Uridine is a nutrient that is largely unknown as a dietary supplement and yet, paradoxically, has a well-established place in nutrition. Indeed, uridine is one of the reasons that fish is known as “brain food” and brewer’s yeast is recognized for its health benefits. These and a number of other foods supply significant amounts of ribonucleic acid (RNA). Uridine, along with adenosine, guanosine, and cytidine, is one of the four components that comprise RNA. When RNA-rich foods are consumed, the RNA is broken down and releases its basic elements for absorption from the small intestine.

The benefits of uridine are wide-ranging. For instance, it is a precursor of brain synapses and nerve cell membrane phospholipids. It acts for these purposes in conjunction with the omega-3 fatty acid docosahexaenoic acid (DHA) and choline sources. It may enhance brain cholinergic functions. Furthermore, under a number of conditions, uridine also supports the health and function of the liver and the mitochondria. Here is a short list of these and other areas being researched:

  • Brain energy utilization
  • Dopamine production and use
  • Synaptic function (i.e., nerve function)
  • Role as a nerve growth factor leading to neurite outgrowth
  • Interactions with choline, CDP-choline, DHA and perhaps other nutrients
  • Endurance sports
  • A role in pain physiology
  • Liver function
  • Regulation of certain forms of localized fat loss

Brain Energy Utilization
Studies in human and animal models suggest that uridine may exert bioenergetic effects, such as increasing brain levels of the energy molecule adenosine triphosphate (ATP) and enhancing energy production from circulating glucose. In vivo tests have shown that uridine enters the brain, a primary requirement for improving brain energy utilization.1 Likewise, uridine is important in an energy pathway utilized by brain cells to maintain ATP production under restricted oxygen conditions.2

Dopamine Neurotransmitter Production and Release
Bioenergetic defects and inadequacies play significant roles in brain neurochemistry. These defects can arise from a number of causes, including impaired mitochondrial function. These factors can lead to lower levels of the neurotransmitter dopamine in the brain neurons due to lack of synthesis or to inadequate release. In one animal model, administration of uridine in the form of its precursor triacetyluridine (TAU) attenuated the depletion of dopamine in the neurons of the substantia nigra, hence was neuroprotective.3

The foregoing finding is not, strictly speaking, a substrate issue. Nevertheless, improving substrate availability in some models leads to similar results. Phosphatidylcholine (PC) is required for cellular growth. Its synthesis is controlled by levels of its precursor, cytidine-5’-diphosphate choline (CDP-choline), which is produced from cytidine triphosphate (CTP) and phosphocholine. Exogenous uridine has been shown in vitro to elevate intracellular CDP-choline levels. In aged male Fischer 344 rats, six weeks consumption of uridine supplemented as uridine-5’-monophosphate disodium (UMP) was sufficient to significantly increase potassium-evoked dopamine release. In this instance, supplementation with UMP was adequate both to increase the production of membrane phosphatides, such as PC, and to increase neurotransmitter release.4

Nerve Growth—Neurite Outgrowth
The same model in which UMP induced dopamine release exhibited another interesting finding. Biomarkers of neurite growth were significantly elevated by supplementation with exogenous UMP in the experiment described above. These results were found at six weeks, but not at one week of supplementation. Again, this probably is an indirect effect of uridine via CDP-choline production. In fact, in one experiment supplementation with CDP-choline in early life induced a stable increase in the dendritic complexity of neurons in the somatosensory cortex of adult rats. The absolute number of neuritis did not differ, but there were significant increases in neurite length, branch points and the total area occupied by the neurons.5

Synaptic Function
Synapses are cellular structures that allow chemical and electrical messages to be passed between neurons or nerve cells. Messages must cross what is known as the synaptic cleft and often involve the branching structures on neurons known as dendrites, although other parts of the nerve cell can become involved. The chemical messengers can include dopamine, acetylcholine and other neurochemicals. Uridine may improve the function of synapses in several ways. As mentioned previously, the level of available uridine helps to regulate intracellular CDP-choline and phosphatidylcholine, the latter being a component of dendrite membranes. Greater availability of phosphatidylcholine supports dendritic membrane health and function. The argument here is that supplementation with uridine increases dendrite spines and that this, in turn, is correlated with the number of available synapses.6 A recent trial with humans supplementing with uridine, the omega-3 polyunsaturated fatty acid docosahexaenoic acid and choline for 24 weeks led to support for the underlying hypothesis.7

Sports
A common thread in uridine’s benefits in the brain is greater energy production. Signally, nutritional and exercise-based interventions that have been used with some success to treat medical conditions such as mitochondrial disease include uridine.8 Two nucleotides, cytosine monophosphate (CMP) and uridine monophosphate (UMP) have been used for the treatment of neuromuscular affictions in humans. Success in these conditions indicates that uridine might be useful in the case of exhausting exercise such as endurance sports. This thesis has been tested in an animal model. In exercised rats treated with CMP/UMP, exercise endurance was measured along with various metabolic enzymes. Results showed that rats treated with CMP/UMP were able to endure longer periods of exercise (treadmill-run). Findings include the discovery that prior to exercise, the treated animals had more glucose in the muscles, suggesting that the nutrient combination improved the uptake of glucose into muscle tissue, hence provided more glucose for energy. With exercise, the amount of glycogen in the liver remained stable rather than falling as expected and two markers of liver stress were significantly lower in the treated animals. Researchers concluded that supplementation improved exercise endurance by altering metabolic parameters.9

Liver Function
An area of significant new findings in uridine research is liver health. Uridine for some time has been recognized as playing a role in preserving and even enhancing hepatic mitochondrial function in the face of challenge by certain liver toxins.10 This has been explored in particular with substances that interfere with the replication of mitochondrial DNA (mtDNA). Less researched have been other areas of liver health that might be affected by uridine supplementation.

Recently, it has been demonstrated that there is an intrinsic link between pyrimidine metabolism—which includes nucleotides, such as uridine—and liver lipid accumulation. Liver lipid accumulation is encouraged by obesity and diets high in fructose and a number of other practices typical of modern diets, hence reducing liver lipids is an issue with current resonance. One recent paper examining an animal model proposed that uridine suppresses the accumulation of fat in the liver by modulating the liver protein acetylation profile, meaning, in part, that it alters the activation of enzymes involved in metabolic, oxidation-reduction, and antioxidation actions. This includes influencing the nicotinamide adenine dinucleotide (NAD)/NADH ratio.11 Other research dating back more than a decade supports uridine’s role in liver detoxification and immune homeostasis.12

Food and Other Sources
RNA-rich foods are considered to be good sources of uridine because of the composition of RNA. Although specially (does he mean specialty?) RNA- and uridine-enriched foodstuffs are available; a number of everyday foods are surprisingly rich in uridine, as indicated in the following (dry weight unless otherwise specified):13

  • Liver (Pig and Beef)—2.12–2.3% for beef and 3.1–3.5% for pig (RNA)
  • Pancreas, the largest source of RNA—6.4–7.8% (pig) and 7.4–10.2% (beef)
  • Fish—0.17–0.47% (RNA), herring having the highest RNA at 1.53%
  • Baker’s Yeast—6.62% RNA
  • Brewer’s Yeast—approximately 3% uridine
  • Mushrooms—Boletus (1.9–2.4% RNA), Champignon (2.05% RNA), and Chestnut (2.1% RNA)
  • Broccoli—2.06% RNA
  • Oats—0.3% RNA
  • Chinese Cabbage, Spinach, and Cauliflower—similar levels at approximately 1.5% RNA
  • Parsley—0.81% RNA
  • Tomatoes—as much as 0.1% uridine

In short, organ meats, fish, yeast, mushrooms and cruciferous vegetables are all relatively rich sources of uridine.

Bioavailability and Nutrient Interactions
Uridine has excellent tolerability in that the maximum tolerated amount without inducing gastrointestinal distress in on the order of 20 to 25 grams for an average sized male, with the maximally tolerated dose in an average-sized adult male being 8.5 grams uridine three times per day.14 Diarrhea is the doselimiting effect. Twenty grams clearly is beyond the normal supplement range, so the next issue is one of bioavailability. Triacetyluridine, the urdine precursor that is reduced to uridine by intestinal and plasma esterases,15 may exhibit as much as 7-fold greater bioavailability.16 There presently is no agreement in the literature as to what constitutes a threshold effective dosage and complex formulations employing as little as 50 mg/day of uridine-5’-monophosphate (disodium salt) have proved beneficial in terms of spatial short term memory, recognition, recall, attention, and executive functions.17

References:

  1. Amante DJ, Kim J, Carreiro ST, Cooper AC, Jones SW, Li T, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K, Ferrante RJ, Rusche J. Uridine ameliorates the pathological phenotype in transgenic G93A-ALS mice. Amyotroph Lateral Scler. 2010 Dec;11(6):520–30.
  2. Balestri F, Giannecchini M, Sgarrella F, Carta MC, Tozzi MG, Camici M. Purine and pyrimidine nucleosides preserve human astrocytoma cell adenylate energy charge under ischemic conditions. Neurochem Int. 2007 Feb;50(3):517–23.
  3. Klivenyi P, Gardian G, Calingasan NY, Yang L, von Borstel R, Saydoff J, Browne SE, Beal MF. Neuroprotective effects of oral administration of triacetyluridine against MPTP neurotoxicity. Neuromolecular Med. 2004;6(2- 3):87–92.
  4. Wang L, Pooler AM, Albrecht MA, Wurtman RJ. Dietary uridine-5’-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. J Mol Neurosci. 2005;27(1):137–45.
  5. Rema V, Bali KK, Ramachandra R, Chugh M, Darokhan Z, Chaudhary R. Cytidine-5-diphosphocholine supplement in early life induces stable increase in dendritic complexity of neurons in the somatosensory cortex of adult rats. Neuroscience. 2008 Aug 13;155(2):556–64. doi
  6. Wurtman RJ, Cansev M, Sakamoto T, Ulus I. Nutritional modifiers of aging brain function: use of uridine and other phosphatide precursors to increase formation of brain synapses. Nutr Rev. 2010 Dec;68 Suppl 2:S88–101.
  7. Scheltens P, Twisk JW, Blesa R, Scarpini E, von Arnim CA, Bongers A, Harrison J, Swinkels SH, Stam CJ, de Waal H, Wurtman RJ, Wieggers RL, Vellas B, Kamphuis PJ. Efficacy of Souvenaid in mild Alzheimer’s disease: results from a randomized, controlled trial. J Alzheimers Dis. 2012;31(1):225–36.
  8. Mahoney DJ, Parise G, Tarnopolsky MA. Nutritional and exercise-based therapies in the treatment of mitochondrial disease. Curr Opin Clin Nutr Metab Care. 2002 Nov;5(6):619–29.
  9. Gella A, Ponce J, Cussó R, Durany N. Effect of the nucleotides CMP and UMP on exhaustion in exercise rats. J Physiol Biochem. 2008 Mar;64(1):9–17.
  10. Banasch M, Goetze O, Knyhala K, Potthoff A, Schlottmann R, Kwiatek MA, Bulut K, Schmitz F, Schmidt WE, Brockmeyer NH. Uridine supplementation enhances hepatic mitochondrial function in thymidineanalogue treated HIV-infected patients. AIDS. 2006 Jul 13;20(11):1554–6.
  11. Le TT, Ziemba A, Urasaki Y, Hayes E, Brotman S, Pizzorno G. Disruption of uridine homeostasis links liver pyrimidine metabolism to lipid accumulation. J Lipid Res. 2013 Apr;54(4):1044–57.
  12. Chong AS, Huang W, Liu W, Luo J, Shen J, Xu W, Ma L, Blinder L, Xiao F, Xu X, Clardy C, Foster P, Williams JA. In vivo activity of leflunomide: pharmacokinetic analyses and mechanism of immunosuppression. Transplantation. 1999 Jul 15;68(1):100–9.
  13. Jonas DA, Elmadfa I, Engel KH, Heller KJ, Kozianowski G, König A, Müller D, Narbonne JF, Wackernagel W, Kleiner J. Safety considerations of DNA in food. Ann Nutr Metab. 2001;45(6):235-54. Also Uridine–In-Depth Scientific Supplement Information | Examine.com.
  14. van Groeningen CJ, Peters GJ, Nadal JC, Laurensse E, Pinedo HM. Clinical and pharmacologic study of orally administered uridine. J Natl Cancer Inst. 1991 Mar 20;83(6):437–41.
  15. Acylated uridine and cytidine and uses thereof (http://www.google.com/patents/US6258795)
  16. Ashour OM, Naguib FN, el Kouni MH. 5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2’,3’,5’-tri-O-acetyluridine, a prodrug of uridine, as modulators of plasma uridine concentration. Implications for chemotherapy. Biochem Pharmacol. 1996 Jun 28;51(12):1601–11.
  17. Richter Y, Herzog Y, Eyal I, Cohen T. Cognitex supplementation in elderly adults with memory complaints: an uncontrolled open label trial. J Diet Suppl. 2011 Jun;8(2):158–68.

Dallas Clouatre, PhD

Dallas Clouatre, Ph.D. earned his A.B. from Stanford and his Ph.D. from the University of California at Berkeley. A Fellow of the American College of Nutrition, he is a prominent industry consultant in the US, Europe, and Asia, and is a sought-after speaker and spokesperson. He is the author of numerous books. Recent publications include "Tocotrienols in Vitamin E: Hype or Science?" and "Vitamin E – Natural vs. Synthetic" in Tocotrienols: Vitamin E Beyond Tocopherols (2008), "Grape Seed Extract" in the Encyclopedia Of Dietary Supplements (2005), "Kava Kava: Examining New Reports of Toxicity" in Toxicology Letters (2004) and Anti-Fat Nutrients (4th edition).

Website: www.dallasclouatre.com