Abstract
There is a general decline in gastrointestinal function in old age including decreased intestinal motility, sensory signaling, and afferent sensitivity. There is also increased prevalence of significant constipation in aged populations. We hypothesized this may be linked to reduced colonic motility and alterations in vagal-gut-brain sensory signaling. Using in vitro preparations from young (3 months) and old (18–24 months) male CD1 mice we report functional age-related differences in colonic motility and jejunal mesenteric afferent firing. Furthermore, we tested the effect of the aminosterol squalamine on colonic motility and jejunal vagal firing rate. Old mice had significantly reduced velocity of colonic migrating motor complexes (MMC) by 27% compared to young mice (p = 0.0161). Intraluminal squalamine increased colonic MMC velocity by 31% in old mice (p = 0.0150), which also had significantly reduced mesenteric afferent single-unit firing rates from the jejunum by 51% (p < 0.0001). The jejunal vagal afferent firing rate was reduced in aged mice by 62% (p = 0.0004). While the time to peak response to squalamine was longer in old mice compared to young mice (18.82 ± 1.37 min vs. 12.95 ± 0.99 min; p = 0.0182), it significantly increased vagal afferent firing rate by 36 and 56% in young and old mice, respectively (p = 0.0006, p = 0.0013). Our results show for the first time that the jejunal vagal afferent firing rate is reduced in aged-mice. They also suggest that there is translational potential for the therapeutic use of squalamine in the treatment of age-related constipation and dysmotility.
Highlights
Old age is associated with increased incidence of chronic constipation, which increases in prevalence with age (Higgins and Johanson, 2004; De Giorgio et al, 2015; Ranson and Saffrey, 2015)
The whole length of the colon was excised and the colonic migrating motor complexes (MMC) were video recorded in our gut motility apparatus during Krebs luminal perfusion for later measurements of MMC velocity, frequency and amplitude
Mean MMC amplitude in old mice was 0.601 ± 0.062 cm, 4.4% smaller than for young mice, 0.628 ± 0.116 cm (p = 0.8356) (Figure 1C). Based on these findings there was a reduction in contractility with age in the colon, with the greatest effect being a reduction in MMC velocity
Summary
Old age is associated with increased incidence of chronic constipation, which increases in prevalence with age (Higgins and Johanson, 2004; De Giorgio et al, 2015; Ranson and Saffrey, 2015). Old animals show delayed gastric emptying, slowed colonic transit and reduced fecal output (Smits and Lefebvre, 1996). Whether age-related changes in intestinal propulsion are due to alterations of smooth muscle function or cells that coordinate or pace contractions such as neurons or interstitial cells of Cajal (ICC), is unclear (Saffrey, 2014). Generation and propagation of colonic migrating motor complexes (CMMCs) in mice are generated by activity of the ENS (Fida et al, 1997; Roberts et al, 2007; Spencer et al, 2018), recorded in vitro (Wang et al, 2010a,b; Wu et al, 2013) and are absent if the ENS is missing or destroyed as in Hirschsprung’s or Chagas’ diseases Neurogenic migrating motor complexes still occur in mutant mice lacking pacemaker-type ICC and slow waves in the small intestine (Spencer et al, 2003)
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