Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration - PubMed
5 hours ago
- #Brain aging
- #Senolytics
- #Neuroinflammation
- The aging brain accumulates senescent glia, chronic neuroinflammation, and is vulnerable to neurodegeneration.
- Causal relationships among glial senescence, neuroinflammation, and neurodegeneration are examined using Bradford Hill criteria, longitudinal studies, genetic approaches, and senolytic trials.
- Glial senescence in astrocytes and microglia initiates neuroinflammatory cascades via the senescence-associated secretory phenotype (SASP), creating self-perpetuating cycles that drive neuronal dysfunction.
- Neuroinflammation can also be a primary event triggered by peripheral signals, blood-brain barrier breakdown, or pathogens, subsequently inducing glial senescence.
- Neuronal damage generates inflammatory signals that activate glia, indicating bidirectional causality.
- Disease-specific patterns vary: in Alzheimer's disease, early microglial activation may precede amyloid pathology, while in Parkinson's disease, gut-brain inflammation may initiate central pathology.
- Feed-forward loops amplify initial insults (senescence, inflammation, or protein aggregation), transcending linear causality.
- A framework is proposed that recognizes critical temporal windows and tipping points, distinguishing reversible from irreversible stages.
- Anti-inflammatory and senolytic interventions show promise preventively or early but have limited efficacy in advanced disease, emphasizing the importance of intervention timing.
- Outstanding questions include identifying earliest causal events, determining points of no return, and understanding genetic-environmental modification of causal pathways.
- Longitudinal multi-omics studies and interventional trials are needed to address these questions.
- Establishing causation beyond correlation enables precision medicine targeting root causes, offering hope for preventing age-related cognitive decline and neurodegeneration.