ReviewInflammatory markers in population studies of aging
Research highlights
► Markers of inflammation are elevated in older adults. ► Visceral abdominal fat and lower sex steroid hormones are associated with higher levels of inflammatory markers. ► Of the markers assessed, IL-6 most robustly predicts disease, disability and mortality in old age.
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.
Section snippets
Visceral adiposity and high fat diet
Body fat increases with age with a shift from the periphery to more central abdominal or visceral location. Adipose tissue acts as an active endocrine organ, capable of secreting several cytokines and adipokines, including IL-6 and TNF-alpha (Trayhurn and Wood, 2005). The production of these cytokines may be greater in visceral adipose tissue vs. subcutaneous adipose tissue (Fried et al., 1998, Schrager et al., 2007) and the production rate is variable during the day (Mohamed-Ali et al., 1997).
Cardiovascular disease
While traditional cardiovascular risk factors are useful for predicting incident events in the younger population, their predictive value decreases with age (Beckett et al., 2000). It is possible that absence of inflammatory markers from these models decreases their predictive accuracy in older age groups suggesting a more substantial role of low-grade inflammation in CVD pathogenesis in older adults than in younger adults. In observational studies of older adults, inflammatory markers are
Possible interventions
The strong associations of inflammatory markers with adverse health outcomes in older adults suggest the potential for targeting inflammation to reduce disability and mortality in old age. Advances have been made in targeting TNF and more recently IL-6 in rheumatic conditions, but whether these are relevant in old age is not yet known. Proteasome inhibitors, IL-6 and IL-6 receptor antibodies are in initial testing stages. Indirect evidence for benefit from reducing inflammatory markers in old
Summary
These epidemiologic studies illustrate the significance of inflammatory markers such as IL-6, TNF-alpha and CRP in older adults. These markers increase with age, potentially as a consequence of declining levels of sex hormones and increase in visceral adipose tissue. Given the large burden of chronic disease in older people, it is also quite possible that these elevated markers summarize total disease burden. Of the inflammatory markers studied in cohort studies of aging, IL-6 is most robustly
Acknowledgements
Dr. Singh and Dr. Newman were supported by R01-AG-023629 and R01-AG-030734.
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