Non-pungent capsiate enhances longevity and healthspan in transient receptor potential (TRP) channels.

Capsiate, a non-pungent capsaicin analog found mainly in low-pungency cultivars of L., exhibits diverse pharmacological and health-promoting properties. However, despite its equipotency, it remains less extensively studied than capsaicin. Here, we systematically investigated the toxicity profile and the life- and health-promoting mechanisms of capsiate using the genetically tractable model organism (). Capsiate was found to be safe and exerted a concentration-dependent biphasic effect, with an optimal dose (10 μmol L) enhancing stress resilience, reducing intracellular reactive oxygen species (ROS) levels, and extending lifespan. Mechanistically, capsiate-mediated effects required the transient receptor potential (TRP) channels TRPA-1 (TRPA1) and OSM-9 (TRPV). Activation of TRPA-1 initiated calcium-sensitive PKC-2 signaling SGK-1, which subsequently activated DAF-16/FoxO to transactivate key longevity-related targets, including and . In parallel, TRPA-1 activation also recruited the CaMKII-p38 MAPK pathway, leading to SKN-1/Nrf2 nuclear localization and upregulation of gerontogenes, , , and . Beyond these molecular effects, capsiate attenuated age-associated declines in learning ability, motor function, and stress resilience, highlighting its potential to promote health during aging. Together, these findings provide the first mechanistic insights into capsiate-mediated healthy lifespan extension and stress resilience in , offering a promising foundation for future therapeutic strategies targeting age-related diseases.