Oxidative Protein Damage Is Associated With Elevated Serum Interleukin-6 Levels Among Older Moderately to Severely Disabled Women Living in the Community

A low-grade proinflammatory state characterized by elevated inflammatory mediators is common among older adults (1), and is associated with pathological processes in multiple systems such as endothelial dysfunction (2), metabolic syndrome (3), atherosclerosis (4), and decline of muscle strength and mass (5–7) that are characteristic of declining health in older individuals. Among older adults, elevated interleukin (IL)-6 levels have been associated with disability (8), decline in physical function (5,9), cognitive decline (10), frailty (11), and increased mortality (12). The underlying triggers for the age-related proinflammatory state have not been well characterized. Reactive oxygen species are ubiquitous reactive derivatives of O2 metabolism that are found in all biological systems, and they are formed as intermediates in reduction-oxidation (redox) processes that lead from oxygen to water. Reactive oxygen species have often been considered as damaging molecules, but there is considerable evidence that they participate in cell signaling. Reactive oxygen species play a critical role in the activation of nuclear factor kappaB (NF-κB) (13,14) and activator protein-1 (AP-1) (15), redox-sensitive transcription factors that are involved in the upregulation of cytokines such as IL-6 (11). Thus, reactive oxygen species may affect health in old age by two parallel mechanisms: directly by damaging biomolecules and indirectly by upregulating the production of proinflammatory cytokines. Protein oxidation is the covalent modification of a protein that is induced directly by reactive oxygen species (16), by products of lipid and free amino acid oxidation (17), or by reactive nitrogen species (18,19). Oxidation preferentially affects certain protein side chains, especially Pro, Arg, Lys, and Thr residues, and when oxidized, these produce carbonyl groups (aldehydes, ketones) (20). Protein carbonyls are the most studied marker of protein oxidation (18–20). In model systems, induced oxidative stress increases protein carbonyls in serum and tissues (16,21). Although protein carbonyls are an important general marker for oxidative protein damage and have been widely applied in epidemiologic studies, the relationship between protein carbonyls and the age-related proinflammatory state has not been well described in humans. We hypothesized that elevated serum protein carbonyls are associated with elevated serum IL-6 in older adults. To examine this hypothesis, we characterized serum protein carbonyls and serum IL-6 among older, moderately to severely disabled women living in the community.