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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 58:M995-M998 (2003)
© 2003 The Gerontological Society of America

EDITORIAL

The Relationship Between Functional Status and Inflammatory Disease in Older Adults

David R. Thomas

Division of Geriatric Medicine, Saint Louis University Health Sciences Center, St. Louis, Missouri.

DECLINE in functional status is a profound predictor of morbidity and mortality, as previously pointed out in an editorial in the Journal (1). Decline in functional status during a hospitalization is a major predictor of risk for nursing home placement (2,3), subsequent acute illness (4), and declining quality of life (5). Functionally impaired nursing home residents tend to become more functionally impaired over time and have a higher death rate. Frailty is related to loss of instrumental activities of daily living and sarcopenia (loss of muscle mass) is strongly related to frailty and functional decline (6–9). A series of articles in the Journal suggested that loss of mobility and a decline in walking speed is related to the development of frailty (10–17).

Recently a body of evidence has emerged that suggests that many of these effects are due to excess production of cytokines. Cytokines are cell-associated proteins produced and secreted by inflammatory cells that have the capacity to act at low concentrations on other cells both locally and systematically via specific cell receptors. Cytokines act principally in a paracrine fashion, and their concentrations in tissues are often several times higher than those found in the peripheral circulation. Aging is characterized by progressively increased concentrations of glucocorticoids and catecholamines and decreased production of growth and sex hormones, a pattern reminiscent of that seen in chronic stress. Plasma levels of interleukin-6 (IL-6) increase with age, probably as the result of catecholamine hypersecretion and sex-steroid hyposecretion. However, the age-associated changes in cytokine production are inconsistent (18,19).

Cohen and colleagues found that IL-6 levels correlate with the functional disability of the community-dwelling elderly person (20). In 3075 older men and women evaluated in the Health ABC study, higher levels of IL-6 or tumor necrosis factor alpha (TNF-{alpha}) were associated with lower muscle mass and strength (21). This suggests that IL-6 may contribute to the increased morbidity and mortality seen in chronically stressed or physiologically aged persons.

In 1723 participants older than 71 years, IL-6 and D-dimer were measured and participants were followed for 5-year mortality and functional status. The relative risk of mortality was 1.28 (95% confidence interval [CI]: 0.98–1.69; p =.06) for those with only IL-6 levels in the highest quartile, 1.53 (95% CI: 1.18–1.97; p =.001) for participants with only D-dimer levels in the highest quartile, and 2.00 (95% CI: 1.53–2.62; p =.0001) for those with levels of both in the highest quartile, as compared with those who were not in either of the highest quartiles. Those participants with high IL-6 and high D-dimer levels had the greatest declines in all measures of function. Thus, activation of the coagulation and inflammatory pathways was associated with mortality and decline in function, and may contribute to the development of a frailty phenotype in elderly people (22).

In high-functioning healthy, nondisabled older persons, serum albumin and plasma IL-6 were measured at baseline and followed for 4 years. Among participants without evidence of IL-6-mediated inflammation, having a lower albumin level was associated with a multiply adjusted relative mortality risk of 2.1, compared with those with higher albumin. In the presence of elevated IL-6 levels, either high and low serum albumin levels had increased risk (adjusted relative risks 4.0 and 3.8, respectively) compared with the group with higher albumin and low IL-6. High serum albumin has a protective effect in healthy older persons who do not have evidence of cytokine-mediated inflammation. This protective effect is not seen in the presence of inflammation (23).

In congestive heart failure (CHF) patients, elevated plasma cytokine levels are associated with poor functional status and a worse prognosis. Elevated levels of TNF-{alpha} are associated with mortality in patients with CHF (24). Cytokine levels also appear to predict the incidence of CHF in asymptomatic individuals. Among 732 elderly Framingham Study participants whose mean age was 78 years and who were free of prior myocardial infarction and CHF, 56 participants developed CHF after a mean of 5.2 years of follow-up. After adjustment for established risk factors, including the occurrence of myocardial infarction on follow-up, there was a 60% (TNF-{alpha}) to 68% (serum IL-6) increase in risk of CHF per tertile increment in cytokine concentration. An elevated serum C-reactive protein (CRP) level was associated with a 2.8-fold increased risk of CHF. Participants with elevated levels of all 3 biomarkers had a markedly increased risk of CHF (hazards ratio 4.07 [95% CI 1.34–12.37], p =.01) compared with the other participants. In this elderly community-based sample, a single determination of serum inflammatory markers, particularly elevated IL-6, predicted an increased risk of CHF in people without prior myocardial infarction (25).

There is increasing evidence that cytokines can produce cognitive impairment (26,27). Thus, cytokines, besides producing a direct effect on muscle function, may also impair functional status by altering central nervous system function. Cognitive impairment has been demonstrated to be associated with functional decline (28–32).

Not all populations show this effect. In participants on maintenance hemodialysis, levels of inflammatory cytokines are uniformly high. When physical activity (measured by accelerometry), physical performance (gait speed, stair-climbing, and chair-raising), physical functioning, and activity scores were measured, there were no significant associations among inflammatory cytokines and physical activity, performance, or function. Tumor necrosis factor-alpha was directly correlated with dietary protein and energy intake; however, no other cytokines were directly or inversely correlated with intake. Dietary intake was associated with physical activity, as measured by gait speed (33).

Cytokines are related to a number of disease conditions, including cancer (34), end-stage renal disease (35), chronic pulmonary disease (36), CHF (37), rheumatoid arthritis (38), and AIDS (39). Cytokines, especially IL-1, IL-6, and TNF-{alpha}, are potent causes of appetite suppression, weight loss, and hypoalbuminemia (40–42). These same conditions are frequently associated with a decline in functional status. Cytokines also decrease hemoglobin levels (43). Decreased hemoglobin concentration have been shown to be associated with frailty (44).

The importance of identifying functional decline lies in the fact that it may be amenable to intervention. Consistent studies in younger adults show that muscle strength and mass increases with high-intensity training (70%–90% of 1-repetition maximum). In older men, upper arm strength increased by 23%–48% (45,46), and lower extremity strength by 107%–226% with exercise (47). Similar increases, in the range of 28%–115%, have been reported in older women (48). Six months of resistive exercise training has improved lower extremity strength by 34% in older diabetics (49), and a benefit has been described even in cognitively impaired participants (50).

Physical training can also reduce the plasma levels of proinflammatory cytokines in patients with diseases such as CHF. This immunomodulatory effect may be related to the training-induced improvement in functional status of patients. Plasma levels of TNF-{alpha}, soluble TNF receptors I and II (sTNF-RI and sTNF-RII, respectively), IL-6, and soluble IL-6 receptor (sIL-6R) were measured in 24 patients with stable CHF and in 20 normal control participants before and after a 12-week program of physical training in a randomized, crossover design. The physical training produced a significant reduction in plasma levels of TNF-{alpha} (7.5 ± 1.0 pg/ml vs 4.6 ± 0.7 pg/ml, p <.001), sTNF-RI (3.3 ± 0.2 ng/ml vs 2.7 ± 0.2 ng/ml, p <.005), sTNF-RII (2.6 ± 0.2 ng/ml vs 2.3 ± 0.2 ng/ml, p =.06), IL-6 (8.3 ± 1.2 pg/ml vs 5.9 ± 0.8 pg/ml, p <.005), and sIL-6R (34.0 ± 3.0 ng/ml vs 29.2 ± 3.0 ng/ml, p <.01). A significant increase in VO2max (16.3 ± 0.7 ml/kg/min vs 18.7 ± 0.8 ml/kg/min, p <.001) was seen. Good correlation was found between a training-induced increase in VO2max and a training-induced reduction in levels of the proinflammatory cytokine TNF-{alpha} (r = -0.54, p <.01) in patients with CHF. In contrast, no significant difference in circulating cytokines was found with physical training in normal participants (51).

Testosterone levels decline with aging in both men (52) and women (53,54). Testosterone replacement in men increases muscle mass (55–57) and strength (54,58), and decreases fat mass (56,59,60). In a forthcoming issue of the Journal, Bhasin (61) shows that testosterone promotes the formation of muscle satellite cell precursors while inhibiting the formation of adipocytes. Adipocytes are a potent source of cytokines such as TNF-{alpha} and leptin. This suggests that the putative effects of testosterone on function may be mediated by reducing cytokine excess (62,63).

Recently, megestrol acetate, a potent orexigenic agent (64), has been shown to produce its effects by decreased cytokine release (65,66). This suggests that one possible approach to preventing functional decline would be to use a cytokine inhibitor.

It would be useful to know which older adults were more likely to experience a decline in functional status. This would identify which older persons were more likely to die or experience a decrease in quality of life. The association of inflammatory cytokines with functional decline suggests that a biological marker may be useful in identifying these persons. Aggressive intervention to ameliorate the inflammatory state, as has been demonstrated with the use of megestrol acetate to reverse weight loss due to inflammatory disease, may lead to improvement in functional status, quality of life, and mortality.

Acknowledgments

Address correspondence to David R. Thomas, MD, Division of Geriatric Medicine, Saint Louis University Health Sciences Center, 1402 S. Grand Blvd., M238, Saint Louis, MO 63104. E-mail: thomasdr{at}slu.edu

Received August 27, 2003

Accepted September 2, 2003

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