Aging varies among individuals due to both genetics and environment, but the underlying molecular mechanisms remain largely unknown. Using a highly recombined Saccharomyces cerevisiae population, we found 30 distinct quantitative trait loci (QTLs) that control chronological life span (CLS) in calorie-rich and calorie-restricted environments and under rapamycin exposure. Calorie restriction and rapamycin extended life span in virtually all genotypes but through different genetic variants. We tracked the two major QTLs to the cell wall glycoprotein genes FLO11 and HPF1 We found that massive expansion of intragenic tandem repeats within the N-terminal domain of HPF1 was sufficient to cause pronounced life span shortening. Life span impairment by HPF1 was buffered by rapamycin but not by calorie restriction. The HPF1 repeat expansion shifted yeast cells from a sedentary to a buoyant state, thereby increasing their exposure to surrounding oxygen. The higher oxygenation altered methionine, lipid, and purine metabolism, and inhibited quiescence, which explains the life span shortening. We conclude that fast-evolving intragenic repeat expansions can fundamentally change the relationship between cells and their environment with profound effects on cellular lifestyle and longevity.

中文翻译：

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细胞壁蛋白基因 HPF1 的基因内重复扩增控制酵母的时间老化。


由于遗传和环境的原因，衰老在个体之间存在差异，但潜在的分子机制仍然很大程度上未知。利用高度重组的酿酒酵母群体，我们发现了 30 个不同的数量性状位点 (QTL)，它们在高热量和低热量环境以及雷帕霉素暴露下控制时间寿命 (CLS)。热量限制和雷帕霉素几乎延长了所有基因型的寿命，但通过不同的遗传变异。我们追踪了细胞壁糖蛋白基因 FLO11 和 HPF1 的两个主要 QTL，我们发现 HPF1 N 端结构域内基因内串联重复的大规模扩展足以导致寿命明显缩短。 HPF1 造成的寿命损害可以通过雷帕霉素来缓冲，但不能通过热量限制来缓冲。 HPF1 重复扩增使酵母细胞从静止状态转变为浮力状态，从而增加了它们与周围氧气的接触。较高的氧合改变了蛋氨酸、脂质和嘌呤的代谢，并抑制了静止，这解释了寿命缩短的原因。我们得出的结论是，快速进化的基因内重复扩增可以从根本上改变细胞与其环境之间的关系，对细胞生活方式和寿命产生深远影响。