Inflammatory markers in population studies of aging

Abstract

Purpose

To review findings from major epidemiologic studies regarding risk factors for and consequences of elevated markers of inflammation in older adults.

Results

Most large, current epidemiologic studies of older adults have measured serum interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-alpha) and some studies also include more extensive batteries of measures including soluble receptors. There are few defined risk factors for the modest elevations in inflammatory markers seen with aging. These include visceral adiposity, lower sex steroid hormones, smoking, depression and periodontal disease. Of the markers assessed, IL-6 is most robustly associated with incident disease, disability and mortality.

Conclusion

Though correlated with age, the etiology of elevated inflammatory markers remains incompletely defined. Inflammation, especially IL-6 may be a common cause of multiple age-related diseases or a final common pathway by which disease leads to disability and adverse outcomes in older adults. Future research targeting inflammation should examine these pathways.

Introduction

A role for inflammation in the process of aging and age-related disease has been clearly established in several large epidemiologic studies of older adults. Interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor alpha (TNF-alpha) are the inflammatory markers most consistently associated with age-related chronic diseases and disability. IL-6 is a cytokine produced by immune cells, vascular endothelial cells, adipocytes and skeletal muscle and has shown to have anti-inflammatory and pro-inflammatory properties (DeRijk et al., 1997, Xing et al., 1998, Maggio et al., 2006b). CRP is an acute phase protein produced by the liver in response to elevations in IL-6. TNF-alpha, another cytokine, is produced mainly by macrophages, but also by lymphoid cells, mast cells, vascular endothelial cells, cardiac myocytes, adipocytes, fibroblasts, and neuronal tissue. TNF-alpha contributes to the production of IL-6 through activation of several pathways (Sawada et al., 1992, Sakamoto et al., 2003, Williams et al., 2008). IL-6 is a major factor driving chronic elevation of CRP in older adults (Roubenoff et al., 1998). Thus, it is not surprising that IL-6, CRP and TNF-alpha are correlated in human population studies.

Acute inflammation is tightly regulated and contributes to the healing process. In younger individuals, cytokine levels are consistently low and typically increase only in response to physiologic stress. In contrast, numerous studies of older adults show that levels of several cytokines, especially IL-6 and TNF-alpha, increase with age even in apparently healthy individuals and in the absence of acute infection (Wei et al., 1992, Ershler et al., 1993, Fagiolo et al., 1993, Cohen et al., 1997, Ferrucci et al., 2005). This age-associated elevation ranges from low to moderate, but is much lower than that seen with acute infection. The etiology of this age-associated increase is not fully understood. Proposed mechanisms include the known increase in total and visceral adiposity with age and declining levels of sex hormones after menopause and andropause. Cumulative oxidative damage, which further invokes an inflammatory response, may be another mechanism leading to an increase in the level of these markers. The consequence of elevated inflammatory markers is better understood. Elevated levels of these cytokines and CRP have been studied extensively as predictors of disease and disability in older adults. White blood cell (WBC) count is also associated with frailty and mortality in older adults (Grimm et al., 1985, Leng et al., 2005, Leng et al., 2007, Leng et al., 2009a, Leng et al., 2009b, Ruggiero et al., 2007), but is not as commonly assessed.

Even after a number of animal and human studies there is still a debate about whether these markers are a direct cause of adverse events or simply summarize the burden of illness in older adults. In this review we summarize results from large epidemiologic studies of older cohorts to illustrate the epidemiological significance of inflammatory markers including IL-6, TNF-alpha and CRP in population studies of aging.