Cellular Senescence and Senolytic Signalling in Brain Aging and Neurodegeneration

Cellular senescence is a state of stable cell cycle arrest accompanied by profound changes in signalling, metabolism, and secretory activity. It is enforced primarily through the p16INK4a-Rb and p53-p21 pathways and is characterized by the senescence-associated secretory phenotype (SASP), a program of pro-inflammatory cytokines, chemokines, and proteases driven by NF-κB and innate immune signalling. In the nervous system, senescence and senescence-like states have been described across neurons, astrocytes, microglia, oligodendrocyte lineage cells, and neural stem and progenitor populations, each engaging distinct molecular programs. Through the SASP and related signalling, senescent cells can reshape the local tissue environment, promote chronic neuroinflammation, and influence the survival and function of neighbouring cells.Cellular senescence is now recognized as an active driver of brain aging and age-related neurological disease. Senescent cells accumulate in the aging brain and have been implicated in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and frontotemporal dementia, other tauopathies, multiple sclerosis, and injury responses following stroke and traumatic brain injury. Senescence in these contexts is triggered by DNA damage, telomere attrition, oxidative and proteotoxic stress, mitochondrial dysfunction, and pathological protein aggregation, and it frequently intersects with inflammaging, cGAS–STING signalling, and impaired proteostasis. Yet major questions remain regarding how post-mitotic neurons enter senescence-like states, how senescence is defined and detected across neural cell types, and how SASP signalling propagates dysfunction across the aging and diseased brain. These uncertainties are increasingly relevant as senolytics and senomorphics advance toward clinical translation.This Research Topic aims to bring together studies that dissect the molecular signalling programs governing cellular senescence in the nervous system and that connect cell-type-specific senescence to defined outcomes in brain aging and neurodegeneration. By integrating molecular, genetic, and pharmacological perspectives, this collection seeks to clarify how neurons and glia engage senescence signalling, how the SASP communicates with neuroinflammatory, mitochondrial, and proteostatic networks, and how these mechanisms can be targeted for therapeutic benefit while preserving homeostatic function.We welcome submissions employing biochemical, genetic, imaging, metabolomic, and multi-omic approaches, including work in genetically engineered animal models, human iPSC-derived neural systems, and organoids. Studies developing robust, cell-type-resolved markers of neural senescence, dissecting SASP signalling, or evaluating senolytic and senomorphic strategies, including pathway-selective biomarkers and small-molecule modulators, are particularly encouraged.Topics of interest include, but are not limited to:• Molecular signalling programs enforcing senescence in neurons, astrocytes, microglia, oligodendrocyte lineage cells, and neural stem or progenitor cells• Cell-type specificity and defining features of senescence and senescence-like states in the nervous system• Triggers of neural senescence, including DNA damage, telomere attrition, oxidative and proteotoxic stress, mitochondrial dysfunction, and protein aggregation• SASP composition and signalling, and its role in propagating neuroinflammation and inflammaging• Crosstalk between senescence and cGAS–STING signalling, innate immune activation, autophagy, and proteostasis in neural cells• Contributions of cellular senescence to brain aging and cognitive decline• Senescence in neurodegenerative disease, including Alzheimer’s disease, Parkinson’s disease, ALS/FTD, and other tauopathies• Senescence in acute and chronic CNS injury, demyelinating disease, and vascular and blood–brain barrier dysfunction• Detection and quantification of senescent cells in neural tissue, including multi-marker and single-cell approaches• Senolytic and senomorphic strategies for neuroprotection, including pathway-selective biomarkers, small-molecule modulators, and translational studies Topic editors: Maria E. Solesio, Cyril Jones Jagaraj, Elisabetta Di Fede Source: https://www.frontiersin.org/research-topics/84709/cellular-senescence-and-senolytic-signalling-in-brain-aging-and-neurodegeneration