Proteostasis in aging: mechanistic insights and therapeutic opportunities

Abstract

Proteostasis, the dynamic balance of protein synthesis, folding, and degradation, is fundamental to cellular homeostasis and organismal health. Aging disrupts proteostasis networks, leading to the accumulation of misfolded and aggregated proteins, which plays a central role in age-related dysfunction and the onset of diseases such as neurodegenerative and metabolic disorders. This review comprehensively explores the components and regulatory mechanisms of proteostasis networks, including key proteolytic systems like the ubiquitin-proteasome system (UPS) and autophagy, as well as the role of molecular chaperones in maintaining protein folding. We discuss hallmark features of aging-related proteostasis dysfunction and highlight its implications in major age-associated diseases, particularly neurodegenerative conditions like Alzheimer's and Parkinson’s, and metabolic disorders such as diabetes and obesity. Additionally, emerging therapeutic strategies aimed at restoring proteostasis for healthy aging are examined, focusing on targeting chaperones, enhancing proteolytic systems, and modulating protein folding pathways. Advances in transcription factor regulation, proteasome activators, and autophagy modulators, as well as promising approaches involving small molecules and gene therapy, are discussed. Finally, we outline future directions and conclude that targeting proteostasis represents a promising avenue for improving health span and mitigating age-related diseases.

Keywords: Proteostasis, proteolytic, dysfunction, neurodegenerative, age-related diseases