Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging [Quantseq_cell]

Small molecular food components contribute to health benefits of diets rich in fruits, vegetables, herbs, and spices. The cellular mechanisms by which non-caloric bioactives promote healthspan are not well understood, limiting their use for disease prevention. Here, we deploy a whole organism, high-content screen in zebrafish to profile food-derived compounds for activation of autophagy, a cellular quality control mechanism promoting healthy aging. We identify thymol and carvacrol as activators of autophagy and mitophagy through short-acting dampening of mitochondrial membrane potential. Chemical stabilization of thymol-induced mitochondrial depolarization blocks mitophagy activation, suggesting a mitochondrial membrane-originating mechanism. Supplementation of thymol prevents excess liver fat accumulation in a diet-induced obesity mouse model, improves pink1-dependent heat stress-resilience in Caenorhabditis elegans and slows decline of skeletal muscle performance and epigenetic aging in SAMP8 mice. Thus, terpenoids from common herbs promote autophagy during aging and metabolic overload, making them attractive for nutrition-based healthspan promotion.