Exploring the ubiquitin-proteasome system in protein homeostasis and healthy aging using Caenorhabditis elegans as a...

Proteostasis is fundamental to cellular health, and its decline is a hallmark of aging. The ubiquitin-proteasome system (UPS) constitutes a critical regulatory node within the proteostasis network, and its function is largely dictated by the dynamic interplay between E3 ubiquitin ligases and deubiquitinating enzymes (DUBs). The nematode Caenorhabditis elegans (C. elegans) serves as a powerful model for dissecting this relationship in the context of aging, because of its genetic tractability and conserved proteostatic machinery. However, while studies in C. elegans have yielded fundamental insights, translational extrapolation requires caution. The worm lacks endogenous counterparts to key human amyloidogenic proteins, such as α-synuclein and 42-amino acid amyloid-beta (Aβ), and the functional scope of conserved UPS components, such as the Parkin homolog PDR-1, is often narrower than in humans, lacking the complexity of cross-pathway crosstalk. This article explores how UPS regulates proteostasis to promote healthy aging in C. elegans, synthesizing recent advances in its molecular mechanisms and potential interventions. This review provides the first systematic integration of existing findings to decipher how UPS components, specifically E3 ubiquitin ligases and proteasomes, regulate protein degradation in C. elegans and impact lifespan. Additionally, the ways in which natural and chemical compounds can potentially enhance UPS function to improve organismal health and delay aging were investigated. By reviewing the impact of the broader proteostasis network on aging and highlighting the regulatory role of UPS, while contextualizing the strengths and limitations of the C. elegans model, this review provides insights into potential anti-aging strategies and therapeutic approaches for age-related diseases.