Rethinking Senescence Hallmarks in the Brain: Lessons From Peripheral Tissues and Challenges in Defining Neuronal...

Cellular senescence is increasingly recognized as a fundamental driver of aging and age-related diseases. Studies in peripheral tissues have revealed that senescence is not a uniform cellular state, but a highly heterogeneous phenotype shaped by distinct combinations of DNA damage, mitochondrial dysfunction, chromatin remodeling, impaired proteostasis, and diverse senescence-associated secretory phenotype. This heterogeneity critically influences both the identification and therapeutic targeting of senescent cells. As senescent cells accumulate with age, they contribute to chronic low-grade inflammation and tissue dysfunction, while their selective elimination can improve health span, establishing senescence as both a pathogenic mechanism and a therapeutic target in systemic aging. Emerging evidence now suggests that post-mitotic neurons and other neural cell types can acquire senescence-like states during aging and neurodegeneration. However, the direct application of canonical peripheral senescence markers to the nervous system remains conceptually and experimentally problematic, raising the risk of inconsistent or misleading interpretations across models and studies. In this review, we integrate insights from peripheral senescence biology to examine how cell type, inducing stressor, and experimental context shape senescence-associated phenotypes across neural systems, including in vitro models, physiologically aged brains, and models of Alzheimer's and Parkinson's disease. By critically evaluating where canonical senescence hallmarks translate and where they fail to translate to post-mitotic neurons, we propose that a refined, neuron-centered framework is essential for moving the field beyond descriptive observations and for rigorously testing the causal contribution of senescent neural cells to neurodegeneration.