The neuro-inflammaging triangle: a self-amplifying circuit of protein pathology, senescence-associated secretory phenotype and innate immunity in neurodegenerative disease

Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and amyotrophic lateral sclerosis, share common pathological features, including abnormal protein aggregation, chronic neuroinflammation and progressive neuronal loss. Ageing is the strongest risk factor, accompanied by a chronic, mild inflammatory state called ‘inflammaging,’ partly due to senescent cells producing senescence-associated secretory phenotype (SASP) factors. Innate immune DNA- and danger-sensing pathways, most notably the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) pathway and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasomes, convert cellular injury into chronic neuroinflammation. Here, we propose that protein pathology, SASP, and innate immune activation form a self-amplifying triangular circuit leading to age-related neurodegeneration. We present the cellular and molecular basis of each part and how microglia, astrocytes, oligodendrocyte precursor cells and neurons contribute. We outline treatment strategies, including senolytics, senomorphics, innate immune pathway inhibitors and metabolic restoration, and identify unresolved questions, including the reversibility of post-mitotic neuronal senescence, the relative contribution of each cell type and the translational challenge of interrupting the cycle. Collectively, the neuro-inflammaging triangle theory shifts focus from individual pathogenic entities to the self-amplifying circuit that sustains them, offering a unified mechanistic model to advance our understanding and treatment of age-related neurodegeneration.