Panorama Research Institute and Regenerative Sciences Institute, Sunnyvale, California 94089, USA.
Rejuvenation Res. 2013 Apr;16(2):152-7. doi: 10.1089/rej.2013.1424.
The dysfunctional changes of aging are generally believed to be irreversible due to the accumulation of molecular and cellular damage within an organism's somatic cells and tissues. However, the importance of potentially reversible cell signaling and epigenetic changes in causing dysfunction has not been thoroughly investigated. Striking evidence that increased oxidative stress associated with hematopoietic stem cells (HSCs) from aging mice causes dysfunction has been reported. Forced expression of SIRT3, which activates the reactive oxygen species (ROS) scavenger superoxide dismutase 2 (SOD2) by de-acetylation to reduce oxidative stress, functionally rejuvenates mouse HSCs. These data, combined with numerous other reports, suggest that ROS act as a signal transducer to play a critical regulatory role in HSCs and at least in some other stem cells. It is likely that ectopic expression of SIRT3 restores homeostasis in gene expression networks sensitive to oxidative stress. This result was surprising because age-associated damage from impaired DNA repair had been thought to be irreversible in old HSCs. The effect of up-regulated SIRT3 in HSCs is one of first examples in which intrinsic cellular aging, not apparently associated with changes in the micro-environment, was reversed. However, the stability of rejuvenation in the absence of continued supplemental SIRT3 expression was not investigated. These data are consistent with a hypothesis that potentially reversible processes, such as aberrant signaling and epigenetic drift, are relevant to cellular aging. If true, rejuvenation of at least some aged cells may be simpler than generally appreciated.
衰老引起的功能障碍变化通常被认为是不可逆转的，这是由于生物体体细胞和组织内分子和细胞损伤的积累所致。然而，潜在的可逆细胞信号和表观遗传变化在引起功能障碍方面的重要性尚未得到彻底研究。有引人注目的证据表明，与衰老小鼠的造血干细胞（HSCs）相关的氧化应激增加会导致功能障碍。强制表达 SIRT3 可通过去乙酰化激活活性氧（ROS）清除剂超氧化物歧化酶 2（SOD2）来减少氧化应激，从而使小鼠 HSCs 功能恢复年轻。这些数据与许多其他报道一起表明，ROS 作为信号转导物在 HSCs 中发挥关键的调节作用，至少在其他一些干细胞中也是如此。很可能是 SIRT3 的异位表达恢复了对氧化应激敏感的基因表达网络的内稳态。这一结果令人惊讶，因为人们曾认为受损的 DNA 修复引起的与年龄相关的损伤在老年 HSCs 中是不可逆转的。在 HSCs 中上调 SIRT3 的作用是内在细胞衰老（与微环境变化无关）被逆转的第一个例子之一。然而，在没有持续补充 SIRT3 表达的情况下，再生的稳定性尚未得到研究。这些数据与这样一种假设一致，即潜在的可逆过程，如异常信号和表观遗传漂移，与细胞衰老有关。如果这是真的，那么至少一些衰老细胞的恢复可能比人们普遍认为的要简单。
