Ub and Down: Ubiquitin Exercise for the Elderly

Conjugation of ubiquitin onto proteins generates a degradation signal or exerts degradation-independent regulatory functions. Ubiquitylation is governed by the antagonistic action of ubiquitin ligases and deubiquitylating enzymes (DUBs). Several recent publications illustrate a balanced interplay of ligases and DUBs at signaling hubs that are central to longevity and protein homeostasis (proteostasis). In addition, stress-induced alterations of ubiquitin conjugation are emerging as key events that drive aging and contribute to the pathology of age-related diseases. This physiological role of dynamic ubiquitylation further extends its well-known function in protein regulation and quality control at the cellular level. Recent work thus significantly advances our understanding of the aging process both at the molecular and organismal level. Ubiquitin signaling is essential for lifespan regulation in metazoan organisms. The CHIP ubiquitin ligase links proteostasis and lifespan regulation through insulin receptor turnover. The antagonistic interplay between ubiquitylation and deubiquitylation controls lifespan-determining events. Regulation of autophagy initiation is sensitive to neurodegenerative protein accumulation.