Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism

Cabreiro, Filipe; Au, Catherine; Leung, Kit‐Yi; Vergara-Irigaray, Nuria; Cochemé, Helena M.; Noori, Tahereh; Weinkove, David; Schuster, Eugene; Greene, Nicholas D. E.; Gems, David

doi:10.1016/j.cell.2013.02.035

Cited by 796 publications

(688 citation statements)

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“…Although we treated worms with 50 m m metformin, C. elegan s has a highly protective cuticle and intestine that generally limit drug uptake; polar drugs, such as metformin, can be applied at a concentration approximately 1,000‐fold higher than their predicted affinity for the target (Holden‐Dye, & Walker, 2007). Nevertheless, it should be considered that under these culture conditions, AMPK‐dependent activation of SKN‐1 could also contribute to metformin‐induced lifespan extension in C. elegans (Cabreiro et al., 2013; Onken & Driscoll, 2010). …”

Section: Discussionmentioning

confidence: 99%

“…Lifespan analysis was conducted at 20°C according to a protocol modified from previous publication (Cabreiro et al., 2013; Wu et al., 2016). Briefly, synchronized L1 animals were seeded onto the standard nematode growth media (NGM) plates until L4 stages.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, the effects of metformin on elongating lifespan have been demonstrated in animal models, including worms (Cabreiro et al., 2013; De Haes et al., 2014; Onken & Driscoll, 2010; Wu et al., 2016), mice (Martin‐Montalvo et al., 2013), and rats (Smith et al., 2010). The current consensus is that metformin targets multiple cellular signaling pathways closely associated with the development of aging, such as inflammation, cellular survival, stress defense, autophagy, and protein synthesis (Barzilai et al., 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Impaired Nrf2‐ARE activity was observed not only in physiological aging (Suh et al., 2004) but also in premature aging disorders (Kubben et al., 2016). In Caenorhabditis elegans , SKN‐1 (Nrf2 homolog) has been implicated in the mechanism of metformin (Cabreiro et al., 2013; Onken & Driscoll, 2010; Wu et al., 2016); however, whether metformin can regulate the antioxidant response associated with human cellular aging and whether Nrf2 is involved in this process remain unanswered questions.…”

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: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…It enhances longevity is a range of model organisms: C. elegans (Cabreiro et al ., 2013), D. melanogaster (Slack et al ., 2012), and M. musculus (Martin‐Montalvo et al ., 2013). However, it should be noted that there are studies showing no effect or only a very small effect of metformin in rats and rodents with normal genetics and longevity (https://www.ncbi.nlm.nih.gov/pubmed/20304770, http://www.ncbi.nlm.nih.gov/pubmed/23900241).…”

Section: Identification Of Candidatesmentioning

confidence: 99%

Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic

et al. 2016

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SummaryIn the coming decades, a massive shift in the aging segment of the population will have major social and economic consequences around the world. One way to offset this increase is to expedite the development of geroprotectors, substances that slow aging, repair age‐associated damage and extend healthy lifespan, or healthspan. While over 200 geroprotectors are now reported in model organisms and some are in human use for specific disease indications, the path toward determining whether they affect aging in humans remains obscure. Translation to the clinic is hampered by multiple issues including absence of a common set of criteria to define, select, and classify these substances, given the complexity of the aging process and their enormous diversity in mechanism of action. Translational research efforts would benefit from the formation of a scientific consensus on the following: the definition of ‘geroprotector’, the selection criteria for geroprotectors, a comprehensive classification system, and an analytical model. Here, we review current approaches to selection and put forth our own suggested selection criteria. Standardizing selection of geroprotectors will streamline discovery and analysis of new candidates, saving time and cost involved in translation to clinic.

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Association Between Preoperative Metformin Exposure and Postoperative Outcomes in Adults With Type 2 Diabetes

et al. 2020

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IMPORTANCE Adults with comorbidity have less physiological reserve and an increased rate of postoperative mortality and readmission after the stress of a major surgical intervention.OBJECTIVE To assess postoperative mortality and readmission among individuals with diabetes with or without preoperative prescriptions for metformin. DESIGN, SETTING, AND PARTICIPANTSThis cohort study obtained data from the electronic health record of a multicenter, single health care system in Pennsylvania. Included were adults with diabetes who underwent a major operation with hospital admission from January 1, 2010, to January 1, 2016, at 15 community and academic hospitals within the system. Individuals without a clinical indication for metformin therapy were excluded. Follow-up continued until December 18, 2018.EXPOSURES Preoperative metformin exposure was defined as 1 or more prescriptions for metformin in the 180 days before the surgical procedure.MAIN OUTCOMES AND MEASURES All-cause postoperative mortality, hospital readmission within 90 days of discharge, and preoperative inflammation measured by the neutrophil to leukocyte ratio were compared between those with and without preoperative prescriptions for metformin. The corresponding absolute risk reduction (ARR) and adjusted hazard ratio (HR) with 95% CI were calculated in a propensity score-matched cohort. RESULTS Among the 10 088 individuals with diabetes who underwent a major surgical intervention, 5962 (59%) had preoperative metformin prescriptions. A total of 5460 patients were propensity score-matched, among whom the mean (SD) age was 67.7 (12.2) years, and 2866 (53%) were women. In the propensity score-matched cohort, preoperative metformin prescriptions were associated with a reduced hazard for 90-day mortality (adjusted HR, 0.72 [95% CI, 0.55-0.95]; ARR, 1.28% [95% CI, 0.26-2.31]) and hazard of readmission, with mortality as a competing risk at both 30 days (ARR, 2.09% [95% CI, 0.35-3.82]; sub-HR, 0.84 [95% CI, 0.72-0.98]) and 90 days (ARR, 2.78% [95% CI, 0.62-4.95]; sub-HR, 0.86 [95% CI, 0.77-0.97]). Preoperative inflammation was reduced in those with metformin prescriptions compared with those without (mean neutrophil to leukocyte ratio, 4.5 [95% CI, 4.3-4.6] vs 5.0 [95% CI, 4.8-5.3]; P < .001). E-value analysis suggested robustness to unmeasured confounding.CONCLUSIONS AND RELEVANCE This study found an association between metformin prescriptions provided to individuals with type 2 diabetes before a major surgical procedure and reduced risk-adjusted mortality and readmission after the operation. This association warrants further investigation.

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Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism

Cited by 796 publications

References 68 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

Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic

Association Between Preoperative Metformin Exposure and Postoperative Outcomes in Adults With Type 2 Diabetes

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