title: Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence.
abstract: Metformin, an oral hypoglycemic agent, has been used for decades to treat type 2 diabetes mellitus. Recent studies indicate that mice treated with metformin live longer and have fewer manifestations of age-related chronic disease. However, the molecular mechanisms underlying this phenotype are unknown. Here, we show that metformin treatment increases the levels of the microRNA-processing protein DICER1 in mice and in humans with diabetes mellitus. Our results indicate that metformin upregulates DICER1 through a post-transcriptional mechanism involving the RNA-binding protein AUF1. Treatment with metformin altered the subcellular localization of AUF1, disrupting its interaction with DICER1 mRNA and rendering DICER1 mRNA stable, allowing DICER1 to accumulate. Consistent with the role of DICER1 in the biogenesis of microRNAs, we found differential patterns of microRNA expression in mice treated with metformin or caloric restriction, two proven life-extending interventions. Interestingly, several microRNAs previously associated with senescence and aging, including miR-20a, miR-34a, miR-130a, miR-106b, miR-125, and let-7c, were found elevated. In agreement with these findings, treatment with metformin decreased cellular senescence in several senescence models in a DICER1-dependent manner. Metformin lowered p16 and p21 protein levels and the abundance of inflammatory cytokines and oncogenes that are hallmarks of the senescence-associated secretory phenotype (SASP). These data lead us to hypothesize that changes in DICER1 levels may be important for organismal aging and to propose that interventions that upregulate DICER1 expression (e.g., metformin) may offer new pharmacotherapeutic approaches for age-related disease.
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Noren Hooten
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.|Pancreatic Islet Development and Regeneration Unit, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Avenida Americo Vespucio, Parque Científico y Tecnologico Cartuja 93, 41092, Sevilla, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martin-Montalvo
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Dluzen
authors.affiliation: Laboratory of Genetics, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Bernier
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Zonderman
authors.affiliation: Laboratory of Genetics, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.affiliation: Laboratory of Genetics, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
authors.forename: Michele K
authors.initials: MK
authors.lastname: Evans
mesh_terms: D000328:Adult; D000375:Aging / Q000187:drug effects / Q000235:genetics; D000818:Animals; D031204:Caloric Restriction; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D003710:Demography; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism
chemical_list: C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C000630987:Hnrpd protein, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D008687:Metformin; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: AUF1; RNA-binding proteins; aging; caloric restriction; diabetes mellitus; microRNA