Chapter 16
Turning Back the Clock
In the diet-restriction group, aging rates were slowed regardless of weight loss, yet in samples from liver tissue and visceral fat, overweight was linked to an acceleration of epigenetic aging. But not even losing 100 pounds after gastric reduction surgery seemed to turn back the clock. Maybe we don’t just have to eat less, but better.
The lifestyle factor most closely tied to slowing aging—even more closely than exercise—is a marker of fruit and vegetable intake, the blood levels of carotenoid phytonutrients such as beta-carotene. An “epigenetic diet” would therefore consist of more fruits and vegetables. On the other hand, meat is the food most clearly associated with accelerating aging. Perhaps that’s also because the level of byproducts of banned pesticides such as DDT in the blood is itself associated with accelerated aging and meat consumption. Long-term exposure to air pollution could also have something to do with accelerated aging, but the data on that are not consistent.
Turning Back the Clock
Our epigenetic age predicts life span and some age-related diseases better than chronological age, and that is a strong indication that DNA methylation is inseparably linked with a fundamental cause of age-related decline. So is this the factor that really drives human aging, or is it merely a passive measure of age? Is the epigenetic clock the cause of aging or its result? If it is an active force, then it can be dialed back.
Do you remember how, in cloning, an adult cell could be reprogrammed so that it fell back into the embryonic state? Not only were the methylation markings erased to free up the entire genome, but all traces of aging seemed to vanish. Of course we don’t want to turn the clock back so far that we become a formless clump of cells, but could we set the clock back a little and rejuvenate our cells?
In a discovery for which he received the Nobel Prize, stem-cell researcher Shinya Yamanaka identified what we now call Yamanaka factors: a small handful of DNA-binding proteins responsible for cellular reprogramming and that, in principle, serve to reset a cell to its factory settings. Using these tools, an international team of researchers set out to turn back the clock, to restore the regenerative properties of nervous tissue. For example, in young children, an entire severed fingertip can actually grow back, bone and all, but we gradually lose such abilities with age. The cells of the optic nerve that connect the eyes to the brain also lose the ability to regenerate. But with a bit of manipulation of the Yamanaka factor, the researchers were able to successfully revert methylation sites to a more youthful state, restore the vision of old mice, and rejuvenate human nerve cells in a Petri dish. The cells seemed to have preserved an exact copy of the epigenetic map from an earlier stage of life, which served as a guide to reversing aging.
Methylation Calibration
If we exercise more, eat more fruits and vegetables, smoke less, and eat less meat, that helps us age more slowly, as proven by the genetic clock, which then runs more slowly. But couldn’t we intervene directly in DNA methylation? Many factors affect methylation patterns, but the changes are hard to interpret. For example, in one study, a high-fat diet in men caused far-reaching changes in DNA methylation within just five days. These affected more than 6000 genes and could be only partially reversed six to eight weeks after the participants returned to their usual diet. In addition, overeating saturated fat caused different methylation changes than excessive intake of polyunsaturated fat, but with what effect? We don’t know. Do the epigenetic changes play a role in the resulting physiological effects, or are they purely random?
We are only just beginning to filter out the effects of epigenetic changes caused by diet and lifestyle. By now we know, for example, that vegans have hypomethylation (lower methylation) of a tumor-suppressor gene as well as a gene that encodes a DNA repair enzyme, which consistently distinguishes them from omnivores. Methylation silences genes, and since plant eaters, in a sense, take the muzzle off their genes, that contributes to their lower overall cancer rate. Similarly, in vegetarians, the enzyme superoxide dismutase is less frequently methylated. This is an antioxidant enzyme that can crush a million free radicals per second. Hypomethylation is associated with a threefold increase in the expression of this detoxifying enzyme, which is used to explain the “greater protection in vegetarians against chronic diseases.”
Beyond tinkering with individual genes, there are indications that large changes in methylation affect health and life expectancy. If you increase the enzyme in fruit flies that triggers methylation, you can increase their average life span by more than 50 percent. If you suppress the enzyme, you shorten their life expectancy. But this strategy still has to prove itself in mammals.
Methylation of human DNA is more complicated. The findings on fruit flies nevertheless suggest that it could be favorable for life expectancy to generally increase methylation.
Turning Over a New Leaf
The most thoroughly studied dietary factor is folic acid, because of its epigenetic effect. Folic acid is a form of folate, a B vitamin found in concentrated amounts in beans and green vegetables and that is converted into a methyl source. (The word folate is related to foliage, and they come from the Latin folium, “leaf.”) The methyl group that ends up on your DNA comes, for example, from the folate in your salad, from the folic acid in a dietary supplement, or from enriched flour. The recommended daily allowance for most adults is 400 micrograms (µg), but the average daily intake in older men and women is under 300 micrograms, with a third even under 200. What are the epigenetic consequences?
In postmenopausal women, folate levels were moderately lowered through diet to study the epigenetic effects. Although folate levels did not fall so far that clinical deficiency symptoms appeared (for example, anemia), all study participants developed genome-wide hypomethylation within two months. However, it was reversed within three weeks when the participants ate enough folate again. A later study with even older participants found the same undermethylation, but it took longer to reverse. That underscores how important it is to maintain adequate levels over the long term.
Even without such a depletion, a meta-analysis of randomized controlled trials of folic acid supplementation, using the most demanding methods of laboratory analysis, found a general increase in methylation, suggesting that most of us may not be getting enough of it from our diet. There is no universal benchmark for “normal” methylation rates, so “hypomethylation” is relative, and it is difficult to interpret such changes in practical terms. But our early ancestors ate far more leaves than we do. They probably got twice as much folate as we do today, so I believe our folate status is suboptimal, because our body always uses the additional methyl group available to it whenever our folic acid levels suddenly increase. But we can easily correct that. For example, just follow my recommendations in the Daily Dozen for legumes and dark green leafy vegetables. (Dr. Greger’s Daily Dozen is available as a free app for iPhone and Android.)
Dangerous mutations?