Ubiquitylome study identifies increased histone 2A ubiquitylation as an evolutionarily conserved aging biomarker

The long- lived proteomeconstitutes a pool of exceptionally stable proteins with limited turnover. Previous studies on ubiquitin-mediated protein degradation primarily focused on relatively short- livedproteins; how ubiquitylation modifies the long- lived proteomeand its regulatory effect on adult lifespan is unclear. Here we profile the age-dependent dynamics of long- lived proteomesin Drosophila by mass spectrometry using stable isotope switching coupled with antibody-enriched ubiquitylome analysis. Our data describe landscapes of long- livedproteins in somatic and reproductive tissues of Drosophila during adult lifespan, and reveal a preferential ubiquitylation of older long- livedproteins. We identify an age-modulated increase of ubiquitylation on long- livedhistone 2A protein in Drosophila, which is evolutionarily conserved in mouse, monkey, and human. A reduction of ubiquitylated histone 2A in mutant flies is associated with longevity and healthy lifespan. Together, our data reveal an evolutionarily conserved biomarkerof agingthat links epigenetic modulation of the long- livedhistone protein to lifespan.