Key importance of nucleotides (underlooked dietary factor)

[cs3000]

Cellular repair growth & replication needs nucleotides as building substance, base of DNA/RNA.
Cells salvage their nucleotide needs (we ingest RNA from foods and re-incorporate it), or cells synthesise some of it (as purines and pyrimidines)

Cells must acquire sufficient levels of each nucleotide species both for RNA synthesis and biomass production, and to ensure efficient and accurate DNA replication during S phase. Obtaining nucleotides for efficient RNA and DNA synthesis can be particularly limiting for cell proliferation

Benjamin Frank, one of the early pioneers who used dietary nucleotides for health
talking about ingesting nucleotides and importance of mitochondria / ATP (core of rays approach to health) in the 1970s
4 minutes in

View: https://www.youtube.com/watch?v=myD7ED6QAxQ#t=4m15s

^ Along with the clinical health improvements he talked about feeling warmth & ability to tolerate cold from dietary RNA,
confirmed in mice study last year, where adding adenosine in diet improved metabolic rate, heat production, body composition https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250134/
(Think human dose comes to ~750mg -1g? will double check)

Temperature differences in center pic.
Interestingly less fat more muscle on slightly higher food intake too (higher metabolic rate)

In conclusion, dietary AMP supplementation increases the food intake and reduces the body fat content of mice without affecting body weight and organs index. In addition, AMP reduces adipose content and increases lean meat content by promoting BAT activation and thermogenesis without affecting body weight.
Meanwhile, AMP treatment also significantly increased the energy metabolism of mice, especially the basic energy expenditure.

Benjamin frank mentioned using 1g in his clinical practice to help parkinsons patients in that video

ATP = Adenosine Triphosphate

Some parts of the body rely way more on dietary intake of nucleotides than others,
especially rapidly replicating ones as the endogenous synthesis alone cant keep up with the high demand.
Ongoing boost from diet especially needed for small intestine cells, immune cells, some brain cells, and i think liver cells.

E.g if you feed someone on low protein diet through the stomach and their immune system crashes, restoring protein doesnt help recover it enough if the diet doesnt contain nucleotides. only nucleotides fully restore the immune system because immune cells rely on the dietary boost.

Although the intestine can synthesize NT from amino acids and other precursors and are thus not [labelled] essential nutrients, NT synthesis appears to be limited and dependent on an exogenous supply of NT
Because the de novo synthesis is metabolically costly, a dietary source of NT may optimize the function of rapidly dividing tissues like the intestine, especially during periods of food deprivation or stress.​

- uridine (UMP) - cytidine
- Adenosine (AMP) - inosine
- Adenine - thymidine
- guanosine - guanine
- hypoxanthine - xanthine

nice writeup of nucleotides here Chapter 1 | Feel Good Nucleotides

Highest sources are animal meats (primarily hearts & sardines), and brewers yeast (typically ~8% RNA. i think highest nucleotide is adenosine in this) (and uridine/inosine supps)
Theres a study showing +2g a day in humans was safe for uric acid levels (gout potential), but 2.9g tipped over to too much

Some suggestion its best to get a mix instead of supplementing only 1 single nucleotide, as in vitro cells can still grow with this but fail to replicate (the single nucleotide signals endogenous production to stop, so imbalance = cell stops replication). unless specifically trying to stop proliferation maybe. But probably doesnt work the same in vivo at regular doses (have seen wound healing accelerates on only uridine for example, feeding solely adenosine didnt seem to be a problem in mice study with their muscle gain) Nucleotide imbalance decouples cell growth from cell proliferation

will add some more studies

 

[Peater]

Interesting, a thyroid supplement I bought contains nucleotides. I wasn't sure if it was just marketing .

 

[cs3000]

Deprivation of dietary nucleotides decreases protein synthesis in the liver and small intestine in rats https://www.sciencedirect.com/science/article/abs/pii/S0016508596002648

2 big endogenous requirements for synthesis = folate, and glucose

Dietary nucleotides accelerate intestinal recovery after food deprivation in old rats - PubMed

Previous studies in very young rats have shown that dietary nucleotides improve small intestine repair after injury or malnutrition.
Food deprivation significantly decreased mucosal growth markers as well as differentiation markers in both jejunum and ileum. The ATP pool was also significantly depressed, but the adenylate energy charge was not significantly altered.
To a certain extent, refeeding restored the losses, but in the rats that were fed the nucleotide-free diet, the restoration of the jejunum was significantly slower and the restoration of the ileum differentiation markers was incomplete compared with the rats fed the nucleotide-supplemented diet. The results suggest that dietary nucleotide intake in the elderly may accelerate the normal physiological intestinal response to refeeding after food deprivation.

* dietary nucleotides have been shown to influence essential fatty acid conversion to their main long chain derivatives
* nucleotides, mainly inosine, increase dietary bioavailability of iron.
* dietary purine and pyrimidine derivatives influence the lymphoproliferative response
* given intravenously have been shown to improve liver regeneration
* de novo purine nucleotide synthesis may not be enough to support an increased need for nucleic acids induced by accelerated growth such as that occurring after intestinal injury. it has also been reported that the small intestine has a limited capacity to synthesis nucleotides by the de novo pathway

* A rapid normalisation of the mitochondria ultrastructure was seen .. as mitochondria DNA is independant from nuclear DNA we hypothesised that dietary nucleotides might serve as preformed precursors for mitochondrial DNA thus enhancing rapid normalisation of intestine structure and function
** nucleotides = precursors for mitochondrial DNA
Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok -/- zebrafish - PubMed increased mitochondrial dna in fish (when both purine nucleosides supplemented, didnt work with only 1

dguok-/- fish have significantly reduced mtDNA levels compared with wild-type (wt) fish. When supplemented with only one purine nucleoside (dGuo), mtDNA copy number in both mutant and wt juvenile animals was significantly reduced, contrasting with previous cell culture studies, possibly because of nucleotide pool imbalance.

However, in adult dguok-/- fish we detected a significant increase in liver mtDNA copy number when supplemented with both purine nucleosides. This study further supports the idea that nucleoside supplementation has a potential therapeutic benefit in mtDNA depletion syndromes by substrate enhancement of the purine nucleoside salvage pathway and might improve the liver pathology in patients.

The role of nucleotides in adult nutrition - PubMed immunity
Dietary RNA is required to restore lost immune function after protein deprivation. Adequate calories and protein alone do not return immune function to normal. <----
protein deficiency role in immunity is for synthesising nucleotides for rapid turnover cells like intestinal cells & lymphocytes,
restoring protein to normal doesnt work if lacking nucleotides with it , so not main source , need in diet to boost
* Dietary nucleotides can restore lost immune function even during protein starvation and weight loss.

Dietary nucleotides, a requirement for helper/inducer T lymphocytes - PubMed 0.25% RNA fed mice restored immune function to normal (>1g?)
Effect of dietary nucleotides on response to bacterial infections - PubMed bacterial infection, 100% mortality in nucleotide free diet vs 56% in 0.25% RNA fed group
say 5 grams feed intake, 25g-30g body weight
200g feed intake per kg, 500mg/kg mice
human equiv ~2.5g
* 2.5g nucleotides restored immunity in low protein intake / starvation

indomethacin induced ileitis, 56% reduction in ulcer number + 67 in size, in yeast RNA receiving by day 8
https://www.proquest.com/openview/876435100156a123676533abb0b710d2/1?pq-origsite=gscholar
(but used pre-emptively in another model gave more damaging effect , maybe due to increased immune cells which start the damage)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5317309/ neuralgia nerve pain improved with nucleotides and b12
Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor - Cell Discovery uridine to mice , 200 microl of 4mg/ml uridine so 800mcg uridine i.p ,
say 30g mouse = ~30mg/kg = 150mg human dose *every other day,
so 75mg a day , Increased tissue repair , heart repair after heart attack *

Uridine treatment also appears to have a beneficial role in mitochondrial activity, as we found augmented gene expression associated with “mitochondrial central dogma”, “mtDNA maintenance”, and “mitochondrial gene expression” in uridine-treated hMSCs
Here, through the cross-species metabolomics analysis and metabolites screening, we identified endogenous metabolite uridine as a potent regeneration promoting factor. Uridine was identified to be more abundant in tissues or cells with higher regenerative potential. In particular, the concentration of uridine decreased in the plasma from aged individuals, suggesting uridine may navigate a delicate balance between aging and regeneration.

uridine supplementation rejuvenated senescent stem cells, promoted the regeneration and repair of multiple mammalian tissues, and improved the fitness of aged mice

human study using 417mg yeast rna (from the 3x 500mg caps) showed slight improvements in IBS symptoms but not much .
+6% improvement for abdominal pain over controls, +4% diarrhoea improvement, +7% fuller evacuations, prevented worsening constipation but no improvement.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1513247/

possibly needed 1g+ for full effect (or small intestine effect better than people with more colon based)

https://onlinelibrary.wiley.com/doi/abs/10.1002/j.1536-4801.1983.tb08502.x ** Small intestine has limited capacity to synthesise the RNA / nucleotides / purines it needs to facilitate proliferation - usually inactive it kicks in when diet devoid of purines - BUT still lower capability than colon

Uridine Treatment of the First Known Case of SLC25A36 Deficiency uridine used to treat rare deficiency characterized by hypothyroidism high insulin high ammonia constipation and language issues - key for mitochondria biogenesis , uridine improved

SLC25A36 is a pyrimidine nucleotide carrier playing an important role in maintaining mitochondrial biogenesis. Deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction. In human beings, diseases triggered by SLC25A36 mutations have not been described yet. We report the first known case of SLC25A36 deficiency in a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. Whole exome analysis identified the homozygous mutation c.803dupT, p.Ser269llefs*35 in the SLC25A36 gene. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with oral uridine led to an improvement of thyroid function and obstipation, increase of growth and developmental progress. Our findings suggest an important role of SLC25A36 in hormonal regulations and oral uridine as a safe and effective treatment.

Comparative study of cardioprotective effects of uridine-5′-monophosphate and uridine-5′-triphosphate during the early periods of acute myocardial ischemia - Bulletin of Experimental Biology and Medicine
worked better and faster than triphosphate for heart blockage (pre-heart attack , heart attack if rupture occurs) ***

 

[cs3000]

Apparently the earliest published life extending experiments using nutrition used yeast RNA

The Effect of Yeast Nucleic Acid on the Survival Time of 600 Day Old Albino Mice

Abstract. The investigation of the effect of nutritional factors on the process of aging has only recently been given attention. In this paper, Dr. Gardner repo

academic.oup.com

 

[cs3000]

https://archive.org/details/nucleicacidthera0000fran/page/34/mode/2up?view=theater

72mg/L nucleotides in infant formula was a good dose to boost antibodies against diphtheria, influenzae in humans (& polio in breast fed)

Modulation of the immune system by human milk and infant formula containing nucleotides - PubMed

Infant formula fortified with nucleotides enhanced H influenzae type b and diphtheria humoral antibody responses. Feeding human milk enhanced antibody responses to OPV. Dietary factors play a role in the antibody response of infants to immunization.

pubmed.ncbi.nlm.nih.gov

up to 1 year of age so say at 6 months, ~8kg bodyweight , 1L milk intake

= ~600mg is effective adult nucleotide/RNA intake for immunity effect. i think pig / chicken heart gives ~200mg-400mg per 100g

 

[cs3000]

standard meat (steak / chicken breast) also good sources not just the organ meats apparently

https://eprints.lancs.ac.uk/id/eprint/174707/1/2015longdenmsc.pdf

(assuming "portion" = 100g)

[Effects of exogenous nucleotides on the proliferation and migration of intestinal epithelial cells] - PubMed uridine UMP, can remarkably abolish the proliferation-inhibiting effects of AMP or GMP on the cell, when AMP or GMP is supplemented. It is concluded that purine nucleotides inhibits proliferation of IEC-6. Pyrimidine nucleotides can abolish the inhibitive effects of purine nucleotides, and Nucleotides mixture promotes migration of IEC-6 after wounded by a TGF beta-independented way. [in vitro]

The degradation of nucleic acids in, and the removal ofbreakdown products from the small intestines of steers
Of the different substances infused into the small intestine, free nucleic acids were removed to extentsgreater than 97 %, adenine, guanine and uracil had completely disappeared, thymine and xanthine toapproximately 80 % and 95 % and hypoxanthine and cytosine to only 51 % and 48 % respectively

Our results show that the highest level of PNP, GDA, and XDH is present in the proximal small intestine. .. Thus, ADA is part of a purine catabolic pathway leading to the production of uric acid that is present at the highest known level in the proximal small intestine

Dietary nucleotides extend the life span in Sprague-Dawley rats - PubMed

1/2 tumor development in the nucleotide fed groups. and the smaller doses worked best

lifespan increase +23% +26%, the lower intake (seems very low though?)
increased lifespan in mice with tumors dose dependantly
0.64% diet ~2g - 3g?

The last rat in the control male group died at the age of 871 days (29.0 months), whereas the NTs-treated males at this age survived 23%, 26%, 12% and 8% longer. Under the effect of NTs, the maximal life span was extended by 131, 40, 82 and 118 days... in the 0.01%, 0.04%, 0.16% and 0.64% NTs-treated male rats, respectively

As for the control females, the rat with the maximal life span survived 845 days (28.2 months), whereas 13.46 % of the NTs-treated female rats survived to this age. Specifically, the last rats in the 0.01%, 0.04%, 0.16% and 0.64% NTs-treated female groups died at the ages of 1140, 895, 1040, and 929 days, with increases of 295, 50, 195 and 40 days (9.83, 1.67, 6.50 and 2.80 months, respectively) compared with the maximal life span of female controls.

The overall mean life spans of tumor-bearing animals were 746±16.3 days for males and 702±17.3 days for females. It should be noted that the tumor-free animals had a much shorter life span (694±17.5 days for males and 627±16.5 days for females) compared with the tumor- bearing animals. NTs significantly extended the life spans of tumor-bearing animals of both sexes (Fig. 3). The mean life spans of tumor-bearing rats treated with NTs were dose-dependently prolonged compared with the controls, with significance in the 0.01%, 0.04% and 0.64% NT-treated group of both sexes

[causes of death, interestingly 11 & 12 in the control group died of intestinal blockage. 0 in all nucleotide intake groups. but more overall spontaneous deaths in for the increased lifespan]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5475326/

improved exercise performance & mitochondria activity in muscle