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

Abstract

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.

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+signaling

“…To visualize the mitochondrial networking in the C. elegans body wall muscle tissue, csa-1, csb-1 , and csa-1;csb-1 mutants were crossed to a myo3::gfp reporter strain (N2 background). Images were acquired with a Zeiss confocal microscopy and analyzed as described previously [53]. Worms were transferred to drug-treated plates from the late L4 stages until Day 7 unless otherwise noted.…”

“…Mitochondrial networking was assessed using an arbitrary scale from 1-5. Healthy, organized mitochondrial networks in which the mitochondria are longer, less circular, aligned with the muscle fibers, and with reduced interconnecting mitochondrial strings received a score of 5 [53]. The mitochondrial networking score was reduced if the mitochondria appeared disorganized and more circular with mitochondria forming a network of irregular shapes.…”

“…At least 30 worms were measured/group and the experiments were conducted three separate times. Swimming analysis was conducted as described previously [53]. At D8, individual worms were transferred from treatment plates onto a 6 cm dish containing 1 mL of M9 buffer.…”

Mitophagy: An Emerging Role in Aging and Age-Associated Diseases

“…Interestingly, tomatidine, a natural compound abundant in unripe tomatoes, inhibits age-related skeletal muscle atrophy in mice and extends health-and lifespan in C. elegans. Mechanistic analysis showed that tomatidine stimulates mitochondrial biogenesis and PINK1-and DCT1related mitophagy and increases healthspan (Fang et al, 2017). Moreover, dct-1, pink-1, and pdr-1 are engaged in lifespan extension induced by mild mitochondrial stress achieved by frataxin depletion-induced iron-starvation in C. elegans (Schiavi et al, 2015).…”

“…In fact, dct-1 is transcriptionally induced under the control of skn-1 and daf-16 [the nematode homolog of mammalian nuclear factor, erythroid 2 like 2 (NFE2L2, better known as NRF2) and forkhead box O3 (FOXO3), respectively] to remove dysfunctional mitochondria via mitophagy and coordinate mitochondrial biogenesis and mitophagy . Mitochondrial biogenesis and mitophagy may cooperate to antagonize the aging process Fang et al, 2017). Interestingly, tomatidine, a natural compound abundant in unripe tomatoes, inhibits age-related skeletal muscle atrophy in mice and extends health-and lifespan in C. elegans.…”