Metformin as a Tool to Target Aging

Barzilai, Nir; Crandall, Jill P.; Kritchevsky, Stephen B.; Espeland, Mark A.

doi:10.1016/j.cmet.2016.05.011

Cited by 802 publications

(677 citation statements)

References 79 publications

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“…Against this background, it might be tempting to suggest that metformin could drive phenotypes of cancer resistance and extended healthspan by promoting more resilient epigenomes that resist aging‐related loss of cell fate and dedifferentiation (Vazquez‐Martin et al., 2012). Yet it remains to be determined the relative weight of such direct effect of metformin to influence the epigenome in comparison with the widely accepted multifaceted capacity of metformin to indirectly target a number of aging‐related metabolic mechanisms (Barzilai et al., 2016), our mechanistic insights might be relevant not only to assist in deconvoluting the epigenetic mechanisms of action of metformin, but also in developing a new generation of KDM6A‐targeted biguanides.…”

Section: Discussionmentioning

confidence: 99%

“…The TAME (Targeting Aging with Metformin) clinical trial has been designed to evaluate the capacity of the antidiabetic biguanide metformin to delay the manifestation of age‐associated disorders (Barzilai, Crandall, Kritchevsky & Espeland, 2016). By enrolling patients aged 65–79 years diagnosed with one single age‐associated condition and then assessing the global impact of metformin on a composite outcome including cardiovascular events, cancer, dementia, mortality, and other functional and geriatric endpoints, this paradigm‐shifting study aimed to target the aging process per se (Newman et al., 2016; Figure S1A).…”

Section: Introductionmentioning

confidence: 99%

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Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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SummaryMetformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure‐ and ligand‐based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3‐specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low‐density lipoprotein receptor‐deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft‐bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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“…Recently, hallmarks of aging, including cellular senescence and stem cell exhaustion, were identified (Lopez‐Otin, Blasco, Partridge, Serrano, & Kroemer, 2013), guiding the research on aging and aging intervention strategies. Furthermore, the first clinical trial, Target Aging with Metformin (TAME), was approved to create a paradigm for evaluating pharmacologic approaches to delay aging (Barzilai, Crandall, Kritchevsky, & Espeland, 2016). The biguanide drug metformin, which is an FDA‐approved first‐line drug for treating type 2 diabetes mellitus, has been used clinically for over 60 years for its effectiveness, safety, and low cost (Bailey & Day, 2004); now, metformin is being considered as a promising geroprotector candidate.…”

Section: Introductionmentioning

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). One well‐accepted mechanism of metformin‐mediated lifespan extension is its ability to mimic the effects of dietary restriction through stimulating adenosine monophosphate‐activated protein kinase (AMPK), the principal energy sensor in cells, to reduce energy‐consuming processes (Martin‐Montalvo et al., 2013; Onken & Driscoll, 2010; Zhou et al., 2001).…”

Section: Introductionmentioning

confidence: 99%

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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“…Advances in understanding the biological basis of aging are leading to the potential of identifying behavioral and pharmacologic intervention targets for increasing health span (9)(10)(11)(12). The National Institute on Aging Interventions Testing Program has been established to organize research toward this goal across model organisms (13,14).…”

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confidence: 99%

Clinical Trials Targeting Aging and Age-Related Multimorbidity

Espeland

Crimmins

Grossardt

et al. 2016

GERONA

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Background: There is growing interest in identifying interventions that may increase health span by targeting biological processes underlying aging. The design of efficient and rigorous clinical trials to assess these interventions requires careful consideration of eligibility criteria, outcomes, sample size, and monitoring plans. Methods: Experienced geriatrics researchers and clinical trialists collaborated to provide advice on clinical trial design. Results: Outcomes based on the accumulation and incidence of age-related chronic diseases are attractive for clinical trials targeting aging. Accumulation and incidence rates of multimorbidity outcomes were developed by selecting at-risk subsets of individuals from three large cohort studies of older individuals. These provide representative benchmark data for decisions on eligibility, duration, and assessment protocols. Monitoring rules should be sensitive to targeting aging-related, rather than disease-specific, outcomes. Conclusions: Clinical trials targeting aging are feasible, but require careful design consideration and monitoring rules.

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Metformin as a Tool to Target Aging

Cited by 802 publications

References 79 publications

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

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

Clinical Trials Targeting Aging and Age-Related Multimorbidity

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