Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway.

Aging is a major international concern and brings with it formidable socioeconomical and healthcare challenges. An attainable approach to improve general health in humans is using small molecules. Tomatidine, a natural compound abundant in unripe tomatoes, inhibits aging-related skeletal muscle atrophy in mice. Here we show that tomatidine extends lifespan and healthspan in the aging animal model C. elegans, which shares many major longevity pathways with those of mammals. Tomatidine improves behaviors related to healthspan, including increased pharyngeal pumping and swimming movement, and also reduces deterioration of muscle cells in worms. Microarray, imaging, and behavioral analysis reveal that tomatidine maintains mitochondrial homeostasis through mitochondrial biogenesis and PINK-1/DCT-1-dependent mitophagy. Mechanistically, tomatidine induces mitochondrial hormesis by mildly inducing ROS production, which in turn activates the cellular antioxidant response SKN-1/Nrf2 pathway, followed by increased mitophagy in worms, primary rat neurons, and human cells. Our data suggest that tomatidine may delay some physiological aspects of aging, and points to new approaches for pharmacological interventions towards diseases of aging.衰老是一项全球性重大关切，伴随而来的是严峻的社会经济与医疗保健挑战。改善人类整体健康水平的一种可行策略，是应用小分子化合物。番茄啶（tomatidine）是一种在未成熟番茄中富集的天然化合物，可在小鼠体内抑制衰老相关的骨骼肌萎缩。本研究证实，番茄啶可延长衰老动物模型秀丽隐杆线虫（C. elegans）的寿命与健康寿命；该线虫与哺乳动物共享诸多核心长寿调控通路。番茄啶可改善与健康寿命相关的行为学表型，包括提升咽泵运动能力与游泳活动能力，同时还能减轻线虫体内的肌细胞退变。通过微阵列分析、成像观察与行为学实验证实，番茄啶可通过线粒体生物发生与依赖PINK-1/DCT-1的线粒体自噬（mitophagy）维持线粒体稳态。从机制层面而言，番茄啶通过轻度诱导活性氧（reactive oxygen species, ROS）生成，触发线粒体毒物兴奋效应，进而激活细胞抗氧化应答通路SKN-1/Nrf2，最终在线虫、原代大鼠神经元以及人类细胞中提升线粒体自噬水平。本研究数据表明，番茄啶或可延缓衰老的部分生理进程，同时为衰老相关疾病的药物干预提供了全新思路。