Lyang, Nora, Kelly, Jeffery, Xu, Jin, Hansen, Malene, Tan, Ee Phie, Nieto-Torres, Jose, Botham, Rachel, Yoon, Leonard, Zaretski, Svaitlana, Johnson, Kristen
[
International Worm Meeting,
2021]
Autophagy is an evolutionarily conserved cellular recycling process with tight links to longevity and healthspan. In particular, autophagy function declines during aging, and is dysregulated in many age-related disorders such as in neurodegenerative diseases. Therefore, identifying interventions that can boost autophagy to prevent such chronic illnesses progression is crucial to improving organismal health. Of note, autophagy is increasingly appreciated as a selective process by which specific types of cytosolic cargo, such as organelles, lipids and protein aggregates, are sequestered into double-membrane structures called autophagosomes that subsequently fuse with hydrolase-containing lysosomes to enable cargo degradation. Interestingly, accumulating evidence suggests that disruptions in selective autophagy can contribute to the development of age-related diseases. For example, chronic inhibition of lipophagy (selective lipid turnover) leads to increased accumulation of lipids, leading to obesity and diabetes. However, treatments that may target and improve selective autophagy to help relieve such illnesses remain underdeveloped. To identify novel chemical compounds that may act as selective autophagy activators, we performed a high-throughput imaging screen in human adenocarcinoma cells to uncover small molecules that activate autophagy and increase lipid clearance. Given the previous links between autophagy and aging, we tested several autophagy activator hit compounds from the screen for autophagy- and lifespan assays in C. elegans. While we found that these compounds all increased autophagosome numbers, only animals fed with small molecule A20 exhibited life- and healthspan extension, along with reduced lipid levels, as observed in human cells. Importantly, this A20-mediated lipid reduction and health benefits were not observed in autophagy mutants. Furthermore, we found that A20 could reduce PolyQ aggregate cargo load in multiple tissues, and we are currently investigating if A20 is affecting additional cytosolic cargos. Notably, inhibition of the nutrient sensor mTORC1 activates autophagy. However, A20 seemed to function independently of mTORC1, and we are currently performing studies to determine how A20 could mediate autophagy. In conclusion, we have identified a new compound A20, which may potentially be applied in future strategies to improve organismal health and alleviate age-related diseases by boosting autophagy.