Journal
AGING-US
Volume 3, Issue 10, Pages 1028-1038Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.100397
Keywords
DNA replication stress; Reactive oxidant species (ROS); H2AX phosphorylation; ATM activation; cell cycle
Categories
Funding
- NCI NIH HHS [R01 CA028704, R01 CA028704-32] Funding Source: Medline
- NIGMS NIH HHS [R01 GM031973] Funding Source: Medline
Ask authors/readers for more resources
We have shown before that constitutive DNA damage signaling represented by H2AX-Ser139 phosphorylation and ATM activation in untreated normal and tumor cells is a reporter of the persistent DNA replication stress induced by endogenous oxidants, the by-products of aerobic respiration. In the present study we observed that exposure of normal mitogenically stimulated lymphocytes or tumor cell lines A549, TK6 and A431 to metformin, the specific activator of 5'AMP-activated protein kinase (AMPK) and an inhibitor of mTOR signaling, resulted in attenuation of constitutive H2AX phosphorylation and ATM activation. The effects were metformin-concentration dependent and seen even at the pharmacologically pertinent 0.1 mM drug concentration. The data also show that intracellular levels of endogenous reactive oxidants able to oxidize 2',7'-dihydro-dichlorofluorescein diacetate was reduced in metformin-treated cells. Since persistent constitutive DNA replication stress, particularly when paralleled by mTOR signaling, is considered to be the major cause of aging, the present findings are consistent with the notion that metformin, by reducing both DNA replication stress and mTOR-signaling, slows down aging and/or cell senescence processes.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available