Colon Aging / Cancer? Due To Low NAD / High Serotonin; Niacinamide Reverses Both

Wagner83

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Thanks. I read some of the studies on the A1-->beta-casomorphin-7-->opioid recepter/histamine/inflammation theory a while ago. I have to get up to date on that issue but at the time I didn't think much of it. Lots of the studies showing the beneficial effects of A2 milk are produced by scientists that are employed by or associated with a company called the A2 milk company in Australia or New Zealand that tried to convince the whole world of the benefits of their product with a huge marketing campaign. I also asked Ray about it and his reply was that he didn't believe any of the major claims made about A1 and A2.
Ray has been drowning in milk for decades and thinks eating starch will cause brain damage. Travis acknowledged that different people could handle these effects better, and he doesn't consume any dairy on a regular basis now. If Ray feels like he has been doing fine with A1 (or A2) milk then even less reason to believe there are issues with it, also he often says the overall effect of the food is what matters, and if you don't eat starch it is hard to avoid dairy. If you look into the studies let us know what you think, dairy always had bad effects on me so Travis or no Travis I have reasons to test its absence from my diet.
 
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goodandevil

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Peat has said many times that the impaired bowel regularity that occurs in aging, hypothyroidism and various pathologies is due to high NO and serotonin. He also said that while serotonin inhibits motility in the colon it increases it in the small intestine. Most doctors do not agree with that view simply because they are being taught in medical school that serotonin increases motility in any portion of the GI tract. As a result of that mistaken dogma a number of serotonin agonist drugs were brought to market with the goal of improving bowel transit and GI health. The most famous of these disasters is Zelnorm (tegaserod), a 5-HT4 agonist that was withdrawn from the market due to its horrible effects (side or primary) and several deaths that were directly attributed to it.
Tegaserod - Wikipedia

The reason I am bringing up Zelnorm is that the study below presents evidence that a 5-HT4 agonist is perhaps the worst drug that can be given for constipation as it is expected to directly age the colon. According to the study below, the aging colon is characterized by reduced bowel movement and output, high TPH expression, high 5-HT4 expression and high serotonin levels, low SERT expression, and finally low NAD/NADH ratio. The constipation is perhaps the most indisputable finding and is ubiquitous in most people over the age of 35. Perhaps the most troubling finding was that the aging colon exhibited signs of hyperplasia and pre-cancerous lesions - without the presence of any mutations. I think this is direct evidence that at least colon cancer is a metabolic issue and not a genetically driven. The good news is that administration of nicotinamide mononucleotide (NMN) reversed the colon aging (and pre-cancerous lesions) completely. Since the study did not mention the NMN dose used or any effect of NMN on serotonin or TPH, I contacted the authors of the study asking about that. Below is my exchange with one of the study authors:

"Me: May I ask what was the dose of NMN used in the study and why you did not use niacinamide, considering it is much cheaper and is just as effective as a precursor to NAD as NMN?"
"Xudong: Sorry that we omitted the information regarding the dosage and we used 500 mg/kg/day for β-NMN administration. We did not use nicotinamide as the NAD+ precursor because it also functions as sirtuin inhibitor (PMID: 12297502, 18987186). Therefore, we prefer to use a direct upstream precursor, β-NMN, rather than nicotinamide/NR, to exclude the potential influence on our colon-aging study. I hope this would answer your questions."
"Me: Thank you, much appreciated! Two last questions - is the dose of 500mg/kg of bodyweight or diet? Did the administration of b-NMN change the serotonin levels or any biomarkers related to its synthesis (e.g. TPH expression, 5-HIAA, etc)?"
"Xudong: The dosage is 500mg per kg body weight per day. Regarding Q2, we actually did some tests on 5-HT release and tph, sert expression upon bNMN treatment in old colons, however the data showed no significant differences between the old colon+/-bNMN, except for a lowered tph2 mRNA level in bNMN-treated colons. Since we could not link these data to phenotypic elucidation, they were not included in the paper."
"Me: Great, thanks! How big was the drop in TPH-2 mRNA, and was it statistically significant?"
"Xudong: Nearly 1.4-fold drop and it was significant (P=0.025)."

So, NMN (and by extension niacinamide) reverses the aging of the colon, AND lowers peripheral serotonin synthesis. The latter effect is likely to benefit not only digestion but also weight loss and diabetes, as inhibitors of TPH2 are now in stage III (i.e. positive results so far) clinical trials for treating obesity and diabetes II. The dose used in the study was high (HED 35 mg/kg) but I think a lower dose taken over a longer period of time would work just as well. Maybe people on the forum that have decreased bowel movement can try a higher dose niacinamide (even for just 2-3 days)??

Nicotinamide adenine dinucleotide replenishment rescues colon degeneration in aged mice
"...The daily faecal output was significantly less in STC-treated groups in comparison to young groups, with an augmented reduction (old: 35.4% versus young: 29.6%) in old group upon Lomotil treatment (Figure 1b). To evaluate whether these amplified defecation difficulty in STC old mice links to age-related colon degeneration, we next examined histological changes between young and old colons. 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 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 (Figures 1g and h). Taken together, these data implicate that the defecation difficulty in the aged mice may stem from the degenerative colonic phenotypes."

"...We next investigated the molecular mechanism linking defecation difficulty with age-associated colonic degeneration. Given serotonin signalling pathway plays a crucial role in regulating gut motility and defecation,9,12 we examined the serotonin release and downstream signalling in young and aged mice. Transcriptional expression of tryptophan hydroxylase 1 (Tph1), the predominant serotonin synthesis enzyme, together with Tph2, were upregulated, while serotonin reuptake transporter Slc6a4 (Sert) was downregulated in old colon in comparison to young colon (Figure 2a). Consistent with upregulated Tph expression, a higher serotonin level (Figure 2b) in parallel with enhanced type IV serotonin receptor (SR4) expression (Figure 2c) were seen in old colons. These results were further confirmed by immunoblotting analysis (Figure 2d), suggesting that the Tph-5-HT-SR4 signalling axis is activated in aged colon."

"...Since several lines of evidence demonstrate that oxidized form of NAD+ or NAD+/NADH ratio is reduced in various age-related pathologies as well as during ageing process,45,46 we next assessed the major NAD+-generating enzyme expression in the salvage pathway to test whether a reduction in these enzymes accounts for the degeneration in the aged colon. Remarkably, transcription of nicotinamide mononucleotide adenylyltransferase 1, 2 and 3 (Nmnat1, 2 and 3), Nampt as well as nicotinamide riboside kinase 1 and 2 (Nmrk1 and 2) 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. To further explore the correlation between NAD+ level and colonic function, we administered the Nampt inhibitor GMX1778 to 2-month-old young mice intraperitoneally twice daily for 4 weeks. Injection of GMX1778 to young mice led to an ageing colon phenotype, including thinning of colonic muscle layer and villus atrophy (Figure 3d), with concurrent reductions in NAD content and faecal output (Figures 3e and f). In contrast, 3-month continuous administration of β-NMN, an NAD+ precursor, restored colonic NAD+ level to that of young mice (Figure 4a) and improved colon function. 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 (Figure 4e). Taken together, these data indicate that NAD+ may serve as a regulator in colon homoeostasis during ageing and repletion of NAD+ is able to improve colon function."
Thanks, this was very interesting. I wasn't aware of the biphasic nature of serotonin in gi tract. I was listening to him recently talk about how digestive nervers, presumabky splanchnic nerve, are difficukt to recover once damaged, so correcring serotonin early aids their survival.
 

Kartoffel

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Ray has been drowning in milk for decades and thinks eating starch will cause brain damage. Travis acknowledged that different people could handle these effects better, and he doesn't consume any dairy on a regular basis now. If Ray feels like he has been doing fine with A1 (or A2) milk then even less reason to believe there are issues with it, also he often says the overall effect of the food is what matters, and if you don't eat starch it is hard to avoid dairy. If you look into the studies let us know what you think, dairy always had bad effects on me so Travis or no Travis I have reasons to test its absence from my diet.

Many people have problems with dairy. I personally can eat as much homemade cottage cheese and drink as much ultra-pasteurized milk as I want without any issues, but if I drink normal pasteurized milk or eat cheese from a store, it upsets my digestion. I just wanted to point out that I don't believe that the kind of casein is the problem.
Have you tried drinking A2 milk or goat milk over a longer period and felt a significant difference?
 

Wagner83

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It's still mucogenic and promote sinusitis. It is possible that dropping starch may be needed for some to make dairy work, Westside mentioned n this happened in a few people. I tried that, found a good jersey cow milk, dropped most starch besides one meal with some potatoes or rice, I thought I was doing good well for a couple of weeks but actually BM weren't ideal (it was a while ago, I don't remember all the details tbh). Then I started getting bad issues. I wasn't eating low-fat and ate cow cheese too, which probably didn't help with digestion. Recently I have had very high days with good environment, no dairy and no wheat for a while. Like I said in the thread I used by and 2 expresso shots. However either I am very sensitive to changes in my diet (wrong fibers, resistant starch in the form of cooked and cooled potatoes or rice) or pushing myself to feel high is not sustainable (induce deficiencies). The former may very well play a part since, despite what Westside said about RS, I get a lot of farts from cooked and cooled potatoes, BM are less frequent too (this should be confirmed soon), the latter doesn't sound far fetched.
I tried quite a bit of goat cheese a couple of months ago and the results weren't good. This was with quality grass/herbs fed goats. As an aside, one of my close family member who lived on to be a century old could not tolerate the sight or smell of dairy.
 
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Wagner83

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@haidut

When I used niacinamide in high doses 1000mg+ it completely cured any digestive issues- like I was eating pints of ice cream with zero digestive issues, which I could never do even with betaine HCL and digestive enzymes. Do you think niacinamide is working on digestive problems soley from the serotonin inverse agonist aspect in the gut (increasing metabolism greatly) or from it's strong anti fungal/bacterial properties from an underling issues that is causing a slow down in digestion?

I'm pretty fine now I'm on my regimen- but I want to add niacinamide back in with the combo of caffeine. I stopped it due to feeling sedated on it. I just liked the fact from niacinamide that it literally keeps any water retention any digestive stress to virtually zero, I feel my metabolism is in overdrive, which is awesome- also put my libido in overdrive along with heavy sleep (which could be good or bad).
 
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DaveFoster

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"Zelnorm" sounds like a comic book villain hellbent on mankind's destruction, so we should all be concerned.
 

tomisonbottom

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The dose used in the study was high (HED 35 mg/kg) but I think a lower dose taken over a longer period of time would work just as well. Maybe people on the forum that have decreased bowel movement can try a higher dose niacinamide (even for just 2-3 days)??

.......In contrast, 3-month continuous administration of β-NMN, an NAD+ precursor, restored colonic NAD+ level to that of young mice (Figure 4a) and improved colon function.

Taken together, these data indicate that NAD+ may serve as a regulator in colon homoeostasis during aging and repletion of NAD+ is able to improve colon function
."

@haidut Based on what I'm reading they did this for 3 months, so I'm trying to understand........why do you think 2-3 days would do it for a human?
 
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haidut

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@haidut Based on what I'm reading they did this for 3 months, so I'm trying to understand........why do you think 2-3 days would do it for a human?

I didn't say the 2-3 days regimen will reverse colon aging. It was just a suggestion to see if it would help, which would indicate a presence of high serotonin, and then they can try a lower dose for longer periods.
 

tomisonbottom

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I didn't say the 2-3 days regimen will reverse colon aging. It was just a suggestion to see if it would help, which would indicate a presence of high serotonin, and then they can try a lower dose for longer periods.

oh gotcha, ok, thanks
 

Mauritio

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Very interesting. Can't believe I haven't read this thread before. Bumping so others see it too .
 

youngsinatra

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@haidut

Do you think a concentrated nicotinamide solution (like 5g/L) could be made and used as an enema for colon cancer specifically?
I just had this idea today, but couldn’t find anything on that matter. Do you know if nicotinamide can be absorbed via the rectal route?
 

WonMore

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Thanks, this was very interesting. I wasn't aware of the biphasic nature of serotonin in gi tract. I was listening to him recently talk about how digestive nervers, presumabky splanchnic nerve, are difficukt to recover once damaged, so correcring serotonin early aids their survival.
Do you know where he talks about it?
 

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