...Wnt signalling makes an unexpected contribution to cellular ageing.

Various different mechanisms are thought to have a role in the ageing of cells and tissues (see the Focus on Ageing in this issue), and understanding them could help to produce therapies that delay the onset of age-related diseases. Three papers now show that Wnt signalling makes an unexpected contribution to cellular ageing.

Liu et al. studied the KLOTHO mouse, which carries a single gene mutation that causes multiple aspects of accelerated ageing. The Klotho gene encodes a transmembrane protein with a large extracellular domain that might be secreted, although the targets for this protein that confer anti-ageing activity are unknown. In 10-week-old KLOTHO mice, the number of skin stem cells was reduced compared with wild-type mice, which indicated a loss of regenerative potential and tissue ageing. KLOTHO was found to interact with WNT3 — a morphogen that can regulate stem-cell numbers — and KLOTHO could block Wnt signalling in cultured cells. Liu et al. therefore propose that KLOTHO is an endogenous Wnt antagonist, which was supported by the finding that Wnt signalling is increased in KLOTHO mice.

Credit: BANANASTOCK

So, does increased Wnt signalling account for the ageing phenotype of KLOTHO mice? The effects are complex, as bone density (which decreases with age) was found to be increased in some bones and reduced in others. However, chronic exposure to WNT3a accelerated cellular senescence in cultured cells and in vivo (as measured by the formation of senescence-associated heterochromatin foci (SAHFs) or activation of the senescence-associated DNA-damage response). These findings strongly suggest that increased Wnt signalling inhibits the proliferative potential of cells and contributes to ageing.

In a second study, Brack et al. also showed that increased Wnt signalling is associated with age-dependent changes in skeletal muscle. Exposure of young skeletal muscle tissue (that contained high numbers of stem cells from a myogenic lineage and few fibrogenic cells) to serum from old mice induced the conversion of many myogenic cells to fibroblasts and connective tissue. These changes could be blocked by Wnt inhibitors or by reducing Wnt activity in the serum, suggesting that Wnt was the crucial ageing factor present in serum from old mice. The application of WNT3a directly to skeletal muscle also induced similar changes.

However, a third study demonstrates the need for caution when extrapolating these results from mouse to human cells. Ye et al. studied the onset of cell senescence by examining the formation of SAHFs in primary human cells. Ye et al. found that Wnt signalling was repressed and the activity of glycogen synthase kinase-3β (which switches off Wnt signalling in cells) was increased during the early stages of senescence. Furthermore, exposure to WNT3a delayed the onset of senescence. Ye et al. concluded that repression of Wnt signalling is a trigger for the formation of SAHFs in senescent cells.

The discrepancies in these studies are hard to understand, but may relate to differences between mouse and human cells, the age of the cells used and to differences in the dose and duration of Wnt exposure. Further studies that help to understand how Wnt signalling changes with age in individual tissues might be the key to understanding these important differences.