~ Methylation - Methylation Equals Life

Methylation Equals Life

A Review of Methyl Magic: Maximum Health Through Methylation by Craig Cooney, PhD with Bill Lawren.

Reviewed by Ivy Greenwell

"Methylation is a major and fundamental determinant of health and sickness, or life and death. Like a car out of gas, life without methyl power comes to a screeching halt" Craig Cooney asserts. It is indeed awesome to ponder how the seemingly simple process methylation - the transfer of methyl groups (CH3) among various compounds in our bodies - is critical for our health, longevity,and our sense of well-being. Cooney's book is the long-awaited popular source that explains how methylation works, how we gradually run out of "methyl power" as we age, and how we can enhance methylation and thus enjoy better health and possibly even extend our life span.

S-adenolmethionine (SAMe), a metabolite of the sulfur-bearing amino acid methionine, is the chief donor of methyl groups. The book calls SAMe "the philanthropist in the methylation process, the Daddy Warbucks of methylation." Every cell in the body uses SAMe. But if you feel you can't afford SAMe, do not despair. There are plenty of inexpensive methyl supplements that effectively raise the levels of SAMe. It is in fact those supplements that are the focus of Cooney's book.

The Importance of Supplementation. Cooney strongly believes that we cannot maintain sufficient incthylation without supplements. He states that "diet alone won't supply enough methyl groups to prevent declines in DNA methylation and thus slow aging and prevent or at least Postpone age-related diseases."

Why do we lose methyl groups as we age? No one knows the definitive answer, but it may have to do with built-in metabolic defects. We could produce a car engine that would last much longer than current engines, but it would also cost a lot more to produce. Likewise, nature too could no doubt provide for more efficient methylation that would promote longer survival-but at a cost ill resources that could instead be used for successful early reproduction. The mechanism of evolution tends to select for reproductive success rather than longevity, per se. Thus we have evolved sufficient rather than optimal methylation.

Our methylation works well enough for reproductive success when we are young, but not for a life span much beyond 100 years. One of the "cruel" principles in biology is "When reproduction is finished, the animal is finished." Being human however, we have other values, and dream of the fulfillment that could come with true "golden years" in the second half of life. Those are the years that seem ideally suited for greater creativity, productivity and enjoyment, providing we stay healthy and vigorous.

Besides the built-in genetic methylation deficiency, part of the problem lies in the fact that the diet we have evolved to eat does not indeed supply sufficient methyl groups for long postreproductive survival. Fortunately we have also evolved a marvelous brain that allows us to come up with solutions designed to bypass these genetic and dietary limitations. Cooney's book is a primer showing us how it can be done.

Cardiovascular Health. According to Cooney, "high homocysteine is now widely recognized by scientists to be the greatest single biochemical risk factor for heart disease." Cooney estimates that homocysteine may be responsible for as much as 90% of cardiovascular disease. Cholesterol does not correlate with the risk of heart disease until it reaches levels above 240. In Cooney's view, however, even so-called "normal" homocysteine levels cause heart disease. In order to obtain protection against cardiovascular disorders, we need to keep homocysteine as low as possible, probably in the 4 - 6 micromolar range. One of the most interesting findings discussed in the book is that in animal studies, "methyl-deficient/ methionine-excessive diets were more likely to produce vascular disease than high-fat diets."

Low homocysteine, on the other hand, correlates with clean arteries. People with Down's syndrome, for instance, have very low homocysteine and also much less cardiovascular disease. Likewise, homocysteine is a risk factor for high blood pressure and stroke. It also plays a role in osteoporosis, and may be involved in diabetes and kidney failure. It seems likely that it is involved in all major degenerative disorders. But we are in luck. As Cooney states, "the fortunate truth is that homocysteine levels are easy to control." It is interesting that in countries with "heart-healthy" diets, such as Spain, France and Japan, homocysteine levels tend to be much lower (7 - 8 micromolar) than in countries such as Finland or the U.S., where homocysteine averages above 10. In fact, the U.S. average is already close to 10 in people still in their 20s, and much higher in older populations. Interestingly, pregnant women have the lowest homocysteine levels, followed by non-pregnant premenopausal women. Homocysteine goes up after menopause. This implies a strong relationship between the so-called female hormones and methylation. It appears that both estrogens and progesterone lower homocysteine.

Recently, it has been discovered that raloxifene lowers homocysteine as well. There are also indications that methylation becomes less efficient during the premenstrual week, when both estradiol and progesterone drop sharply. Hence methyl supplements hold out a promise of improving PMS symptoms. Above all, the evidence that hormone replacement therapy lowers homocysteine and thus improves women's methylation status is another important reason annynVT imnnryany reason for encouraging postmenopausal women to use hormones. Cooney warns, however, that women should take methyl supplements together with their supplemental hormones. For one thing, safe estrogen metabolism depends on efficient methylation, and diet alone does not supply enough methyl groups. Women taking oral contraceptives likewise need more methyl supplements, particularly vitamin B6.

Cancer. In a fascinating chapter, Cooney shows just how complex the process of methylation can really be. What we see in cancer is both hypomethylation and hypermethylation. Methylation regulates gene expression. It "silences" those genes that are not needed by a particular cell. An enzyme called DNA methyltransferase detaches methyl groups from SAMe and transfers them to various parts of DNA. This enzyme also preserves the methylation pattern from one cell generation to the next. Cancer is chiefly a disease of aging, so it is not surprising that the decreased methylation and higher homocysteine seen in the elderly correlate with increased incidence of cancer. Animal studies showed that low methylation is associated with more breakage in DNA strands, including the area bearing the cancer-suppressing gene known as p53. Also, as cancer progresses, methylation decreases at each stage, switching on more of the cancer-promoting "oncogenes." At the same time, some DNA sequences (the tumor-suppressor genes) in the cancer cells become hypermethylated and thus silenced. Consequently, it is more correct to speak of abnormal methylation in cancer, rather than low methylation.

Can methyl supplements prevent cancer? So far we know that supplementation with SAMe helps protect rats from liver cancer. In humans, folic acid appears to offer a high degree of protection against colon cancer and cervical cancer (the folate has to come from supplements rather than diet in order to be effective. An eye-opening study by Bruce Ames showed that when people who were folate-deficient were supple-mented with 5mg of folic acid for eight weeks, they showed 20 times less DNA damage. Those who had normal folate levels at the start of the study showed three times less DNA damage in response to high folate supplementation. The high dose of folate used in this study makes one wonder about the RDA. How much cancer, heart disease and Alzheimer's disease could be prevented if it were easy for people to take a few milligrams of folic acid, without the current restriction to 800 mcg per capsule? Can folic acid be used in the treatment of cancer?

The issue is unfor-tunately complicated. There is more to the metabolism of folic acid than improving methylation and lowering homocysteine and DNA damage. But more knowledge should bring us closer to victory over cancer, which according to predictions will soon become the number one killer, ahead of heart disease. "If one could control the folate cycles that the body uses both to make methyl groups and to manufacture the 'building blocks' for DNA, then control of cell growth should follow," Cooney asserts. Cooney is of course cautious enough to warn that we do not have enough knowledge to recommend methyl supplements to those who already have cancer. We need a lot more research into this area. One promising supplement is choline. Besides its function in methylation, it also regulates chemical signaling in cell membranes. In animal studies, folic acid has already been shown to enhance the effectiveness of chemotherapy while reducing its side effects. Ultimately, Cooney foresees cancer treatment that consists of severe modification of the diet and selective chemotherapy combined with methylating agents.

Methylation and the Brain. The brain seems almost insatiable in its demand for both SAMe and choline. Whether it's the production of neurotransmitters or the maintenance of the myelin sheath around nerves fibers, SAMe plays a crucial role. The best-known therapeutic role of SAMe is as an effective antidepres-sant. SAMe has been found to be more effective than imipramine, for instance. The fascinating finding was that those patients on imipramine who showed the greatest improvement also showed a rise in SAMe levels. Folic acid (more often referred to as "folate") has also been found to be an effective antidepres-sant. Interestingly, lack of response to Prozac seems to go hand in hand with low folate levels. TMG likewise seems promising as an anti-depressant. Altogether it is high time for more research into the connection between depression and deficient methylation, and the effectiveness of various methyl supplements as antidepressants (though one can easily imagine the dismay of drug companies if people started using something as cheap as folic acid, B12, and TMG instead of Prozac). Because SAMe is also involved in the clearance of excess serotonin and dopamine, two chief mood regulators, it is likely to be involved in schizophrenia and the manic-depressive disorder. While we do not yet have data on SAMe as a possible adjuvant treatment for schizophrenia, we know that schizo-phrenics have elevated homocys-teine, and that their symptoms significantly improve when they are treated with methylfolate (an active form of folic acid).

It is also interesting that schizophrenia has a male prevalence, since estradiol is known to activate certain methylating enzymes in the brain, and also to alleviate schizophrenic symptoms. The manic depressive disorder presents a more complicated case, since the use of SAMe may shift the balance toward manic elation. Hence SAMe is recommended only for unipolar melancholic depression, and not for the bipolar disorders. Alzheimer's disease is also associated with high homocysteine and low levels of folate and B12, as well as low levels of SAMe in the brain. Improved methylation is probably one crucial way we can protect our-selves against devastating brain diseases. In view of the brain's insatiable appetite for both SAMe and choline, it would be fascinating to see if the combined treatment with these two nutrients (perhaps) substitute CDP-choline for ordinary choline) could prevent, delay or at least slow down the progression of Alzheimer's disease. Cooney also points out that multiple sclerosis (MS) has symptoms that resemble those of folate or B12 deficiency. Since methylation is essential for the formation of the myelin sheath that insulates nerve fibers, he suggests that a combination of methyl supplements and antiinflammatory fatty acids be used for the treatment of this disease. (Again, we know that steroid hormones are also very important. The recent findings on the role of progesterone are particularly encouraging.)

How About Arthritis? The discovery of the benefits of increased methylation for osteoarthritis was due to a happy accident. SAMe was being tested in an Italian study of its usefulness against depression. Some of the depressed patients also happened to have arthritis. These patients experienced an improvement not only in their mood, but also in their joint paint. SAMe was found to be as effective as NSAIDs such as ibuprofen, without ibuprofen's disastrous side effects. It's not only that nonselective NSAIDs such as ibuprofen and indomethacin can cause ulcers and the leaky gut syndrome. They actually inhibit the formation of new cartilage. Ultimately they make arthritis worse, and the pain less responsive to painkillers. The current mainstream treatment of osteoarthritis is a devil's bargain: in the end the cure is worse than the disease. One of the pathological aspects of arthritis is the shrinking in the molecular size of proteoglycans-the building blocks of cartilage - and hence a deterioration in the capacity of cartilage to act as a shock absorber.

We now know that SAMe improves the quality of cartilage by increasing the size of proteoglycans. Since glucosamine sulfate has also been found helpful in arthritis, Cooney suggests that the treatment of arthritis should include either SAMe or SAMe increasing methylating agents in combination with glucosamine sulfate. Cooney, however, does not cite the study that found the effectiveness of folic acid and vitamin B6 in osteoarthritis. This confirms his hypothesis that methyl donors are indeed helpful against the most common type of arthritis. Animal studies have also shown greater thickness and density of cartilage in SAMesupplemented animals, with higher concentration of proteoglycans (possibly thanks to a greater activation of the polyamine pathway, leading to more protein synthesis).

Other studies have shown that SAMe counteracts the effects of inflammatory cytokines such as the tumor necrosis factor (TNF), inhibits the enzymes that destroy cartilage, and probably increases glutathione levels in the damaged joint. In vitro (meaning in cell colonies outside the body), SAMe also increases the number of cartilage cells (chondrocytes). Finally, SAMe reduces homocysteine, which results in better blood circulation and other anti-arthritis effects. In sharp contrast to NSAIDs, the benefits of SAMe for joint health increase over time. Also in contrast to NSAIDs, SAMe protects the liver, kidneys and the gastrointestinal tract while it helps build healthier cartilage. Rheumatoid arthritis (RA) is a more severe form of arthritis, with a much more pronounced autoimmune component. It has indeed been found that the T-cells of RA-sufferers have lower DNA methylation. Patients with rheumatoid arthritis also tend to have higher homocysteine, and lower levels of vitamin B6 The implications are clear, although studies on the efficacy of methylating agents in RA are yet to be done. We do, however, have one very promising Italian study showing the benefits of SAMe in the treatment of fibromyalgia, which some experts regard as having an autoirmmune component and being related to arthritis.

Millions of older people suffer from osteoarthritis and other arthritisrelated conditions. The estimated yearly cost of these diseases is $50 billion. According to various studies, it takes mega-doses of methylating agents such as folic acid, as well as mega-doses of glucosamine and chondroitin sulfate, to effectively combat osteoarthritis. It also helps enormously to be taking proven anti inflammatories such as vitamin E, fish oil, and grape seed extract. Because of the urgent need to find a non-toxic treatment for these debilitating con ditions, a lot more publicity should be given to the efficacy of SAMe and SAMe-raising methylating agents in improving joint health. Slowly, we're getting there. Natural hormone replacement is also tremendously important for pre serving youthful cartilage produc tion. Here again it is too bad that Cooney does not discuss in more detail the role of methylation in estrogen metabolism. It turns out that one of the estrogen metabolites methoxyestradiol, appears to protect cartilage, besides providing the won derful bonus of breast cancer preven tion. All arthritis-related disorders have a huge female predominance with osteoarthritis being primarily postmenopausal. Women especially need to know about the joint-protective role of estrogen, when it is taken more safely, with sufficient antioxidants (to make sure estrogen is regenerated to its antioxidant form) and methylating agents, to ensure sufficient production of the methylated varieties.

The Aging Process. This is the most fascinating chapter in the whole book. There is strong evidence for the theory that impaired methylation is one of the key mechanisms of aging. Just as longlived animals have strong antioxidant defenses, so too can they maintain methylation much better than short-lived animals. The big question of course is whether enhancing methylation and lowering homocysteine can extend life span. Cooney presents a curve showing the inexorable rise in homocysteine with aging. The peripheral blood vessels start clogging up first, and eventually we seem doomed to end up with homocysteine-related damage to blood vessels, the nervous system, bone density and so forth - the very changes that define aging. "It could be that homocysteine is one thing that limits our life span to the often assumed limit of 120 years," Cooney states. Even the development of cataracts is related to rising levels of homocysteine, and thus inadequate methylation. When the lens proteins are damaged, a special enzyme uses SAMe to methylate them and repair them. Even hair graying seems to have something to do with deficient methylation! It would be fascinating to see if correct methyl supplementation (together with the avoidance of obesity; obesity goes hand in hand with higher homocysteine) would prevent such "inevitable" developments of aging as cataracts and gray hair. And if you are wondering if it is possible to lower homocysteine levels in the elderly, the answer is a resounding yes. Cooney quotes a study that showed elderly subjects supplemented with folic acid, B12 and B6 ended up with homocysteine levels lower than those usually seen in healthy 35-year-olds.

Most important, however, might be the prevention of depression. Depression doesn't just lower the quality of life. It is also a major risk factor for heart disease and cancer, and even osteoporosis. Depression in the elderly is endemic, and one can certainly point to various social and cultural factors besides the deteriorating neurochemistry. While no one is suggesting that simply taking SAMe or megadoses of folic acid and TMG would be the end of all depressive illness, methyl supplements could indeed make a terrific difference. If, in addition to preventing and alleviating depression, these supplements could also at least delay Alzheimer's disease, old age would look very different than now. Perhaps we could even speak about the "golden years" and mean it. Our great good luck is that it is easy to lower homocysteine levels and enhance methylation. The ideal of aging as maturation rather than ever-accelerating mental and physical deterioration does seem within reach. Here, the phrase "methyl magic" certainly applies.

Actually the slowing down of aging might start already in the womb-with the mother's methylation status. Fertile women might be very interested in how maternal methyl supplements affect the health and longevity of their offspring. Cooney does try his best to provide guidance for pregnant women. The issue is obviously of prime importance. Let us hope that it receives more research emphasis.

The Book's Strengths, Weaknesses. One of the disappointments of this book is that Cooney pays little attention to the role of hormones in methylation. He duly notes gender differences: premenopausal women and women on hormone replacement have lower levels of homocys teine-pregnant women have the lowest levels-than men, but men have higher levels of SAMe. Yet he doesn't go on to discuss those fascinating findings. Some studies indicate that hormones have a considerable impact on methylation. Testosterone, for instance, appears to increase the activity of the enzyme SAMe-synthase, thus raising the levels of SAMe. In turn, it seems that SAMe increases testosterone production. And all women need to know that efficient methylation is crucial for safe estrogen metabolism, and that elevated homocysteine inhibits this process.

But the book's greatest drawback is the lack of an extensive discussion of SAMe. This supreme methylator, the biochemical superstar whose importance has been compared to that of ATP, our Energy molecule, is quickly summarized in three pages, with cursory statements such as, "SAMe is a major player in the synthesis of acetylcholine, one of the most important neurotransmitters," or, "SAMe also plays an important part in the metabolism of estrogen." The fact that SAMe may thus help prevent Alzheimer's disease and breast cancer is of tremendous interest to women readers. I think many women would be more motivated to take either SAMe or other less expensive methyl supplements if they could learn in more detail about these matters, and would appreciate such information a lot more than the pages devoted to recipes. Educated women would likely prefer learning more about SAMe. Then there is the publisher's pressure to keep the book as popular as possible. Hence, the "magic" in the title and the constant use of the phrase "methyl magic supplements" rather than simply "methyl supplements."

There are also the superfluous metaphors such as the Mickey Mouse cap that is supposed to make us visualize the methyl group (but wouldn't that require three ears?), and the strive toward a chatty style that maintains a precarious balance between solid factual writing and "biochemistry for dummies." But these are minor complaints, considering that when the book does discuss a topic in depth, it becomes fascinating. Cooney's honesty in stating that we do not know the optimal doses for the various supplements is appreciated. (Editor's note: The Life Extension Foundation has discovered that indi-vidual testing of serum homocysteine is the only way of optimizing a supplement program.) Nor do we know how much folate, B12 and TMG to take for antidepressant effects that might be equivalent to those of taking an antidepressant dose of SAMe.

He is also careful to state precautions about taking methyl supplements in conditions such as Parkinson's disease or epilepsy. The cover states: "Methylation prevents heart disease and stroke, boosts brain power, cures depression, treats arthritis and many other diseases, prevents cancer, slows down aging." Craig Cooney does a fine job of documenting these claims. He has expanded our knowledge of the aging process to include gradual loss of methylation. Even better, he also tells us how to enhance methylation. Altogether, the wealth of quality information in Methyl Magic is outstanding. It is an excellent book for anyone interested in health and longevity.

Diet, Supplements, Exercise and Sauna. In Methyl Magic, Craig Cooney's most radical suggestion is that half of our calories should come from vegetables and fruit. "Vegetables should be your top priority," Cooney states. He grudgingly allows some potatoes, as long as they comprise no more than ten percent of our vegetable intake. This very strong emphasis on vegetables, as opposed to the fattening starches recommended by the USDA pyramid, is also known as "the California pyramid."

Cooney also allows some fruit juice, as long as it is diluted with water, since fruit juice contains a lot of sugar Diluted grape juice and orange juice is recommended, since they contain choline and folic acid, respectively, as well as other phytonutrients. He is also strongly in favor of beans-even canned beans are a good source of folate.

Likewise, he is in favor of seafood and good fats, such as those provided by nut butters. In gener-al terms, his diet is broadly compatible with The Zone,and probably would also accomplish purpose of insulin reduction. This is an important anti-aging bonus. Basically, however, we can't rely on the diet to provide us sufficient amounts of methylating agents. For anyone middle-aged or beyond, supplements are a must. Here is a brief summary of the methyl supplements recommended by Cooney:
  • Choline and trimethylglycine. While choline does contain three methyl groups, for methylation purposes it needs to be converted to trimethylglycine (TMG), which in turn is a very efficient methylator. Choline has many vital functions in the body, including serving as a precursor for the production of the neurotransmitter acetylcholine. One animal study indicated that coffee strongly potentiates the action of choline in raising the levels of acetylcholine. TMG, on the other hand, is very effective at raising the levels of SAMe and lowering homocysteine. Seafood, beets and spinach contain TMG, but for the methyl-deficient older people, supplements are highly recommended. Interestingly, moderate alcohol intake together with TMG can result in higher levels of SAMe than TMG alone.
  • Methionine is the dietary amino acid that is the precursor of SAMe. Too much methionine, however, can result in elevated homocysteine, particularly if methyl nutrients are insufficient. Unfortunately we do not know the optimal levels of methionine in relation to the levels of methylators such as folic acid. Cooney strongly warns against taking methionine supplements, especially if you regularly eat meat and other animal protein. Taking methionine in addition to eating meat could lead to abnormally high methionine levels, with resulting higher SAMe but also high homocysteine, with both compounds rising and failing in spikes. Cooney is particularly concerned about body builders who use protein mixes, and hence are in effect supplementing methionine. Possibly taking methyl supplements with methionine might make methiunine supplementation safe, but we simply do not know what doses of methyl supplements it would take.
  • Folic acid and vitamin B12 are vital for remethylating homocysteine back to methionine. A coenzyme form of vitamin B12, methylcobalamin, is necessary for the enzyme methionine synthase, which catalyzes the methylation of homocysteine to methionine.
  • Vitamin B6 (pyridoxine) helps convert homocysteine to cysteine. Cooney warns that too much B6 (over 200mg) may result in too much.
  • Selenium participates in methylation as selenomethionine. Animal studies have shown that selenomethionine raises the levels of SAMe - conversion to cysteine rather than methionine, land consequently in impaired methylation.
  • Zinc is part of various enzymes that help methylate homocysteine. The enzyme DNA methyltran also contains zinc.
  • SAMe. Cooney has chosen not to discuss using SAMe, which seems to be the hottest new supplement on the market, one with tremendous promise. We know it can improve mood and cognition while helping reverse arthritis, liver disorders and many other problems. If there is a second edition of this book, I hope it includes "SAMe magic." For now, those who wish to try SAMe should know that it should be taken with methyl supplements. The reason is that part of SAMe gets converted to homocysteine as part of a continual cycle. If you wish to keep your supplements to a minimum, Cooney suggests folic acid, B12 and TMG. These are pirticularly efficient at supplying methyl groups for the conversion of homocysteine to methionine and SAMe. Cooney admits that we do not have enough data to work out either optimal doses of supplements or an optimal diet.
  • Inositol facilitates the action agents. point what we have is educated guesses. One of his most intriguing suggestions is that food could be engineered to contain much greater amounts of beneficial nutrien.


Cooney also states that moderate exercise is important for better methylation. He too warns against strenuous exercise such as marathon running, which has been found to decrease the levels of choline, among other things. Moderate exercise, however, is vital for improving circulation. Good circulation, in turn, insures better handling of homocysteine. Cooney recommends exercise that is sufficiently vigorous to make a person sweat, and one that alternately dilates and constricts blood vessels in the extremities. Sauna followed by cooling down has a similar effect. Cooney mentions that massage likewise enhances circulation. Exercise also helps us stay slender. In general, the lower the body mass index (BMI), the lower the homocysteine.


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