Following on the heels of comprehensive reviews of mitochondria, senescence and cancer as they relate to aging, Vernace et al a nice overview of the role of protein degradation in the process. Motivated by recent findings in neurodegenerative disease, they focus on the possibility that dwindling efficiency of the ubiquitin/proteasome pathway may limit cellular lifespan:
Aging and regulated protein degradation: who has the UPPer hand?
In all cells, protein degradation is a constant, ongoing process that is critical for cell survival and repair. The ubiquitin/proteasome pathway (UPP) is the major proteolytic pathway that degrades intracellular proteins in a regulated manner. It plays critical roles in many cellular processes and diseases. Disruption of the UPP is particularly relevant to pathophysiological conditions that provoke the accumulation of aberrant proteins, such as in aging as well as in a variety of neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. For unknown reasons, most of these neurodegenerative disorders that include familial and sporadic cases exhibit a late onset. It is possible that these neurodegenerative conditions exhibit a late onset because proteasome activity decreases with aging. Aging-dependent impairment in proteolysis mediated by the proteasome may have profound ramifications for cell viability. It can lead to the accumulation of modified, potentially toxic proteins in cells and can cause cell injury or premature cell death by apoptosis or necrosis. While it is accepted that aging affects UPP function, the question is why does aging cause a decline in regulated protein degradation by the UPP? Herein, we review some of the properties of the UPP and mechanisms mediating its age-dependent impairment. We also discuss the relevance of these findings leading to a model that proposes that UPP dysfunction may be one of the milestones of aging.
In addition to simply allowing misfolded proteins to accumulate, of course, alterations in the pathway will also result in changes to the half-lives of proteins that are regulated by ubiquitin-mediated degradation; this could also have important ramifications in the biology of aging (see Ubiquitin, the proteasome, and aging).