It is well understood in the research community that enhancement of the cellular maintenance process of autophagy, and in particular the recycling of damaged mitochondria known as mitophagy, is a desirable goal. Many of the methods of modestly slowing aging in laboratory species feature enhanced autophagy, and decline of mitochondrial function is a prominent aspect of the aging process. That part of the aging research community interested in slowing human aging, as opposed to aiming for rejuvenation, includes a number of groups that work on autophagy. Still, little progress has been made towards clinical therapies based on safely increased levels of autophagy. There are many examples of research papers like this one from the past decade, as the life span of short-lived species is very plastic in response to circumstances and metabolic adjustments, but nothing of practical use for humans has yet emerged.
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.