Beyond biochemical cascades: novel bio-mechanical and epigenetic paradigms of glial SASP in brain aging.

One of the most pressing scientific challenges of the current century is the mounting loss of cognitive function and vulnerability to neurodegenerative disorders associated with brain aging. This requires a paradigm shift beyond traditional neuron-focused models to address the central importance of non-neuronal glial cells, most notably astrocytes, in promoting age-related neuroinflammation. While the pro-inflammatory secretome of senescent cells, known as the senescence(definition)-associated secretory phenotype (SASP), is well-characterized in peripheral tissues, its specific role in the central nervous system remains a critical knowledge gap. This narrative review synthesizes current evidence to propose that the SASP of glial and vascular cells acts as a contributor mechanism, where it interacts with other aging hallmarks to amplify the pathological environment rather than acting as the sole link. Moving beyond standard biochemical signaling cascades, we propose conceptually transformative frameworks to explain central SASP aggression. The glymphatic-SASP traffic jam, establishing a bio-mechanical feedback loop where waste clearance failure traps secretomes in localized hotspots; and the metabolic energy vampire paradigm, demonstrating the active competition for resources between hyper-secretory glia and energy-starved neurons, were explored. Also, the innate immune mimicry triggered by retrotransposon awakening, explaining how unleashed genetic elements actively fuel self-propagating inflammation, and the loss of glial identity dictated by epigenomic state drift and SASP mosaicism were demonstrated. Furthermore, we evaluate the classic regulatory cross-talk between the SASP and nutrient-sensing pathways like AMPK and mTOR(definition), and discuss the therapeutic potential of selectively targeting the SASP through senomorphics and metabolic resetters. Elucidating these complex, brain-specific SASP dynamics is paramount for translating these concepts into effective interventions against age-related neurological diseases.