Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea.
Mech Ageing Dev. 2013 Sep;134(9):381-90. doi: 10.1016/j.mad.2013.07.003. Epub 2013 Jul 24.
Age-related changes in stem cells could have a profound impact on tissue aging and the development of age-related diseases such as cancer. However, the effects of metformin, a recently recognized anti-cancer drug, on stem cell aging remain largely unknown. In the present study, an experiment was set up to investigate the underlying mechanism of metformin's beneficial effects on age-related changes in intestinal stem cells (ISCs) derived from Drosophila midgut. Results showed that metformin reduced age- and oxidative stress-related accumulation of DNA damage marked by Drosophila γH2AX foci and 8-oxo-dG in ISCs and progenitor cells. Metformin also inhibited age and- oxidative stress-related ISC hyperproliferation as well as intestinal hyperplasia. Our study further revealed that the inhibitory effects of metformin on DNA damage accumulation may be due to the down-regulation of age-related and oxidative stress-induced AKT activity. These data indicate that metformin has beneficial effects on age-related changes in ISCs derived from Drosophila midgut. Further, our results suggest a possible impact of DNA damage on stem cell genomic instability, which leads to the development of age-related diseases. Additionally, our study suggests that Drosophila midgut stem cells can be a suitable model system for studying stem cell biology and stem cell aging.
年龄相关的干细胞变化可能对组织衰老和癌症等与年龄相关的疾病的发展产生深远影响。然而，二甲双胍（一种最近被认可的抗癌药物）对干细胞衰老的影响在很大程度上仍不清楚。在本研究中，设计了一项实验来研究二甲双胍对来源于果蝇中肠的肠干细胞（ISCs）的与年龄相关的变化的有益作用的潜在机制。结果表明，二甲双胍减少了与年龄和氧化应激相关的 DNA 损伤积累，这些损伤在 ISCs 和祖细胞中表现为果蝇 γH2AX 焦点和 8-oxo-dG。二甲双胍还抑制了与年龄和氧化应激相关的 ISC 过度增殖以及肠道过度增生。我们的研究进一步表明，二甲双胍对 DNA 损伤积累的抑制作用可能是由于下调了与年龄相关和氧化应激诱导的 AKT 活性。这些数据表明二甲双胍对来源于果蝇中肠的 ISCs 的与年龄相关的变化具有有益作用。此外，我们的结果表明 DNA 损伤可能对干细胞基因组不稳定性产生影响，从而导致与年龄相关的疾病的发生。此外，我们的研究表明，果蝇中肠干细胞可以作为研究干细胞生物学和干细胞衰老的合适模型系统。
