Autophagy activator AA-20 improves proteostasis and extends Caenorhabditis elegans lifespan

• 成果类型: Article
• 署名作者: Tan, Ee Phie; Lyang, Nora; Doroodian, Saam; Sanz-Martinez, Pablo; Xu, Jin; Zaretski, Sviatlana; Nieto-Torres, Jose L.; Ebata, Hiroshi; Lim, Shaun H. Y.; Hou, William C.; Clay, Khalyd J.; Yoon, Leonard; Rhoades, Derek; Garza, Danny; Johnson, Kristen A.; To, Alan; Ambaye, Lydia; Bentley, Emily P.; Petrascheck, Michael; Stolz, Alexandra; Kelly, Jeffery W.; Hansen, Malene
• 署名单位: Universidad CEU Cardenal Herrera; Sanford Burnham Prebys Medical Discovery Institute; Scripps Research Institute; Buck Institute for Research on Aging; Goethe University Frankfurt; Goethe University Frankfurt; Scripps Research Institute; Scripps Research Institute; Scripps Research Institute; Scripps Research Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8707
• DOI: 10.1073/pnas.2423455122
• 发表日期: 2025-08-04
• 关键词: differential function; protein aggregation; mutant huntingtin; mammalian target; fatty-acids; mtor; disease; roles; degradation; mechanisms

摘要

The degradation of cellular components through autophagy is essential for longevity and healthy aging. However, autophagy function decreases with aging, contributing to age-related diseases. In this study, we characterized a small-molecule activator of autophagy called AA-20 that enhances autophagy and lipid droplet clearance in human cells and in the nematode Caenorhabditis elegans. AA-20 reduces polyglutamine aggregation in an autophagy-dependent manner in both human cells and C. elegans, where it also promotes fitness. Consistently, we found that AA-20 extends lifespan in WT C. elegans, but not in autophagy-deficient mutants. Interestingly, our findings suggest that AA-20 acts, at least in part, through a mechanism involving the transcription factor EB, but without inhibiting the protein kinase mammalian target of rapamycin complex 1. Collectively, our results identify an autophagy activator AA-20, which may have potential therapeutic implications for aging-related proteinopathies and lipid storage disorders.