Genome protective effect of metformin as revealed by reduced level of constitutive DNA damage signaling
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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.
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In a dose-dependent manner, metformin prevents activation of ATM protein kinase, lowering ROS and gammaH2AX.
“in a dose-dependent manner, metformin prevents activation of ATM-protein kinase, thereby lowering ROS and γH2AX-a sensitive marker of DNA-double stranded breaks and genomic instability”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Halicka et al. 2011
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- Authors
- Halicka, H. D., Zhao, H., Li, J., Traganos, F., Zhang, S., Lee, M., & Darzynkiewicz, Z.
- Affiliations
- New York Medical College (US)
- Brander Cancer Research Institute and Department of Pathology, New York Medical College, Valhalla, NY 10595, USA
- Venue
- Aging
- Publisher
- Impact Journals, LLC
- Published
- 2011-10-28
- Volume
- 3
- Issue
- 10
- Pages
- 1028-1038
- ISSN
- 1945-4589 (ISSN-L)
- PMC
- PMC3229966
- OpenAlex
- W2120518749
- Cited by
- 53
- References
- 80
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 6 · 2018: 3 · 2017: 2 · 2016: 4 · 2015: 5 · 2014: 4 · 2013: 5 · 2012: 14
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Aging (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA028704)
- National Institute of General Medical Sciences (R01GM031973)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- metformin, DNA damage signaling, H2AX phosphorylation, ATM activation, replication stress, reactive oxygen species, AMPK, mTOR signaling, cellular senescence, lymphocytes, lung cancer cells
- MeSH terms
- Animals, Cell Line, DNA, DNA Damage, DNA Replication, DNA-Binding Proteins, Histones, Humans, Hypoglycemic Agents, Metformin, Signal Transduction, Genome, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Cell Cycle Proteins, Tumor Suppressor Proteins, TOR Serine-Threonine Kinases, Ataxia Telangiectasia Mutated Proteins
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