Hypothesis: cell signalling influences age-related risk of colorectal cancer.

We propose that ageing is linked to colonic carcinogenesis through crosstalk between Wnt activity and signalling pathways related to ageing and senescence: progerin, klotho and mTOR. Mutations in the Wnt signalling pathway are responsible for the majority of colorectal cancers (CRCs); however, hyperactivation of Wnt signalling by butyrate, a breakdown product of dietary fibre, induces CRC cell apoptosis. This effect of butyrate may in part explain the protective action of fibre against CRC. Hutchinson-Gilford progeria syndrome is a premature ageing disorder caused by accumulation of the progerin protein; however, healthy individuals also produce progerin in the course of their normal ageing. Progerin activates expression of the Wnt inhibitors HES1 and TLE1. Thus, we hypothesize that with age, the increasing expression of progerin suppresses butyrate-mediated Wnt hyperactivation and apoptosis, leading to increased CRC risk. Wild-type klotho contributes to a significantly increased lifespan; however, Klotho gene variants differ significantly between newborns and elderly. Klotho inhibits basal Wnt signalling activity; thus, the protein may function as a tumour suppressor for CRC. However, similar to progerin, klotho variants associated with lifespan differences may repress butyrate-mediated Wnt hyperactivation, and thus increase the risk of CRC. Finally, mTOR signalling has also been linked to human ageing, and crosstalk between Wnt and mTOR signalling may influence colonic tumourigenesis. Understanding how progerin, klotho and mTOR link ageing with colonic neoplastic development may lead to novel preventive and therapeutic strategies against CRC associated with age.