Dietary mono-unsaturated fatty acids (MUFAs) are linked to longevity in several species. But the mechanisms by which MUFAs extend lifespan remain unclear. Here we show that an organelle network involving lipid droplets and peroxisomes is critical for MUFA-induced longevity in Caenorhabditis elegans. MUFAs upregulate the number of lipid droplets in fat storage tissues. Increased lipid droplet number is necessary for MUFA-induced longevity and predicts remaining lifespan. Lipidomics datasets reveal that MUFAs also modify the ratio of membrane lipids and ether lipids—a signature associated with decreased lipid oxidation. In agreement with this, MUFAs decrease lipid oxidation in middle-aged individuals. Intriguingly, MUFAs upregulate not only lipid droplet number but also peroxisome number. A targeted screen identifies genes involved in the co-regulation of lipid droplets and peroxisomes, and reveals that induction of both organelles is optimal for longevity. Our study uncovers an organelle network involved in lipid homeostasis and lifespan regulation, opening new avenues for interventions to delay aging.

膳食单不饱和脂肪酸 (MUFA) 与多个物种的长寿有关。但单不饱和脂肪酸延长寿命的机制仍不清楚。在这里，我们表明，涉及脂滴和过氧化物酶体的细胞器网络对于 MUFA 诱导的秀丽隐杆线虫寿命至关重要。 MUFA 上调脂肪储存组织中脂滴的数量。脂滴数量的增加对于 MUFA 诱导的寿命是必要的，并可预测剩余寿命。脂质组学数据集显示，MUFA 还可以改变膜脂和醚脂的比例，这是与脂质氧化减少相关的特征。与此相一致的是，MUFA 可以减少中年人的脂质氧化。有趣的是，MUFA 不仅上调脂滴数量，还上调过氧化物酶体数量。有针对性的筛选鉴定了参与脂滴和过氧化物酶体共同调节的基因，并揭示了这两种细胞器的诱导对于长寿是最佳的。我们的研究揭示了参与脂质稳态和寿命调节的细胞器网络，为延缓衰老的干预措施开辟了新途径。