Gerosuppressant Metformin: less is more

Menéndez, Javier A.; Cufí, Sílvia; Oliveras‐Ferraros, Cristina; Vellón, Luciano; Joven, Jorge; Vázquez-Martín, Alejandro

doi:10.18632/aging.100316

Cited by 53 publications

(43 citation statements)

References 134 publications

(171 reference statements)

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“…33 As such, alterations in cellular metabolism such as the restriction of mitochondrial biosynthetic capacity imposed by the biguanide metformin should manifest in global epigenetic effects. 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).…”

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confidence: 76%

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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confidence: 76%

Metformin targets histone acetylation in cancer-prone epithelial cells

et al. 2016

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“…Although female mice were initially found to show a better response to metformin supplementation, recent results from our laboratory indicated no gender or stain differences in the actions of metformin (Martin-Montalvo et al 2013). Therefore, to establish the molecular mechanisms and pathways of aging, it is imperative to investigate potential hormone-metformin interactions in male and female animals of varying ages, as the age of starting metformin treatment determines whether an increase in mean and maximum life span occurs (Menendez et al 2011;Anisimov et al 2015). There are not enough studies to conclude whether there are epigenetic/genetic differences in metformin effect on aging, life span, and tumorigenesis.…”

Section: Discussionmentioning

confidence: 98%

Metformin: A Hopeful Promise in Aging Research

Novelle

Ali

Diéguez

et al. 2016

Cold Spring Harb Perspect Med

143

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Even though the inevitable process of aging by itself cannot be considered a disease, it is directly linked to life span and is the driving force behind all age-related diseases. It is an undisputable fact that age-associated diseases are among the leading causes of death in the world, primarily in industrialized countries. During the last several years, an intensive search of antiaging treatments has led to the discovery of a variety of drugs that promote health span and/or life extension. The biguanide compound metformin is widely used for treating people with type 2 diabetes and appears to show protection against cancer, inflammation, and agerelated pathologies. Here, we summarize the recent developments about metformin use in translational aging research and discuss its role as a potential geroprotector.

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“…[77][78][79][80][81] Of note, the bioenergetic crisis imposed by metformin may involve enhanced mitochondrial biogenesis and oxidative stress and the activation of an ataxia telangiectasia mutated (ATM)-mediated DNA damage response (DDR). [82][83][84] Moreover, in their exploration for new strategies able to provide longterm protection of normal cells from chemotherapy in cell culture, Blagosklonny's group has recently reported that a combination of two drugs targeting the mTOR pathway (i.e., metformin and rapamycin) also protected normal cells in lowglucose conditions, whereas, in contrast, it was cytotoxic for cancer cells. 85 Based on these data, and because hypoxic and transformed cells to mimic conditions when patients are diagnosed with a tumor, tumor growth was completely suppressed by the anti-diabetic drug metformin and the non-steroidal, anti-inflammatory drug sulindac and notably delayed by the fatty acid synthase inhibitor cerulenin and the cholesterol-lowering drug simvastatin.…”

Section: Cancer Metabolic Diseases and Metforminmentioning

confidence: 99%