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The transcription factor SKN-1 drives lysosomal enlargement during aging to maintain function [1]

['Xinyu Wang', 'School Of Life Sciences', 'Chongqing University', 'Chongqing', 'Huimin Liu', 'Xiaoman Wang', 'Ben Zhou', 'Shanghai Institute Of Nutrition', 'Health', 'University Of Chinese Academy Of Sciences']

Date: 2025-12 

Lysosomes are critical hubs for both cellular degradation and signal transduction, yet their function declines with age. Aging is also associated with significant changes in lysosomal morphology, but the physiological significance of these alterations remains poorly understood. Here, we find that a subset of aged lysosomes undergo enlargement resulting from lysosomal dysfunction in C. elegans. Importantly, this enlargement is not merely a passive consequence of functional decline but represents an active adaptive response to preserve lysosomal degradation capacity. Blocking lysosomal enlargement exacerbates the impaired degradation of dysfunctional lysosomes. Mechanistically, lysosomal enlargement is a transcriptionally regulated process governed by the longevity transcription factor SKN-1, which responds to lysosomal dysfunction by restricting fission and thereby induces lysosomal enlargement. Furthermore, in long-lived germline-deficient animals, SKN-1 activation induces lysosomal enlargement, thereby promoting lysosomal degradation and contributing to longevity. These findings unveil a morphological adaptation that safeguards lysosomal homeostasis, with potential relevance for lysosomal aging and life span.

Funding: This work was supported by the National Natural Science Foundation of China (Grant nos. 32271212 and 32071163 [to S.P.] and Grant nos. 32370828 and 32070754 [to H.T.]), the National Key R&D Program of China (Grant no. 2023YFA1801100 to B.Z.), the Fundamental Research Funds for the Central Universities (2024CDJXY016), the Natural Science Foundation of Chongqing, China (Grant no. cstc2021ycjh-bgzxm0138 [to S.P.]). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2025 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

In this study, we investigated the regulation and function of lysosomal morphological changes during aging using C. elegans as a model organism. We found that a subset of aged lysosomes undergo enlargement. Unlike lysosomal tubulation, which responds to cellular changes such as increased autophagic demand, lysosomal enlargement is an adaptive response to their own dysfunction, aiming to preserve lysosomal degradation capacity. Remarkably, this adaptive response is governed by transcriptional regulation through SKN-1, known for its role in promoting longevity. Consistent with these findings, SKN-1-mediated lysosomal enlargement improves lysosomal function and extends life span in germline-deficient, long-lived C. elegans, suggesting a potential connection between lysosomal enlargement and aging.

Another hallmark of lysosomal aging is extensive morphological alteration [ 5 ]. The complex relationship between organellar morphology and function underscores the pivotal role of morphology in dictating organellar function, as exemplified in mitochondrial research [ 6 , 7 ]. Similarly, lysosomes, as highly dynamic organelles, undergo continuous modulation of morphology through fusion and fission events [ 8 , 9 ]. Lysosomes adopt two main morphologies: tubular and vesicular. Aged lysosomes frequently form extensive tubular networks [ 5 ], a feature also observed in long-lived diet-restricted animals, where lysosomal tubulation contributes to life span extension [ 10 ]. It has been proposed that increased autophagic demand during aging and nutrient deficiency may drive lysosomal tubulation [ 10 ]. Vesicular lysosomal enlargement represents another form of morphological change. This enlargement is a hallmark of lysosomal storage diseases (LSDs) [ 8 ] and is implicated in the pathogenesis of Parkinson’s disease [ 11 ]. However, the functional implications of lysosomal size changes during aging remain poorly understood, and its causal relationship with lysosomal function is unclear.

Lysosomes, as centers for degradation and recycling, are crucial for the maintenance of cellular homeostasis. Various intracellular and extracellular factors can impair lysosomal function, which is strongly associated with aging and numerous human diseases [ 1 , 2 ]. Studies in model organisms, such as yeast and C. elegans, reveal that lysosomal phenotypes, including acidity and degradation capacity, decline with age [ 3 – 5 ]. Conversely, several long-lived mutants maintain healthy lysosomes and extend life span in a lysosome-dependent manner [ 5 ], highlighting the critical role of functional lysosomes in promoting longevity. Therefore, understanding how aged lysosomes preserve their degradation functions is of particular importance, yet this question remains largely unexplored.

Results

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[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003540

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