A Senomorphlytic Three‐Drug Combination Discovered in Salsola collina for Delaying Aging Phenotypes and Extending Healthspan

Abstract The pursuit of pharmacological interventions in aging aims focuses on maximizing safety and efficacy, prompting an exploration of natural products endowed with inherent medicinal properties. Subsequently, this work establishes a unique library of plant extracts sourced from Yunnan Province, China. Screening of this herbal library herein revealed that Salsola collina (JM10001) notably enhances both lifespan and healthspan in C. elegans . Further analysis via network pharmacology indicates that the p53 signaling pathway plays a crucial role in mediating the anti‐aging effects of JM10001. Additionally, this work identifies that a composition, designated as JM10101 and comprising three chemical constituents of JM10001, preserves the original lifespan‐extending activity in C. elegans . Both JM10001 and JM10101 mitigate aging symptoms in senescence‐accelerated mice treated with doxorubicin and in naturally aged mice. Notably, JM10101 exhibits a more sophisticated senomorphlytic role encompassing both senomorphic and senolytic functions than JM10001 in the modulation of senescent cells, offering a promising strategy for the discovery of combination drugs in the rational development of anti‐aging therapies.