Thyme and Oregano Terpenoids Activate Autophagy and Protect Against Hepatic Steatosis

Abstract Caloric restriction has been shown to reduce chronic illness in aging and increase life expectancy in most living organisms including mammals. Autophagy, a ubiquitous catabolic pathway of cellular quality control, is a key mechanism mediating the benefits of caloric restriction. In addition, mutations in genes involved in autophagy have been associated with the early onset of age-related diseases such as neurodegeneration, highlighting autophagy as a potential therapeutic target. Here, we aimed to discover autophagy inducers from a library of edible molecules for potential use in food applications. To this end, we developed a novel in vivo high-content screening strategy using fluorescent reporter zebrafish that monitor autophagy flux in skeletal muscle. We identify the thyme and oregano constituent thymol as a novel potent autophagy inducer in zebrafish, human cells and mouse tissues. Mechanistically, thymol triggers an hormetic effect on mitochondria in synergism with a calcium-dependent autophagy response which, in turn, leads to mobilization of intracellular lipid stores. We tested the effects of chronic thymol supplementation in mice fed a high-fat diet and showed that thymol mobilizes fatty acids, reduces liver triglycerides and improves markers of liver damage. In sum, we validate the use of zebrafish screening as a discovery model for autophagy-based therapeutics and demonstrate that thymol is an autophagy inducer with potential for the prevention of chronic metabolic diseases and other age-related conditions.