Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence.

Nicole Noren Hooten,Myriam Gorospe,Alan B Zonderman,Michele K Evans,Yongqing Zhang,Douglas F Dluzen,Michel Bernier,Alejandro Martin‐Montalvo,Kevin G Becker,Rafael Cabo

doi:10.1111/acel.12469

Nicole Noren Hooten, Myriam Gorospe + Show 8 more

Open Access

https://doi.org/10.1111/acel.12469

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Abstract

SummaryMetformin, 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.

Highlights

Metformin has been used to treat type 2 diabetes mellitus since the 1950s
Our results indicate that metformin upregulates DICER1 through a post-transcriptional mechanism involving the RNA-binding protein AU-rich elementbinding factor 1 (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

Summary

Introduction

Metformin enhances insulin sensitivity and lowers blood glucose levels by inhibiting gluconeogenesis in the liver. Metformin elicits these effects by inhibiting the mitochondrial respiratory-chain complex I and glycerophosphate dehydrogenase (mGPD) and by activating adenosine monophosphate-activated protein kinase (AMPK) (Foretz et al, 2014; Madiraju et al, 2014). Activation of AMPK, in turn, leads to a plethora of signaling cascades that regulate energy homeostasis and metabolism (Hardie et al, 2012). AMPK-independent pathways activated by metformin have been described (Pollak, 2012; Foretz et al, 2014) and recent data suggest that systemic effects of metformin may have different mechanisms of action in different tissues (Duca et al, 2015). Gaps in our knowledge about the mechanisms that underlie its therapeutic effects persist

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