A miR-10a-5p-γCaMKII axis links periphery-to-brain signaling to cognitive vulnerability during female midlife.

Although women live longer, they paradoxically face heightened susceptibility to cognitive and systemic decline emerging in midlife-an underexplored transition from resilience to vulnerability. Here, we investigate biological processes associated with this female-biased vulnerability and their molecular regulation. Senescence-associated features were preferentially elevated in middle-aged females in human brain and spleen tissues, with similar changes in mice. In female mice, epigenetic upregulation of the X-linked RNA-binding protein RBMX promoted midlife increases in splenic miR-10a-5p, while complementary in vivo approaches supported a peripheral contribution to cerebral miR-10a-5p abundance. miR-10a-5p repressed calcium/calmodulin-responsive kinase γCaMKII, and modulation of this axis influenced mitochondrial function, cellular senescence, and memory in mice. In neurons derived from Alzheimer's disease patients and in model mice, miR-10a-5p inhibition attenuated disease-associated phenotypes, supporting relevance to pathological aging. Together, these findings link periphery-to-brain communication to emerging brain vulnerability during female midlife and indicate that this transition may remain amenable to intervention.