Altered intracellular protein degradation in aging: A possible cause of proliferative arrest

Abstract

Many proteins that control cell-cycle progression are short-lived. Therefore, alterations in protein degradation are as likely as changes in transcription and/or translation in causing the proliferation arrest of senescent cells. Several different pathways of intracellular protein degradation have been identified, and both cytosolic and lysosomal pathways operate in most cells. We have used red cell-mediated microinjection to study degradation of radiolabelled proteins introduced into IMR-90 human diploid fibroblasts at early and late population doubling levels. Lysosomal pathways of protein degradation are reduced in senescent cells, and this defect may account for many characteristics of aging, including the accumulation of posttranslationally altered proteins. These abnormal proteins may then stimulate cytosolic, ubiquitin-dependent proteolytic pathways that are also responsible for the degradation of crucial regulatory proteins. Unknown short-lived proteins are also required for some step in lysosomal proteolysis, and this connection between the two degradative systems may cause the age-related changes in protein degradation to be progressive. Several experimental approaches are available to test whether altered protein degradation significantly contributes to proliferative arrest of senescent cells.