Epigenetics Shapes the Future of Health
By Matt Windsor and Emily Delzell | Illustrations by Ron Gamble
Trygve Tollefsbol believes you can change your destiny—with broccoli. The UAB biologist, a pioneer in the booming field of epigenetics, has the data to make his case. In a widely publicized review paper published this spring in the journal Clinical Epigenetics, Tollefsbol and colleagues at UAB explained how a diet rich in broccoli, green tea, grapes, and other key ingredients can fight off cancer and other aging-related diseases.
UAB scientists are hardly the first experts to tout the health benefits of “superfoods” like leafy vegetables and wine. But epigeneticists like Tollefsbol explain how they help on a genetic level. Their investigations offer new insights on ways to slow the aging process, reduce cancer risk, and more.
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Tollefsbol, who holds doctorates in molecular biology and osteopathic medicine, has published eight books on epigenetics, with more on the way. He is a leader in a discipline that contains a heartening message of biochemical empowerment. Epigenetics is the study of factors that affect your genes without changing the underlying DNA code. To put it another way, epigeneticists try to understand how the genetic instructions contained in our DNA are carried out in the real world.
“The most important concept of epigenetics is that you can take control of your genes,” Tollefsbol says. “What you do affects your genes. In other words, you're not predestined to a certain life because of your genetics, as we once thought. The genes you get from your mother and father aren't going to necessarily limit you for the rest of your life.”
In the grand nature-versus-nurture debate, epigenetics offers a surprising middle ground. Genes are profoundly important, epigeneticists say, but so are environmental factors. The food we eat, the viruses we catch, and the cigarette smoke we breathe all have the power to shape our bodies' underlying structures, even when they don't directly alter our genetic code.
Chemistry and Consequences
Scientists now know that DNA doesn't have to change in order to create serious problems. The outside of the DNA helix is actually covered with a series of chemical markers that act as crucial crib notes for the body's cellular machinery. One common marker is DNA methylation, which occurs when the enzyme DNA methyltransferase adds a methyl group to the DNA base cytosine. Although the cytosine remains cytosine, the methyl add-ons make it more likely that the affected gene will be suppressed.
These epigenetic markers tell the body to ramp up or slow down gene expression, or the production of key proteins. DNA is also wrapped around large proteins called histones, whose properties also have a significant impact on gene expression. (See “Epigenetics in 60 Seconds.”)
These factors are referred to as the epigenome, since they are above and beyond, but directly linked with, the genome. The field of epigenetics has exploded in the last 10 years, as researchers at UAB and elsewhere have discovered that the epigenome plays a vital role in our lives from conception to death—and even reaches beyond the grave to influence our children and grandchildren.
Epigenetics and Cancer
“Epigenetics does not get much hotter than it is right now," Tollefsbol says. “And probably the biggest area is in cancer research.” Scientists once thought that mutations were the most important factor causing cancer, Tollefsbol explains. “Now the prevailing opinion is that epigenetic modifications probably cause cancer more often than mutations do.”
The body has a host of tumor suppressor genes, “which put the brakes on cells and keep them from proliferating,” Tollefsbol says. “Research has shown that these genes can undergo key epigenetic changes so that we become more predisposed to developing cancer.” The gene p53, for example, plays a role in “at least 50 percent of cancers,” Tollefsbol notes. “Essentially, what epigenetics does is turn genes on or off, and a lot of cancer—and aging, for that matter—has to do with the turning on or off of particular genes.”
Enter the Telomere
Another crucial target for epigenetics researchers are tumor promoters, especially the telomeres. One of the most intriguing structures in all of biology, the telomere resides at the endpoints of the chromosomes. These repetitive sections of DNA (which repeat the genetic “code” TTAGGG) solve one of the great problems of mammalian cell division. Every time cells divide—and many divide daily—they lose a little bit of the ends of each DNA strand. If these losses contained important genetic information, life would quickly peter out. That’s why DNA strands are capped with telomeres, which provide a cushion of expendable DNA that can be lost with each rotation of the cell cycle.
The trouble is that “the gene for the enzyme that maintains the telomeres, referred to as telomerase, is actually inactivated before we are born,” says Tollefsbol, “which causes telomeres to get shorter and shorter with each cell division.” Telomeres are a kind of slow-burning fuse—when they run out, cells often self-destruct or become dormant. Scientists theorize that the loss of telomeres could be a major factor driving the aging process.
So what if we found a way to build telomeres back up? Many researchers, including Tollefsbol, think this could be a promising way to make people live longer. “There was a paper in Nature in November 2010 where researchers were able to continually express telomerase in a mouse model,” Tollefsbol says. “The mice lived longer and had fewer diseases. So there is hope that telomerase may be able to extend our lifespan.”
Unfortunately, there is a piranha lurking in this fountain of youth: cancer. “Cancer cells are addicted to telomerase,” says Tollefsbol. “They need it in order to maintain telomeres and keep proliferating.” And these cells have already figured out a way to epigenetically turn on the gene that encodes telomerase, which regenerates telomeres and allows cancer cells to become effectively immortal.
“Just like in Star Wars, telomeres have a good side and a dark side,” Tollefsbol says. “There is a fine balance here, because if we turn on telomerase in people and lengthen their telomeres, we could find out that they’re getting a lot more cancers.” Telomere research is a booming area of epigenetics, and Tollefsbol’s UAB lab, which has studied telomerase and telomeres for more than a decade, is a major player in this work.
Where Nature Meets Nurture
A telomere-based approach to disease would involve miraculous feats in the laboratory, but Tollefsbol is even more excited by the simple-but-powerful epigenetic changes people can accomplish in their own homes.
“We think that environmental and lifestyle factors are probably the most interesting thing about epigenetics,” Tollefsbol says. “Life affects epigenetics: What you eat, whether or not you smoke, your exposure to the sun—all of these bring changes in the epigenome.”
The importance of environmental factors was highlighted in a seminal 2005 study in the Proceedings of the National Academy of Sciences. The paper explained why identical twins, who share the same genes, aren’t carbon copies of each other: Their epigenetic markers are different from birth, and they continue to diverge as twins age.
“The reason for that is the interaction between epigenetics and the environment,” Tollefsbol says. “Maybe one of the twins stayed out in the sun at the beach more than the other and got more wrinkled skin or developed cancer. Studies like this showed that the epigenetic expression of many genes changes each year.”
Scientists once thought that epigenetic changes were temporary, but it is now clear that they can be passed down to the next generation—and beyond. “We are becoming very interested in ‘transgenerational epigenetics,’ or how epigenetic changes can be transferred from the mother to the fetus,” Tollefsbol says. “We do have studies that indicate that what a mother eats while she is pregnant can affect the genome of the fetus that she is carrying. In fact, it can have a major influence on that individual throughout his or her life.”
In one famous epigenetics paper, Swedish scientists reported that the grandchildren of men who had survived famines in a rural county in Sweden in the 19th century were more likely to live longer—six years on average—than the grandchildren of men who had been born during times of relative abundance. “This is still fairly new, but there are some studies that say what your grandfather ate may influence how your life is going,” Tollefsbol says. “I think more proof is needed, but it’s exciting.”
Superfoods to the Rescue?
Dietary factors, which are a key focus of Tollefsbol’s lab, seem to be particularly important, he says. One major takeaway from that research, Tollefsbol says, is that reducing “empty calories” from sugar is beneficial for anyone. “Our work has shown that sugar can predispose a person to cancer,” he notes. “We took precancerous cells—these are cells destined to become cancer cells—and we found that when we reduced the amount of sugar in the culture where the cells were growing, it killed those cells.”
But the “real exciting” development, Tollefsbol says, was his lab’s work on a 2009 study published in the Journal of the Federation of American Societies for Experimental Biology(FASEB Journal). “We found that we could make normal cells live longer by reducing their glucose. That was the first time that was ever seen. A major part of our aging is due to epigenetic processes, and both the quantity and quality of the calories we eat can affect both aging and cancer.”
What if we could reset epigenetic markers with a drug? “There are several so-called ‘epigenetic drugs’ that have been approved by the Federal Drug Administration,” Tollefsbol says—including decitabine. “These are compounds that, for example, inhibit the DNA methyltransferases, which allows tumor suppressors to reactivate in cancer patients.” These drugs, while exciting, have so far been most successful in blood-borne cancers, which are more accessible to drug treatments than solid tumors (cancer of the breast or prostate, for example).
But as Tollefsbol and his team demonstrated in their Clinical Epigenetics paper in 2011, it is fairly easy to eat your way to better health, one cup of green tea or one broccoli spear at a time. They even coined a term for their vegetable prescription: the epigenetics diet.
The Epigenetics Diet
“Many of these dietary compounds work on the particular enzymes that cause epigenetic changes,” Tollefsbol says, “in order to moderate them and keep them in check so that they will not allow cancers to form.” The vitamin folate, found in high quantities in dark green leafy vegetables such as spinach, for example, is a methyl donor. “It keeps genes methylated, which counters the decreased methylation that comes with increasing age.”
“The epigenetics diet can be adopted easily, because the concentrations of the compounds needed for a positive effect are readily achievable,” adds lead author Syed Meeran, Ph.D., a research assistant professor in Tollefsbol’s lab.
Drinking the equivalent of three cups of green tea per day has been shown to suppress breast cancer growth in animal models, Meeran says. The equivalent of a cup of broccoli sprouts each day has been shown to reduce the risk of developing several different cancers in animals.
The beneficial effects of healthy foods aren’t restricted to cancer, either. “Compounds in the epigenetics diet foods can, at the very least, help us to lead healthier lives and help prevent potentially debilitating diseases” such as Alzheimer’s, Tollefsbol says. He is now working on a book called Epigenetics in Human Disease, which will detail the epigenetic components of Alzheimer’s and other conditions, including schizophrenia, dementia, and diabetes.
Tollefsbol says he eats a “90 percent plant diet” and has “cut down on sugar a lot” over the course of his epigenetics research, but he is quick to point out that the epigenetics diet is not a magic cure-all. “We’re not saying that all you have to do is drink a few cups of green tea and you’ll be cancer-free guaranteed,” he says. But the evidence indicates that avoiding excess sun exposure, eating a healthy diet, and adopting other behaviors that are conducive to avoiding negative epigenetic changes can pay off in the long run.
“We are learning more and more that your behavior, in terms of the choices you make during your life, has a huge effect on your body,” Tollefsbol says. “Studies indicate that the earlier you start, the better, but these behaviors are beneficial to everybody.”