Whether and how regulation of genes and pathways contributes to physiological aging is topic of intense scientific debate. By performing an RNA expression-based screen for genes downregulated during aging of three different species, we identified glycine-C-acetyltransferase (GCAT, EC 2.3.1.29). Impairing gcat expression promotes the lifespan of C. elegans by interfering with threonine catabolism to promote methylglyoxal (MGO; CAS 78-98-8) formation in an amine oxidase-dependent manner. MGO is a reactive dicarbonyl inducing diabetic complications in mammals by causing oxidative stress and damaging cellular components, including proteins. While high concentrations of MGO consistently exert toxicity in nematodes, we unexpectedly find that low-dose MGO promotes lifespan, resembling key mediators of gcat impairment. These were executed by the ubiquitin-proteasome system, namely PBS-3 and RPN-6.1 subunits, regulated by the stress-responsive transcriptional regulators SKN-1/NRF2 and HSF-1. Taken together, GCAT acts as an evolutionary conserved aging-related gene by orchestrating an unexpected nonlinear impact of proteotoxic MGO on longevity.

中文翻译：

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L-苏氨酸分解代谢受损可通过甲基乙二醛介导的蛋白质激素促进健康。

基因和途径的调控是否以及如何促进生理衰老是激烈的科学辩论的话题。通过对三个不同物种的衰老过程中被下调的基因进行基于RNA表达的筛选，我们确定了甘氨酸-C-乙酰基转移酶（GCAT，EC 2.3.1.29）。受损的gcat表达通过干扰苏氨酸分解代谢以胺氧化酶依赖性方式促进甲基乙二醛（MGO; CAS 78-98-8）的形成，从而延长线虫的寿命。MGO是一种反应性二羰基化合物，它通过引起氧化应激并破坏包括蛋白质在内的细胞成分，在哺乳动物中引起糖尿病并发症。尽管高浓度的MGO始终会对线虫产生毒性，但我们出乎意料地发现，低剂量的MGO可以延长寿命，类似于gcat损伤的关键介质。这些是由遍在蛋白-蛋白酶体系统，即PBS-3和RPN-6.1亚基，由应激反应转录调节因子SKN-1 / NRF2和HSF-1调节的。综上所述，GCAT通过协调蛋白毒性MGO对寿命的意外非线性影响，充当了进化保守的衰老相关基因。