RT Journal Article
T1 Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence
A1 Noren Hooten, Nicole
A1 Martin-Montalvo, Alejandro
A1 Dluzen, Douglas F.
A1 Zhang, Yongqing
A1 Bernier, Michel
A1 Zonderman, Alan B.
A1 Becker, Kevin G.
A1 Gorospe, Myriam
A1 de Cabo, Rafael
A1 Evans, Michele K.
K1 aging
K1 AUF1
K1 caloric restriction
K1 diabetes mellitus
K1 microRNA
K1 RNA-binding proteins
K1 Messenger-rna decay
K1 Life-span
K1 Stress
K1 Ampk
K1 Phosphorylation
K1 Mechanisms
K1 Elegans
K1 Pathway
K1 Mir-34a
K1 Binding
AB 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.
PB Wiley
SN 1474-9718
YR 2016
FD 2016-06-01
LK http://hdl.handle.net/10668/18981
UL http://hdl.handle.net/10668/18981
LA en
DS RISalud
RD Apr 9, 2025