Glaxosmithkline, Oncology Synthetic Lethal Research Unit, Collegeville, PA 19426.
Merck, West Point, PA 19486.
Mol Biol Cell. 2022 May 1;33(5):ar36. doi: 10.1091/mbc.E20-08-0523. Epub 2022 Feb 23.
Cellular senescence is a terminal cell fate characterized by growth arrest and a metabolically active state characterized by high glycolytic activity. Human fibroblasts were placed in a unique metabolic state using a combination of methionine restriction (MetR) and rapamycin (Rapa). This combination induced a metabolic reprogramming that prevented the glycolytic shift associated with senescence. Surprisingly, cells treated in this manner did not undergo senescence but continued to divide at a slow rate even at high passage, in contrast with either Rapa treatment or MetR, both of which extended life span but eventually resulted in growth arrest. Transcriptome-wide analysis revealed a coordinated regulation of metabolic enzymes related to one-carbon metabolism including three methyltransferase enzymes (KMT2D, SETD1B, and ASH1L), key enzymes for both carnitine synthesis and histone modification. These enzymes appear to be involved in both the metabolic phenotype of senescent cells and the chromatin changes required for establishing the senescence arrest. Targeting one of these enzymes, ASH1L, produced both a glycolytic shift and senescence, providing proof of concept. These findings reveal a mechanistic link between a major metabolic hallmark of senescence and nuclear events required for senescence.
细胞衰老（Cellular senescence）是一种终末细胞命运，其特征是生长停滞和代谢活跃状态，表现为高糖酵解活性。通过使用蛋氨酸限制（MetR）和雷帕霉素（Rapa）相结合的方法，将人类成纤维细胞置于独特的代谢状态中。这种组合诱导了一种代谢重编程，防止了与衰老相关的糖酵解转变。令人惊讶的是，用这种方式处理的细胞不会衰老，而是继续以缓慢的速度分裂，即使在高传代时也是如此，这与雷帕霉素或蛋氨酸限制都不同，这两种方法都延长了寿命，但最终导致生长停滞。全转录组分析显示，与一碳代谢相关的代谢酶的协调调控，包括三种甲基转移酶（KMT2D、SETD1B 和 ASH1L），这两种酶都是肉碱合成和组蛋白修饰的关键酶。这些酶似乎既参与衰老细胞的代谢表型，也参与建立衰老抑制所必需的染色质变化。靶向这些酶中的一种，ASH1L，既产生了糖酵解转变，也产生了衰老，这为概念验证提供了依据。这些发现揭示了衰老的主要代谢特征与衰老所必需的核事件之间的机制联系。
