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

haidut

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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 The most famous of these disasters is Zelnorm (tegaserod), a 5-HT4 agonist that was withdrawn from the market due to its horrible effects (side or primary) and several deaths that were directly attributed to it.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."
 

Fisherman94

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I doubt Serotonin will be high in cancer.
I think its more likely that IDO and kynurenire is high and there is no tryptophane for Serotonin, melatonin.
 

High_Prob

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I doubt Serotonin will be high in cancer.
I think its more likely that IDO and kynurenire is high and there is no tryptophane for Serotonin, melatonin.

It's good that you brought this up, I don't believe there is much discussion about the Kynurenine Pathway on this forum...
 

Kartoffel

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I doubt Serotonin will be high in cancer.
I think its more likely that IDO and kynurenire is high and there is no tryptophane for Serotonin, melatonin.

There are several types of tumors for which serum serotonin levels seem to be a very accurate prognosis.

Curr Mol Med. 2015;15(1):62-77.
Serotonin and cancer: what is the link?
Sarrouilhe D, Clarhaut J, Defamie N, Mesnil M1.
Author information
Abstract

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine that acts as a neurotransmitter in the central nervous system, local mediator in the gut and vasoactive agent in the blood. Serotonin exerts its multiple, sometimes opposing actions through interaction with a multiplicity of receptors coupled to various signalling pathways. In addition to its well-known functions, serotonin has been shown to be a mitogenic factor for a wide range of normal and tumoral cells. Serotonin exhibits a growth stimulatory effect in aggressive cancers and carcinoids more often through 5- HT1 and 5-HT2 receptors. In contrast, low doses of serotonin can inhibit tumour growth via the decrease of blood supply to the tumour, suggesting that the role of serotonin on tumour growth is concentration-dependent. Data are also available on serotonin involvement in cancer cell migration, metastatic processes and as a mediator of angiogenesis. Moreover, the progression of some tumours is accompanied by a dysregulation of the pattern of serotonin receptor expressions. Serum serotonin level was found to be suitable for prognosis evaluation of urothelial carcinoma in the urinary bladder, adenocarcinoma of the prostate and renal cell carcinoma. In some cases, antagonists of serotonin receptors, inhibitors of selective serotonin transporter and of serotonin synthesis have been successfully used to prevent cancer cell growth. This review revaluates serotonin involvement in several types of cancer and at different stages of their progression.
 

lampofred

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How do you convert 500 mg/kg for mice into the equivalent dose for humans?
 

Wagner83

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Maybe people on the forum that have decreased bowel movement can try a higher dose niacinamide (even for just 2-3 days)??
Following the order of the authoritative Amamaniac, I started 30 mg niacinamide with each meal (but will stop using it for dinner) , unfortunately it happens that I also stopped all dairy besides butter and wheat. Travis made a good case for the former slowing down digestion significantly, particularly A1 cow dairy products, while he admires the latter as much as he dislikes fermented mangoes. Anyways with a more stimulating environment, the changes in diet, the low dose niacinamide, an expresso shot after lunch and breakfast I had several bouts of my best days ever, but followed by a few shorter relapses. As you would expect, bowel movements increased to, I'd say 2.5 a day. Right now it has slowed down again so go figure, I have a few guesses in mind. Outside the bowel movement world, it seems to be a really nice dose for clearing fatty - acids and increasing carbs tolerance.

PS: Why the hell can't I tolerate any MB? I can see some of its benefits but always end up feeling tensed and with heavy limbs (blood pressure?). I even tried very low doses but it's still the same. I know it lowers NO potently but I won't take NO for an answer.
 
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Kartoffel

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Following the order of the authoritative Amamaniac, I started 30 mg niacinamide with each meal (but will stop using it for dinner) , unfortunately it happens that I also stopped all dairy besides butter and wheat. Travis made a good case for the former slowing down digestion significantly, particularly A1 cow dairy products, while he admires the latter as much as he dislikes fermented mangoes. .

Could you point me to the post/thread where he makes the good case against dairy?
 

Wagner83

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@Wagner83 Have you considered goat milk that travis often talks about positively, or A2 milk? How are you getting calcium?
I did try it before, it did seem to be androgenic and better than cow dairy for sure, a few times my voice got deeper/resonated more on it, I felt great. However dairy in general tends to be mucogenic and source of sinusitis. Last time I went to run my breathing was already better. I love the taste of feta cheese and mozzarella di buffala, I think feta cheese may be the okayest of cheese, along with some of the fresh soft goat cheese (but then depending on what they eat, allergenic herbs or not, it can be worse).
 

raypeatclips

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I did try it before, it did seem to be androgenic and better than cow dairy for sure, a few times my voice got deeper/resonated more on it, I felt great. However dairy in general tends to be mucogenic and source of sinusitis. Last time I went to run my breathing was already better. I love the taste of feta cheese and mozzarella di buffala, I think feta cheese may be the okayest of cheese, along with some of the fresh soft goat cheese (but then depending on what they eat, allergenic herbs or not, it can be worse).

Interesting. I need to give goats milk more of a try. Is that allergenic weeds thing something you have experienced or referencing that Peat quote?
 

Wagner83

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Interesting. I need to give goats milk more of a try. Is that allergenic weeds thing something you have experienced or referencing that Peat quote?
I have noticed more issues from certain goat cottage cheese and less from others. It could have been that I was consuming too much dairy overall when the bad effects happened. It can be tempting to see dairy products entirely fed on herbsFor calcium I'm not sure, I do my own orange juice with each meal (most of the time) and do dark leafy greens broth, cost is limiting me though, I prefer kale over spinach.
 

raypeatclips

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I have noticed more issues from certain goat cottage cheese and less from others. It could have been that I was consuming too much dairy overall when the bad effects happened. It can be tempting to see dairy products entirely fed on herbsFor calcium I'm not sure, I do my own orange juice with each meal (most of the time) and do dark leafy greens broth, cost is limiting me though, I prefer kale over spinach.

What issues did you notice, just the mucus and sinus ones you mentioned before? Kale wrecks my gut :(
 

Wagner83

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What issues did you notice, just the mucus and sinus ones you mentioned before? Kale wrecks my gut :(
I don't like most fibers, I just drink the broth. Fibers affect me negatively, fruits fibers too. With kale I fart instantly, it's a miracle. The effects on mucus and sinus are always present, but sometimes I'd get more brain fog or feel like ***t overall as an added bonus.
 

Kartoffel

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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.
 
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