Depression, Inflammation, and the Moderating Role of Metformin: Results from the Midlife in the United States (MIDUS) Study and Sacramento Area Latino Study on Aging (SALSA)

Abstract

Abstract Objective Depression can promote inflammation and accelerate aging. Metformin, a widely prescribed antidiabetic, has shown promising preclinical evidence of aging-related health benefits, including decreased inflammation. The current study examined whether metformin usage buffers the association between depressive symptoms and inflammatory markers in two large samples of middle-aged and older, primarily white adults, and older Latino adults. Methods Data from the Midlife in the United States Study (MIDUS; N = 1255) and the Sacramento Area Latino Study on Aging (SALSA; N = 1786) included information on medication use, depressive symptoms, and inflammatory markers, namely IL-6, TNF-α, and CRP. These data were merged into a harmonized sample, and the sample group variable was included in a three-way interaction for analysis. Results Specifically, in the MIDUS sample, metformin buffered the association between depressive symptoms and CRP (b = -0.029, SE = 0.013, p = .007) and IL-6 (b = 0.21, SE = 0.010, p = .046), while no significant association was found with TNF-α. Metformin non-users displayed higher depressive symptoms associated with elevated CRP (b = 0.01, SE = 0.003, p < .001) and IL-6 (b = 0.011, SE = 0.003, p < .001), whereas this association was not present among metformin users (ps > .068). Conversely, in the SALSA sample, metformin use did not show a significant protective link. Conclusion Results from mostly white, highly educated adults supported a mitigating role of metformin in ties between depression, a well-known behavioral risk factor, and inflammation, a key source of biological aging. However, the benefits did not extend to a large sample of older Mexican Americans. The findings reveal a hidden potential benefit of this therapeutic agent and raise important questions around its health equity. Trial Registration: The study was pre-registered on OSF (https://osf.io/c92vw/).