Cycloastragenol extends lifespan and enhances stress resistance in Caenorhabditis elegans by inhibiting IIS pathway and activating p38 MAPK-mediated innate immunity.

Aging is a complex physiological process characterized by progressive functional decline, yet effective pharmacological interventions from medicine-food homologous sources remain limited. While Cycloastragenol (CAG), a bioactive triterpenoid from Astragalus membranaceus, is known for telomerase activation, its non-telomeric mechanisms require elucidation. This study investigated the longevity-promoting effects of CAG using the Caenorhabditis elegans model, identifying 0.2 μM as the optimal concentration that extended mean lifespan by 30.64%. Beyond longevity, CAG treatment significantly ameliorated aging-associated phenotypes, including enhanced locomotion, reduced lipofuscin accumulation, improved stress resistance, and strengthened immunity against Pseudomonas aeruginosa. Mechanistic analyses revealed that CAG promotes nuclear translocation of the FOXO transcription factor DAF-16 and elevates antioxidant enzyme activities. Crucially, using specific mutant strains and gene expression profiling, we provide the first evidence that CAG extends healthspan through a telomerase-independent mechanism involving the simultaneous inhibition of the Insulin/IGF-1 Signaling (IIS) pathway and activation of the p38 MAPK (SEK-1/PMK-1/SKN-1) axis. This study establishes a novel link between CAG-mediated innate immune enhancement and longevity, distinguishing its mode of action from previous telomere-centric models. These findings clarify the pharmacological basis of CAG and support its potential development as a safe therapeutic agent for age-related disorders.