Can Betaine Beat Homocysteine?

Betaine Helps Fight Cardiovascular Disease

Can Betaine Beat Homocysteine?
This vital nutrient from beets helps “rehabilitate”
a molecular villain, turning it harmless
By Richard P. Huemer, M.D.

He who does not prevent a crime
when he can, encourages it.
— Seneca

e’ve said it before, and we’ll say it again: homocysteine is an artery-ravaging, heart-wrecking villain of the worst sort. Its molecular mug shot should hang in the post office. Homocysteine may be a normal constituent of our bodies (it’s produced by metabolism of the nutrient amino acid methionine), but we wish it weren’t. In low-normal concentrations, it’s harmless enough, but give it a little encouragement, and it can start a physiological rampage from which few bodily systems are safe. The risk increases with age, because so do our homocysteine levels (especially in men).

Homocysteine, an amino acid sometimes metaphorically (but inaccurately) dubbed “the new cholesterol,” is widely regarded as a major independent risk factor for cardiovascular disease. It was first fingered in this regard by the American physician Kilmer McCully in 1969. Reading the medical literature, he was struck by something interesting regarding children who had died of a rare genetic disease called homocystinuria, which severely afflicts many parts of the body.* The symptoms result from malfunctions in different enzyme systems that cause homocysteine levels to rise dangerously.


*Homocystinuria means excessive levels of homocystine in the urine. Homocystine is a dimer (double molecule) of homocysteine and is produced by oxidation of the latter. A primary treatment for homocystinuria is with betaine.


McCully noticed that victims of different types of homocystinuria showed postmortem evidence of severe atherosclerosis (arterial plaque) and thrombosis (blood clots). They also had very high blood levels of homocysteine—the only metabolic abnormality that was common to all the cases.

How Heresy (and Persistence) Paid Off

McCully speculated that: (1) there might be a similar link between elevated homocysteine levels and the development of atherosclerosis in genetically healthy adults, and (2) the reason for the excess homocysteine could be deficiencies of three vitamins that play vital roles in its metabolism. These vitamins are folic acid (a B-vitamin without a number—it’s usually called folate), vitamin B12, and vitamin B6. McCully’s theory was heretical. His work on it generated intense interest but was highly controversial, and it finally cost him his job at Harvard University in 1976. Undaunted, he continued his research elsewhere, and the homocysteine link with heart disease became his life’s work.1

Fast-forward to the present: the importance of elevated homocysteine levels in the development of cardiovascular disease (CVD) is now widely acknowledged by the medical profession, as is the pivotal role of folate and vitamins B12 and B6 in controlling homocysteine. These vitamins, it is believed, can help prevent not just CVD, but many other diseases and disorders as well. The rate of publication of new studies on homocysteine and disease is now over 1000 annually. Dr. McCully’s persistence (he’s still doing research, by the way) certainly paid off.

Homocysteine’s Appalling Rap Sheet

Hunting for homocysteine’s grubby fingerprints in various diseases has also paid off for many other scientists with a good nose for “health crime” (as well as sources of research funding). Following is a summary of the many such crimes of which this dastardly molecule stands indicted, either as perpetrator or accomplice:

  • Cardiovascular, cerebrovascular, and peripheral vascular diseases
  • Hypertension
  • Inhibition of the growth of new blood vessels
  • Cancer, notably colorectal
  • Depression
  • Schizophrenia
  • Alzheimer’s disease, vascular dementia, and, perhaps, dementia of Parkinson’s disease
  • Osteoporosis (see the sidebar “Homocysteine vs. Bones”)
  • Complications of alcoholism
  • Kidney failure
  • Neural tube defects (severe birth defects of the nervous system)
  • Increased risk for certain diseases, including type 2 diabetes, rheumatoid arthritis, hypothyroidism, and inflammatory bowel disease

In light of that appalling criminal record, it’s a blessing that homocysteine can be relatively easily controlled. As Dr. McCully exhorts, take your B-vitamins! Optimal levels of these vitamins help to ensure a proper balance between methionine and homocysteine, keeping the latter in check. (For more on this, see the sidebar “The Importance of a Single Carbon Atom” in the article “Add Brain Assault to Homocysteine’s Rap Sheet” in the February 2006 issue.)

Homocysteine vs. Bones

To homocysteine’s prodigious list of offenses, add osteoporosis, that condition of decreased bone mineral density (BMD) that comes with aging (in men as well as women) and can cause broken bones. From researchers in Norway and England this year came a study of risk factors for osteoporosis involving 5338 middle-aged (47–50) and elderly (71–75) men and women.1 They were tested for BMD at the hip, and the data were corrected for other factors known or suspected to be linked with osteoporosis.

In both groups of women, but not in the men, low BMD values were modestly associated with elevated homocysteine levels and with low folate levels. There was no association either way with vitamin B12 levels, but such an association has been observed recently in the Framingham Osteoporosis Study.2 Although the results of the present study do not establish any causal links, they do offer the hope that some measure of mitigation of osteoporosis—a disease responsible for more than 1.5 million fractures in the United States each year, mostly in women—may be possible through supplementation with B-vitamins.

References

  1. Gjesdal CG, Vollset SE, Ueland PM, Refsum H, Drevon CA, Gjessing HK, Tell GS. Plasma total homocysteine level and bone mineral density. Arch Intern Med 2006;166:88-94.
  2. Tucker KL, Hannan MT, Qiao N, Jacques PF, Selhub J, Cupples LA, Kiel DP. Low plasma vitamin B12 is associated with lower BMD: The Framingham Osteoporosis Study. J Bone Miner Res 2005;20:152-8.

The Homocysteine Hole and the Helicopter Trick

The B-vitamins are not solely responsible for controlling homocysteine, however. Other molecules are essential too, especially under conditions of B-vitamin deficiency. One of them is betaine, an alkaloid widely distributed in plants and animals. Betaine is also called trimethylglycine because it’s a derivative of the amino acid glycine with three methyl groups attached. Its primary biological role is to donate one of those methyl groups (–CH3), containing a single carbon atom, to another molecule that needs one. This process, called methylation, may sound as exciting as earwax, but it’s tremendously important for many life processes. We’ll get back to methylation shortly—but first, consider the following fable:

Your daily commute includes a toll bridge that crosses a dreaded abyss called the Homocysteine Hole, and you have to pay $3.00 to cross the bridge and get home safely. Today, however, you got mugged in the parking lot after work, so you have no money—and you’re approaching the bridge. What will you do? Naturally, you press a secret button under the dashboard of your car, and a helicopter rotor pops up from the roof (did I mention that you bought the car from James Bond?). You roar into the sky and soar across the abyss—cool!

Betaine Can Do the Trick

Something akin to that little drama can happen in your own body. Ordinarily, to avoid plunging into the homocysteine hole of chronic disease, you must pay a daily nutritional toll of 3 “dollars,” in the form of folate, vitamin B12, and vitamin B6. But what if you were starving (humor me here) and had no B-vitamins? Your body would need some kind of “helicopter trick” to bail you out.

Luckily, your body does have such a trick up its, uh, sleeve: it’s betaine, a molecular chopper that can come to the rescue and help recycle your homocysteine back to methionine. And how does it do that? By donating a methyl group to homocysteine, which thereby—voilà!—becomes methionine again. (Folate, which is also a methyl-group donor, works the same way.) Unlike vitamins, which, like money, must be acquired from without, betaine is manufactured within our bodies, according to need (it’s also found in some foods). Thus you always have some betaine handy, and it’s always working for you, even when you have plenty of vitamin “money” in your wallet.

Does this mean that betaine is a viable substitute for B-vitamins, always able to fly you to safety without your having to pay the bridge toll? Certainly not—vitamins are absolutely essential (by definition) for good health, and for life itself, so you must obtain them. Betaine is essential too, though, and if your B-vitamin levels do decline for whatever reason, it will assume an increasingly important role—up to a point—in abating your homocysteine levels. Beyond that point … well, it’s not a pretty picture.

With Age We Need More Betaine

Chemists discovered betaine in the juice of sugar beets (Beta vulgaris) in the nineteenth century. It also occurs in significant amounts in seafood (especially shellfish), wheat germ or bran, and spinach.2 We ingest about 1.0–2.5 g of betaine in our food daily, and more comes from the oxidation of dietary choline—which is why choline is an effective antihomocysteine agent (see “Choline Battles Homocysteine” in the April 2005 issue).

Betaine is produced mainly in our liver and kidneys, but not necessarily in optimal amounts for good health, especially as we age. Supplemental amounts of 1–6 g/day of betaine are used to reduce elevated homocysteine levels, and they’re perfectly safe; 20-g doses have been used, in fact, in treating a certain liver disease.

Betaine Reduces Homocysteine, and More

In a recent study in Finland, 10 healthy, middle-aged men and women were given 1, 3, or 6 g of betaine orally, causing their blood levels to increase sharply, in a dose-dependent manner.3 Betaine peaked in about 1 hour, and the 3-g and 6-g doses caused significant reductions in homocysteine within 2 hours. Interestingly, these two doses reduced the volunteers’ homocysteine levels even though they were normal to begin with. The reduction with the 6-g dose persisted for at least 24 hours and was accompanied by increased urinary excretion of dimethylglycine, indicating that betaine (trimethylglycine) had shed one methyl group.

Besides acting as a methylating agent, betaine serves other functions as well. In the form of betaine hydrochloride, e.g., it’s widely used as an efficient vehicle for hydrochloric acid delivery to people whose stomachs produce inadequate amounts of that acid for proper digestion of their food. This problem is common in the elderly (see the sidebar “Homocysteine Survival for Seniors”). Betaine is also potentially useful as an anti-inflammatory agent, as shown by a recent Korean study on aged rats.4

Homocysteine Survival for Seniors

Excessive homocysteine levels can arise in many ways. Genetic defects can produce either severe elevations (which are rare) or, more commonly, mild elevations. (In view of homocysteine’s many harmful effects, one wonders whether the standard term “mild elevation” is even appropriate here.) Environmental causes include nutritional deficiencies of protein, folic acid, and vitamins B12 and B6; strict vegan diets, which lack eggs and milk, are notoriously low in B12. Alcoholism correlates with elevated homocysteine, probably because it induces nutritional deficiencies. Other environmental influences include smoking, lack of exercise, and excessive coffee consumption.

A major factor, alas, is age. Nutritional deficiencies may account for some of this effect, but not all. When elderly participants in the Framingham Heart Study were evaluated in 1993, 29% had elevated homocysteine levels, which were strongly associated with low folate, B12, and B6 levels, as well as with age.1 That led researchers to conclude that most such cases could be attributed to vitamin deficiencies.

Such deficiencies can occur even if you’re taking the generally recommended amounts, because your system may not be absorbing the vitamins efficiently. After all, it’s not how much you ingest that counts, but how much you absorb. Poor absorption of vitamin B12, in particular, is a common problem of aging. It’s due in part to the normal, age-related decrease in stomach acid, which can be aggravated by excessive use of antacid remedies and acid-blocking drugs. As for folate, deficiencies are common even in younger people, and overall, about 10% of the U.S. population is folate-deficient.

For seniors, more liver, whole wheat, and leafy green vegetables, such as spinach, would provide them with more of the protective B-vitamins—and betaine—but perhaps not enough. Supplementing with folate and vitamin B12 is important (they should always be taken together, because an excess of one can mask a deficiency in the other), as well as vitamin B6. Betaine can be valuable too, as the accompanying article shows.

Reference

  1. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270(22):2693-8.

Something to Celebrate

For many reasons, we can celebrate betaine even as we condemn homocysteine. If the latter is an archvillain who robs us of our health, the former is a cop on the beet (sorry!) who protects us. But betaine doesn’t “execute” homocysteine—it rehabilitates homocysteine and turns it into a good guy, methionine. It’s as Voltaire said: “The punishment of criminals should be of use; when a man is hanged, he is good for nothing.” In the form of methionine, rehabilitated homocysteine is good for you.

References

  1. McCully KS. Homocysteine and heart disease. Available at www.touchbriefings.com/pdf/1102/mccully.pdf.
  2. Craig SAS. Betaine in human nutrition. Am J Clin Nutr 2004;80(3):539-49.
  3. Schwab U, Törrönen A, Meririnne E, Saarinen M, Alfthan G, Aro A, Uusitupa M. Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans. J Nutr 2006;136:34-8.
  4. Go EK, Jung KJ, Kim JY, Yu BP, Chung HY. Betaine suppresses proinflammatory signaling during aging: the involvement of nuclear factor-kappaB via nuclear factor-inducing kinase/IkappaB kinase and mitogen-activated protein kinases. J Gerontol A Biol Sci Med Sci 2005 Oct;60(10):1252-64.


Dr. Richard P. Huemer received his M.D. from UCLA and did postdoctoral research in cancer immunology at CalTech. He has specialized in orthomolecular medicine for most of his career, has written and lectured extensively on alternative medicine, and has served on the editorial boards of professional journals. His published books include The Roots of Molecular Medicine: A Tribute to Linus Pauling and, with coauthor Jack Challem, The Natural Health Guide to Beating the Supergerms.

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