Genome-wide RNAi analysis in adult Caenorhabditis elegans unveils genes controlling age-related fat accumulation

IF 5.3 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development Pub Date : 2025-07-03 DOI:10.1016/j.mad.2025.112089

Chunxia Qin , Zicheng Liu , Duo Duan , Lianfeng Wu

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引用次数: 0

Abstract

Fat accumulation with aging occurs in adults across species, yet its underlying mechanisms remain poorly understood, partly due to limited number of studiesspecifically targeting adulthood. Here, we present the first genome-wide analysis of age-associated fat accumulation during adulthood in Caenorhabditis elegans. Unprecedently, our adult-specific RNAi screen identified a limited subset of genes influencing adult fat dynamics, contrasting with the extensive gene sets uncovered in prior developmental RNAi screens. This disparity suggests a unique genetic architecture governing age-related lipid deposition. Central to this network is the evolutionarily conserved transcription factor DAF-16/FoxO, which progressively accumulates in nuclei during aging. Genetic ablation of daf-16 abolished adult fat accumulation, while its adult-specific knockdown reduced adiposity without compromising healthspan or longevity, highlighting its therapeutic potential. Critically, knockdown of the top hits, pals-17 and rege-1, markedly attenuated the nuclear localization of DAF-16 and failed to reduce the adult fat content daf-16-deficient animals, establishing DAF-16 as their essential effector. Overall, our work uncouples developmental and adult lipid regulatory mechanisms and highlights potential targets for understanding and managing adult-onset obesity.

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成年秀丽隐杆线虫全基因组RNAi分析揭示了控制年龄相关脂肪积累的基因。

随着年龄的增长，脂肪积累在不同物种的成年人中都存在，但其机制仍然知之甚少，部分原因是专门针对成年人的研究有限。在这里，我们提出了秀丽隐杆线虫成年期年龄相关脂肪积累的第一个全基因组分析。前所未有的是，我们的成人特异性RNAi筛选鉴定了影响成人脂肪动力学的有限基因子集，与先前发育性RNAi筛选发现的广泛基因集形成对比。这种差异表明一种独特的遗传结构控制着与年龄相关的脂质沉积。这个网络的核心是进化上保守的转录因子DAF-16/FoxO，它在衰老过程中逐渐在细胞核中积累。基因消融daf-16可消除成人脂肪积累，而成人特异性敲除可减少肥胖，而不影响健康寿命或寿命，突出了其治疗潜力。至关重要的是，敲除顶端基因pal -17和rege-1显著减弱了DAF-16的核定位，但未能降低DAF-16缺陷动物的成年脂肪含量，这表明DAF-16是它们的主要效应物。总的来说，我们的工作将发育和成人脂质调节机制分开，并强调了理解和管理成人发病肥胖的潜在目标。

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

Mechanisms of Ageing and Development 医学-老年医学

CiteScore

11.10

自引率

1.90%

发文量

审稿时长

32 days

期刊介绍： Mechanisms of Ageing and Development is a multidisciplinary journal aimed at revealing the molecular, biochemical and biological mechanisms that underlie the processes of aging and development in various species as well as of age-associated diseases. Emphasis is placed on investigations that delineate the contribution of macromolecular damage and cytotoxicity, genetic programs, epigenetics and genetic instability, mitochondrial function, alterations of metabolism and innovative anti-aging approaches. For all of the mentioned studies it is necessary to address the underlying mechanisms. Mechanisms of Ageing and Development publishes original research, review and mini-review articles. The journal also publishes Special Issues that focus on emerging research areas. Special issues may include all types of articles following peered review. Proposals should be sent directly to the Editor-in-Chief.