Sousa-Victor Pedro, García-Prat Laura, Muñoz-Cánoves Pura
Buck Institute for Research on Aging, Novato, CA, USA.
Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), and ICREA, Barcelona, Spain.
Oncotarget. 2015 Sep 15;6(27):23052-4. doi: 10.18632/oncotarget.5563.
Over the past decade, our understanding of the molecular and cellular mechanisms presiding over cellular and tissue decline with aging has greatly advanced. Classical hallmarks of aging cell include increasing levels of reactive oxygen species, DNA damage and senescence entry, which disrupt tissue architecture and function. Tissue dysfunction with aging has been shown to correlate with a cellular switch from a G0 reversible quiescence state into a G0 irreversible senescence state (geroconversion), causing a permanent proliferative block. The TOR (target of rapamycin) kinase has been shown to promote geroconversion. Rapamycin and other rapalogs specifically suppress activity of the mammalian TOR (mTOR) complex 1 (mTORC1) -but not mTOR complex 2 (mTORC2)- and decrease senescence entry, thus preserving proliferative potential. In this perspective, we briefly comment recent progress of Leontieva and colleagues showing a new class of non-rapalog drugs that target simultaneously mTORC1 and mTORC2 and prevent geroconversion in a more efficient way than rapamycin. Its potential future use as rejuvenating, anti-aging therapeutics is therefore proposed.
在过去十年中，我们对随着衰老而导致细胞和组织衰退的分子和细胞机制的理解有了很大进展。衰老细胞的经典特征包括活性氧水平升高、DNA损伤和进入衰老状态，这些会破坏组织结构和功能。已表明衰老导致的组织功能障碍与细胞从G0可逆静止状态转变为G0不可逆衰老状态（老年转化）相关，从而导致永久性增殖阻滞。雷帕霉素靶蛋白（TOR）激酶已被证明可促进老年转化。雷帕霉素和其他雷帕霉素类似物特异性抑制哺乳动物TOR（mTOR）复合物1（mTORC1）——而非mTOR复合物2（mTORC2）——的活性，并减少衰老的发生，从而保留增殖潜力。从这个角度来看，我们简要评论一下列昂季耶娃及其同事的最新进展，他们展示了一类新型非雷帕霉素类似物药物，这些药物同时靶向mTORC1和mTORC2，并且比雷帕霉素更有效地预防老年转化。因此，有人提出了其作为恢复活力、抗衰老疗法的潜在未来用途。
