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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59:M924-M929 (2004)
© 2004 The Gerontological Society of America

EDITORIAL

Cytokine-Related Aging Process

John E. Morley1 and Richard N. Baumgartner2

1 GRECC, VA Medical Center, and Division of Geriatric Medicine, Saint Louis University, St. Louis, Missouri.
2 Division of Epidemiology and Preventive Medicine, Aging and Genetic Epidemiology Program, Department of Internal Medicine, University of New Mexico, Albuquerque.

CYTOKINES are soluble peptide messengers that are synthesized by lymphocytes (thus, they were originally called lymphokines), neutrophils, macrophages, and neuronal cells. The first experimental evidence that circulating factors could modulate the immune system was published in 1932 (1). It was not, however, until more than 30 years later that peptide mediators of lymphocyte activity were identified (2). Two years later, Gery and colleagues (3) isolated soluble peptide messengers from macrophages, and the concept of cytokines as "the great communicators" between immune and somatic cells in response to inflammation was born. Today, it is recognized that cytokines can be both proinflammatory and antiinflammatory and have a wide range of effects on organ systems throughout the body (Figure 1). Originally, each cytokine was named after the function it was recognized to perform. However, it soon was realized that cytokines produced multiple functions, and, thus, in 1979, a consensus committee decided to rename the cytokines "interleukins" followed by a number (4). Nonetheless, some cytokines have retained other names, for example, tumor necrosis factors (TNFs) (originally cachectins), interferons, and, most recently, the adipocyte-produced cytokines, or adipocytokines, such as adiponectin and leptin. Recently, there has been an increasing awareness that the cytokine response to nonspecific inflammation may be a component of the pathophysiology of frailty, functional decline, and death in older persons (5,6). Some cytokines, such as interleukin-10 (IL-10), are antiinflammatory and oppose the actions of the proinflammatory cytokines. Westendorp has suggested that the balance between proinflammatory and antiinflammatory cytokines favors either a long life or reproductive success (7). Thus, persons with high levels of tumor necrosis factor alpha (TNF{alpha}) and low levels of IL-10 will have few children but live a long time. This is the modern version of Thomas Kirkwood's "disposable soma" theory, which stated that investment in maintenance and repair comes at the expense of investment in reproduction.



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  		Figure 1. Effects of cytokines on multiple organ systems, which can result in the development of frailty. IL = interleukin; TNF = tumor necrosis factor

 
Tissue destruction or infection leads to a nonspecific acute-phase response. Markers of this nonspecific response are C-reactive protein (CRP) and serum amyloid protein, which increase rapidly (within 6 hours and peak within 48 hours) following an acute-phase stimulus. CRP derived its name from its ability to precipitate the C-polysaccharide of streptococcus pneumoniae (8). Both CRP and serum amyloid protein are members of the pentraxin family (Gk. penta = five; ragos = berries). When CRP binds to damaged cell membranes or lipids, it activates the classical complement pathway through C1q. CRP is increased after acute and chronic infection, in arthritic and other inflammatory disorders, tissue necrosis, neoplasia, cardiovascular disease, insulin resistance syndromes, obesity, smoking, stress, atrial fibrillation, oral estrogen intake, smoking, and coffee consumption (9). Liver disease, weight loss, exercise, moderate alcohol intake, and hepatic hydroxymethyl glutaryl coenzyme A (HMGCoA) reductase inhibitors are associated with lower CRP levels. Autoimmune diseases, such as systemic lupus erythematosus, fail to produce a CRP response. Thus, while CRP is a sensitive marker of disease processes, it is notoriously nonspecific. In older persons, CRP has been shown to be a marker of functional decline and mortality (10–13). Because of the nonspecificity of CRP, there has been a search for more specific markers that could explain the pathophysiology of functional deterioration with aging, sarcopenia, and the anorexia of aging (6,14–21).

Interleukin-6 (IL-6) was one of the first cytokines to be linked to the aging process, and has been termed the "geriatric cytokine" (22). IL-6 is released from macrophages and T lymphocytes. Both TNF{alpha} and interleukin-1 beta (IL-1ß) are potent releasers of IL-6. IL-6, on the other hand, once released, feeds back to down-regulate the release of TNF{alpha} and IL-1ß giving it an antiinflammatory, as well as a proinflammatory role. Increased IL-6 leads to loss of muscle and bone mass, fever, activation of the hypothalamic-pituitary-adrenal axis, activation of the hepatic acute phase response, and hemodilution, resulting in a decline in hemoglobin levels (23–26). In bone, IL-6 is produced by osteoblasts and promotes osteoclast activity and subsequent bone resorption (27). Testosterone, which declines with aging in men (28,29), suppresses IL-6 production from bone (30). Parathyroid hormone levels, which increase with the age-associated decline in vitamin D (31), increase the production of IL-6 from osteoblasts (32). Parathyroid hormone also results in hepatic production of IL-6 and its soluble receptor (33). In older persons, elevated IL-6 levels have been shown cross-sectionally to be inversely associated with muscle mass and strength, physical performance, balance, and walking speed, and positively associated with death (13,35–37). Ferrucci and colleagues (38) reported in a cross-sectional study that elevated IL-6 levels predicted development of disability over the subsequent 4 years. It has been known for several years that IL-6 stimulates muscle protein degradation in diseases such as cancer, end-stage renal disease, and AIDS via effects on both lysosomal (cathepsin) and nonlysosomal (ubiquitin-proteasome) pathways (39–43). The association of lower levels of IL-6 with the gradual loss of muscle during normal aging (sarcopenia) is a more novel finding.

Interleukin-1ß is a proinflammatory cytokine that induces TNF{alpha} and IL-2 by activating T-helper cells, and produces tissue inflammatory actions by activating cyclooxygenase-2 to produce prostaglandin E2, inducible nitric oxide, and intercellular adhesion molecules such as ICAM-1 (intercellular adhesion molecule-1) (44). IL-1ß also induces its own release, creating a vicious inflammatory cycle. Biochemically, IL-1ß activates, after phosphorylation by a kinase, the tumor necrosis factor receptor-associated factor-Y, which then activates nuclear factor kappa ß to bind to the DNA in the nucleus and produce its effects. IL-1ß produces fever, sickness behavior, and anorexia. In addition, it causes a decline in the ability to acquire and retain new memories. This occurs both indirectly, by activating ascending fibers in the autonomic nervous system, and directly, by crossing the blood–brain barrier (45). IL-1ß can be considered the trigger for the inflammatory cascade, and, as such, results in an increase in CRP and serum amyloid protein (44). Within the central nervous system, IL-1ß may be the trigger for increased amyloid precursor protein and the development of subsequent Alzheimer's disease (46,47). Cytokines are also involved in the pathogenesis of delirium (48).

Tumor necrosis factor alpha is produced from macrophages and adipocytes. It is proinflammatory, working in concert with IL-1ß. It produces anorexia, stimulates lipolysis, and inhibits lipoprotein lipase, thus leading to the cachexia syndrome (49,50). It has direct effects resulting in decreased function of the myocardium and produces apoptotic cell death (51). TNF{alpha} appears to be one of the mediators of receptor activator of nuclear factor kappa ß ligand's (RANKL) effects in promoting osteoporosis (52). As noted previously, it stimulates release of IL-6, which causes increased protein degradation.

Numerous other cytokines have been identified and their effects are listed in Table 1.


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  		Table 1. Cytokines and Their Actions.

 
Soluble cytokine receptors are produced either through proteolytic cleavage from the membrane-bound form, or, alternatively, they are produced by alternative splicing of mRNA, which leads to the formation of a transcript, which encodes a soluble receptor (53). These circulating soluble receptors then act as cytokine-binding proteins, which can down-regulate the effects of circulating cytokines. However, soluble receptors, either in combination with the cytokine or by themselves, can activate certain cells. Thus, IL-6/SIL-6R (soluble IL-6 receptor) complex is a particularly potent proinflammatory mediator, as it induces secretion of IL-8 and IL-6 from leukocytes and synthesis of adhesion molecules in endothelial cells (54,55). Overall, soluble cytokine receptors tend to have longer half-lives than their cytokines, and as their secretion appears to parallel that of the cytokine, they may be better markers of chronic cytokine activity.

A word of caution is necessary regarding the measurements of cytokines and their soluble receptors. Firstly, the analytic enzyme-linked immunosorbent assay kits have been shown to have widely differing standards, and even kits from the same manufacturer may have standards that differ by as much as 50% (56). The quality of laboratory performance can also markedly affect the assay outcome. Samples can be frozen at –70°C and assayed at a later date. The exact length of time the samples can be stored, however, is uncertain. It is important that authors report interassay and intraassay coefficients of variation for all their assays. International reference standards for cytokines should be used and, where available, external proficiency testing should be put in place for a laboratory measuring cytokines.

From the geriatrician's viewpoint, a major role of cytokines is in their ability to accelerate the loss of muscle mass in sarcopenia and/or cachexia. The multiple mechanisms by which cytokines can lead to the severe tissue wasting seen in cachexia are outlined in Figure 2 (57). Megestrol acetate, which is used to treat anorexia, reduces IL-6 (58), and its orexigenic effects have been shown to be related to circulating cytokine effects (59). The role of cytokines in sarcopenia is less well established (19,20,60,61). It would appear that lower levels of circulating cytokines interact with hormone deficiency (62–64), the decline in physical activity (65), obesity, and the anorexia of aging (15,16,66–68) to lead to the loss of muscle that characterizes the occurrence of sarcopenia. An article in this issue of the Journal suggests that sarcopenia, like osteoporosis, is dictated to some extent by the development of muscle mass in youth (69). While osteoporosis can be considered a pediatric disorder, both genetic and environmental factors, for example, obesity or early menopause, can modulate the rate at which osteoporosis eventually develops (70,71). A similar constellation of factors may be involved in the pathogenesis of sarcopenia.



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  		Figure 2. The role of cytokines in the pathophysiology of cachexia. TNF = tumor necrosis factor; IL = interleukin; LDL = low-density lipoprotein; VDL = vasodepressor lipid; CRP = C-reactive protein; SAP = serum amyloid protein; RMR = resting metabolic rate

 
The relationship of inflammatory markers to muscle mass, muscle strength, and physical performance has been investigated in a number of studies (11–13,35–38,72–78). These results are summarized in Table 2. Overall, these studies suggest that nonspecific markers of inflammation (e.g., CRP and IL-6) are strongly associated with the loss of muscle mass and decline in performance. Other cytokines, particularly TNF{alpha} and its soluble receptors, have been inadequately studied to determine their role in the pathogenesis of frailty and disability. However, the suggestive role of TNF{alpha} in cardiac cachexia and its overproduction in obese persons suggests a potential role for this cytokine (79,80). Other cytokines, such as adiponectin and leptin, which appear to play a role in the insulin resistance syndrome, also deserve further study to determine their long-term role in the development of frailty (81–86).


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  		Table 2. Correlations of Cytokines With Frailty-Associated Factors in Older Persons.

 
In conclusion, we suggest that the Cytokine-Related Aging Process should be considered a true, and potentially reversible, syndrome. The Cytokine-Related Aging Process appears to be related to a constellation of age-related findings including loss of muscle and bone mass, anemia, cognitive decline, and immune dysfunction. This raises the possibility that cytokine modulators such as thalidomide, soluble cytokine receptors, or antibodies to cytokines, may modulate the aging process. The role of antiinflammatory cytokines is also potentially exciting in this regard.

References

  1. Rich AR, Lewis MR. The nature of allergy in tuberculosis as revealed by tissue culture studies. Bull Johns Hopkins Hosp. 1932;50:115-131.
  2. Dumonde DC, Wolstencroft RA, Panayi GS, et al. "Lymphokines": non-antibody mediators of cellular immunity generated by lymphocytes activation. Nature. 1969;224:38-42.[Medline]
  3. Gery I, Gershon RK, Waksman BH. Potentiation of cultured mouse thymocyte responses by factors released by peripheral leucocytes. J Immunol. 1971;107:1778-1780.[Abstract/Free Full Text]
  4. Anonymous. Nomenclature for secreted regulatory proteins of the immune system (interleukins). WHO-IUIS Nomenclature Subcommittee on Interleukin Designation. Bull World Hlth Org. 1991;69:483-486.
  5. Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol Med Sci. 2004;59:255-263.
  6. Morley JE, Perry HM, Miller DK. Something about frailty. J Gerontol Med Sci. 2002;57A:M698-M704.
  7. Westendorp RGJ. Are we becoming less disposable? EMBO Reports. 2004;5:2-6.[Medline]
  8. Lagrand WK, Visser CA, Hermens WT, Niessen HW, Verheugt FW, Wolbink GJ, Hack CE. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation. 1999;100:96-102.[Abstract/Free Full Text]
  9. Hirschfield GM, Pepys MB. C-reactive protein and cardiovascular disease: new insights from an old molecule. QJM. 2003;96:793-807.[Abstract/Free Full Text]
  10. Thomas DR. The relationship between functional status and inflammatory disease in older adults. J Gerontol Med Sci. 2003;58A:995-998.
  11. Reuben DB, Cheh AI, Harris TB, Ferrucci L, Rowe JW, Tracy RP, Seeman TE. Peripheral blood markers of inflammation predict mortality and functional decline in high-functioning community-dwelling older persons. J Am Geriatr Soc. 2002;50:638-644.[Medline]
  12. Cesari M, Penninx BWJH, Pahor M, et al. Inflammatory markers and physical performance in older persons: the InCHIANTI study. J Gerontol Med Sci. 2004;59A:242-248.
  13. Tilvis RS, Kahonen-Vare MH, Jolkkonen J, Valvanne J, Pitkala KH, Strandberg TE. Predictors of cognitive decline and mortality of aged people over a 10-year period. J Gerontol Med Sci. 2004;59A:268-274.
  14. Morley JE. Sarcopenia revisited. J Gerontol Med Sci. 2003;58:909-910.
  15. Marcell TJ. Sarcopenia: causes, consequences, and preventions. J Gerontol Med Sci. 2003;58A:911-916.
  16. Hamerman D. Molecular-based therapeutic approaches in treatment of anorexia of aging and cancer cachexia. J Gerontol Med Sci. 2002;57A:M511-M518.
  17. Bortz WM. A conceptual framework of frailty: a review. J Gerontol Med Sci. 2002;57A:M283-M288.
  18. Chapman IM, MacIntosh CG, Morley JE, Horowitz M. The anorexia of ageing. Biogerontology. 2002;3:67-71.[Medline]
  19. Lipsitz LA. Dynamics of stability: the physiologic basis of functional health and frailty. J Gerontol Biol Sci. 2002;57A:B115-B125.
  20. Cohen HJ. In search of the underlying mechanisms of frailty. J Gerontol Med Sci. 2000;55A:M706-M708.
  21. Morley JE. Anorexia, sarcopenia, and aging. Nutrition. 2001;17:660-663.[Medline]
  22. Ershler WB. Biological interactions of aging and anemia: a focus on cytokines. J Am Geriatr Soc. 2003;51:(3 Suppl): S18-S21.[Medline]
  23. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Ann Rev Med. 2000;51:245-270.[Medline]
  24. Thomas DR. Anemia and quality of life: unrecognized and undertreated. J Gerontol Med Sci. 2004;59:238-241.
  25. Cesari M, Penninx BWJH, Lauretani F, Russo CR, Carter C, Bandinelli S, Atkinson H, Onder G, Pahor M, Ferrucci L. Hemoglobin levels and skeletal muscle: results from the InCHIANTI study. J Gerontol Med Sci. 2004;59A:249-254.
  26. Leng S, Chaves P, Koenig K, Walston J. Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J Am Geriatr Soc. 2002;50:1268-1271.[Medline]
  27. Grey A, Mitnick MA, Shapses S, Ellison A, Gundberg C, Insogna K. Circulating levels of interleukin-6 and tumor necrosis factor-alpha are elevated in primary hyperparathyroidism and correlate with markers of bone resorption—a clinical research center study. J Clin Endocrinol Metab. 1996;81:3450-3454.[Abstract]
  28. Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol Med Sci. 2002;57A:M76-M99.
  29. Morley JE, Kaiser FE, Perry HM. Patrick et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metab Clin Exper. 1997;46:410-413.[Medline]
  30. Hofbauer LC, Ten RM, Khosla S. The anti-androgen hydroxyflutamide and androgens inhibit interleukin-6 production by an androgen-responsive human osteoblastic cell line. J Bone Miner Res. 1999;14:1330-1337.[Medline]
  31. Perry HM, Horowitz M, Morley JE, et al. Longitudinal changes in serum 25-hydroxyvitamin D in older people. Metab Clin Exper. 1999;48:1028-1032.[Medline]
  32. Radeff JM, Nagy Z, Stern PH. Involvement of PKC beta in PTH, TNF-alpha, and IL-1 beta effects on IL-6 promoter in osteoblastic cells and on PTH-stimulated bone resorption. Exp Cell Res. 2001;268:179-188.[Medline]
  33. Mitnick MA, Grey A, Masiukiewicz U, et al. Parathyroid hormone induces hepatic production of bioactive interleukin-6 and its soluble receptor. Am J Physiol Endocrin Metab. 2001;280:E405-E412.
  34. Morley JE. Mobility performance: a high-tech test for geriatricians. J Gerontol Med Sci. 2003;58A:712-714.
  35. Payette H, Roubenoff R, Jacques PF, et al. Insulin-like growth factor-1 and interleukin 6 predict sarcopenia in very old community-living men and women: the Framingham Heart Study. J Am Geriatr Soc. 2003;51:1237-1243.[Medline]
  36. Visser M, Pahor M, Taaffe DR, et al. Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study. J Gerontol Med Sci. 2002;57A:M326-M332.
  37. Cohen HJ, Pieper CF, Harris T, Rao KMK, Currie MS. The association of plasma IL-6 levels with functional disability in community-dwelling elderly. J Gerontol Med Sci. 1997;52A:M201-M208.
  38. Ferrucci L, Penninx BWJH, Volpato S, et al. Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels. J Am Geriatr Soc. 2002;50:1947-1954.[Medline]
  39. Tisdale MJ. Loss of skeletal muscle in cancer: biochemical mechanisms. Frontiers Biosci. 2001;6:D164-D174.[Medline]
  40. Costelli P, Bossola M. Muscaritoli M, et al. Anticytokine treatment prevents the increase in the activity of ATP-ubiquitin- and Ca2+-dependent proteolytic systems in the muscle of tumour-bearing rats. Cytokine 2002;19:1-5.[Medline]
  41. Yeh SS. Schuster MW. Geriatric cachexia: the role of cytokines. Am J Clin Nutr. 1999;70:183-197.[Abstract/Free Full Text]
  42. Raj DSC, Shah H, Shah VO. Ferrando et al. Markers of inflammation, proteolysis, and apoptosis in ESRD. Am J Kidney Dis 2003;42:1212-1220.[Medline]
  43. Tsujinaka T, Ebisui C, Fujita J, Kishibuchi M, Yano M, Monden M. Muscle wasting and IL-6. Basic Appl Myol. 1998;8:361-370.
  44. Raeburn CD, Sheppard F, Barsness KA, Arya J, Harken AH. Cytokines for surgeons. Am J Surg. 2002;183:268-273.[Medline]
  45. Banks WA, Farr SA, La Scola ME, Morley JE. Intravenous human interleukin-1 alpha impairs memory processing in mice: dependence on blood-brain barrier transport into posterior division of the septum. J Pharmacol Exper Ther. 2001;299:536-541.[Abstract/Free Full Text]
  46. Banks WA, Morley JE. Memories are made of this: recent advances in understanding cognitive impairments and dementia. J Gerontol Med Sci. 2003;58A:314-321.
  47. Wilson CJ, Finch CE, Cohen HJ. Cytokines and cognition—the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc. 2002;50:2041-2056.[Medline]
  48. Flacker JM, Lipsitz LA. Neural mechanisms of delirium: current hypotheses and evolving concepts. J Gerontol Biol Sci. 1999;54A:B239-B246.
  49. Baez-Franceschi D, Morley JE. Physiopathology of the catabolism associated with malnutrition in the elderly. Zeitschrift Gerontol Geriatr. 1999;32:12-19.
  50. Faltraco F, Burger K, Zill P, et al. Interleukin-6-174 G/C promoter gene polymorphism C allele reduces Alzheimer's disease risk. J Am Geriatr Soc. 2003;51:578-579.[Medline]
  51. Feldman AM, Combes A, Wagner D, et al. The role of tumor necrosis factor in the pathophysiology of heart failure. J Am Coll Cardiol. 2000;35:537-544.[Abstract/Free Full Text]
  52. Zou W, Hakim I, Tschoep K, Endres S, Bar-Shavit Z. Tumor necrosis factor-alpha mediates RANK ligand stimulation of osteoclast differentiation by an autocrine mechanism. J Cell Biochem. 2001;83:70-83.[Medline]
  53. Montero-Julian FA. The soluble IL-6 receptors: serum levels and biological function. Cell Mol Biol. 2001;47:583-597.[Medline]
  54. Modur V, Li Y, Zimmerman GA, Prescott SM, McIntyre TM. Retrograde inflammatory signaling from neurophils to endothelial cells by soluble interleukin-6 receptor alpha. J Clin Invest. 1997;100:2752-2756.[Medline]
  55. Romano M, Sironi M, Toniatti C, et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity. 1997;6:315-325.[Medline]
  56. Aziz N, Nishanian P, Mitsuyasu R, Detels R, Fahey JL. Variables that affect assays for plasma cytokines and soluble activation markers. Clin Diagnostic Lab Immunol. 1999;6:89-95.[Abstract/Free Full Text]
  57. Kotler DP. Cachexia. Ann Int Med. 2000;133:622-634.[Abstract/Free Full Text]
  58. Lambert CP, Sullivan DH, Evans WJ. Effects of testosterone replacement and/or resistance training on interleukin-6, tumor necrosis factor alpha, and leptin in elderly men ingesting megestrol acetate: a randomized controlled trial. J Gerontol Med Sci. 2003;58A:165-170.
  59. Yeh SS, Wu WY, Levine DM, Parker TS, Olson JS, Stevens MR, Schuster MW. The correlation of cytokine levels with body weight after megestrol acetate treatment in geriatric patients. J Gerontol Med Sci. 2001;56A:M48-M54.
  60. Roubenoff R. Sarcopenia: effects on body composition and function. J Gerontol Med Sci. 2003;58:1012-1017.
  61. Morley JE, Baumgartner RN, Roubenoff R, Mayer J, Nair KS. Sarcopenia. J Lab Clin Med. 2001;137:231-243.[Medline]
  62. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increase muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol Med Sci. 2003;58A:618-625.
  63. Iannuzzi-Sucich M, Prestwood KM, Kenny AM. Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women. J Gerontol Med Sci. 2002;57A:M772-M777.
  64. Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev. 1999;107:123-136.[Medline]
  65. Wilson MMG, Morley JE. Aging and energy balance. J Appl Physiol. 2003;95:1728-1736.[Abstract/Free Full Text]
  66. Morley JE, Silver AJ. Anorexia in the elderly. Neurobiol Aging. 1988;9:9-16.[Medline]
  67. Morley JE. Anorexia and weight loss in older persons. J Gerontol Med Sci. 2003;58A:131-137.
  68. Morley JE. Orexigenic and anabolic agents. Clin Geriatr Med. 2002;18:853.[Medline]
  69. Aihie Sayer A, Syddall HE, Gilbody HJ, Dennison EM, Cooper C. Does sarcopenia originate in early life? Findings from the Hertfordshire Cohort Study. J Gerontol Med Sci. 2004:;59A:930-934.
  70. Perry HM, Morley JE, Horowitz M, Kaiser FE, Miller DK, Wittert G. Body composition and age in African-American and Caucasian women—relationship to plasma leptin levels. Metab Clin Exper. 1997;46:1399-1405.[Medline]
  71. Perry HM, Bernard M, Horowitz M, et al. The effect of aging on bone mineral metabolism and bone mass in Native American women. J Am Geriatr Soc. 1998;46:1418-1422.[Medline]
  72. Abbatecola AM, Ferrucci L, Grella R, et al. Diverse effect of inflammatory markers on insulin resistance and insulin-resistance syndrome in the elderly. J Am Geriatr Soc. 2004;52:399-404.[Medline]
  73. Reuben DB, Judd-Hamilton L, Harris TB, Seeman TE. The associations between physical activity and inflammatory markers in high-functioning older persons: MacArthur studies of successful aging. J Am Geriatr Soc. 2003;51:1125-1130.[Medline]
  74. Taaffe DR, Harris TB, Ferrucci L, Rowe J, Seeman TE. Cross-sectional and prospective relationships of interleukin-6 and C-reactive protein with physical performance in elderly persons: MacArthur Studies of Successful Aging. J Gerontol Med Sci. 2000;55A:M709-M715.
  75. Bruunsgaard H, Andersen-Ranberg K, Jeune B, Pedersen AN, Skinhoj P, Pedersen BK. A high plasms concentration of TNF-alpha is associated with dementia in centenarians. J Gerontol Med Sci. 1999;54A:M357-M364.
  76. Dentino AN, Peiper CF, Rao KMK, Currie MS, Harris T, Blazer DG, Cohen HJ. Association of interleukin-6 and other biologic variables with depression in older people living in the community. J Am Geriatr Soc. 1999;47:6-11.[Medline]
  77. Rosenthal AJ, Sanders KM, McMurtry CT, Jacobs MA, Thompson DD, Gheorghiu D, Little KL, Adler RA. Is malnutrition overdiagnosed in older hospitalized patients—association between the soluble interleukin-2 receptor and serum markers of malnutrition. J Gerontol Med Sci. 1998;53A:M81-M86.
  78. Rosenthal AJ, McMurtry CT, Sanders KM, Jacobs M, Thompson D, Adler RA. The soluble interleukin-2 receptor predicts mortality in older hospitalized men. J Am Geriatr Soc. 1997;45:1362-1364.[Medline]
  79. Cesari M, Penninx BWJH, Newman AB, et al. Inflammatory markers and cardiovascular disease (The Health, Aging and Body Composition [Health ABC] Study). Am J Cardiol. 2003;92:522-528.[Medline]
  80. Testa M, Yeh M, Lee P, Fanelli R, Loperfido F, Berman JW, Lejemtel TH. Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J Am Coll Cardiol. 1996;28:964-971.[Abstract]
  81. Morley JE. The metabolic syndrome. J Gerontol Med Sci. 2004;59A:139-143.
  82. Banks WA, Altmann J, Sapolsky RM, Phillips-Conroy JE, Morley JE. Serum leptin levels as a marker for a syndrome X-like condition in wild baboons. J Clin Endocrin Metab. 2003;88:1234-1240.[Abstract/Free Full Text]
  83. Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and metabolic syndrome. Atheroscler Thromb Vasc Biol. 2004;24:29-33.[Abstract/Free Full Text]
  84. Zamboni M, Zoico E, Fantin F, et al. Relation between leptin and the metabolic syndrome in elderly women. J Gerontol Med Sci. 2004;59A:396-401.
  85. Morley JE, Perry HM, Baumgartner RP, Garry PJ. Commentary: Leptin, adipose tissue and aging—is there a role for testosterone? J Gerontol Biol Sci. 1999;54A:B108-B109.
  86. Zoico E, Di Francesco V, Mazzali G, et al. Adipocytokines, fat distribution, and insulin resistance in elderly men and women. J Gerontol Med Sci. 2004;59A:935-939.



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A. L. Ray, R. D. Semba, J. Walston, L. Ferrucci, A. R. Cappola, M. O. Ricks, Q.-L. Xue, and L. P. Fried
Low Serum Selenium and Total Carotenoids Predict Mortality among Older Women Living in the Community: The Women's Health and Aging Studies
J. Nutr., January 1, 2006; 136(1): 172 - 176.
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