Proteostasis and ageing dissidence

Proteostasis, the process governing the dynamic regulation of protein synthesis, folding and degradation, is critical for maintaining cell function and organismal health. Ageing disrupts this intricate system, leading to inactive, misfolded and/or aggregated proteins that contribute to age-associated pathologies. Here, we explore current findings on proteostasis and its deterioration during ageing with an attention to three major pathways: molecular chaperone (MC), ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway. Components in all three paths undergo age-dependent decline in both expression and function, with each impairment having select initial outcomes on the health of a proteome. For example, loss in the MC path may cause nascent chain defects, whereas a decline in the UPS may result in the accumulation of toxic aggregates. Notably, the interconnectedness of these pathways results in reciprocal reactions in all three. Understanding how each path connects to the others and how these connections are regulated offers promising strategies to restore proteome integrity and extend a healthy lifespan. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.