Depression, Inflammation, and the Moderating Role of Metformin: Results From the Midlife in the United States Study and Sacramento Area Latino Study on Aging

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 ( N = 1255) and the Sacramento Area Latino Study on Aging ( N = 1786) included information on medication use, depressive symptoms, and inflammatory markers, namely, interleukin 6 (IL-6), tumor necrosis factor α, and C-reactive protein (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 Midlife in the United States Study sample, metformin buffered the association between depressive symptoms and CRP ( b = -0.029, standard error [SE] = 0.013, p = .007) and IL-6 ( b = 0.21, SE = 0.010, p = .046), whereas no significant association was found with tumor necrosis factor α. Metformin nonusers 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 ( p values > .068). Conversely, in the Sacramento Area Latino Study on Aging sample, metformin use did not show a significant protective link. CONCLUSIONS: 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 preregistered on OSF ( https://osf.io/c92vw/ ).