Senescent cell heterogeneity in brain aging and neurodegenerative disease

Abstract

Summary Senescent cells in the aging and diseased brain are increasingly recognized as highly heterogeneous catalysts of dysfunction, originating from diverse cell types, and characterized by wide-ranging molecular signatures and functional outcomes. Additionally, technological advances in single-cell transcriptomics and mouse modeling have helped reframe senescence from a static fate to a dynamic trajectory that is heavily influenced by evolving environmental cues. In this review, we identify key hubs of heterogeneity in brain cell senescence. We discuss how differences in senescence induction, cell-cycle arrest mechanism, cell-type biology, and microenvironments contribute to the diverse senescence programs observed in the central nervous system. We also synthesize insights from the recent wave of single-cell transcriptomic studies and discuss how advances in spatial omics technologies could transform our ability to study senescent cells within intact neural circuits. Finally, we argue that integrating multimodal molecular profiling with functional studies in mice will be essential for advancing mechanistic understanding and therapeutic targeting of senescent cells in brain aging and disease.