Perceived Stress is Associated with Accelerated Monocyte/Macrophage Aging Trajectories in Clinically Normal Adults

•Stress and aging are associated with macrophage and microglia activation in animals.•High-stress adults demonstrated accelerated age-related macrophage cytokine elevations.•Macrophage cytokines mediated the relationship between age and cognition in high-stress adults.•Stress interventions may target age-related inflammation to benefit cognition in aging. Chronic stress is associated with poorer age-related cognition, but the mechanisms of this relationship are not well understood. Aging increases expression of activated macrophages, leading to exacerbated immune responses to stressors. We examined the impact of stress and aging on macrophage-related inflammation and cognition in clinically normal adults. Three hundred eighty clinically normal adults were followed longitudinally (age M = 73 years; visit range: 1–8; M = 2.5 visits). Participants completed the Perceived Stress Scale, a neuropsychological battery, and blood draws. Plasma was analyzed for cytokines related to macrophage function (interleukin 6, tumor necrosis factor alpha, macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta). Linear mixed-effects examined the effects of age, baseline stress, and their interaction predicting macrophage cytokines, adjusting for sex, education, and depressive symptoms. Latent growth curve models assessed the mediating role of macrophage cytokines in the relationship between age and cognition in high or low stress. Baseline perceived stress interacted with age to predict macrophage cytokines longitudinally. Specifically, high-stress adults demonstrated accelerated age-related elevations in macrophage cytokines across time. Macrophage cytokines negatively tracked with executive functioning longitudinally. Macrophage cytokines mediated 19% of the relationship between age and executive function in high-stress, but not low-stress, adults. Our data provide evidence of accelerated immune aging among individuals with high stress. Elevated macrophage cytokine trajectories mediated the effect of age on executive function only in individuals with high stress, suggesting these constructs may be more tightly linked in elevated stress contexts. Stress interventions are warranted to optimize immune aging, with possible downstream cognitive benefits among even clinically normal adults.