Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway.
Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway.
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DOI：
10.1038/srep46208
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发表时间：
2017-04-11
影响因子：
4.6
通讯作者：
Becker KG
中科院分区：
文献类型：
--
作者：
Fang EF;Waltz TB;Kassahun H;Lu Q;Kerr JS;Morevati M;Fivenson EM;Wollman BN;Marosi K;Wilson MA;Iser WB;Eckley DM;Zhang Y;Lehrmann E;Goldberg IG;Scheibye-Knudsen M;Mattson MP;Nilsen H;Bohr VA;Becker KG
老龄化是一个重大的国际问题，带来了巨大的社会经济和医疗保健挑战。能够改善老年人健康的小分子正在探索中。增强细胞抗应激能力的小分子是缓解人类衰老过程中出现的衰退的一种有希望的途径。番茄替丁是一种天然化合物，在未成熟的番茄中含量丰富，可抑制小鼠年龄相关的骨骼肌萎缩。在这里，我们表明，番茄碱延长寿命和健康的C。elegans是一种衰老的动物模型，与哺乳动物共享许多主要的长寿途径。番茄红素改善了许多C.与健康和肌肉健康相关的行为，包括增加咽泵，游泳运动和减少严重受损肌肉细胞的百分比。微阵列、成像和行为分析显示，番茄碱通过调节线粒体生物发生和PINK-1/DCT-1依赖性线粒体自噬来维持线粒体稳态。从机制上讲，番茄替丁通过温和诱导ROS产生来诱导线粒体兴奋效应，这反过来激活SKN-1/Nrf 2途径和可能的其他细胞抗氧化反应途径，然后增加线粒体自噬。这种机制发生在C。线虫、原代大鼠神经元和人类细胞。我们的数据表明，番茄碱可能会延迟衰老的某些生理方面，并指出了衰老疾病的药理学干预的新方法。
Aging is a major international concern that brings formidable socioeconomic and healthcare challenges. Small molecules capable of improving the health of older individuals are being explored. Small molecules that enhance cellular stress resistance are a promising avenue to alleviate declines seen in human aging. Tomatidine, a natural compound abundant in unripe tomatoes, inhibits age-related skeletal muscle atrophy in mice. Here we show that tomatidine extends lifespan and healthspan in C. elegans, an animal model of aging which shares many major longevity pathways with mammals. Tomatidine improves many C. elegans behaviors related to healthspan and muscle health, including increased pharyngeal pumping, swimming movement, and reduced percentage of severely damaged muscle cells. Microarray, imaging, and behavioral analyses reveal that tomatidine maintains mitochondrial homeostasis by modulating mitochondrial biogenesis and PINK-1/DCT-1-dependent mitophagy. Mechanistically, tomatidine induces mitochondrial hormesis by mildly inducing ROS production, which in turn activates the SKN-1/Nrf2 pathway and possibly other cellular antioxidant response pathways, followed by increased mitophagy. This mechanism occurs in C. elegans, 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 for diseases of aging.