Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

Haes, Wouter De; Frooninckx, Lotte; Assche, Roel Van; Smolders, Arne; Depuydt, Geert; Billen, Johan; Braeckman, Bart P.; Schoofs, Liliane; Temmerman, Liesbet

doi:10.1073/pnas.1321776111

Cited by 286 publications

(223 citation statements)

References 64 publications

(92 reference statements)

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“…We have also provided the evidence of H2O2-induced mitohormetic effects in yeast [35]. Just recently, metformin has been proven to promote worm lifespan through mitohormesis via the peroxiredoxin PRD-2 [36]. In the present study, we have also validated that ART, SNP, ARG, or H2O2 can mimic CR to induce SOD, CAT, and GSH for effective ROS scavenging.…”

Section: Discussionsupporting

confidence: 72%

Artemisinin mimics calorie restriction to initiate antioxidative responses and compromise telomere shortening

Wang

et al. 2014

Preprint

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Calorie restriction (CR) is known to extend lifespan among organisms with the putative mechanism underlying nitric oxide (NO)-enhanced mitochondrial biogenesis. However, whether NO maintains telomere intact that is implicated in life expectancy remains unknown. We report here the artemisinin derivative artesunate in a low concentration up-regulates mitochondrial SIRT3-SOD2 expression among global activation of antioxidative networks via the NO signaling cascade AMPK→Akt→ eNOS→SIRT1→PGC-1α. While the NO donor sodium nitroprusside and the NO precursor L-arginine replicate the antioxidative responses, exogenous low-dose hydrogen peroxide also leads to attenuated oxidative stress. The tumor suppressor BRCA1 and other DNA repair partners are down-regulated after scavenging of reactive oxygen species. Upon treatment, telomere shortening is damped without telomerase up-regulation, highlighting telomere maintenance rather than telomere elongation. In conclusion, artesunate can mimic CR to activate antioxidative responses and alleviate telomere attrition via NO signaling, thereby maintaining the stability and integrity of chromosomes, which are the hallmarks of longevity.

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Section: Discussionsupporting

confidence: 72%

Artemisinin mimics calorie restriction to initiate antioxidative responses and compromise telomere shortening

Wang

et al. 2014

Preprint

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“…The unresolved question is how metformin activates Nrf2. One possibility is that metformin induces mitohormesis through perturbing the mitochondrion respiratory chain (De Haes et al., 2014; Foretz et al., 2010). However, very high concentrations of metformin (5 m m ) were required to observe significant inhibition of mitochondrion respiratory chain complex 1 activity (He & Wondisford, 2015).…”

Section: Discussionmentioning

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%

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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“…In line with recent studies proposing a "substrate limitation" model of metformin action, 34,35 we recently revealed that the anti-diabetic/antiaging drug metformin [36][37][38][39] impedes the production of several mitochondrial-dependent biosynthetic intermediates by reducing the anaplerotic flux of glucose, glutamine, and likely branched-chain amino acids, 40 into the tricarboxylic acid (TCA) cycle, leading to the depletion of acetyl-CoA and malonyl-CoA required for de novo lipid biosynthesis and inhibition of mTOR-driven protein synthesis in anabolism-addicted BRCA1 haploinsufficient cells. 41 To mark histones post-translationally, chromatin modifiers use metabolic intermediates such as acetyl-CoA, the key cofactor used by histone acetyltransferases (HATs). Hence, histone modifications may reflect the metabolic status of cells and be influenced by the concentrations of epigenetic metabolites such as acetyl-CoA.…”

mentioning

confidence: 99%

Metformin targets histone acetylation in cancer-prone epithelial cells

et al. 2016

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The usage of metabolic intermediates as substrates for chromatin-modifying enzymes provides a direct link between the metabolic state of the cell and epigenetics. Because this metabolism-epigenetics axis can regulate not only normal but also diseased states, it is reasonable to suggest that manipulating the epigenome via metabolic interventions may improve the clinical manifestation of age-related diseases including cancer. Using a model of BRCA1 haploinsufficiency-driven accelerated geroncogenesis, we recently tested the hypothesis that: 1.) metabolic rewiring of the mitochondrial biosynthetic nodes that overproduce epigenetic metabolites such as acetyl-CoA should promote cancer-related acetylation of histone H3 marks; 2.) metformin-induced restriction of mitochondrial biosynthetic capacity should manifest in the epigenetic regulation of histone acetylation. We now provide one of the first examples of how metformin-driven metabolic shifts such as reduction of the 2-carbon epigenetic substrate acetyl-CoA is sufficient to correct specific histone H3 acetylation marks in cancer-prone human epithelial cells. The ability of metformin to regulate mitonuclear communication and modulate the epigenetic landscape in genomically unstable pre-cancerous cells might guide the development of new metabolo-epigenetic strategies for cancer prevention and therapy. KEYWORDS BRCA1; epigenetics; histone acetylation; metformin; mitochondria While metabolic rewiring of cancer cells can be a direct consequence of the concerted action of oncogenes and tumor suppressor genes that drive aberrant growth of cancer tissues, altered metabolism might also play a primary, causative role in oncogenesis. Accordingly, metabolic reprogramming is increasingly appreciated as a candidate hallmark of tumorigenesis. [1][2][3][4][5] In a recently proposed metabolism-centered model of carcinogenesis, known as geroncogenesis 2 the possibility of acquiring genetic aberrations increases when aging itself operates as a driver of cancer-like metabolic landscapes. Tumor formation might therefore depend not only on accumulating mutations in the genome, but also on the decline in the homeostasis or metabolic health that naturally occurs in aging cells. Indeed, after many years of being subordinated to the nucleus as the commander-in-chief, able to initiate biological events, the capacity of metabolism to independently dictate cellular actions is increasingly recognized among most cell biologists. Accordingly, the research community now acknowledges that aging-driven alteration of metabolic homeostasis might be sufficient to favor an imbalance in self-amplifying metabolic landscapes that ultimately manifest as aging-driven diseases, including cancer. 6Metabolic programs: From anabolic supporters of genomic instability to epigenetic regulators of carcinogenesisThe metabolic health of our cells might be a key determinant factor pushing the risk balance or cancer risk-meter toward health or the risk of cancer.1,2 On the one hand, genomic instability, a charac...

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Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

Cited by 286 publications

References 64 publications

Artemisinin mimics calorie restriction to initiate antioxidative responses and compromise telomere shortening

Artemisinin mimics calorie restriction to initiate antioxidative responses and compromise telomere shortening

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

Metformin targets histone acetylation in cancer-prone epithelial cells

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