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Choline + Uridine: Build New Neurons and Protect Against Alzheimer’s!

It’s a fact of life, age-related memory loss affects millions of Americans. And we’re not just talking about Alzheimer’s and other age-related dementias (though we will later). We’re talking about simple forgetfulness that seems to increase as we age.

However, this inevitable decline in brainpower is not inevitable thanks to two naturally occurring compounds in your body—choline (one of the B vitamins) and uridine (a building block of RNA)—and a fascinating, naturally occurring self-maintenance system going on in your brain right now.The trick is to support this natural self-maintenance system by “feeding” it properly. Do that, and it will support your brain function … now and as you get older.

Here’s how this system can support your brainpower … right now. Controlled studies have shown that daily administration of choline to support this self-maintenance system improved the immediate recall and attention in a group of healthy young adult men ages 19 – 38.1

Some of the most recent—and most exciting— research is being conducted at the Massachusetts Institute of Technology (MIT).

Researchers at MIT have been studying brain chemistry for over 30 years. Their recent efforts have shown that uridine has significant impact on repairing the neurons in gerbils, whose brain chemistry is remarkably like ours.2

These and numerous other clinical studies demonstrate that when you provide essential nutrients to this natural repair system, you halt its tendency to slow down with age.

Take good care of it, and you can expect to remain sharp well into your 70s, 80s, and beyond.

A simple picture of a complex system …and how to keep it firing at top efficiency

It’s easy to bolster your brain’s self-maintenance system in a few minutes. But first, let’s take a quick tour of your brain’s “wiring.” This way you can see how effectively your brain is able to keep functioning at top performance when taken care of properly.

All your physical actions, all your thoughts and ideas, all your memories result from nerve impulses traveling along and between neurons. When you think, move, or remember, these long, thin cells conduct electrical impulses down them and then send the impulse along to another neuron.

The electrical impulses are sent to the next neuron one of two ways. If the neurons are physically connected, the nerve impulse is carried on directly.
If there is a gap between the neurons—called a synapse—one or more of several chemicals called neurotransmitters carry it across the tiny gap. The most common neurotransmitter is acetylcholine —or ACh for short. Notice the word “choline” imbedded here. This is important.

All brain functions use neurons and neurotransmitters. Without them, you have nothing.

For lasting brain health and brainpower: Repair … Rebuild … and Re-supply

So how important are choline and uridine to your brain’s self-maintenance system?

They are the self-maintenance system!

Choline is a simple B vitamin that occurs naturally in many foods. One of its most crucial functions is as a precursor to the neurotransmitter ACh.

If you did not have choline in your system, you wouldn’t have any ACh. No ACh … no brain activity. Quite literally, without choline, we couldn’t move, think, sleep, or remember anything. We would not be alive!

“… without choline, we couldn’t move, think, sleep, or remember anything.

We would not be alive! ”

Without going into detail, ACh is broken down by enzymes once it carries nerve impulses across synapses. It’s then reassembled later for reuse.
But this breakdown/reassembly system isn’t perfect. ACh gets lost in the process. More ACh needs to be made … from choline. When there’s adequate choline in the blood and brain tissues, ACh gets made.

If there isn’t enough choline, then your brain doesn’t replace the lost ACh. Your brain starts to malfunction. You forget things. It’s harder to make complex decisions. Clear thought becomes more difficult.

But your brain’s self-maintenance system has a trick up its sleeve to help prevent choline shortages

The outside of neurons—the neuron’s cell membrane—is made of a phospholipid called phosphatidylcholine (PC for short). Again, notice the “choline” in the name. That’s because choline is part of the PC molecule making up the outer part of neuron membranes.

What happens when there’s a shortage of choline in the blood and brain tissue? The PC in the neuron membrane starts releasing its choline. You are protected (temporarily at least) from having your brain starved of choline.
If this goes on too long, you’re back to the bleak picture of not having enough choline to synthesize ACh. In addition, your neurons’ membranes are compromised.

When the PC in the membranes loses too much choline, neurons lose integrity. Nerve impulses aren’t transmitted properly. And you lose mental abilities.3

What we’ve just discussed, really, is what happens when your brain ages … or in dementias and even Alzheimer’s. (Although other complex mechanisms are at work in Alzheimer’s as well.)

The hard fact is that—without intervention —choline will decrease in your brain as you get older. 4

Uridine … the missing bridge in boosting brainpower

Where does uridine fit into this tightly balanced scheme of maintenance and repair?

Until recently, researchers focused on choline in trying to understand the biochemistry of memory and cognition. It was felt, with good reason, that administering choline was sufficient to assist the brain’s natural self-maintenance system.

Researchers got excellent results reversing declining cognitive function5 as well as boosting normal function6 with choline. Having found good results, researchers dug deeper.

One of the ways science is advanced is by trial and error. The scientific method dictates that researchers form a hypothesis and test it, discarding negative results and moving forward on positive results.

If you find one compound that helps improve condition X, you might try similar compounds to see how they work. Or if 18 different compounds were found in an assay of brain tissue, you might want to try each of these 18 compounds separately and in combination.

Taking this approach, the top researchers at MIT examined other likely candidates for supporting the brain’s self-maintenance system. Uridine—a compound of the same class as the building blocks of RNA—showed great promise. For example, in one study when uridine was combined with choline and omega-3 DHA (all components of cell membranes), brain levels of PC rose by 45%.7

“… when uridine was combined with choline andomega-3 DHA, brain levels of PC rose by 45%.”

Other research has pointed to the bottom line importance of uridine as well. Studies reported in 2006 and 2007 indicate that uridine works as a kind of bridge between choline and neuron membrane synthesis.

Uridine is a critically necessary component in synthesizing the membrane phospholipid PC. In this process, uridine is first converted to a bioactive form of choline called CDP-choline. CDP-Choline is then synthesized into new PC.8 This new PC is used to repair damaged neuronal membranes and to build new membranes.

Uridine also has been shown to enhance protein synthesis of brain proteins known to exist within the synapse.9 MIT suggests that these findings could indicate that uridine (when administered with the fatty acid DHA) increases the quantity of neuron membrane.

These findings are exciting. MIT’s research has shown that administration of uridine increases the production of neurites and dendrites. These outgrowths from the nerve cell body are a natural part of neuron development.
When a neuron has these outgrowths, it is more likely to make connections with other neurons—not only more connections but more complex connections. Simply stated, the higher number of dendrites, the better cognitive function.

Beyond membrane repair

Uridine’s conversion to CDP-choline in the brain makes additional choline available throughout the brain. So uridine doesn’t just build new neurons and repair damaged ones. It also acts as an additional source of choline throughout the brain.

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This additional choline increases production of ACh.10 Lower ACh production is not just a symptom of age-related mental decline. It is also an important marker for Alzheimer’s disease. (More about this dreadful scourge shortly.)

In addition to increasing ACh synthesis directly by providing additional choline, uridine administration also increases the production of another neurotransmitter, dopamine. 11 Wurtman and his colleagues propose that this dopamine increase could be due the uridine-promoted increase in neuronal membrane synthesis.

This is a lot to absorb … Let’s make it a little easier. Here’s a quick look at how uridine works in your brain’s self-maintenance program.

Table 1: Uridine’s Effects in the Brain

Gets synthesized into PC via CDP-choline intermediary
Repairs and rebuilds neuronal membrane
Enhances synthesis of synaptic brain proteins
Increases production of neurites and dendrites
Makes additional choline available through synthesis of CDP-choline
Increases synthesis of ACh
Increases levels of dopamine (neurotransmitter)

Your brain’s self-maintenance system is constantly under attack … but you can win the fight!

A fitting question right now might be which is more important: choline or uridine? The simple answer is both!

These two compounds work together synergistically to keep your brain functioning at top pitch. The effect of both of them working together is greater—far greater at times—than each working separately.

The take away is this:

Your brain’s remarkable ability to repair, maintain, and build membranes and to synthesize neurotransmitters is dependent on having adequate levels of both choline and uridine in your body.

But natural levels of choline and uridine in your body decrease with age, environmental assault, and disease. When this happens, your self-maintenance system slows or breaks down.

“Your brain’s remarkable ability to repair, maintain, and build membranes and to synthesize neurotransmitters is dependent on having adequate levels of both choline and uridine in your body.”

However, this steady, age-related decline is reversible. Most of the experiments proving this have been performed on animals.

Impoverished … sick … old all improved with supplementation

But the conclusions from these experiments are clear. In one experiment, animals were raised in what were termed “impoverished conditions.” Exposure to the impoverished environment impaired certain types of learning and memory. Supplementation with uridine prevented these cognitive problems. These same researchers observed similar results when impoverished animals were treated with choline.12

Similar improvement in behavior was found in aged animals13 and in animals that had developed cognitive problems due to spontaneous hypertension when treated with combined choline and uridine.14

In reporting their findings on aged animals, the researchers stated:
“In conclusion, the present data suggest that chronic dietary supplementation with UMP [uridine] might prove a useful therapeutic strategy to delay or diminish the cognitive deficits associated with poor environmental conditions or aging, as well as the changes in membrane lipid composition associated with the aging process. Because the membrane lipid composition can be significantly affected by the aging process, it is feasible that the protective function may arise from UMP’s ability to enhance the production of brain membrane phosphatides.” {ref15}

It’s easy to get lost in the scientific jargon. But what the scientists at MIT are saying is that you have far less to worry about when it comes to the “inevitable” age-related mental decline.

Feed your brain’s self-maintenance system with uridine and choline, and it will take good care of your cognitive ability silently, behind the scenes.

Get the most muscle out of choline’s power

If you’ve been using nutritional supplements for long, you know that not all forms of a supplement are necessarily the same. Some forms work better than others.

That’s true of choline. The most effective form for supplementation is alpha-gycerylphosphorylcholine (GPC). GPC is not the ordinary form of choline we’ve been hearing about (or even taking) for years. It is a source of both phospholipids (the prime building blocks of life) and choline.

GPC is water-soluble. After it’s ingested it quickly passes the blood/brain barrier into the brain, where it protects neurons and improves signal transmission.

It supports brain function and learning processes by directly increasing the synthesis and secretion of acetylcholine, as your body needs it.

Here’s a brief glance at what GPC has been shown to accomplish:

  • Improve memory and learning ability in laboratory animals16
  • Counteract brain aging in animals by increasing cholinergic receptor sites17
  • Restore the bioavailability of acetylcholine18
  • Increase nerve growth factor receptors in the brain19
  • Slow down undesirable structural changes in the brain20
  • Counter the age-related loss of nerve cells and fibers in the brain
  • Protect the brain and other organs against toxic waste buildup
  • Increase growth hormone secretion in both the young and the old21
  • Increase the release of the neurotransmitter dopamine 22
  • Improve memory and cognitive performance in patients with Alzheimer’s dementia23

Unlike choline, uridine works best in its native form … just plain uridine. You’ve already seen uridine’s power in Table 1. But just for a reminder, once uridine enters the brain, it’s converted to a form of choline called GDP-choline. As such, it achieves all the accomplishments of choline listed above, plus …

  • Enhances synthesis of synaptic brain proteins
  • Increases production of neurites and dendrites
  • Makes additional choline available through synthesis of CDP-choline
  • Increases levels of dopamine (neurotransmitter)

What about the scourge of Alzheimer’s?

Uridine and choline are so effective as part of your brain’s self-maintenance program, you can’t help wonder if they could be effective against Alzheimer’s.

In fact, many of the signs of Alzheimer’s—such as damaged, shrunken synapses—are similar to the damage seen in the laboratory studies at MIT.
The clinical studies that have been done—such as the one reported by Parnetti and others in the journal Drugs and Aging—show good promise.24 But the problem is there haven’t been enough clinical studies treating Alzheimer’s patients with choline or uridine to be able to make a clear determination about their potential benefits.

However, uridine’s ability to enhance synaptic membrane levels—especially when administered with omega-3 polyunsaturated fats—is exciting. The MIT researchers have speculated that this combination may enhance synaptic levels in “patients with neurodegenerative diseases …”.25

The final word on keeping your brain in peak condition …

Your body is a remarkable piece of work. Considering how soft and vulnerable it should be, it has amazing powers of self-healing, self-repair, and self-maintenance.

Nowhere is this ability to heal itself seen better than in your brain’s self-maintenance program. Given the potential fragileness of your neural structures, it is amazing that we are able to keep the high level of brainpower for as long as we do.

And that’s thanks to the relatively simple self-maintenance system you’ve seen at work today.

However, this self-maintenance system lies victim to the same assaults of aging, environmental toxins, free radicals, and diseases that the rest of your body does. But in this case, you have control over the fate of your brain’s self-maintenance system. If you feed it properly with choline and uridine, you are giving it the nutrients it needs to work at peak efficiency.
And when your brain’s self-maintenance system works at peak efficiency … so do you

References

  1. Canal, N, et al. Effect of L-gyceryl-phopshorylcholine on amnesia caused by scopolamine. Intl J Clin Pharmacol Ther Toxicol. 1991; 29;103-7.Canal, N, et al. Comparison of the effects of pretreatment with choline alfoscerate, idebenone, aniracetam, and placebo on scopalomine-iduced amnesia. Le Basi Razionali della Terapia. 1993;23;:102-7.
  2. Wurtman, R J, et al. Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Research. 2006;1088;83 – 92.
  3. Wurtman RJ. Choline metabolism as a basis for the selective vulnerability of cholinergic neurons. Trends Neurosci. 1992;15(4):117-22.
  4. Michalek H, Fortuna S, Pintor A. Age-related differences in brain choline acetyltransferase, cholinesterases and muscarinic receptor sites in two strains of rats. Neurobiol Aging. 1989 Mar-Apr;10(2):143-8.
    Abstract
    B. M. Cohen, P. F. Renshaw, A. L. Stoll, R. J. Wurtman, D. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. JAMA. Vol. 274 No. 11, September 20, 1995.
    Abstract

  5. Lisa A. Teathe and Richard J. Wurtman. Chronic Administration of UMP Ameliorates the Impairment of Hippocampal-Dependent Memory in Impoverished Rats. Journal of Nutrition; (2006); 136; 2834-2837.
    Abstract
    De Bruin NM, Kiliaan AJ, De Wilde MC, Broersen LM. Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats. Neurobiology of Learning and Memory. Volume 80, Issue 1, July 2003, Pages 63-79.
    Abstract

  6. Canal, N, et al. Comparison of the effects of pretreatment with choline alfoscerate, idebenone, aniracetam, and placebo on scopalomine-iduced amnesia. Le Basi Razionali della Terapia. 1993;23;:102-7.
  7. Wurtman RJ, Ulus IH, Cansev M, et al. Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Res. 2006 May 9;1088(1):83-92.
  8. Lei Wang, Amy M. Pooler, Meredith A. Albrecht, and Richard J. Wurtman. Dietary Uridine-5’-Monophosphate Supplementation Increases Potassium-Evoked Dopamine Release and Promotes Neurite Outgrowth in Aged Rats. Journal of Molecular Neuroscience. September 2005, Volume 27, Issue 1, pps. 137-146.
    Abstract
    Ulus IH, Watkins CJ, Cansev M, Wurtman RJ. Cytidine and uridine increase striatal CDP-choline levels without decreasing acetylcholine synthesis or release. Cellular and Molecular Neurobiology 2006 Jul-Aug;26(4-6):563-77.
    Abstract

  9. M. Cansev and R. J. Wurtman. Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils.Neuroscience 148 (2007) 421–431.
    Abstract
    Richard J. Wurtman, Ismail H. Ulus, Mehmet Cansev, Carol J. Watkins, Lei Wang, George Marzloff. Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Research, 1088 (2006), 83-92.
    Abstract

  10. Wang, L. , Albrecht, M.A. , Wurtman, R.J. Dietary supplementation with uridine-5′-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat. Brain Research. Volume 1133, Issue 1, 16 January 2007, Pages 42-48.
  11. Lei Wang, Amy M. Pooler, Meredith A. Albrecht, and Richard J. Wurtman. Dietary Uridine-5’-Monophosphate Supplementation Increases Potassium-Evoked Dopamine Release and Promotes Neurite Outgrowth in Aged Rats. Journal of Molecular Neuroscience. September 2005, Volume 27, Issue 1, pps. 137-146.
  12. Lisa A. Teathe and Richard J. Wurtman. Chronic Administration of UMP Ameliorates the Impairment of Hippocampal-Dependent Memory in Impoverished Rats. Journal of Nutrition; (2006); 136; 2834-2837.
  13. Teather LA, Wurtman RJ. Dietary CDP-choline supplementation alleviates age-associated spatial reference memory deficits in rats.Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:711-717.
  14. De Bruin NM, Kiliaan AJ, De Wilde MC, Broersen LM. Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats. Neurobiology of Learning and Memory. Volume 80, Issue 1, July 2003, Pages 63-79.
  15. Teather LA, Wurtman RJ. Dietary CDP-choline supplementation alleviates age-associated spatial reference memory deficits in rats.Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:711-717.
  16. Parnetti L, Abate G, Bartorelli L, Cucinotta D, Cuzzupoli M, Maggioni, M, Villardita C, Senin U. Multicentre study of l-alpha-glyceryl-phosphorylcholine vs ST200 among patients with probable senile dementia of Alzheimer’s type. Drugs Aging 1993 Mar-Apr;3(2):159-64. 
    Abstract
    Drago F, Mauceri F, Nardo L, Valerio C, Lauria N, Rampello L, Guidi G. Behavioral effects of L-alpha-glycerylphosphorylcholine: influence on cognitive mechanisms in the rat. Pharmacol Biochem Behav 1992 Feb;41(2):445-8.
    Abstract
    Schettini G, Ventra C, Florio T, Grimaldi M, Meucci O, Scorziello A, Postiglione A, Marino A. Molecular mechanisms mediating the effects of L-alpha-glycerylphosphorylcholine, a new cognition-enhancing drug, on behavioral and biochemical parameters in young and aged rats. Pharmacol Biochem Behav1992 Sep;43(1):139-51. 
    Abstract

    Lopez CM, Govoni S, Battaini F, Bergamaschi S, Longoni A, Giaroni C. Effect of a new cognition enhancer, alpha-glycerylphosphorylcholine, on scopolamine-induced amnesia and brain acetylcholine. Pharmacol Biochem Behav 1991 Aug;39(4):835-40.
    Abstract

  17. Amenta F, Liu A, Zeng YC, Zaccheo D. Muscarinic cholinergic receptors in the hippocampus of aged rats: influence of choline alphoscerate treatment. Mech Ageing Dev 1994 Oct 1;76(1):49-64.Amenta F, Franch F, Ricci A, Vega JA. Cholinergic neurotransmission in the hippocampus of aged rats: influence of L-alpha-glycerylphosphorylcholine treatment. Ann N Y Acad Sci1993 Sep 24;695:311-3.
  18. Bronzetti E, Felici L, Amenta F. Effect of ipsilateral lesioning of the nucleus basalis magnocellularis and of L-alpha-glyceryl phosphorylcholine treatment on choline acetyltransferase and acetylcholinesterase in the rat fronto-parietal cortex. Neurosci Lett1993 Dec 24;164(1-2):47-50.Trabucchi M, Govoni S, Battaini F. Changes in the interaction between CNS cholinergic and dopaminergic neurons induced by L-alpha-glycerylphosphorylcholine, a cholinomimetic drug.Farmaco [Sci] 1986 Apr;41(4):325-34.
  19. Vega JA, Cavallotti C, del Valle ME, Mancini M, Amenta F. Nerve growth factor receptor immunoreactivity in the cerebellar cortex of aged rats: effect of choline alfoscerate treatment. Mech Ageing Dev 1993 Jun;69(1-2):119-27.
  20. Amenta F, Ferrante F, Vega JA, Zaccheo D. Long term choline alfoscerate treatment counters age-dependent microanatomical changes in rat brain. Prog Neuropsychopharmacol Biol Psychiatry. 1994 Sep;18(5):915-24.Neuropsychopharmacol Biol Psychiatry 1994 Sep;18(5):915-24. Amenta F, Del Valle M, Vega JA, Zaccheo D. Age-related structural changes in the rat cerebellar cortex: effect of choline alfoscerate treatment. Mech Ageing Dev 1991 Dec 2;61(2):173-86.
  21. Ceda GP, Ceresini G, Denti L, Marzani G, Piovani E, Banchini A, Tarditi E, Valenti G. alpha-Glycerylphosphorylcholine administration increases the GH responses to GHRH of young and elderly subjects. Horm Metab Res 1992 Mar;24(3):119-21.Ceda GP, Ceresini G, Denti L, Magnani D, Marchini L, et al. Effects of cytidine 5’-diphosphocholine administration on basal and growth hormone-releasing hormone-induced growth hormone secretion in elderly subjects. Acta Endocrinol (Copenh).1991;124(5):516-20.
  22. Trabucchi M, Govoni S, Battaini F. Changes in the interaction between CNS cholinergic and dopaminergic neurons induced by L-alpha-glycerylphosphorylcholine, a cholinomimetic drug.Farmaco [Sci]. 1986;41(4):325-34.Agut J, Ortiz JA, Wurtman RJ. Cytidine (5’)diphosphocholine modulates dopamine K(+)-evoked release in striatum measured by microdialysis. Ann N Y Acad Sci. 2000;920:332-5.
  23. Parnetti L, Abate G, Bartorelli L, Cucinotta D, Cuzzupoli M, Maggioni, M, Villardita C, Senin U. Multicentre study of l-alpha-glyceryl-phosphorylcholine vs ST200 among patients with probable senile dementia of Alzheimer’s type. Drugs Aging 1993 Mar-Apr;3(2):159-64.
  24. Parnetti L, Abate G, Bartorelli L, Cucinotta D, Cuzzupoli M, Maggioni, M, Villardita C, Senin U. Multicentre study of l-alpha-glyceryl-phosphorylcholine vs ST200 among patients with probable senile dementia of Alzheimer’s type. Drugs Aging 1993 Mar-Apr;3(2):159-64.
  25. M. Cansev and R. J. Wurtman. Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils.Neuroscience 148 (2007) 421–431.

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