Proteostasis collapse halts G1 progression and delimits replicative lifespan

Abstract

AbstractLoss of proteostasis and cellular senescence are key hallmarks of cell aging, but whether they are subject to direct cause-effect relationships is not known. We show that most yeast cells arrest in G1 before death with low nuclear levels of cyclin Cln3, a key activator of Start extremely sensitive to chaperone status. Chaperone availability is seriously compromised in aged cells, and the G1 arrest coincides with massive aggregation of a metastable chaperone-activity reporter. A mathematical model integrating autocatalytic protein aggregation and a minimal Start network recapitulates empirical observations. As key predictions, G1-cyclin overexpression increases lifespan in a chaperone-dependent manner, and lifespan reduction by enforced protein aggregation is greatly alleviated by increased expression of specific chaperones or cyclin Cln3. Overall, our data indicate the crucial role of chaperone malfunction in setting lifespan in yeast cells, and configure a molecular pathway whereby proteostasis breakdown acts as a direct effector of cell senescence.