:S173.
  226. Liao CY, Rikke BA, Johnson TE, et al. Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging Cell 2010; 9:92.
  227. 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; 489:318.
  228. Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009; 325:201.
  229. Lee HW, Blasco MA, Gottlieb GJ, et al. Essential role of mouse telomerase in highly proliferative organs. Nature 1998; 392:569.
  230. Rudolph KL, Chang S, Lee HW, et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999; 96:701.
  231. Salpea KD, Humphries SE. Telomere length in atherosclerosis and diabetes. Atherosclerosis 2010; 209:35.
  232. Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care 2014; 17:324.
  233. Hoare M, Narita M. Transmitting senescence to the cell neighbourhood. Nat Cell Biol 2013; 15:887.
  234. Sahin E, Colla S, Liesa M, et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 2011; 470:359.
  235. Miller RA, Harrison DE, Astle CM, et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 2011; 66:191.
  236. Walter LC, Covinsky KE. Cancer screening in elderly patients: a framework for individualized decision making. JAMA 2001; 285:2750.
  237. Newman AB, Arnold AM, Sachs MC, et al. Long-term function in an older cohort--the cardiovascular health study all stars study. J Am Geriatr Soc 2009; 57:432.
  238. Britton A, Shipley M, Singh-Manoux A, Marmot MG. Successful aging: the contribution of early-life and midlife risk factors. J Am Geriatr Soc 2008; 56:1098.
  239. Perls TT, Wilmoth J, Levenson R, et al. Life-long sustained mortality advantage of siblings of centenarians. Proc Natl Acad Sci U S A 2002; 99:8442.
  240. Atzmon G, Rincon M, Rabizadeh P, Barzilai N. Biological evidence for inheritance of exceptional longevity. Mech Ageing Dev 2005; 126:341.
  241. Libina N, Berman JR, Kenyon C. Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 2003; 115:489.
  242. Franceschi C, Motta L, Valensin S, et al. Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE). Aging (Milano) 2000; 12:77.
  243. Willcox DC, Willcox BJ, Todoriki H, et al. Caloric restriction and human longevity: what can we learn from the Okinawans? Biogerontology 2006; 7:173.
  244. Willcox BJ, Willcox DC, He Q, et al. Siblings of Okinawan centenarians share lifelong mortality advantages. J Gerontol A Biol Sci Med Sci 2006; 61:345.