AMPK‐upregulated microRNA‐708 plays as a suppressor of cellular senescence and aging via downregulating disabled‐2 and mTORC1 activation

Senescence‐associated microRNAs (SA‐miRNAs) are important molecules for aging regulation. While many aging‐promoting SA‐miRNAs have been identified, confirmed aging‐suppressive SA‐miRNAs are rare, that impeded our full understanding on aging regulation. In this study, we verified that miR‐708 expression is decreased in senescent cells and aged tissues and revealed that miR‐708 overexpression can alleviate cellular senescence and aging performance. About the molecular cascade carrying the aging suppressive action of miR‐708, we unraveled that miR‐708 directly targets the 3′UTR of the disabled 2 (Dab2) gene and inhibits the expression of DAB2. Interestingly, miR‐708‐caused DAB2 downregulation blocks the aberrant mammalian target of rapamycin complex 1 (mTORC1) activation, a driving metabolic event for senescence progression, and restores the impaired autophagy, a downstream event of aberrant mTORC1 activation. We also found that AMP‐activated protein kinase (AMPK) activation can upregulate miR‐708 via the elevation of DICER expression, and miR‐708 inhibitor is able to blunt the antiaging effect of AMPK. In summary, this study characterized miR‐708 as an aging‐suppressive SA‐miRNA for the first time and uncovered a new signaling cascade, in which miR‐708 links the DAB2/mTOR axis and AMPK/DICER axis together. These findings not only demonstrate the potential role of miR‐708 in aging regulation, but also expand the signaling network connecting AMPK and mTORC1. Schematic depicting the AMPK prevents senescence via miR‐708‐mediated signaling cascade. Oxidative stress decreases the expression of miR‐708, but AMPK activation promotes miR‐708 maturation in a DICER‐dependent manner. miR‐708 directly targets the Dab2 3′‐UTR to reduce DAB2 expression and mTORC1 activity and autophagy inhibition, ultimately suppresses cellular senescence and mouse aging.