A hazy shade of Wnt

The Wnt signaling pathway, originally discovered in a developmental context, is now known to play a key role in the homeostasis of many tissues; furthermore, its signaling via ß–catenin (one of Wnt’s several receptors) is perturbed in a variety of tumors. Now two complementary papers have demonstrated that Wnt may play a causative role in aging.

The first study focuses on the klotho mouse model, in which a loss-of-function mutation results in accelerated aging. Liu et al. demonstrate that in wildtype mice, Klotho protein binds Wnt in the serum and thereby antagonizes Wnt interactions with its receptors. In the absence of Klotho (i.e., in the klotho-/- mutants), Wnt has free reign and augmented activity. The authors further demonstrate that high Wnt signaling accelerates cellular senescence, a phenomenon increasingly implicated in age-related decline in tissue function. (The identification of the specific receptor involved is left as a future exercise.)

The deleterious consequences of a hyperactive Wnt axis are elaborated by Brack et al., who show that increased Wnt signaling (in this case mediated via the less well-studied receptor Frizzled) is associated with a lineage conversion in myogenic progenitors. As Wnt activity increases during aging, muscle cell progenitors switch from a myogenic (i.e., regenerative) mode to a fibrogenic (i.e., inflammatory) mode; this can be prevented with specific blocking antibodies. It is easy to that the resulting increased fibrogenesis, at the cost of regenerative capacity, could cause muscular weakness and sarcopenia in late life.

Happily, some attention is already being paid to pharmaceutical intervention in Wnt pathways, in the context of seeking antagonists that might be useful in the treatment of cancer (see here and here). These efforts currently focus on the consequences of signaling via ß-catenin, which may or may not be relevant to the findings reported above (in the first paper, events downstream of ß-catenin are used as readouts of Wnt activity, but it’s not clear whether ß-catenin is actually required for the increase in senescence; in the second paper, it’s clear that a distinct receptor, Frizzled, at least plays a significant role). Nonetheless, if drug designers aim high enough in the pathway (i.e., at soluble Wnt, where the Klotho interaction is) they might be able to hit two birds with one stone.