Inflammaging and Cellular Senescence in Postmenopausal Depression: Linking Estrogen Deficiency, Immune Dysregulation, and Brain Aging

Postmenopausal depression is clinically heterogeneous and cannot be explained by estrogen deficiency alone. We propose a conceptual, testable neuroimmune-aging model in which endocrine decline may interact with inflammaging, cellular senescence, and brain vulnerability in a subset of women. The evidentiary base is uneven: direct studies of senescence in well-phenotyped postmenopausal depression are lacking; clinical endocrine data come mainly from perimenopausal depression; molecular-senescence findings come from late-life depression or general major depressive disorder; and most cellular and brain mechanisms are supported by aging or preclinical models. Reduced estrogen signaling may weaken immune homeostasis, whereas peripheral cytokines or senescence-associated secretory phenotype factors could influence vascular and neural interfaces, glia, neurotransmitter metabolism, stress signaling, mitochondrial function, and neuroplasticity. These pathways are candidate mediators, not established causal mechanisms. Clinically established care remains diagnosis-based antidepressant treatment, evidence-based management of vasomotor and sleep symptoms, and individualized menopausal hormone therapy for appropriate candidates. Anti-inflammatory, microbiome-based, and senescence-targeted strategies remain investigational; no senolytic or senomorphic is approved for depression or menopause-related mood symptoms. Prospective studies integrating menopausal staging, prespecified confounders, senescence biomarkers, neuroimaging, and mood outcomes are needed to test this model.