Metformin: A Hopeful Promise in Aging Research

Novelle, Marta G.; Ali, Ahmed; Diéguez, Carlos; Bernier, Michel; Cabo, Rafael de

doi:10.1101/cshperspect.a025932

Cited by 123 publications

(86 citation statements)

References 109 publications

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“…Metformin, the most widely used antidiabetic drug in the world, has been reported to favorably influence metabolic and cellular processes closely associated with the development of aging and even to delay aging in animal models (Novelle et al., 2016). However, there is still insufficient evidence to prove the geroprotective effects of metformin in normal human diploid cells.…”

Section: Discussionmentioning

confidence: 99%

“…Although studies have reported that metformin regulates redox metabolism in mitochondria (Novelle, Ali, Dieguez, Bernier, & de Cabo, 2016), little is known about the effects of metformin on the redox signaling associated with the ER. In mammalian cells, there are three peroxidases located in the ER, namely glutathione peroxidase 7 (GPx7) (Wang, Zhang, Niu, Sitia, & Wang, 2014), glutathione peroxidase 8 (GPx8) (Ramming, Hansen, Nagata, Ellgaard, & Appenzeller‐Herzog, 2014), and peroxiredoxin 4 (Prx4) (Zito et al., 2010).…”

Section: Introductionmentioning

confidence: 99%

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Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

et al. 2018

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SummaryMetformin, an FDA‐approved antidiabetic drug, has been shown to elongate lifespan in animal models. Nevertheless, the effects of metformin on human cells remain unclear. Here, we show that low‐dose metformin treatment extends the lifespan of human diploid fibroblasts and mesenchymal stem cells. We report that a low dose of metformin upregulates the endoplasmic reticulum‐localized glutathione peroxidase 7 (GPx7). GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence. We also indicate that metformin increases the nuclear accumulation of nuclear factor erythroid 2‐related factor 2 (Nrf2), which binds to the antioxidant response elements in the GPX7 gene promoter to induce its expression. Moreover, the metformin‐Nrf2‐GPx7 pathway delays aging in worms. Our study provides mechanistic insights into the beneficial effects of metformin on human cellular aging and highlights the importance of the Nrf2‐GPx7 pathway in pro‐longevity signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

et al. 2018

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“…Our results may also have relevance in regard to the use of metformin in the general population as an antiaging and cancer chemoprevention drug. 56 Metformin has not previously been reported to protect the genome from DNA damage and mutation. However, such activity would go a long way toward explaining why it can.…”

Section: Discussionmentioning

confidence: 99%

Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice

Zhang

Tang

Deater

et al. 2016

Blood

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• The widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in a preclinical murine model of FA.• Metformin reduces DNA damage in human FA patient-derived cells.Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2 2/2 mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2 2/2 mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2 2/2 Trp53 1/2 mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells. (Blood. 2016; 128(24):2774-2784

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“…Not surprisingly, drugs that inhibit mitochondrial function were examined in this context, and metformin was shown to extend longevity in worms(2) and mice(3) (although not in Drosophila(275)). Metformin has now been found to target several age-related pathways(3, 276, 277), but the mechanisms by which metformin extends lifespan are far from clear. A randomized clinical trial, TAME (“Targeting aging with metformin”)(6), has been planned to test the effect of metformin on the time to the new occurrence of a composite outcome that includes cardiovascular events, cancer, dementia, and mortality as an endpoint in 3,000 subjects who are 65-79 years of age(6).…”

Section: A Role For Metformin In Cancer and Agingmentioning

confidence: 99%

Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity

Romero

Erez

Hüttemann

et al. 2017

American Journal of Obstetrics and Gynecology

193

120

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Metformin is everywhere. Originally introduced in clinical practice as an anti-diabetic agent, its role as a therapeutic agent is expanding to include treatment of pre-diabetes, gestational diabetes, polycystic ovarian disease, and more recently, experimental studies, as well as observations in randomized clinical trials, suggest that metformin could have a place in the treatment or prevention of preeclampsia. This article provides a brief overview of the history of metformin in the treatment of diabetes, reviews the results of meta-analyses of metformin in gestational diabetes, and the treatment of obese non-diabetic pregnant women to prevent macrosomia. We highlight the results of a randomized clinical trial in which metformin administration in early pregnancy did not reduce the frequency of large-for-gestational-age infants (primary endpoint), but did decrease the frequency of preeclampsia (a secondary endpoint). The mechanisms by which metformin may prevent preeclampsia include a reduction in the production of anti-angiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin), and improving endothelial dysfunction, probably through an effect on the mitochondria. Another potential mechanism whereby metformin may play a role in the prevention of preeclampsia is its ability to modify cellular homeostasis and energy disposition, mediated by mTOR. Metformin has a molecular weight of 129 Dalton, and therefore, readily crosses the placenta. There is considerable evidence suggesting that this agent is safe during pregnancy. New literature on the role of metformin in the prevention of cancer, a chemotherapeutic adjuvant, and in prolonging life and protecting against aging, is briefly reviewed. Herein we discuss the mechanisms of action and potential benefits of metformin.

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Metformin: A Hopeful Promise in Aging Research

Cited by 123 publications

References 109 publications

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice

Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity

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