Han Shuo, Schroeder Elizabeth A, Silva-García Carlos G, Hebestreit Katja, Mair William B, Brunet Anne
Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
Genetics Graduate Program, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
Nature. 2017 Apr 13;544(7649):185-190. doi: 10.1038/nature21686. Epub 2017 Apr 5.
Chromatin and metabolic states both influence lifespan, but how they interact in lifespan regulation is largely unknown. The COMPASS chromatin complex, which trimethylates lysine 4 on histone H3 (H3K4me3), regulates lifespan in Caenorhabditis elegans. However, the mechanism by which H3K4me3 modifiers affect longevity, and whether this mechanism involves metabolic changes, remain unclear. Here we show that a deficiency in H3K4me3 methyltransferase, which extends lifespan, promotes fat accumulation in worms with a specific enrichment of mono-unsaturated fatty acids (MUFAs). This fat metabolism switch in H3K4me3 methyltransferase-deficient worms is mediated at least in part by the downregulation of germline targets, including S6 kinase, and by the activation of an intestinal transcriptional network that upregulates delta-9 fatty acid desaturases. Notably, the accumulation of MUFAs is necessary for the lifespan extension of H3K4me3 methyltransferase-deficient worms, and dietary MUFAs are sufficient to extend lifespan. Given the conservation of lipid metabolism, dietary or endogenous MUFAs could extend lifespan and healthspan in other species, including mammals.
染色质和代谢状态都会影响寿命，但它们在寿命调节中如何相互作用在很大程度上尚不清楚。COMPASS染色质复合体可使组蛋白H3上的赖氨酸4发生三甲基化（H3K4me3），并调节秀丽隐杆线虫的寿命。然而，H3K4me3修饰因子影响寿命的机制，以及该机制是否涉及代谢变化，仍不清楚。在这里，我们表明，H3K4me3甲基转移酶缺乏会延长寿命，并促进蠕虫体内脂肪积累，且单不饱和脂肪酸（MUFA）会特异性富集。H3K4me3甲基转移酶缺陷型蠕虫中的这种脂肪代谢转换至少部分是由包括S6激酶在内的生殖系靶点的下调以及上调δ-9脂肪酸去饱和酶的肠道转录网络的激活介导的。值得注意的是，MUFA的积累是H3K4me3甲基转移酶缺陷型蠕虫延长寿命所必需的，而饮食中的MUFA足以延长寿命。鉴于脂质代谢的保守性，饮食或内源性MUFA可能会延长包括哺乳动物在内的其他物种的寿命和健康寿命。
