Targeting cellular senescence through nutritional senotherapeutics in brain aging and neurodegenerative diseases

Cellular senescence has emerged as a key contributor to brain aging and neurodegenerative diseases, which are increasing in prevalence as life expectancy rises. Senescent cells accumulate in multiple brain cell populations and secrete the senescence-associated secretory phenotype (SASP), promoting chronic neuroinflammation, mitochondrial dysfunction, blood-brain barrier disruption, and progressive neuronal damage. This review examines the role of cellular senescence in brain aging and neurodegenerative diseases and discusses senotherapeutic strategies aimed at either eliminating senescent cells (senolytics) or modulating the SASP (senomorphics). Particular emphasis is placed on nutritional senotherapeutics, naturally occurring bioactive compounds derived from dietary sources that target molecular pathways involved in cellular senescence. Senomorphic compounds such as sulforaphane, curcumin, and resveratrol primarily attenuate oxidative stress and inflammatory signaling, whereas senolytic agents including quercetin and fisetin selectively promote the elimination of senescent cells by disrupting pro-survival pathways. Current evidence from experimental models and emerging clinical studies suggests that nutritional senotherapeutics represent promising complementary strategies for modulating cellular senescence and promoting brain health. However, their clinical translation remains constrained by limited human evidence, low bioavailability, and unresolved challenges related to optimal dosing and blood-brain barrier penetration, highlighting the need for well-designed clinical trials before their therapeutic potential can be fully established.