Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and...

The aging brain is characterized by accumulation of senescent glia, chronic neuroinflammation, and vulnerability to neurodegeneration. While their co-occurrence is established, causal relationships remain poorly understood-a critical gap for developing mechanism-based therapies rather than symptomatic treatments. This review examines evidence for causality among glial senescence, neuroinflammation, and neurodegeneration using Bradford Hill criteria, longitudinal studies, genetic approaches, and senolytic trials. Glial senescence in astrocytes and microglia initiates neuroinflammatory cascades through the senescence-associated secretory phenotype (SASP), creating self-perpetuating cycles driving neuronal dysfunction. However, neuroinflammation also emerges as a primary event triggered by peripheral signals, blood-brain barrier breakdown, or pathogens, subsequently inducing glial senescence. Neuronal damage generates inflammatory signals activating glia, indicating bidirectional causality. Disease-specific patterns are heterogeneous: in Alzheimer's disease, early microglial activation may precede amyloid pathology, while in Parkinson's disease, gut-brain inflammation may initiate central pathology. Common feed-forward loops amplify initial insults-senescence, inflammation, or protein aggregation-transcending linear causality. We propose a framework recognizing critical temporal windows and tipping points, distinguishing reversible from irreversible stages. Anti-inflammatory and senolytic interventions show promise preventively or early but limited efficacy in advanced disease, emphasizing intervention timing. Outstanding questions include identifying earliest causal events, determining points of no return, and understanding genetic-environmental modification of causal pathways. Addressing these requires longitudinal multi-omics studies and interventional trials. Establishing causation beyond correlation enables precision medicine targeting root causes, offering hope for preventing age-related cognitive decline and neurodegeneration.