Lyttle Nathan, Amirthalingam Mohankumar, Bali Julia, Wong Alan Yazid Chavez Hita, Flores Iga Juan Gerardo, Tawata Shinkichi, Nimmakayala Padma, Reddy Umesh K
Department of Biology, Gus R. Douglass Institute, West Virginia State University, Institute, WV 25112, USA.
George Washington High School, Charleston, WV 25314, USA.
Food Funct. 2025 Jul 28;16(15):6064-6079. doi: 10.1039/d5fo01607j.
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.
辣椒素酯是一种主要存在于辣椒低辣度品种中的无辣味辣椒素类似物，具有多种药理和促进健康的特性。然而，尽管它与辣椒素具有同等效力，但与辣椒素相比，对它的研究仍较少。在这里，我们使用遗传易处理的模式生物秀丽隐杆线虫，系统地研究了辣椒素酯的毒性特征以及促进生命和健康的机制。结果发现辣椒素酯是安全的，并产生浓度依赖性的双相效应，最佳剂量（10μmol/L）可增强应激恢复力、降低细胞内活性氧（ROS）水平并延长寿命。从机制上讲，辣椒素酯介导的效应需要瞬时受体电位（TRP）通道TRPA-1（TRPA1）和OSM-9（TRPV）。TRPA-1的激活启动了钙敏感的PKC-2信号传导至SGK-1，随后激活DAF-16/FoxO以反式激活关键的长寿相关靶点，包括和。同时，TRPA-1的激活还募集了CaMKII-p38 MAPK途径，导致SKN-1/Nrf2核定位和老年基因、、和的上调。除了这些分子效应外，辣椒素酯还减弱了与年龄相关的学习能力、运动功能和应激恢复力的下降，突出了其在衰老过程中促进健康的潜力。总之，这些发现首次为辣椒素酯介导的秀丽隐杆线虫健康寿命延长和应激恢复力提供了机制性见解，为未来针对年龄相关疾病的治疗策略提供了有希望的基础。
