title: Mechanism of metformin: inhibition of DNA damage and proliferative activity in Drosophila midgut stem cell.
abstract: 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.
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Na
authors.forename: Joung-Sun
authors.initials: JS
authors.lastname: Park
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Pyo
authors.forename: Shin-Hae
authors.initials: SH
authors.lastname: Lee
authors.forename: Ho-Jun
authors.initials: HJ
authors.lastname: Jeon
authors.forename: Young-Shin
authors.initials: YS
authors.lastname: Kim
authors.forename: Mi-Ae
authors.initials: MA
authors.lastname: Yoo
mesh_terms: D000375:Aging; D000818:Animals; D030801:Animals, Genetically Modified; D001973:Bromodeoxyuridine / Q000737:chemistry; D049109:Cell Proliferation; D016922:Cellular Senescence; D004249:DNA Damage / Q000187:drug effects; D004330:Drosophila / Q000378:metabolism / Q000502:physiology*; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry; D007422:Intestines / Q000166:cytology*; D008297:Male; D008687:Metformin / Q000737:chemistry*; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects*; D013696:Temperature
chemical_list: D007004:Hypoglycemic Agents; D049452:Green Fluorescent Proteins; D008687:Metformin; D051057:Proto-Oncogene Proteins c-akt; D001973:Bromodeoxyuridine
keywords: Aging; DNA damage; Drosophila; Intestinal stem cells; Metformin