List of transcription factors in RNAi screening.

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 Caenorhabditis elegans (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.溶酶体（lysosomes）是细胞降解与信号转导的关键枢纽，但其功能随衰老逐渐衰退。衰老同样伴随溶酶体形态的显著改变，但此类形态改变的生理学意义仍不甚明晰。本研究在秀丽隐杆线虫（Caenorhabditis elegans，简称C. elegans）中发现，部分衰老溶酶体因溶酶体功能障碍出现肿大。值得注意的是，这种肿大并非功能衰退的被动伴随结果，而是为维持溶酶体降解能力而启动的主动适应性应答。抑制溶酶体肿大会加重功能异常溶酶体的降解缺陷。机制层面，溶酶体肿大是受转录调控的过程，由长寿转录因子SKN-1介导：SKN-1感知溶酶体功能障碍后，通过抑制溶酶体分裂诱导溶酶体肿大。此外，在生殖细胞缺失的长寿个体中，SKN-1的激活可诱导溶酶体肿大，进而增强溶酶体降解能力，助力机体长寿。本研究揭示了一种可维持溶酶体稳态的形态适应性机制，该机制与溶酶体衰老及寿命调控存在潜在关联。