Autophagy activator AA-20 improves proteostasis and extends <i>Caenorhabditis elegans</i> lifespan
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (23)
Ee Phie Tan
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute
Nora Lyang
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute
Saam Doroodian
Buck Institute for Research on Aging
Pablo Sanz-Martinez
Institute of Biochemistry, Goethe University
Jin Xu
Sviatlana Zaretski
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute
José L. Nieto-Torres
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute
Hiroshi Ebata
Buck Institute for Research on Aging
Shaun H. Y. Lim
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute
William C. Hou
Department of Chemistry, The Scripps Research Institute
Khalyd J. Clay
Department of Molecular and Cellular Biology, The Scripps Research Institute
Leonard Yoon
Department of Chemistry, The Scripps Research Institute
Lynée A. Massey
Department of Chemistry, The Scripps Research Institute
Derek Rhoades
Department of Chemistry, The Scripps Research Institute
Danny Garza
Department of Chemistry, The Scripps Research Institute
Kristen A. Johnson
Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute
Alan To
Department of Molecular and Cellular Biology, The Scripps Research Institute
Lydia Ambaye
Department of Chemistry, The Scripps Research Institute
Emily P. Bentley
Department of Chemistry, The Scripps Research Institute
Michael Petrascheck
Department of Molecular and Cellular Biology, The Scripps Research Institute
Alexandra Stolz
Institute of Biochemistry, Goethe University
Jeffery W. Kelly
Department of Chemistry, The Scripps Research Institute
Malene Hansen
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute