Decreases in mucosally-evoked tachykinin signaling pathways can explain age-related reductions in murine colonic motility patterns.

Background: Increasing age increases the incidence of chronic constipation and fecal impaction. The contribution of the natural aging process to this phenotype is unclear. This study explored the effects of age on key motility patterns in the murine colon and determined the contribution that altered neurokinin 2 (NK) -mediated signaling made to the aging phenotype.

Methods: Mucosal reflexes, colonic migrating motor complexes (CMMCs) and colonic motility assays were explored in isolated ex vivo colons from 3, 12-14, 18- and 24-months old mice and the NK-mediated response determined. Electrical field stimulation (EFS) or exogenous drug application were used to explore the role of the mucosa in colonic segments.

Key Results: Aging reduced the force of contraction of the distal colon mucosal reflex, the frequency and force of contraction of CMMCs and the NK-mediated component of both motility patterns. Ondansetron, a 5-HT receptor antagonist, blocked a component of both motility patterns in full thickness but not in mucosa-free segments of the distal colon. 5, hydroxytryptamine (5-HT) and EFS-evoked NK-dependent contractions were reduced with increasing age. Smooth muscle sensitivity to 5-HT or neurokinin A (NKA) was not altered with age. In isolated colon motility assays application of NKA decreased transit time in 24-months colon and the NK antagonist GR159897 increased transit times in both 3- and 24-months old colons.

Conclusions And Inferences: Aging impairs key motility patterns in the murine colon. These changes involve a decrease in mucosally-evoked NK-mediated signaling. Targeting NK-mediated signaling may provide a novel approach to treating age-related motility disorders in the lower bowel.