Zhu X, Shen W, Wang Y, Jaiswal A, Ju Z, Sheng Q. Nicotinamide adenine dinucleotide replenishment rescues colon degeneration in aged mice. Signal Transduct Target Ther. 2017 Jul 7;2:17017. doi: 10.1038/sigtrans.2017.17. eCollection 2017. PubMed PMID: 29263919; PubMed Central PMCID: PMC5657423.
Compared to 3-month-old young controls, 2-year-old mice showed a spectrum of degenerative colonic phenotypes[.] ... Indeed, a significant reduction in villus number was found in the old colon versus the young colon (Figure 1c). Villus atrophy was seen in both vehicle and STC old mice (Figure 1d), while aged colon exhibited a higher frequency of hyperplasia independent of Lomotil treatment (Figure 1e). Lomotil-induced STC per se did not change the villus number or promote hyperplasia (data not shown). In addition, β-galactosidase (SA-β-gal) assay [a marker of senescent cells] revealed more positive stains in aged colon while almost none in the young colon (Figure 1f), suggesting an increased incidence of age-associated colonic senescence. This was further confirmed by decreased intestinal stem cell marker Lgr5 and increased cell senescence marker cdkn2a (p16) seen in aged colon ...
[Aged mice also] 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. ... Remarkably, transcription of nicotinamide mononucleotide adenylyltransferase 1, 2 and 3 (Nmnat1, 2 and 3) [convert NMN to NAD+], Nampt [converts NAM to NMN], as well as nicotinamide riboside kinase 1 and 2 (Nmrk1 and 2) [ie, the enzymes responsible for converting NR to NMN and thence NAD+] were all downregulated in old colon versus that in young colon (Figure 3a), which was further evidenced as aged colon exhibited a significantly lowered NAD+/NADH ratio (Figure 3b). Interestingly, almost no positive immunofluorescent staining of Nampt was seen in those hyperplastic tissues from aged colon (Figure 3c), suggesting that lowered NAD+ level may correlate with vulnerability of hyperplasia/tumorigenesis. ...
Three-month continuous administration of beta nicotinamide mononucleotide, a NAD+ precursor, elevated colonic NAD+ level and improved defecation in aged mice. [It's not clear to me whether this was "preventive" (initiated at 21 months, in time for the 24 month mark) or 24 month -MR]. ... Specifically, old mice receiving β-NMN favoured an increased colonic c-kit+ population (Figure 4b) and significantly improved faecal output (Figure 4c). In addition, enhanced proliferation was seen in the isolated colon epithelial cells (Figure 4d) as well as proliferating cell nuclear antigen-stained from aged mice receiving β-NMN ... 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.
It's notable that they showed the rising burden of senescent cells and loss of stem cells in aged untreated colon, but don't say anything about either of these things in the aged NMN-treated animals: it would seem odd not to test this effect, and I wonder if they looked and didn't report a non-result — bad practice, but not unheard-of.
Although they only looked at the transcriptional level, it's notable that this is not only annother report of age-related reduction of NAMPT, but the first report AFAIK of lower NMAT and NRK transcription. If this corresponds to lower protein levels and/or activity, the molar efficacy of all NAD+ precursors would be reduced with age, which would contribute to lower NAD+ levels with age in addition to the increased consumption and also potentially be additional reasons why a somewhat higher dose might be required to achieve similar elevations.