Chapter 17
Folic Acid Is Not Folate
So-called MTHFR mutations are a popular scapegoat, often invoked by alternative medicine practitioners to prescribe special dietary supplements for a number of common complaints (which they just so happen to sell themselves). The enzyme MTHFR is produced by our body to activate folate. A common variant of the MTHFR gene with the DNA code letter T instead of the more typical C at position 677 forms a less functional enzyme. That can have epigenetic effects, since people who inherited the T variant from both parents (about 10 percent of the world’s population) have reduced DNA methylation, but only if they eat little folate. Those who consume enough folate are at the same methylation level, regardless of whether they have the T variants. Similarly, those with two genes of the T variant have an increased cancer risk, but again only if they don’t consume enough folate. Nor do you need any special folate. The folate in foods and the folic acid in dietary supplements and fortified foods are perfectly usable, no matter what genotype you have.
Everyone should try to get enough folate, so no one needs a routine genetic test to determine which variant they have. That’s why major medical professional organizations advise against MTHFR testing. The only thing you might do differently, if you know you ended up with a double dose of the less functional enzyme, would be to be careful with alcohol. Acetaldehyde, the breakdown product of alcohol, can destroy folate in the body, so those with the double T variant should have less than one drink per day. But since everyone should try to keep their alcohol consumption as low as possible, I also believe there’s little benefit in knowing your MTHFR genetics.
Folic Acid Is Not Folate
A review of more than 100 meta-analyses of population studies shows that those who consume more folate from food tend to live longer and are protected from cardiovascular diseases, multiple types of cancer, and multiple chronic diseases. But some randomized controlled trials with folic acid supplementation found a higher cancer risk. As I explore in see.nf/folic, the puzzle was solved when scientists realized that we are not rats.
Natural folate doesn’t keep for long, but we have an enzyme in the liver that converts stable, synthetic folic acid, such as that found in dietary supplements, into an active form of folate. The original experiments were done in rats, and as it turned out, their livers are 50 times more efficient than ours at this conversion, so unprocessed folic acid can circulate in our body, which can impair cancer defenses. For example, randomized controlled trials showed that men who take folic acid supplements considerably increase their prostate cancer risk. Randomized studies also found that people who take folic acid as a dietary supplement for longer than three years are more likely to develop colorectal polyps. Therefore, natural folate sources such as beans and green vegetables are best, although women who want to become pregnant should take folic acid as a dietary supplement, because it has been shown to effectively reduce birth defects.
In addition to diet and dietary supplements, the third way to improve your folate levels is to delegate part of the production to the gut flora. A folate transporter in the colon appears to be there to absorb folate produced by good bacteria such as Bifidobacterium when we feed them fiber. When you eat more fiber, little folate factories arise in the gut.
Food for Thought
The epigenome, characterized by the pattern of DNA methylation, can be imagined as a lens that filters our genetic information. Unfortunately, this lens can become blurry over time. Luckily, epigenetic changes are reversible, so we can clean the lens and it becomes sharp again. Fewer calories, better diet and lifestyle, more exercise, quitting smoking, more vegetables, eating less meat—these can slow the epigenetic clock. If we consume methyl-rich nutrients such as folate in sufficient amounts, that also has an overall impact on methylation capacity.
To help support this anti-aging pathway, you should daily:
Glycation
If you’re a foodie or watch cooking shows, you may have heard of the Maillard reaction. It gives seared steaks, roasted dumplings, grilled marshmallows, or freshly baked cookies their browning, texture, and flavor. In 1912, the French chemist Louis Camille Maillard discovered somewhat by chance that a mixture of proteins and sugars turns brown when heated. In the 100 years since, more than 50 000 scientific articles have been published on this so-called Maillard reaction, in which proteins are irreversibly bound through glycation with sugar. The same reaction can occur at body temperature, leading to an accumulation of advanced glycation endproducts, or advanced glycation end products (AGEs), which we now know are among the main factors in the aging process.
Advanced Glycation End Products
If you have diabetes, you’re familiar with the HbA1c test, which measures blood sugar and indicates the average levels over the past two or three months. The blood test shows only the percentage of hemoglobin in the blood that has bound with sugar. (Hemoglobin is the protein in red blood cells that transports oxygen.) The higher your blood sugar is, the more of your proteins are glycated. Since red blood cells live about 100 days, the test gives you an average value for that period.
Diabetes is defined as an HbA1c value of at least 6,5 percent, which means that 6,5 percent or more of the hemoglobin has bound to sugar. Prediabetes is 5,7 to 6,4 percent; lower values are considered normal. So even if you have normal blood sugar levels, some proteins and other molecules in your body are irreversibly glycated. With short-lived proteins like hemoglobin, which are quickly recycled and newly created, that’s not a problem, but what about long-lived proteins like the crystallins in the lens of your eye?
The half-life of hemoglobin—that is, the pace at which half of it is renewed—is about 50 days. For collagen in the skin it’s more like 15 years, and for collagen in the intervertebral discs an estimated at least 95. Similarly, elastin, another connective tissue protein, is formed in childhood and has to last a lifetime. In glycation, proteins cross-link, which makes tissue stiff—worrisome in arteries and in the heart muscle itself. This reduced elasticity can lead to high blood pressure, peripheral artery occlusive disease, heart disease, and even cancer. (Rigid breast tissue is associated with an increased cancer risk.) The abbreviation AGE (English “age”) for advanced glycation end products was deliberately chosen to emphasize their role in the aging process.
Inflammation Out of Control
There are AGEs, and there is RAGE. Advanced glycation end products not only glue proteins together, but also trigger chronic, systemic inflammation. In searching for the mechanism behind this reaction, researchers discovered receptors for AGEs that trigger the inflammation cascade in the body, and called them RAGE (English “rage”): receptors for advanced glycation end products. RAGEs can function like a main switch. When AGEs ignite RAGEs, an entire army of inflammatory genes is activated, which promotes further RAGE expression, leading to a vicious cycle with far-reaching pathological effects.
AGEs accumulate in bones, joints, and muscles and contribute to osteoporosis, arthritis, and muscle wasting—that is, weakening, shrinking, and loss of muscle mass with age. AGEs bring about age-related memory loss, poorer wound healing, skin aging, cataracts, Alzheimer’s, and erectile dysfunction (in which stiffening of the penile arteries causes the penis to no longer become rigid). AGEs damage virtually all tissues and organs. As one pathologist put it, it is hard to “find an age-related disease in which AGEs are not involved.”