Targeting phospholipase PLAG-15 promotes healthy aging in C. elegans via lysosomal-related genes

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-06-16 DOI:10.1016/j.isci.2025.112880

Sanne van der Rijt , Marte Molenaars , Rashmi Kamble , Weisha Li , Bauke V. Schomakers , Adrie D. Dane , Simone W. Denis , Michel van Weeghel , Frédéric M. Vaz , Alessandra Tammaro , Georges E. Janssens , Arwen W. Gao , Riekelt H. Houtkooper

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引用次数: 0

Abstract

Complex lipid metabolism plays a crucial role in regulating aging. We recently discovered that the phospholipid bis(monoacylglycero)phosphate (BMP) increases in aged human muscles and many mouse tissues. The phospholipase PLA2G15 is reportedly involved in BMP synthesis, however, its specific role in aging remains unknown. To elucidate the role of PLA2G15 in aging, we used Caenorhabditis elegans as a model. When silencing plag-15, the predicted worm orthologue of PLA2G15, we observed improved healthspan and lifespan extension. Semi-targeted lipidomics highlighted that instead of changes related to BMP, plag-15 RNAi led to lower levels of lysophosphatidic acid, lysophosphatidylcholine, and lysophosphatidylethanolamine. Transcriptome-guided epistasis experiments identified that the lifespan extension of plag-15 RNAi worms is regulated by transcription factors hlh-30 and elt-3, and lysosomal vitamin B12 transporter pmp-5 (human TFEB, GATA, and ABCD4 respectively). Overall, we conclude that targeting phospholipid remodeling through plag-15 could be a promising strategy to promote healthy aging.

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靶向磷脂酶PLAG-15通过溶酶体相关基因促进秀丽隐杆线虫的健康衰老

复杂的脂质代谢在调节衰老中起着至关重要的作用。我们最近发现，在衰老的人类肌肉和许多小鼠组织中，磷脂（单酰基甘油）磷酸（BMP）增加。据报道，磷脂酶PLA2G15参与BMP合成，但其在衰老中的具体作用尚不清楚。为了阐明PLA2G15在衰老中的作用，我们以秀丽隐杆线虫为模型。当沉默PLA2G15的预测同源蠕虫plag-15时，我们观察到健康寿命和寿命延长。半靶向脂质组学强调，plag-15 RNAi导致溶血磷脂酸、溶血磷脂酰胆碱和溶血磷脂酰乙醇胺水平降低，而不是与BMP相关的变化。转录组引导的上位实验发现，plag-15 RNAi蠕虫的寿命延长受转录因子hlh-30和elt-3以及溶酶体维生素B12转运蛋白mpp -5（分别为人TFEB、GATA和ABCD4）的调控。总之，我们得出结论，通过plag-15靶向磷脂重塑可能是一种促进健康衰老的有希望的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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