The metabolic state of an organism instructs gene expression modalities, leading to changes in complex life history traits, such as longevity. Dietary restriction (DR), which positively affects health and life span across species, leads to metabolic reprogramming that enhances utilisation of fatty acids for energy generation. One direct consequence of this metabolic shift is the upregulation of cytoprotective (CyTP) genes categorized in the Gene Ontology (GO) term of “Xenobiotic Detoxification Program” (XDP). How an organism senses metabolic changes during nutritional stress to alter gene expression programs is less known. Here, using a genetic model of DR, we show that the levels of polyunsaturated fatty acids (PUFAs), especially linoleic acid (LA) and eicosapentaenoic acid (EPA), are increased following DR and these PUFAs are able to activate the CyTP genes. This activation of CyTP genes is mediated by the conserved p38 mitogen-activated protein kinase (p38-MAPK) pathway. Consequently, genes of the PUFA biosynthesis and p38-MAPK pathway are required for multiple paradigms of DR-mediated longevity, suggesting conservation of mechanism. Thus, our study shows that PUFAs and p38-MAPK pathway function downstream of DR to help communicate the metabolic state of an organism to regulate expression of CyTP genes, ensuring extended life span.

生物体的代谢状态指示基因表达方式，导致复杂的生命史特征的变化，例如寿命。饮食限制（DR）对不同物种的健康和寿命产生积极影响，导致代谢重新编程，从而增强脂肪酸用于能量产生的利用。这种代谢转变的一个直接后果是细胞保护（CyTP）基因的上调，这些基因属于“异生物质解毒计划”（XDP）的基因本体（GO）术语。生物体如何在营养应激期间感知代谢变化以改变基因表达程序尚不清楚。在这里，使用 DR 的遗传模型，我们发现多不饱和脂肪酸 (PUFA)，特别是亚油酸 (LA) 和二十碳五烯酸 (EPA) 的水平在 DR 后增加，并且这些 PUFA 能够激活 CyTP 基因。 CyTP 基因的这种激活是由保守的 p38 丝裂原激活蛋白激酶 (p38-MAPK) 途径介导的。因此，PUFA 生物合成和 p38-MAPK 途径的基因是 DR 介导的长寿的多种范例所必需的，这表明机制的保守性。因此，我们的研究表明，PUFA 和 p38-MAPK 通路在 DR 下游发挥作用，有助于传达生物体的代谢状态，从而调节 CyTP 基因的表达，从而确保延长寿命。