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

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Evandro Fei Fang, Tyler B Waltz, Henok Kassahun, Qiping Lu, Jesse S Kerr, Marya Morevati, Elayne M Fivenson, Bradley N Wollman, Krisztina Marosi, Mark A Wilson, Wendy B Iser, David Mark Eckley, Yongqing Zhang, Elin Lehrmann, Ilya G. Goldberg, Morten Scheibye-Knudsen, Mark P. Mattson, Hilde Nilsen, Vilhelm A Bohr, Kevin G. Becker

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.

Original languageEnglish
Article number46208
JournalScientific Reports
Volume7
ISSN2045-2322
DOIs
Publication statusPublished - 2017

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