MYCN/LIN28B/Let-7/HMGA2 pathway implicated by meta-analysis of GWAS in suppression of post-natal proliferation thereby potentially contributing to aging.

Mammalian organ and body growth slows and finally terminates because of a progressive suppression of cell proliferation, however little is known about the genetic regulatory mechanisms responsible. A meta-analysis of genome-wide association studies using growth and development-related traits revealed that two genes, HMGA2 and LIN28B, had multiple associations. Altered HMGA2 expression has been shown to result in both overgrowth and pygmy phenotypes in mice and overgrowth in humans. These genes are members of the MYCN/LIN28B/Let-7/HMGA2 pathway and homologs of LIN28B and let-7 are known to regulate developmental timing in Caenorhabditis elegans. Strikingly, expression levels of let-7 and Hmga2 in murine stem cells continue to increase and decrease, respectively, after growth terminates, suggesting that this pathway may contribute to regulating the pace of both development and age-related degenerative phenotypes.