Signal relay in C. elegans: A tissue-perspective on coordinating organismal proteostasis and its impact on aging

Oct 20, 2025Cell stress & chaperones

How communication between tissues in C. elegans helps maintain protein balance and influences aging

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Understanding inter-tissue communication in proteostasis regulation may provide insights into combating aging.

Aging is associated with a decline in protein homeostasis, leading to the accumulation of misfolded proteins in cells.
The proteostasis network helps protect cells from the harmful effects of protein aggregates by activating stress response and degradation mechanisms.
Longevity pathways, such as those involving insulin-like signaling, are influenced by signaling between tissues like the nervous system and intestine.
Cell nonautonomous signaling may enhance lifespan and resilience to stress while reducing the buildup of harmful protein aggregates.
Discoveries in the invertebrate model C. elegans have significantly contributed to understanding organismal proteostasis and its regulation.
Research in mammals is necessary to further validate findings from C. elegans and develop potential therapies targeting proteostasis pathways.

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As the global demographics shifts towards an increasingly aging population, understanding the effects and molecular mechanisms underlying aging becomes more and more important within biomedical research. A hallmark of aging is the progressive deterioration of protein homeostasis (proteostasis), characterized by the accumulation of misfolded protein aggregates within the cell. The proteostasis network is essential in mitigating the harmful effects of proteotoxic aggregates by activating stress response and degradation pathways. Significant discoveries in aging research are often inherently intertwined with proteostasis, many of which were made using the invertebrate Caenorhabditis elegans. Many longevity pathways, such as the insulin-like signaling pathway, initially identified in C. elegans, are mediated through inter-tissue stress signaling from the nervous system, intestine, or gonad. These cell nonautonomous signaling pathways not only enhance lifespan and stress resilience but also limit age-related accumulation of protein aggregates that exacerbate age-associated diseases. Thus, findings from aging research were often key to providing new insights into cell nonautonomous regulation of stress responses and organismal proteostasis. In this review, we outline key discoveries made using C. elegans as a model system and highlight their contributions that led to our current understanding of inter-tissue communication in organismal proteostasis regulation. We furthermore highlight emerging concepts and discuss the translational relevance of conserved cell nonautonomous proteostasis regulation in mammals. We emphasize the importance of mammalian research to support the research done in C. elegans, with the future goal of developing potential therapeutic interventions targeting these inter-tissue proteostasis signaling pathways to combat aging.

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Signal relay in C. elegans: A tissue-perspective on coordinating organismal proteostasis and its impact on aging

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