Chemically induced reprogramming to reverse cellular aging.
Chemically induced reprogramming to reverse cellular aging.
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DOI：
10.18632/aging.204896
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发表时间：
2023-07-12
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真核衰老的一个标志是表观遗传信息的丢失，这一过程是可以逆转的。我们之前已经证明，在哺乳动物中异位诱导山中因子 OCT4、SOX2 和 KLF4 (OSK) 可以恢复年轻的 DNA 甲基化模式、转录谱和组织功能，而不会消除细胞身份，而这一过程需要主动 DNA 去甲基化。为了筛选能够在不改变基因组的情况下逆转细胞衰老并使人类细胞恢复活力的分子，我们开发了基于高通量细胞的检测方法，可以区分年轻细胞、老年细胞和衰老细胞，包括基于转录的衰老时钟和实时核细胞质区室化（NCC）检测。我们确定了六种化学混合物，它们在不到一周的时间内，在不损害细胞身份的情况下，恢复了年轻的全基因组转录谱和逆转录组年龄。因此，逆转年龄可以实现返老还童，不仅可以通过遗传手段，还可以通过化学手段。
A hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.