The role of lipid metabolism in neuronal senescence

Senescence is a complex cellular state characterised by irreversible growth arrest and metabolic reprogramming. In neurons, senescence has been mainly observed in the context of ageing and age-related neurodegeneration. Lipid metabolism plays a critical role in cellular homeostasis, with emerging evidence suggesting that alterations in lipid species, including fatty acids, cholesterol, sphingolipids and phospholipids, fundamentally drive or contribute to the senescent phenotype in both neuronal and non-neuronal cells in the brain. Namely, changes in lipid species levels result in the accumulation of lipid droplets (LDs), leading to dysregulation of membrane dynamics, and in turn to the production of bioactive lipid mediators, which collectively shape the senescence-associated secretory phenotype (SASP) in the brain. In this review, we describe the cell type-specific patterns of lipid dysregulation in neurons, astrocytes, microglia and other glial cells during senescence, highlighting the role of key lipid species and their association with senescence markers and phenotypes. Furthermore, we discuss the bidirectional relationship between lipid metabolism and mitochondrial dysfunction in cellular senescence. We also examine the molecular mechanisms through which lipid metabolic pathways can orchestrate neural senescence and their contribution to ageing and age-related neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Finally, we review emerging therapeutic strategies targeting lipid metabolic pathways to modulate neural senescence and potentially ameliorate age-associated brain pathology.