Inflammation gone awry: aging or disease

Comment on Ferrucci et al, page 2294

In a cohort analysis of elderly Italians, Ferrucci and colleagues found that the dysregulation of proinflammatory mediators, considered by many to be at the root of aging, may more aptly be considered at the root of cardiovascular disease.

Now and again, unifying concepts emerge with relevance to diverse clinical domains. This is clearly true for the robust expansion of appreciation for inflammation gone awry, which has now been implicated in the pathogenesis of disease processes as diverse as gingivitis, diabetes, atherosclerosis, sarcopenia, osteoporosis, and dementia. For gerontologists interested in the biology of aging, the proinflammatory cytokine interleukin-6 (IL-6) has been particularly interesting, inasmuch as animal models and clinical series have time and time again demonstrated an age-associated rise in serum or tissue levels, with the most dramatic change observed in those who develop the phenotype of frailty. For example, in an epidemiologic study of more than 4000 community-dwelling elderly, IL-6 levels were positively associated with functional impairment (mobility and activities of daily living), depression, and mortality.¹  Other large cohorts, including the Health Aging and Body Composition Study (Health ABC)²  and the Cardiovascular Health Study,³  have demonstrated similar changes in IL-6 and other proinflammatory molecules or acute phase proteins, such as C-reactive protein (CRP) and fibrinogen. Invariably, to the extent that these factors are present, negative clinical consequences are observed.

Yet it remains to be determined whether the presence of these mediators of inflammation is the consequence of aging (ie, a decline in those factors that regulate proinflammatory cytokines) or a reflection of an underlying disease, such as atherosclerosis. If the former were true, one would expect increased cytokine levels in at least some individuals in the absence of demonstrable inflammatory disease. In this issue of Blood, Ferrucci and colleagues report data from a large cohort of thoroughly studied older adults. From their analysis, there appears to be a tight correlation of inflammatory signals with cardiovascular disease, as most (but not all) of the measured markers were not demonstrably correlated with age once the data were adjusted for cardiovascular risk factors or morbidity. As is typical from well-constructed epidemiologic studies, these findings will raise as many questions as they answer. And the big one still remains: which comes first—the cytokines or the disease? Do those factors that render an individual at risk for cardiovascular disease do so by altering proinflammatory cytokine regulation? Is there a genetic predisposition to cytokine dysregulation increasing susceptibility to atherosclerosis?

The study by Ferrucci and colleagues goes as far as a cross-sectional analysis can. At this point, what is sorely needed is a longterm longitudinal analysis of healthy individuals as they traverse from middle age to old age, with interval checks of these important markers and a cataloguing of clinical conditions and incipient disease processes. From there, rational experimental interventions in laboratory animals and humans can be derived with the ultimate goal of retarding either, or both, aging and age-related diseases. ▪