Slowing Senescence with Wnt

Abstract

The Wnt signaling pathway has key roles in development and generally promotes proliferation of stem cells and inhibits apoptosis. These effects are essentially opposite to the changes that occur in senescent stem cells. Thus, Ye et al . examined whether reduced Wnt signaling might have a role inhibitory in senescence. They monitored the formation of specialized domains of heterochromatin known as senescence-associated heterochromatin foci or SAHF, which are thought to repress transcription of genes that promote proliferation. In human WI38 fibroblasts, expression of Wnt2 mRNA was decreased as cells approached senescence. Formation of SAHF was inhibited when pharmacological inhibitors were used to decrease activity of glycogen synthase kinase 3β (a kinase activated downstream of Wnt). Furthermore, small hybrid RNAs were used to decrease expression of Wnt2 in young fibroblasts, and this promoted formation of SAHF, the authors’ marker of senescence. Accordingly, exposure of cells to a Wnt ligand delayed formation of SAHF and the onset of senescence. The authors note that their findings implicate Wnt as the second extracellular ligand proposed to regulate senescence, along with plasminogen activator inhibitor-1, which appears to promote senescence. X. Ye, B. Zerlanko, A. Kennedy, G. Banumathy, R. Zhang, P. D. Adams, Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. Mol. Cell 27 , 183-196 (2007). [PubMed]