Susceptibility of gastrointestinal dysmotility increases with age-associated colonic degeneration.A paucity of remedies reversing colonic degeneration per se hinders the fundamental relief of symptoms.Here we discover...Susceptibility of gastrointestinal dysmotility increases with age-associated colonic degeneration.A paucity of remedies reversing colonic degeneration per se hinders the fundamental relief of symptoms.Here we discovered the correlation between colon degeneration and altered nicotinamide adenine dinucleotide(NAD)level in aged mice.Compared to 3-month-old young controls,2-year-old mice showed a spectrum of degenerative colonic phenotypes and exhibited a significant elongated transit time and slowed stool frequency in the context of Lomotil-induced slow-transit constipation.Despite upregulated colonic tryptophan hydroxylases expression,serotonin release and expression of colon-predominant type IV serotonin receptor,reduced viability of interstitial cells of Cajal while enhanced aquaporins(Aqp1,3 and 11)led to a less colonic motility and increased luminal dehydration in aged mice.Notably,this colonic degeneration was accompanied with reduced key NAD^(+)-generating enzyme expression and lowered NAD^(+)/NADH ratio in aged colon.Three-month continuous administration of beta nicotinamide mononucleotide,a NAD^(+)precursor,elevated colonic NAD^(+)level and improved defecation in aged mice.In contrast,pharmacological inhibition of nicotinamide phosphoribosyltransferase,the rate-limiting enzyme for NAD^(+)biosynthesis,induced a reduction in colonic NAD content and impaired gastrointestinal function in young mice.Taken together,these findings suggest the beneficial effect of NAD^(+)in maintaining colonic homoeostasis and reactivating NAD^(+)biosynthesis may represent a promising strategy to counteract age-related gastrointestinal degeneration.展开更多
基金This work was supported by grants from the Natural Science Foundation of Zhejiang province(Y13H030005)to QS,National Natural Science Foundation of China(81400221)Hangzhou Normal University(PF14002004017)to XZ。
文摘Susceptibility of gastrointestinal dysmotility increases with age-associated colonic degeneration.A paucity of remedies reversing colonic degeneration per se hinders the fundamental relief of symptoms.Here we discovered the correlation between colon degeneration and altered nicotinamide adenine dinucleotide(NAD)level in aged mice.Compared to 3-month-old young controls,2-year-old mice showed a spectrum of degenerative colonic phenotypes and exhibited a significant elongated transit time and slowed stool frequency in the context of Lomotil-induced slow-transit constipation.Despite upregulated colonic tryptophan hydroxylases expression,serotonin release and expression of colon-predominant type IV serotonin receptor,reduced viability of interstitial cells of Cajal while enhanced aquaporins(Aqp1,3 and 11)led to a less colonic motility and increased luminal dehydration in aged mice.Notably,this colonic degeneration was accompanied with reduced key NAD^(+)-generating enzyme expression and lowered NAD^(+)/NADH ratio in aged colon.Three-month continuous administration of beta nicotinamide mononucleotide,a NAD^(+)precursor,elevated colonic NAD^(+)level and improved defecation in aged mice.In contrast,pharmacological inhibition of nicotinamide phosphoribosyltransferase,the rate-limiting enzyme for NAD^(+)biosynthesis,induced a reduction in colonic NAD content and impaired gastrointestinal function in young mice.Taken together,these findings suggest the beneficial effect of NAD^(+)in maintaining colonic homoeostasis and reactivating NAD^(+)biosynthesis may represent a promising strategy to counteract age-related gastrointestinal degeneration.
