By Kara Fitzgerald, ND, IFMCP

When it comes to DNA, it takes millennia for a meaningful change to take hold throughout a species. DNA methylation, on the other hand, can create changes to your genetic expression quickly—so quickly as to be almost instantaneous, especially when compared to the glacial pace of evolution. Remember, methylation is happening in every cell of the body all the time.

Your body is constantly deciding where to lay down and where to remove methyl groups from the DNA based on what you’re experiencing—getting a decent night’s sleep, opting for a handful of seeds for a snack instead of chips, moving your body, doing some activity you love, or meditating can all have a beneficial effect that can show up in just a couple of hours. When you consciously make these choices again and again over the long term, you can likely regain the DNA methylation patterns of a younger you.

Conversely, if you don’t pay attention to what you eat or take steps to mitigate the toxins or stress you’re exposed to, you can speed up the pace at which your DNA methylation gets disordered. One study found that short periods of exposure to air tainted with particulate matter from car traffic caused noticeable epigenetic changes on genes that govern blood leukocytes (a type of immune cell). While there were bigger impacts with longer exposures of four and seven days, there were still noticeable changes after only four hours.¹

How DNA Methylation Changes Become Lasting

Whatever epigenetic changes you experience—positive or negative—they become lasting because some of your cells are replicating through division all the time. When they do, your DNA creates a new copy of itself, so that there’s a new, daughter strand as well as the original strand. Because methyl groups bind to your DNA strand with a strong bond, known as a covalent bond, and there is an enzyme whose sole job is to accurately copy these methyl groups on identical positions at the daughter strand, at every cell division, these methyl groups can stick around. The more you make those changes to your epigenome, the more cells adopt those changes. This is how something you’re exposed to today can create changes to your DNA methylation patterns and genetic expression that last inside your cells and can even be passed down to future generations of offspring.

One caveat: epigeneticist Lucia Aronica thinks that those with chronic disease (and associated accelerated aging) might need to stick with epigenetic-nourishing activities over a longer time frame to create lasting beneficial changes to the epigenome than people who don’t have chronic disease, because their epigenomes may be more resistant to change. 

So, while we know that people with health challenges can perhaps reverse bio age more significantly than healthy peers, it might take longer. We hope to answer this question in future studies.

Although changes can happen quickly, it’s really the choices you make every day over a sustained period of time that impact your long-term health—and even the health of your offspring—most significantly.

Much of what we understand today in terms of the heritability of epigenetic changes and the role of nutrition in what gets handed down was first illuminated by Randy L Jirtle, PhD, a professor of epigenetics at North Carolina State University and senior scientist at the McArdle Laboratory for Cancer Research at the University of Wisconsin at Madison.

A true pioneer in the field of epigenetics, Jirtle conducted an experiment on female agouti yellow mice—a strain of mouse that has an expressed (ie, not hypermethylated and thus inhibited) agouti gene that makes the mice obese and gives them a distinctive yellow coat. Jirtle, and his postdoc Robert Waterland, supplemented their diets with vitamin B12, folic acid, choline, and betaine—these are key players in the methylation process, known as methyl donors—before, during, and after pregnancy. The offspring of these mothers were normal weight, and their coats were either mottled with brown or fully brown, rather than the distinctive yellow. The methyl donors had in effect shut the agouti gene off. It was a true “wow” moment; his paper describing this study has gone on to be the most cited study in the history of science.²

We already knew that a mother’s nutrient levels had a huge impact on the health of her child. For example, we’ve long known that mothers with low levels of folate have a higher rate of giving birth to babies with birth defects, which is why grains have been required to be fortified with folic acid since 1998 (and why rates of birth defects have come down, although there are perils to folic acid supplementation, too).

Turns out that’s because folate is an important component of the methylation process throughout the body, including DNA methylation. But our understanding of just how impactful the nutrition of pregnant human mothers is on the health outcomes of their children was furthered by three relatively recent epidemiological studies.

The first, a 2013 study, looked at children who were born to women who were pregnant during what’s known as the Dutch Hunger Winter. In September 1944, at the tail end of World War II, train workers in the Netherlands went on strike, hoping to slow the movements of Nazi troops and give the Allies a leg up. The Nazis retaliated by implementing a blockade that prevented food supplies from reaching the country, plunging the Western half of the Netherlands into famine conditions. Until the country was liberated in May 1945, most people in the affected area subsisted on somewhere between four hundred and eight hundred calories a day. More than twenty thousand Dutch people died of starvation.

Perhaps not surprisingly, scientists who evaluated the health of the people who were born during and just after the Dutch Hunger Winter found that they experienced health issues that even their own siblings (who were not in utero during the winter in question, either because they were already born or hadn’t been conceived yet) didn’t. What is a surprise is that this cohort, in adulthood, was more likely to be overweight and have higher levels of LDL cholesterol and triglycerides—all things associated with eating too much food, not too little. They also had obesity, diabetes, and interestingly, schizophrenia at higher rates, as well as a 10 percent higher incidence of death from any cause by the time they were sixty-eight.³ Put simply, the early life experiences caused accelerated biological aging and early mortality.

These findings flummoxed the scientists who first observed the higher incidence of obesity. And then, in 2018, thanks to advances in science that allow lab researchers to observe the methylation marks present on over 350,000 different spots on the genome, came a big “Aha!” moment: they saw evidence that those who were in utero during the Dutch Hunger Winter were more likely to have more methyl groups on a gene known as PIM3, which is involved in metabolism, and different methylation patterns on other genes implicated in cell growth, lipid metabolism, and glucose tolerance. Perhaps the mothers’ hunger caused hypermethylation on this gene and imbalanced methylation patterns on other genes, and thus their children’s metabolism always ran a little slower in an effort to hang on to food a little longer, leading to gaining weight.⁴

Another foundational study found a similar result. The Överkalix cohort study analyzed multiple environmental factors on the population of Överkalix—a small city in Sweden where for decades they kept copious records, such as the size of the harvest and the price of food. The researchers were seeking to determine the effect of the amount of food readily available on epigenetic inheritance in populations born in 1890, 1905, and 1920, as well as in those populations’ children and grandchildren. The researchers found that eating too much in childhood—specifically in boys in preadolescence, when sperm are actively maturing—in generation zero correlated with diabetes and diabetes-related mortality in the subsequent three generations! Interestingly, the same study shows a protective effect from eating less, suggesting that there is a sweet spot of food consumption—not too much, not too little, but just right.⁵

The third study that has shaped our understanding of the inheritance of epigenetic changes came in 2014, when Moshe Szyf, Suzanne King, and team conducted a study called Project Ice Storm. In it, they evaluated the DNA methylation of children born to mothers who lived in Montreal and were pregnant during a severe two-week 1998 ice storm that cut the power off in large swaths of Ontario, Quebec, upstate New York, and Maine.

The mothers did not starve, but rather experienced profound physical and psychological stress. King’s team found that these children were likely to develop a distinctive DNA methylation pattern on the genetic code in their T cells—an important immune system cell—and were more prone to displaying symptoms of asthma and autism.⁶

It may seem like bad news that if your mother was exposed to stress or trauma when she was pregnant, you’re doomed to have genes that don’t work as well as they could. When in truth, the opposite is true: knowing that you can influence DNA methylation, and how to do it, can help you make mindful choices that optimize the genetic—and the circumstantial—hand you’re dealt. Even genetic conditions where your fate seems carved in stone can be minimized by bolstering your DNA methylation.

Folate Versus Folic Acid—Understanding the Difference

Folate (vitamin B9) is an essential nutrient and a primary methyl donor—a crucial component of DNA methylation. Folate also helps make both DNA and RNA and repairs DNA.

Folic acid, on the other hand, is a synthetic form of folate. Importantly for food and supplement manufacturers, it is shelf stable. The body can turn folic acid into folate, but the process is time—and energy—consuming, and many people don’t convert it all that well. Because it’s such a key player in processes related to DNA and RNA, folate is needed wherever cell division is happening. As such, folate plays an important role in embryonic development. When it’s deficient, the neural tube (the precursor to what will eventually become the baby’s brain, spine, and nervous system) may not close properly, possibly leading to birth defects.

We’ve known about the connection between folate levels in the mother and the risk of neural tube defects since 1991. As a result of this knowledge, the United States started fortification with folic acid in 1996, and it became mandatory in 1998.

Like most things in life, and nearly every nutrient, there is a U-shaped curve to folate’s benefits. Having too little or too much carries risks.

If you don’t have enough folate, your DNA can become unstable, contributing to a range of conditions—from birth defects and ulcerative colitis to cancer and dementia. Excess folate intake also carries risks, such as increased cancer, especially in older populations. On either leg of the U-shaped curve, the mechanisms behind the cancer risk are different—with too little folate, the synthesis and repair of DNA is hindered, while too much can potentially increase cell proliferation and DNA methylation. In other words, tumor-suppressor genes and other “good-guy” genes are more likely to be inhibited.

The flat portion of the U curve is the sweet spot of lowest risk and highest benefit—and that can be achieved most readily by eating a diet rich in naturally-occurring folate. While fortifying foods with folic acid seemingly supports the goal of helping more people meet their folate needs, it’s by no means clear-cut.

Fortification of folic acid seems like it has been a public health win. In the United States alone, the occurrence of neural tube defects has dropped by as much as 31 percent since we started fortifying⁷—but there are two main problems to consider:

Many people can’t process folic acid into folate easily, resulting in excess “unmetabolized” folic acid in the blood. In one study examining older adults with low B12, high levels of circulating unmetabolized folic acid was associated with reduced cognitive performance.⁸

For people who can process folic acid into folate efficiently, high intake of fortified foods, combined with folate supplementation, can push DNA methylation into potentially dangerous territory—resulting in more methyl groups being added to more DNA (including onto beneficial genes like tumor-suppressor and anti-inflammatory genes, and perhaps even shutting those genes off).
—If cancer is present, folate can increase the synthesis of tumor cells and promote DNA methylation in an unhelpful way. Indeed, the rate of colorectal cancer in the United States started to tick upward (some researchers called it an “abrupt reversal”⁹) in 1996 after a fifteen-year decline, peaking in 1998—the very year that all grain manufacturers were required to fortify their products with folic acid. While mere timing doesn’t prove causation, a 2010 study found that in individuals with high blood folate, two tumor-suppressor genes were hypermethylated and turned off.¹⁰

There are some countries that are exploring ending folic acid fortification because of the potential risks (I would not be surprised if the United States considers this step in the future), and still other countries deciding against starting fortification programs.

It’s clear that while we need adequate folate, we don’t need to source it from folic acid, fortified foods, or from routine supplementation. In my view, the best way to obtain nutrient requirements is through a whole foods diet, and a healthy microbiome can play a role, too.

Beneficial gut bugs produce vitamins, and folate is one of them (B1, B2, B12, biotin, B6, vitamin K, and PABA are others).¹¹ In the clinical trial I helped develop, we increased circulating folate solely via food and by prescribing a probiotic that contains Lactobacillus plantarum—a strain that some research suggests it makes folate.

To be clear, there are times when high-dose supplementation with folate is needed. For example, a condition called cerebral folate deficiency—an autoimmune disease where folate can’t get from the blood into the brain, creating a host of neurological issues including memory loss, vision loss, and hearing loss—can be completely resolved with high doses of folinic acid.¹² Some other conditions where I think supplemental folate is warranted (often along with B12 or other nutrients) include pregnancy, macrocytic anemia, certain neurological conditions, elevated homocysteine, malabsorptive conditions, and some dietary limitations. Otherwise, generally speaking, it’s preferable to source folate through whole foods like dark green leafy greens, asparagus, broccoli, legumes, liver, and eggs.

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Kara Fitzgerald, ND, IFMCP, is a leading voice in the intersection of nutrition, epigenetics, and aging. Receiving her doctorate from National University of Natural Medicine, she is on the faculty at the Institute for Functional Medicine and has a clinical practice in Connecticut.

Well Being Journal adapted this excerpt from Younger You: Reduce Your Bio Age and Live Longer, Better by Kara Fitzgerald, ND. Copyright © 2022. Available from Hachette Go, an imprint of Hachette Book Group, Inc.

References

1. Andrea Baccarelli et al, “Rapid DNA Methylation Changes After Exposure to Traffic Particles,” American Journal of Respiratory and Critical Care Medicine 179, no 7 (April 1, 2009): 572–578, doi: 10.1164/rccm.200807-1097OC.
2. R A Waterland and R L Jirtle, “Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation,” Molecular and Cellular Biology 23, no 15 (August 2003): 5293–5300, doi: 10.1128/MCB.23.15.5293-5300.2003.
3. E W Tobi et al, “DNA Methylation as a Mediator of the Association Between Prenatal Adversity and Risk Factors for Metabolic Disease in Adulthood,” Science Advances 4, no 1 (January 31, 2018): eaao4364, doi: 10.1126/sciadv.aao4364.
4. Carl Zimmer, “The Famine Ended 70 Years Ago, but Dutch Genes Still Bear Scars,” New York Times, January 31, 2018, www.nytimes.com/2018/01/31/science/dutch-famine-genes.html; Elmar W Tobi et al,“DNA Methylation as a Mediator of the Association Between Prenatal Adversity and Risk Factors for Metabolic Disease in Adulthood,” Science Advances 4, no 1 (January 31, 2018): EAAO4364, doi: 10.1126/sciadv.aao4364.
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6. Lei Cao-Lei et al, “DNA Methylation Signatures Triggered by Prenatal Maternal Stress Exposure to a Natural Disaster: Project Ice Storm,” PlosOne (September 19, 2014), doi: 10.1371/journanl.pone.0107653; Anne-Marie Turcotte Tremblay et al, “Prenatal Maternal Stress Predicts Childhood Asthma in Girls: Project Ice Storm” Biomedical Research International 2014 (2014): 201717, doi:10.1155/2014/201717.
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8. M S Morris et al. “Circulating Unmetabolized Folic Acid and 5-Methyltetrahydrofolate in Relation to Anemia, Macrocytosis, and Cognitive Test Performance in American Seniors” [published correction appears in American Journal of Clinical Nutrition 92, no 4 (October 2010):1002], American Journal of Clinical Nutrition 91, no 6 (2010):1733–1744
9. J B Mason et al. “A Temporal Association Between Folic Acid Fortification and an Increase in Colorectal Cancer Rates May Be Illuminating Important Biological Principles: A Hypothesis,” Cancer Epidemiology, Biomarkers & Prevention 16, no 7 (July 2007):1325–1329
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11. Confirmed via email exchange with Marvin Singh, MD, coeditor of Integrative Gastroenterology, Oxford University Press (2019).
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