Adipose tissue as a systemic modulator of brain aging: mechanistic links between metabolism, inflammation and neurodegeneration

Brain aging involves progressive declines in neuroplasticity, metabolic flexibility, cerebrovascular integrity and immune homeostasis. Although traditionally viewed as brain-intrinsic, growing evidence indicates that peripheral metabolic organs substantially influence neural aging trajectories. Among these, adipose tissue is increasingly recognized as a dynamic endocrine and immune organ capable of modulating central nervous system (CNS) structure and function across the lifespan. Epidemiological, neuroimaging and experimental studies consistently link adipose tissue dysfunction, particularly the expansion and inflammatory remodeling of visceral fat depots, to accelerated brain aging, cognitive decline and increased susceptibility to neurodegenerative disease. These relationships extend beyond conventional cardiometabolic risk, implicating adipose-derived mechanisms with direct relevance for neural aging. Chronic low-grade inflammation, impaired insulin signaling, dyslipidemia, adipokine imbalance and senescence-associated secretory activity originating in adipose tissue act on the aging brain by promoting microglial dysfunction, cerebrovascular impairment, blood-brain barrier (BBB) disruption and synaptic vulnerability. In parallel, adipose-derived extracellular vesicles and microRNAs have been identified as direct molecular mediators of adipose-brain communication. Importantly, adipose tissue is structurally and functionally heterogeneous, and its impact on brain aging is strongly depot- and context-dependent. While dysfunctional visceral adipose tissue amplifies neuroinflammatory and neurodegenerative processes, preserved subcutaneous and thermogenic depots may support brain resilience by sustaining metabolic homeostasis and neurotrophic signaling. By integrating molecular, translational and human evidence, this review frames adipose tissue as a central and modifiable systemic determinant of brain aging. Framing brain aging within a peripheral metabolic context reconciles findings across disciplines and highlights adipose-targeted interventions as promising strategies for preserving cognitive function and reducing neurodegenerative risk.