Nicotinamide adenine dinucleotide replenishment rescues colon degeneration in aged mice

Abstract

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.

Rhamnan sulphate from green algae Monostroma nitidum improves constipation with gut microbiome alteration in double-blind placebo-controlled trial

“…Moreover, it ameliorates experimental colitis in mice by improving host defence and enhancing bacterial clearance in Citrobacter rodentium -induced colitis 36 and Staphylococcus aureus infection in mice 37 , 38 . Furthermore, NAD replenishment ameliorates constipation in aged mice 39 , suggesting that one of the therapeutic mechanisms of RS is the increase in bacteria related to nicotinamide synthesis and/or secretion. In particular, our functional analysis based on PICRUSt and KEGG Mapper is just a prediction; further studies are necessary to demonstrate our speculation.…”

Tolerance to NADH/NAD+ imbalance anticipates aging and anti-aging interventions

“…NADH has also become a point of interest in gerontobiology. In this context, the augmentation of the NAD + pool resulted in the partial reversal of aging and other related pathological phenotypes across organisms ( Das et al., 2018 ; Mendelsohn and Larrick, 2014 ; Wei et al., 2017 ; Zhu et al., 2017 ), and senescent and neoplastic cells have been found to present imbalances of the NADH/NAD + ratio ( Braidy et al., 2011 ; Schwartz and Passonneau, 1974 ; Wiley et al., 2016 ). Furthermore, the newly discovered roles of NADPH and the emergent concept of NADH/NAD + as a master regulator of redox homeostasis and senescence are all in line with the metabolic stability theory of aging ( Demetrius, 2004 ).…”

NAD+ flux is maintained in aged mice

“…Aged liver exhibits a signi cant decline in mRNA expression of Nmnat1 and trends towards lower expression of Nmnat2 and Nmnat3 (Camacho-Pereira, 2016). Similarly, expression levels of NMNAT isoforms are reduced in the kidneys, oocytes and colons of aged mice (Guan Y, 2017;Wu X, 2019;Zhu X, 2017). These observations suggest the alternative hypothesis that NAD + decline could be driven at least in part by decreased synthesis.…”