Journal of the American Aging Association

, Volume 23, Issue 2, pp 103–115 | Cite as

Endocrine and metabolic changes in human aging

Article

Abstract

Numerous alterations in hormonal secretion occur with aging. In general, these tend towards a disintegration of the normal cyclic secretory patterns resulting in lower total circulating levels. In addition, declines in receptors and postreceptor function further decreases the ability of the hormonal orchestra to maintain coordinated function throughout the organism. Clues to some of these age-related changes in humans may come from the study of simpler organisms where regulatory systems are known to modulate the aging process. In particular, the interactions among the environment, hormones, and insulin receptor genes have led to new insights into the genetic control of longevity and the development of syndrome X.

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References

  1. 1.
    Mooradian, AD, Morley JE, and Korenman SG: Endocrinology in aging. Dis. Mon., 34:393–461, 1988.PubMedGoogle Scholar
  2. 2.
    Baumgartner, RN, Waters, DL, Gallagher, D, Morley, JE, and Garry, PJ: Predictors of skeletal muscle mass in elderly men and women. Mech. Ageing Dev., 107: 123–36, 1999.PubMedGoogle Scholar
  3. 3.
    Morley, JE, and Thomas, DR: Anorexia and aging: pathophysiology. Nutrition, 15:499–503, 1999.PubMedGoogle Scholar
  4. 4.
    Baumgartner, RN, Ross, RR, Waters, DL, Brooks, WM, Morley, JE, Montoya, GD, and Garry, PJ: Serum leptin in elderly people: associations with sex hormones, insulin, and adipose tissue volumes. Obes. Res., 7:141–9, 1999.PubMedGoogle Scholar
  5. 5.
    Friedman, EA: Advanced glycosylated end products and hyperglycemia in the pathogenesis of diabetic complications. Diabetes Care, 22:B65–71, 1999.PubMedGoogle Scholar
  6. 6.
    Morley, JE: Geriatrics, in Yearbook of Endocrinology, 1993, edited by Bagdade JD, St. Louis, Mosby, 1993, pp. 61–65.Google Scholar
  7. 7.
    Snowdon, DA, Kane, RL, Beeson, WL, Burke, GL, Sprafka, JM, Potter, J, Iso, H, Jacobs DR Jr, and Phillips, RL: Is early natural menopause a biologic marker of health and aging? Am. J. Public Health, 79:709–14, 1989.PubMedGoogle Scholar
  8. 8.
    Notelowitz, M: Menopause, in Endocrinology of Aging, edited by Morley, JE, VandenBerg, L, Totowa, NJ, Humana Press, 2000, pp. 161–181.Google Scholar
  9. 9.
    Sullivan, JM, and Fowlkes, LP: The clinical aspects of estrogen and the cardiovascular system. Obstet. Gynecol., 87: 36S–43S, 1996.PubMedGoogle Scholar
  10. 10.
    Prouder, AJ, Ahmed, Al, and Crook, D: Hormone replacement therapy and serum angiotensin-converting enzyme activity in postmenopausal women. Lancet, 346:89–90, 1995.Google Scholar
  11. 11.
    Newcomb, PA, and Storer, BE: Postmenopausal hormone use and risk of large bowel cancer. J. Natl. Cancer Inst., 87:1067–1071, 1995.PubMedGoogle Scholar
  12. 12.
    Flynn, BL: Pharmacologic management of Alzheimer disease, Part I: Hormonal and emerging investigational drug therapies. Ann. Pharmacother., 33:178–87, 1999.PubMedGoogle Scholar
  13. 13.
    Birge, SJ: Is there a role for estrogen replacement therapy in the prevention and treatment of dementia? J. Am. Geriatr. Soc., 44:865–70, 1996.PubMedGoogle Scholar
  14. 14.
    Flood, JF, and Morley, JE: Learning and memory in the SAMP8 mouse. Neurosci. Biobehav. Rev., 22: 1–20, 1998.PubMedGoogle Scholar
  15. 15.
    Henderson, BE, Paganini-Hill, A, and Ross, RK: Decreased mortality in users of estrogen replacement therapy. Arch. Intern. Med., 151:75–78, 1991.PubMedGoogle Scholar
  16. 16.
    Gray, A, Berlin, JA, McKinlay, JB, and Longcope C: An examination of research design effects on the association of testosterone and male aging: results of a meta-analysis. J. Clin. Epidemiol., 44:671–84, 1991.PubMedGoogle Scholar
  17. 17.
    Morley, JE, Kaiser, FE, Perry, HM 3rd, Patrick, P, Morley, PM, Stauber, PM, Vellas, B, Baumgartner, RN, and Garry PJ: Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism, 46:410–13, 1997.PubMedGoogle Scholar
  18. 18.
    Korenman, SG, Morley, JE, Mooradian, AD, Davis, SS, Kaiser, FE, Silver, AJ, Viosca, SP, and Garza, D: Secondary hypogonadism in older men: its relation to impotence. J. Clin. Endocrinol. Metab. 71:963–9, 1990.PubMedGoogle Scholar
  19. 19.
    Morley, JE, and Perry, HM 3rd: Androgen deficiency in aging men. Med. Clin. North Am., 8: 1279–89, 1999.Google Scholar
  20. 20.
    Veldhuis, JD: Recent insights into neuroendocrine mechanisms of aging of the human male hypothalamic-pituitary-gonadal axis: J. Androl., 20:1–17, 1999.PubMedGoogle Scholar
  21. 21.
    Pincus, SM, Veldhuis, JD, Mulligan, T, Iranmanesh, A, and Evans, WS: Effects of age on the irregularity of LH and FSH serum concentrations in women and men. Am. J. Physiol., 273:E989–95, 1997.PubMedGoogle Scholar
  22. 22.
    Pincus, SM, Mulligan, T, Iranmanesh, A, Gheorghiu, S, Godschalk, M, and Veldhuis, JD: Older males secrete luteinizing hormone and testosterone more irregularly, and jointly more asynchronously, than younger males. Proc. Natl. Acad. Sci. USA, 93:14100–5, 1996.Google Scholar
  23. 23.
    Haji, M, Kato, KI, Nawata, H, and Ibayashi, H: Age-related changes in the concentrations of cytosol receptors for sex steroid hormones in the hypothalamus and pituitary gland of the rat. Brain Res., 204:373–86, 1980.Google Scholar
  24. 24.
    Krithivas, K, Yurgalevitch, SM, Mohr, BA, Wilcox, CJ, Batter, SJ, Brown, M, Longcope, C, McKinlay, JB, and Kantoff, PW: Evidence that the CAG repeat in the androgen receptor gene is associated with the age-related decline in serum androgen levels in men. J. Endocrinol., 162:137–42, 1999.PubMedGoogle Scholar
  25. 25.
    Snyder, PJ, Peachey, H, Hannoush, P, Berlin, JA, Loh, L, Lenrow, DA, Holmes, JH, Dlewati, A, Santanna, J, Rosen, CJ, and Strom, BL: Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J. Clin. Endocrinol. Metab., 84:2647–53, 1999.PubMedGoogle Scholar
  26. 26.
    Urban RJ: Effects of testosterone and growth hormone on muscle function. J. Lab. Clin. Med., 134: 7–10, 1999.PubMedGoogle Scholar
  27. 27.
    Morley, JE, Perry, HM 3rd, Kaiser, FE, Kraenzle, D, Jensen, J, Houston, K, Mattammal, M, and Perry, HM Jr: Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J. Am. Geriatr. Soc., 41:149–52, 1993.PubMedGoogle Scholar
  28. 28.
    Sih, R, Morley, JE, Kaiser, FE, Perry, HM 3rd, Patrick, P, and Ross, C: Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J. Clin. Endocrinol. Metab., 82:1661–7, 1997.PubMedGoogle Scholar
  29. 29.
    Urban, RJ, Bodenburg, YH, Gilkison, C, Foxworth, J, Coggan, AR, Wolfe, RR, and Ferrando, A: Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am. J. Physiol., 269: E820–6, 1995.PubMedGoogle Scholar
  30. 30.
    Snyder, PJ, Peachey, H, Hannoush, P, Berlin, JA, Loh, L, Holmes, JH, Dlewati, A, Staley, J, Santanna, J, Kapoor, SC, Attie, MF, Haddad, JG Jr, and Strom, BL. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J. Clin. Endocrinol. Metab., 84:1966–72, 1999.PubMedGoogle Scholar
  31. 31.
    Janowsky, JS, Oviatt, SK, and Orwoll, ES: Testosterone influences spatial cognition in older men. Behav. Neurosci., 108:325–32, 1994.PubMedGoogle Scholar
  32. 32.
    Flood, JF, Farr, SA, Kaiser, FE, LaRegina, M, and Morley, JE: Age-related decrease of plasma testosterone in SAMP8 mice: replacement improves age-related impairment of learning and memory. Physiol. Behav., 57:669–73, 1995.PubMedGoogle Scholar
  33. 33.
    Barrett-Connor, EL: Testosterone and risk factors for cardiovascular disease in men. Diabete. Metab., 21:156–61, 1995.PubMedGoogle Scholar
  34. 34.
    Rosano, GM, Leonardo, F, Pagnotta, P, Pelliccia, F, Panina, G, Cerquetani, E, della Monica, PL, Bonfigli, B, Volpe, M, and Chierchia, SL: Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation, 99:1666–70, 1999.PubMedGoogle Scholar
  35. 35.
    Zhao, SP, Li, XP: The association of low plasma testosterone level with coronary artery disease in Chinese men. Int. J. Cardiol., 63:161–4, 1998.PubMedGoogle Scholar
  36. 36.
    Hajjar, RR, Kaiser, FE, and Morley, JE: Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J. Clin. Endocrinol. Metab., 82:3793–6, 1997.PubMedGoogle Scholar
  37. 37.
    Perry, HM 3rd, Horowitz, M, Morley, JE, Patrick, P, Vellas, B, Baumgartner, R, and Garry, PJ: Longitudinal changes in serum 25-hydroxyvitamin D in older people. Metabolism, 48:1028–32, 1999.PubMedGoogle Scholar
  38. 38.
    Jones, G, Strugnell, SA, and DeLuca, HF: Current understanding of the molecular actions of vitamin D. Physiol. Rev., 78:1193–231, 1998.PubMedGoogle Scholar
  39. 39.
    Chapuy, MC, Arlot, ME, Delmas, PD, Meunier, PJ: Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. BMJ, 308:1081–2, 1994.PubMedGoogle Scholar
  40. 40.
    Labrie, F, Belanger, A, Cusan, L, Gomez, JL, and Candas, B: Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J. Clin. Endocrinol. Metab., 82: 2396–402, 1997.PubMedGoogle Scholar
  41. 41.
    Flood, JF, Morley, JE, and Roberts, E: Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc. Natl. Acad. Sci. USA, 89:1567–1571, 1992.PubMedGoogle Scholar
  42. 42.
    Daynes, RA, and Aranco, BA: Prevention and reversal of some age-associated changes in immunologic responses by supplemental dehydroepiandrosterone sulfate therapy. Aging Immun. Infect. Dis., 3:135–154, 1992.Google Scholar
  43. 43.
    Arlt, W, Callies, F, van Vlijmen, JC, Koehler, I, Reincke, M, Bidlingmaier, M, Huebler, D, Oettel, M, Ernst, M, Schulte, HM, and Allolio, B: Dehydroepiandrosterone replacement in women with adrenal insuffiency. N. Engl. J. Med., 341:1013–1020, 1999.PubMedGoogle Scholar
  44. 44.
    Morales, AJ, Haubrich, RH, Hwang, JY, Asakura, H, and Yen, SS: The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin. Endocrinol. (Oxf)., 49:421–32, 1998.Google Scholar
  45. 45.
    Morales, AJ, Nolan, JJ, Nelson, JC, and Yen, SS. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J. Clin Endocrinol. Metab., 78:1360–7, 1994.PubMedGoogle Scholar
  46. 46.
    Barnhart, KT, Freeman, E, Grisso, JA, Rader, DJ, Sammel, M, Kapoor, S, Nestler, JE: The effect of deydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and health-related quality of life. J. Clin. Endocrinol. Metab., 84:3896–3902, 1999.PubMedGoogle Scholar
  47. 47.
    Morley, JE, Kaiser, F, Raum, WJ, Perry, M 3rd, Flood, JF, et al. Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate. Proc. Natl. Acad. Sci. USA, 94:7537–7542, 1997.PubMedGoogle Scholar
  48. 48.
    McGavack, TH, Chevalley, J, and Weissberg, J: The use of D5 pregnenolone in various clinical disorders. J. Clin. Endocrinol. Metab., 11:559–577, 1951.PubMedGoogle Scholar
  49. 49.
    Flood, JF, Morley, JE, and Roberts, E: Pregnenolone sulfate enhances post-training memory processes when injected in very low doses into limbic system structures: the amygdala is by far the most sensitive. Proc. Natl. Acad. Sci. USA, 92:10806–10, 1995.Google Scholar
  50. 50.
    Steiger, A, Trachsel, I, Guldner, J, Hemmeter, U, Rothe, B, Rupprecht, R, Vedder, H, Holsboer, F: Neurosteroid pregnenolone induces sleep-EEG changes in man compatible with inverse agonistic GABAA-receptor modulation. Brain Res., 615:267–274, 1993.PubMedGoogle Scholar
  51. 51.
    Pincus, G, Hoagland, H, Wilson, CH, and Fay, NJ: Effects on industrial production of the administration of 5 pregnenolone to factory workers, II. Psychosom. Med. 7:342–346, 1945.Google Scholar
  52. 52.
    Sih, R, Morley, JE, Kaiser, FE, and Herning, M: Effects of pregnenolone on aging. J. Investig. Med. 45:348A, 1997.Google Scholar
  53. 53.
    Rudman, D: Growth hormone, body composition, and aging. J. Am. Geriatr. Soc., 33:800–7, 1985.PubMedGoogle Scholar
  54. 54.
    Lieberman, SA, and Hoffman, AR: The somatopause: should growth hormone deficiency in older people be treated? Clin. Geriatr. Med., 13:671–84, 1997.PubMedGoogle Scholar
  55. 55.
    Kaiser, FE, Silver, AJ, and Morley, JE: The effect of recombinant human growth hormone on malnourished older individuals. J. Am. Geriatr. Soc., 39:235–40, 1991.PubMedGoogle Scholar
  56. 56.
    Demling, R: Growth hormone therapy in critically ill patients. N. Engl. J. Med., 341:837–9, 1999.PubMedGoogle Scholar
  57. 57.
    Margulis, L: Genetic and evolutionary consequences of symbiosis. Exp. Parasitol., 39:277–349, 1976.PubMedGoogle Scholar
  58. 58.
    Margulis, L: Symbiosis and evolution. Sci. Am., 225:48–57, 1971.PubMedGoogle Scholar
  59. 59.
    Hayflick, L: Aging, longevity, and immortality in vitro. Exp. Gerontol., 27:363–8, 1992.PubMedGoogle Scholar
  60. 60.
    Vijg, J, and Wei, JY: Understanding the biology of aging: the key to prevention and therapy. J. Am. Geriatr. Soc. 43:426–34, 1995.PubMedGoogle Scholar
  61. 61.
    Ashok, BT, and Ali R: The aging paradox: free radical theory of aging. Exp. Gerontol., 34:293–303, 1999.PubMedGoogle Scholar
  62. 62.
    Veldhuis, JD: Recent insights into neuroendocrine mechanisms of aging of the human male hypothalamic-pituitary-gonadal axis. J. Androl., 20:1–17, 1999.PubMedGoogle Scholar
  63. 63.
    Morley, JE: Anorexia of aging: physiologic and pathologic. Am. J. Clin. Nutr., 66:760–73, 1997.PubMedGoogle Scholar
  64. 64.
    Gosnell, BA, Levine, AS, and Morley, JE: The effects of aging on opioid modulation of feeding in rats. Life Sci., 32: 2793–9, 1983.PubMedGoogle Scholar
  65. 65.
    Kavaliers, M, Teskey, GC, and Hirst, M: The effects of aging on day-night rhythms of kappa opiatemediated feeding in the mouse. Psychopharmacology (Berl)., 87:286–91, 1985.Google Scholar
  66. 66.
    Jahnberg, T: Gastric adaptive relaxation. Effects of vagal activation and vagotomy. An experimental study in dogs and in man. Scand. J. Gastroenterol. Suppl., 46:1–32, 1977.PubMedGoogle Scholar
  67. 67.
    Desai, KM, Sessa, WC, and Vane, JR: Involvement of nitric oxide in the reflex relaxation of the stomach to accomodate food or fluid. Nature, 351:477–9, 1991.PubMedGoogle Scholar
  68. 68.
    Jones, KL, Doran, SM, Hveem, K, Bartholomeusz, FD, Morley, JE, Sun, WM, Chatterton, BE, and Horowitz, M: Relation between postprandial satiation and antral area in normal subjects. Am. J. Clin. Nutr. 66:127–32, 1997.PubMedGoogle Scholar
  69. 69.
    Cook, CG, Andrews, JM, Jones, KL, Wittert, GA, Chapman, IM, Morley, JE, and Horowitz, M: Effects of small intestinal nutrient infusion on appetite and pyloric motility are modified by age. Am. J. Physiol., 273: R755–61, 1997.PubMedGoogle Scholar
  70. 70.
    Silver, AJ, Flood, JF, Morley, JE: Effect of gastrointestinal peptides on ingestion in old and young mice. Peptides, 9:221–5, 1988.PubMedGoogle Scholar
  71. 71.
    Miyasaka, K, Kanai, S, Ohta, M, and Funakoshi, A: Aging impairs release of central and peripheral cholecystokinin (CCK) in male but not in female rats. J. Gerontol. A Biol. Sci. Med. Sci., 52:M14–8, 1997.PubMedGoogle Scholar
  72. 72.
    James, WPT and Ralph, A. New understanding in obesity research. Proc. Nutr. Soc 58:385–393, 1999.PubMedGoogle Scholar
  73. 73.
    Perry, HM 3rd, Morley, JE, Horowitz, M, Kaiser, FE, Miller, DK, and Wittert, G: Body composition and age in African-American and Caucasian women: relationship to plasma leptin levels. Metabolism, 46:1399–405, 1997.PubMedGoogle Scholar
  74. 74.
    Morley, JE, Perry, HM 3rd, Baumgartner, RP, and Garry, PJ: Leptin, adipose tissue and aging—is there a role for testosterone? J. Gerontol. Ser. A Biol. Sci. Med. Sci., 54:B108–9, 1999.Google Scholar
  75. 75.
    Larsson, H, Elmstahl, S, Berglund, G, Ahren, B: Evidence for leptin regulation of food intake in humans. J. Clin. Endocrinol. Metab., 83:4382–5, 1998.PubMedGoogle Scholar
  76. 76.
    Mott, JW, Wang, J, Thornton, JC, Allison, DB, Heymsfield, SB, and Pierson, RN, Jr: Relation between body fat and age in 4 ethnic groups. Am. J. Clin. Nutr., 69:1007–13, 1999.PubMedGoogle Scholar
  77. 77.
    Silver, AJ, Guillen, CP, Kahl, MJ, and Morley, JE: Effect of aging on body fat. J. Am. Geriatr. Soc., 41:211–3, 1993.PubMedGoogle Scholar
  78. 78.
    Wilson, MMG, Vaswani, S, Liu, D, Morley, JE, and Miller, DK. Prevalence and causes of undernutrition in medical outpatients. Am. J. Med., 104:56–63, 1998.PubMedGoogle Scholar
  79. 79.
    Baez-Franceschi, D, and Morley, JE: Physiopathology of the catabolism associated with malnutrition in the elderly. Z. Gerontol. Geriatr. 32:12–19, 1999.Google Scholar
  80. 80.
    Morley, JE: The elderly Type 2 diabetic patient: special considerations. Diabet. Med., 15:S41–6, 1998.PubMedGoogle Scholar
  81. 81.
    Sensi, M, Pricci F, Andreani, D, and DiMario U: Advanced nonenzymatic glycation endproducts (AGE): their relevance to aging and the pathogenesis of late diabetic complications. Diabetes Res. 16:1–9, 1991.PubMedGoogle Scholar
  82. 82.
    Arner, P, Pollare, T, and Lithell, H: Different aetiologies of type 2 (non-insulin-dependent) diabetes mellitus in obese and non-obese subjects. Diabetologia, 34:483–487, 1991.PubMedGoogle Scholar
  83. 83.
    Meneilly, GS, Elahi, D, Minaker, KL, Sclater, AL, Rowe, JW: Impairment of noninsulin-mediated glucose disposal in the elderly. J. Clin. Endocrinol. Metab., 63:566–571, 1989.Google Scholar
  84. 84.
    Meneilly, GS, Elliott, T, Tessier, D, Hards, L, Tildesley, H: NIDDM in the elderly. Diabetes Care, 19:1320–5, 1996.PubMedGoogle Scholar
  85. 85.
    Miller, DK, Lui, LY, Perry, HM 3rd, Kaiser, FE, and Morley, JE: Reported and measured physical functioning in older inner-city diabetic African Americans. J. Gerontol. Ser. A Biol. Sci. Med. Sci., 54:M230–6, 1999.Google Scholar
  86. 86.
    Meneilly, GS: Pathophysiology of type 2 diabetes in the elderly. Clin. Geriatr. Med., 15:239–253, 1999.PubMedGoogle Scholar
  87. 87.
    Ferrannini, E, Vichi, S., Beck-Nielsen, H, Laakso, M, Paolisso G, Smith, U. Insulin action and age. European Group for the Study of Insulin Resistance (EGIR). Diabetes, 45:947–53, 1996.PubMedGoogle Scholar
  88. 88.
    Daniel, PM, Love, ER, and Pratt, OE: The effect of age upon the influx of glucose into the brain. J. Physiol. (London), 274:141–148, 1978.Google Scholar
  89. 89.
    De Vivo, DC, Trifiletti, RR, Jacobson, RI, Ronen GM, Behmand, RA, and Harik SI: Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhacia, seizures, and developmental delay. N. Engl. J. Med., 325:703–709, 1991.PubMedGoogle Scholar
  90. 90.
    Forbes, A, Elliott, T, Tildesley, H, Finegood, D, Meneilly, GS: Alterations in non-insulin-mediated glucose uptake in the elderly patient with diabetes. Diabetes 47:1915–9, 1998.PubMedGoogle Scholar
  91. 91.
    Meneilly, GS, Milberg, WP, and Tuokko, H: Differential effects of human and animal insulin on the responses to hypoglycemia in elderly patients with NIDDM. Diabetes, 44:272–277, 1995.PubMedGoogle Scholar
  92. 92.
    Banks, WA, Jaspan, JB, and Kastin, AJ: Selective, physiological transport of insulin across the blood-brain barrier: Novel demonstration by species-specific radioimmunoassays. Peptides, 18:1257–1262, 1997.PubMedGoogle Scholar
  93. 93.
    Das, UN: GLUT-4, tumor necrosis factor, essential fatty acids and daf-genes and their role in insulin resistance and non-insulin dependent diabetes mellitus. Prostaglandins Leukot. Essent. Fatty Acids, 50:13–20, 1999.Google Scholar
  94. 94.
    Hekimi, S, Lakowski, B, Barnes, TM, Ewbank, JJ: Molecular genetics of life span in C. elegans: how much does it teach us? Trends Genet., 14:14–20, 1998.PubMedGoogle Scholar
  95. 95.
    Kimura, KD, Tissenbaum, HA, Liu, Y, and Ruvkun, G: daf-2, an Insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science, 277:942–946, 1997.PubMedGoogle Scholar
  96. 96.
    Kops, GJ, de Ruiter, ND, De Vries-Smits, AM, Powell, DR, Bos JL and Th. Burgering, BM: Direct control of the forkhead transcription factor AFX by protein kinase B. Nature, 398:630–634, 1999.PubMedGoogle Scholar
  97. 97.
    Nakae, J, Park, B-C, and Accili, D: Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on Serine 253 through a Wortmannin-sensitive pathway. J. Biol. Chem., 274:15982–15985, 1999.Google Scholar
  98. 98.
    Vanfleteren, JR, and De Vreese, A: The gerontogenes age-1 and daf-2 determine metabolic rate potential in aging Caenorhabditis elegans. FASEB J., 9:1355–61, 1995.PubMedGoogle Scholar
  99. 99.
    Lakowski, B, and Hekimi, S: The genetics of caloric restriction in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA, 95:13091–6, 1998.Google Scholar
  100. 100.
    Paolisso, G, Tagliamonte, MR, Rizzo, MR, and Giugliano, D: Advancing age and insulin resistance: new factors about an ancient history. Eur. J. Clin. Invest., 29:758–769, 1999.PubMedGoogle Scholar
  101. 101.
    Taub, J, Lau, JF, Ma, C, Hahn, JH, Hoque, F, Rothblatt, J and Chalfie, M: A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature, 399:162–166, 1999.PubMedGoogle Scholar
  102. 102.
    Honda, Y, and Honda, S: The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J., 13:1385–1393, 1999.PubMedGoogle Scholar
  103. 103.
    Yasuda, K, Adachi, H, Fujiwara, Y, and Ishii, N. Protein carbonyl accumulation in aging dauer formation-defective (daf) mutants of Caenorhabditis elegans. J. Gerontol., 54:B47–51, 1999.Google Scholar
  104. 104.
    Banks, WA, Kastin, AJ, Huang, W, Jaspan, JB, and Maness, LM: Leptin enters the brain by a saturable system independent of insulin. Peptides, 17:305–311, 1996.PubMedGoogle Scholar
  105. 105.
    Campfield, LA, Smith FJ, Guisez, Y, Devos, R, and Burn, P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science, 269:546–549, 1995.PubMedGoogle Scholar
  106. 106.
    Halaas, JL, Gajiwala, KS, Maffei, M, Cohen, SL, Chait, BT, Rabinowitz, D, Lallone, RL, Burley, SK, and Friedman, JM: Weight-reducing effects of the plasma protein encoded by the obese gene. Science, 269: 543–546, 1995.PubMedGoogle Scholar
  107. 107.
    Pelleymounter, MA, Cullen, MJ, Baker, MB, Hecht, R, Winters, D, Boone, T, and Collins, F: Effects of the obese gene product on body weight regulation in ob/ob mice. Science, 269:540–543, 1995.PubMedGoogle Scholar
  108. 108.
    Zhang, Y, Proenca, R, Maffel, M, Barone, M, Leopold, L, and Friedman, JM: Positional cloning of the mouse obese gene and its human homologue. Nature, 372:425–432, 1994.PubMedGoogle Scholar
  109. 109.
    Banks, WA, DiPalma, CR, and Farrell CL: Impaired transport of leptin across the blood-brain barrier in obesity. Peptides, 20:1341–5, 1999.PubMedGoogle Scholar
  110. 110.
    Corica, F, Allegra, A, Corsonello, A, Buemi, M, Calapai, G, Ruello, A, Nicita Mauro, V, and Ceruso, D: Relationship between plasma leptin levels and the tumor necrosis factor-alpha system in obese subjects. Int. J. Obes. Relat. Metab. Disord., 23:355–60, 1999.PubMedGoogle Scholar
  111. 111.
    Paolisso, G, Rizzo, MR, Mazziotti, G, Tagliamonte, MR, Gambardella, A, Rotondi, M, Carella, C, Giugliano, D, Varricchio, M, and D’Onofrio, F: Advancing age and insulin resistance: role of plasma tumor necrosis factor-α. Am. J. Physiol., 275:E294–299, 1998.PubMedGoogle Scholar
  112. 112.
    Nilsson, J, Jovinge, S, Niemann, A, Reneland, R, and Lithell, H: Relation between plasma tumor necrosis factor-alpha and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus. Arterioscler. Thromb. Vasc. Biol., 18:1199–202, 1998.PubMedGoogle Scholar
  113. 113.
    Zinman, B, Hanley, AJ, Harris, SB, Kwan, J, and Fantus, IG: Circulating tumor necrosis factor-alpha concentrations in a native Canadian population with high rates of type 2 diabetes mellitus. J. Clin. Endocrinol. Metab., 84:272–8, 1999.PubMedGoogle Scholar
  114. 114.
    Hube, F, Birgel, M, Lee, YM, and Hauner, H: Expression pattern of tumour necrosis factor receptors in subcutaneous and omental human adipose tissue: role of obesity and non-insulin-dependent diabetes mellitus. Eur. J. Clin. Invest. 29:672–8, 1999.PubMedGoogle Scholar
  115. 115.
    Lang, CH, Dobrescu, C, and Bagby, GJ: Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology, 130:43–52, 1992.PubMedGoogle Scholar
  116. 116.
    Hotamisligil, GS: Mechanisms of TNF-alpha-induced insulin resistance. Exp. Clin. Endocrinol. Diabetes, 107:111–2, 1999.Google Scholar
  117. 117.
    Uysal, KT, Wiesbrock, SM, Marino, MW, and Hotamisligil, GS: Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature, 389:610–4, 1997.PubMedGoogle Scholar
  118. 118.
    Cheung, AT, Ree, D, Kolls, JK, Fuselier, J, Coy, DH, and Bryer-Ash, M: An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance: evidence for differential regulation of insulin signaling by TNF-alpha. Endocrinology, 139:4928–35, 1998.PubMedGoogle Scholar
  119. 119.
    Miles, PD, Romeo, OM, Higo, K, Cohen, A, Rafaat, K, and Olefskyk, JM: TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes, 46:1678–83, 1997.PubMedGoogle Scholar
  120. 120.
    Hofmann, C, Lorenz, K, Braithwaite, SS, Colca, JR, Palazuk, BJ, Hotamisligil, GS, and Spiegelman, BM: Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance. Endocrinology, 134:264–70, 1994.PubMedGoogle Scholar
  121. 121.
    Kwon, G, Xu, G, Marshall, CA, and McDaniel, ML: Tumor necrosis factor alpha-induced pancreatic beta-cell insulin resistance is mediated by nitric oxide and prevented by 15-deoxy-Delta12,14-prostaglandin J2 and aminoguanidine. A role for peroxisome proliferator-activated receptor gamma activation and inos expression. J. Biol. Chem., 274:18702–8, 1999.Google Scholar
  122. 122.
    Winkler, G, Lakatos, P, Salamon, F, Nagy, Z., Speer, G, Kovacs, M, Harmos, G, Dworak, O., and Cseh, K. Elevated serum TNF-alpha level as a link between endothelial dysfunction and insulin resistance in normotensive obese patients. Diabet. Med., 16:207–11, 1999.PubMedGoogle Scholar
  123. 123.
    McKendrick, JD, Salas, E., Dube, GP, Murat, J., Russell, JC, and Radomski, MW: Inhibition of nitric oxide generation unmasks vascular dysfunction in insulin-resistant, obese JCR:LA-cp rats. Brit. J. Pharmacol., 124: 361–9, 1998.Google Scholar
  124. 124.
    Estrada, C, Gomez, C, Martin, C, Moncada, S, and Gonzalez C: Nitric oxide mediates tumor necrosis factor-α cytotoxicity in endothelial cells. Biochem. Biophys. Res. Commun., 186:475–482, 1992.PubMedGoogle Scholar
  125. 125.
    Polte, T, and Schroder, H: Cyclic AMP mediated endothelial protection by nitric oxide. Biochem. Biophys. Res. Commun., 251:460–465, 1998.PubMedGoogle Scholar
  126. 126.
    Baron, AD: The coupling of glucose metabolism and perfusion in human skeletal muscle. The potential role of endothelium-derived nitric oxide. Diabetes, 45:S105–9, 1996.PubMedGoogle Scholar

Copyright information

© American Aging Association, Inc. 2000

Authors and Affiliations

  1. 1.Division of Geriatric MedicineSaint Louis University Medical SchoolSt. Louis
  2. 2.Geriatric Research, Education and Clinical CenterSt. Louis VAMCSt. Louis

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