Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.
Molecular and Biomedical Sciences, University of Maine, Orono, ME 04467, USA.
Aging (Albany NY). 2023 Jul 12;15(13):5966-5989. doi: 10.18632/aging.204896.
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.
真核生物衰老的一个标志是表观遗传信息的丧失，这一过程是可以逆转的。我们之前已经表明，在哺乳动物中异位诱导 Yamanaka 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，而不会抹去细胞身份，这一过程需要主动的 DNA 去甲基化。为了筛选不改变基因组就能逆转细胞衰老并使人类细胞年轻化的分子，我们开发了高通量基于细胞的测定法，该方法可以区分年轻、衰老和衰老细胞，包括基于转录的衰老时钟和实时核质区室化（NCC）测定法。我们确定了六种化学鸡尾酒，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并逆转了转录组年龄。因此，不仅可以通过遗传手段，还可以通过化学手段实现衰老的逆转。
