Unidad de Genómica Avanzada (Langebio), Centro de Investigación y de Estudios Avanzados del IPN, Irapuato, Guanajuato, Mexico.
Aging Cell. 2018 Jun;17(3):e12749. doi: 10.1111/acel.12749. Epub 2018 Mar 25.
Dietary restriction is arguably the most promising nonpharmacological intervention to extend human life and health span. Yet, only few genetic regulators mediating the cellular response to dietary restriction are known, and the question remains which other regulatory factors are involved. Here, we measured at the genomewide level the chronological lifespan of Saccharomyces cerevisiae gene deletion strains under two nitrogen source regimens, glutamine (nonrestricted) and γ-aminobutyric acid (restricted). We identified 473 mutants with diminished or enhanced extension of lifespan. Functional analysis of such dietary restriction genes revealed novel processes underlying longevity by the nitrogen source quality, which also allowed us to generate a prioritized catalogue of transcription factors orchestrating the dietary restriction response. Importantly, deletions of transcription factors Msn2, Msn4, Snf6, Tec1, and Ste12 resulted in diminished lifespan extension and defects in cell cycle arrest upon nutrient starvation, suggesting that regulation of the cell cycle is a major mechanism of chronological longevity. We further show that STE12 overexpression is enough to extend lifespan, linking the pheromone/invasive growth pathway with cell survivorship. Our global picture of the genetic players of longevity by dietary restriction highlights intricate regulatory cross-talks in aging cells.
饮食限制可以说是延长人类寿命和健康寿命最有前途的非药物干预措施。然而，目前已知的介导细胞对饮食限制反应的遗传调控因子很少，仍不清楚其他哪些调节因子参与其中。在这里，我们在两种氮源方案下（谷氨酰胺[非限制]和γ-氨基丁酸[限制]），测量了酿酒酵母基因缺失菌株的时序寿命，在全基因组水平上进行了测量。我们鉴定出了 473 个具有寿命缩短或延长的突变体。对这些饮食限制基因的功能分析揭示了氮源质量对长寿的潜在新过程，这也使我们能够生成一个协调饮食限制反应的转录因子优先目录。重要的是，转录因子 Msn2、Msn4、Snf6、Tec1 和 Ste12 的缺失导致寿命延长缩短和营养饥饿时细胞周期停滞缺陷，表明细胞周期的调节是时序长寿的主要机制。我们进一步表明，STE12 的过表达足以延长寿命，将激素/侵袭性生长途径与细胞存活联系起来。我们通过饮食限制对长寿的遗传参与者的全面了解突出了衰老细胞中复杂的调控交叉对话。
