Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

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.

Profiling of m6A RNA modifications identified an age‐associated regulation of AGO2 mRNA stability

“…This indicates that methylation on AGO2 mRNA is implicated in mRNA stability, but DROSHA mRNA methylation may affect different stages of mRNA metabolism such mRNA maturation and translation. Interestingly, the mRNA encoding DICER1, a ribonuclease that processes primary microRNAs, was decreased in the old PBMCs possibly via an RNA decay factor, AUF1 as observed previously (Noren Hooten et al., 2016) had no detectable methylation both in young and old PBMCs. These results implicate that cells utilize various mechanisms to regulate mRNA stability for fine‐tuning regulation of gene expression in a given context.…”

“…For RNA profiling, a subcohort of young (30 years) and old (64 years) participants from the “Healthy Aging in Neighborhoods of Diversity across the Life Span study” (HANDLS) (Evans et al., 2010; Noren Hooten et al., 2016) was chosen for examination of m6A modification, total transcriptome, and miRNA microarray by age. Clinical information on this subcohort has been described previously and is also listed in Figure 1a ( n  = 11/group) (Noren Hooten et al., 2010, 2016).…”

“…Clinical information on this subcohort has been described previously and is also listed in Figure 1a ( n  = 11/group) (Noren Hooten et al., 2010, 2016). The HANDLS study is approved by the Institutional Review Board of the National Institute of Environmental Health Sciences, National Institutes of Health.…”

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

“…Interestingly, chronic treatment with 100 μ m metformin, comparable to the plasma concentrations in metformin‐treated diabetic patients, suppressed HDF and HMSC senescence. Very recently, it was reported that 500 μ m metformin upregulates DICER1 expression to decrease cellular senescence in stress‐induced senescence models (Noren Hooten et al., 2016). It is likely that metformin at different concentrations impacts different signaling pathways in human cells.…”

Metformin-Induced Changes of the Coding Transcriptome and Non-Coding RNAs in the Livers of Non-Alcoholic Fatty Liver Disease Mice

“…Based on examinations of the miRNA profile in breast cancer cells, Blandino et al reported that metformin can modulate DICER, which is a key protein in miRNA biogenesis, to elicit a systematic alteration of miRNA expression and an anticancer effect [18]. Noren Hooten et al demonstrated that the targeting of DICER by metformin plays a role in cellular senescence [19]. To date, only one miRNA transcriptome dataset regarding liver diseases has been published; Katsura et al profiled the miRNA expression in a methionine- and choline-deficient (MCD) diet mouse model of NASH [20].…”