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Metformin Slows Aging and Cancer Formation by Blocking Expression of Inflammatory Cytokine Genes

By BiotechDaily International staff writers
Posted on 18 Apr 2013
Metformin, a drug used to treat type II diabetes slows aging and inhibits cancer cell formation by preventing the expression of genes coding for multiple inflammatory cytokines usually activated during cellular senescence.

Cellular senescence is the phenomenon by which normal diploid cells cease to divide, normally after about 50 cell divisions in vitro. Cells can also be induced to senesce by certain toxins, irradiation, or the activation of certain oncogenes. In response to DNA damage cells either age or self-destruct (apoptosis) if the damage cannot be easily repaired. Though they no longer replicate, senescent cells remain metabolically active and generally adopt phenotypes including flattened cell morphology, altered gene expression and secretion profiles (known as the senescence-associated secretory phenotype), and positive senescence-associated beta-galactosidase staining. Cellular senescence is causally implicated in generating age-related phenotypes, and removal of senescent cells can extend the lifespan of an organism by preventing or delaying tissue dysfunction.

Metformin is used alone or with other medications, including insulin, to treat type II diabetes. The drug helps to control the amount of glucose in the blood by decreasing the amount of glucose absorbed from food and the amount of glucose made by the liver. Metformin also increases the body's response to insulin. Metformin is not used to treat type I diabetes where the body does not produce insulin due to autoantibodies that attack pancreatic beta cells.

Investigators at the University of Montreal (Canada) and their colleagues at McGill University (Montreal, Canada) reported in the March 23, 2013, online edition of the journal Aging Cell that metformin inhibited the expression of genes coding for multiple inflammatory cytokines seen during cellular senescence. Conditioned medium (CM) from senescent cells stimulated the growth of prostate cancer cells but treatment of senescent cells with metformin inhibited this effect.

Bioinformatic analysis of genes down regulated by metformin suggested that the drug blocked the activity of the transcription factor NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells). This finding was confirmed by experiments that showed that metformin prevented the translocation of NF-kappaB to the nucleus and inhibited the phosphorylation of proteins required for activation of the NF-kappaB pathway.

“The genes that code for cytokines are normal, but a protein that normally triggers their activation called NF-kappaB cannot reach them in the cell nucleus in metformin treated cells,” said senior author Dr. Gerardo Ferbeyre, professor of biochemistry at the University of Montreal. “We also found that metformin does not exert its effects through a pathway commonly thought to mediate its antidiabetic effects. We have suspected that metformin acts in different ways on different pathways to cause effects on aging and cancer.”

“Cells normally secrete these inflammatory cytokines when they need to mount an immune response to infection, but chronic production of these same cytokines can also cause cells to age,” said Dr. Ferbeyre. “Such chronic inflammation can be induced, for example by smoking, and old cells are particularly proficient at making and releasing cytokines. We were surprised by our finding that metformin could prevent the production of inflammatory cytokines by old cells.”

Related Links:

University of Montreal
McGill University



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