Mizutani Shoko, Furuya Kanji, Mure Ayumi, Takahashi Yuuki, Mori Akihiro, Sakurai Nozomu, Suito Takuto, Nagao Kohjiro, Umeda Masato, Watanabe Kaori, Hattori Yukako, Uemura Tadashi
Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
Radiation Biology Center, Kyoto University, Kyoto, Japan.
EMBO Rep. 2025 Jul 10. doi: 10.1038/s44319-025-00503-8.
The nutritional environment in early life, referred to as the nutrition history, exerts far-reaching health effects beyond the developmental stage. Here, with Drosophila melanogaster as a model, we fed larvae on diets consisting of a variety of yeast mutants and explored the resulting histories that impacted adult lifespan. A larval diet comprised of yeast nat3 KO shortened the lifespan of male adults; and remarkably, this diet diminished the function of histone acetyltransferase Gcn5 in larvae. Concordantly, perturbation of Gcn5-mediated gene regulation in the larval whole body or neurons significantly contributed to the earlier death of adults. The nat3 KO diet is much more abundant in long-chain fatty acids and branched-chain amino acids (BCAAs) than the control yeast diet. Supplementing the control diet with a combination of oleic acid, valine, and acetic acid recapitulated the effects of the nat3 KO diet on the larval transcriptome and the lifespan of males. Our findings strongly suggest a causal link between a fatty acids- and BCAA-rich diet in developmental stages and lifespan reduction via the adverse effect on the Gcn5 function.
生命早期的营养环境，即营养史，其对健康的影响远不止于发育阶段。在此，我们以黑腹果蝇为模型，用多种酵母突变体组成的饲料喂养幼虫，并探究由此产生的影响成虫寿命的营养史。由酵母nat3基因敲除体组成的幼虫饲料缩短了雄性成虫的寿命；值得注意的是，这种饲料削弱了幼虫中组蛋白乙酰转移酶Gcn5的功能。同样，在幼虫全身或神经元中干扰Gcn5介导的基因调控显著导致成虫过早死亡。与对照酵母饲料相比，nat3基因敲除体饲料中的长链脂肪酸和支链氨基酸（BCAAs）含量要丰富得多。用油酸、缬氨酸和乙酸的组合补充对照饲料，可重现nat3基因敲除体饲料对幼虫转录组和雄性寿命的影响。我们的研究结果有力地表明，发育阶段富含脂肪酸和支链氨基酸的饮食与通过对Gcn5功能的不利影响而导致寿命缩短之间存在因果关系。
