Epigenetic Clocks

You can’t buy an epigenetic clock, but you can use one to measure the age of your tissues and cells and to predict health outcomes and life expectancy.

In our first story, we look at how epigenetics have surpassed telomere length as the best age predictor.

Epigenetics—the differential expression of genes—both establishes the character and function of a cell, and maintains that identity over time through round after round of cell division. So, a heart cell stays a heart cell, and divides to make more heart cells, instead of skin cells or kidney cells––even though all our main cells have the same entire complement of DNA to potentially be anything. This is accomplished by methylation, chemical markers that silence inappropriate genes in a particular cell. The fidelity of that maintenance of methylation is good—97 percent to 99.9 percent every division—but not perfect. Over time, those tiny errors may add up and may help explain why the methylation patterns of identical twins drift apart as they age.

The epigenetic markers of young identical twin pairs are essentially indistinguishable, but then diverge over time. Identical twins have the same DNA, the same genes, but the differences in gene expression among older identical twin pairs were found to be about four times greater than those observed in young pairs. This may result in them each getting different diseases.

An age-related disease like Alzheimer’s only has an identical twin concordance rate of about 50 percent––meaning if one twin gets it, there’s only about a coin flip chance that the other will too, despite identical DNA. Or, even if they both do get it, the disease may manifest decades apart.

Any epigenetic differences that may contribute to differential disease rates may arise from having different diets and lifestyles, or may be a result of random epigenetic drift. However, there are certain DNA sites on our chromosomes that predictably methylate or demethylate as we age. So predictable, in fact, it’s like clockwork.

One of the earliest attempts to study aging and the epigenome (which is only like a dozen years ago) found that the DNA from a 103-year-old appeared to be less methylated overall than the DNA of a newborn infant, suggesting, perhaps, that aging involves the general loss of epigenetic markings. We now know it’s more complicated than that. Of the methylation sites that reliably change as we age, about 60 percent go from methylated to unmethylated, and the other 40 percent become more methylated over time. Some so reliably change with age that they’ve been considered a “molecular crystal ball for human aging.”

In a remarkable triumph of Big Data, out of the millions of methylation sites in our DNA, a tiny subset so dependably shift over time that you can predict someone’s age within a few years just by strategically measuring the methylation pattern in a few hundred, or even just a few dozen, sites in someone’s three-billion-letter genome.

Over just the last few years, these “epigenetic clocks” have become established as robust measures of chronological age, surpassing telomere length as the best age predictor. Who cares, though? Why invent some costly Rube Goldberg approach to divining someone’s age when you can simply ask them? Well, you can imagine forensic applications, the determination of an unidentified victim’s age with a blood sample, but that’s just scratching the surface. The kicker is that epigenetic clocks don’t just track your chronological age, but appear to measure your true biological age. In other words, your epigenetic age can better predict your remaining life expectancy than your calendar age.

It’s like science fiction. Feed a drop of blood into some futuristic machine that scans the placement of chemical markers on a strand of DNA, and it spits out your true age, reflecting a lifetime of lifestyle choices. If the machine calculated that you have the DNA methylation pattern of a 60-year-old, but you’ve only had 50 birthdays, that would be an example of “epigenetic age acceleration”––when your epigenetic clock age is older than your actual chronological age. That would be an indication that you’re aging too fast. As a 50-year-old, you’d think you have another 30 years on this Earth, but because the epigenetic clock showed that you’re aging at such an accelerated pace, it’s more like you only have about another 20 years left. Every five years of epigenetic age acceleration is associated with an 8 to 15 percent increased risk of mortality.

In addition to predicting time-to-death, epigenetic clocks also appear to foretell healthspan indicators, such as cognitive decline, frailty, arthritis, and the progression of diseases like Alzheimer’s and Parkinson’s. As you can imagine, the insurance industry has jumped on this, and your premiums may soon be determined by your epigenetic age. But it’s not some gypsy fortune teller curse set in stone. You can change the rate at which you age, and may soon be able to use epigenetic clocks to track your progress, potentially presenting a radically faster and cheaper way to test anti-aging interventions.

In our next story, we look at unbelievable fact that a baby with a heavy surrogate mother and a thin biological mom may harbor a greater risk of becoming obese than a baby with a slim surrogate mom and a heavy biological one.

Identical twins don’t just share DNA; they also shared a uterus. Might that also help account for some of their metabolic similarities? Fetal overnutrition, evidenced by an abnormally large birth weight, seems to be a strong predictor of obesity in childhood and later in life. Could it be you are what your mom ate?

A dramatic illustration from the animal world is the cross breeding of Shetland ponies with massive draft horses. Either way, the offspring are half pony/half horse, but in the pony uterus they come out much smaller (thank heavens for the poor pony). This is presumably the same reason why the mule (donkey dad and mare) is larger than the hinny (stallion and donkey mom). The way you test this in people is to study the size of babies from surrogate mothers after in vitro fertilization.

Who do you think most determines the birth weight of a test-tube baby—the donor mom who provided all the DNA, or the surrogate mom who provided the intrauterine environment? When it was put to the test, the womb won. Incredibly, a baby born to an obese surrogate mother with a skinny biological mom may harbor a greater risk of becoming obese than a baby from a big biological mom born to a slim surrogate. The researchers conclude, “the environment provided by the human mother is more important than her genetic contribution to birth weight.”

The most compelling data come from comparing obesity rates in siblings born to the exact same mother before and after her bariatric surgery. Compared to their brothers and sisters born before the surgery, those born when mom weighed about 100 pounds less had lower rates of inflammation, metabolic derangements, and, most critically, three times less risk of developing severe obesity (affecting 35 percent of those born before the weight loss compared to 11 percent born after). The researchers conclude “these data emphasize how critical it is to prevent obesity and treat it effectively to prevent further transmission to future generations.”

But wait. Mom had the same DNA before and after surgery. She passed the same genes down. How could her weight during pregnancy affect the weight destiny of her children any differently? Darwin himself admitted that the greatest error he committed “has been not allowing sufficient weight to the direct action of the environment, like food…independently of natural selection.” We finally figured out the mechanism by which this can happen: epigenetics.

Epigenetics (literally meaning “above genetics”) layers an extra level of information on top of the DNA sequence that can be both affected by our surrounds and potentially passed on to our children. This is thought to explain the “developmental programming” that can occur in the womb depending on the weight of the mother, or even your grandmother. Since all the eggs in your infant daughters’ ovaries are already preformed before birth, a mother’s weight status during pregnancy could potentially affect the obesity risk of her grandchildren too. Either way, you can imagine how this could result in an intergenerational vicious cycle where obesity begets obesity.

Is there anything we can do about it? Well, breastfed infants may be at lower risk for later obesity, though the benefits may be confined to exclusive breastfeeding, as the effect may be due to growth factors triggered by exposure to the excess protein in baby formula. The breastfeeding data is controversial though, with charges leveled of a “white hat bias.” That’s the concern that public health researchers might disproportionally shelve research results that doesn’t fit into some goal for the greater good (in this case, preferably publishing breastfeeding studies showing more positive results)––but of course that’s coming from someone who works for an infant formula company. Breast is best regardless; its role in the childhood obesity epidemic just remains arguably uncertain.

Prevention may be the key. Given the epigenetic influence of maternal weight during pregnancy, a symposium of experts on pediatric nutrition concluded that “planning of pregnancy, including prior optimization of maternal weight and metabolic condition, offers a safe means to initiate the prevention rather than treatment of pediatric obesity.” Easier said than done, but overweight moms-to-be may take comfort in the fact that after the weight loss in the surgery study, even the moms who gave birth to kids with three times lower risk were still, on average, obese themselves, suggesting weight loss before pregnancy is not an all-or-nothing proposition.

Finally today, how the anti-inflammatory and antioxidant properties of plant-based diets may help explain why they can effectively reverse cellular aging by elongating telomeres.

Identifying simple strategies to prevent or delay age-related diseases is a major public health concern. How could you measure the effects of such strategies? Well, telomere length is a reliable hallmark of biological aging and the risk of developing age-related chronic diseases. What is a telomere, and why does it matter how long they are?

Telomere comes from the Greek for end part of our chromosomes. Telomeres cap the ends of our chromosomes like shoelace tips to keep our DNA from fraying. Telomere length is important, since there’s a minimum length required. But every time our cells divide, a bit of the telomere is lost, and once they get too short, the cell can die. That’s why telomeres are sometimes called the molecular clock of cells. Every year, they get shorter and shorter, kind of like life’s fuse. But in some people, that fuse burns faster than in others. Accelerated telomere shortening has been identified as a key biomarker for accelerated aging, disease risk, and diminished longevity. But, there’s some good news.

Telomere shortening can be counteracted by an enzyme in our cells called telomerase. Telomerase can replenish the lost bits and elongate our telomeres. So, how can we boost this enzyme to, in effect, reverse cellular aging? Exercise may help. Those with high levels of physical activity have longer telomeres, whereas obese individuals and smokers tend to have shorter telomeres, along with those getting inadequate sleep. But what about nutrition?

Globally, we might expect that any antioxidant or anti-inflammatory diet could be protective for telomeres. So, we’re talkin’ like a whole food plant-based diet, with a reduced intake of meat, and in fact, swapping out animal protein in general in favor of plant-based proteins. Given that plant-based foods have well-known antioxidant and anti-inflammatory effects, there are fair grounds to believe that the consumption of plant-based foods can help to counteract telomere attrition. But you don’t know if it actually would, until you put it to the test.

Dr. Dean Ornish, along with the Nobel laureate who co-discovered the telomerase enzyme, studied the effects of comprehensive lifestyle changes on telomerase activity and telomere length, using the same plant-based diet and lifestyle program shown to reverse the progression of heart disease and early-stage prostate cancer and maybe even early-stage Alzheimer’s. And, telomere length shortened in the control group, and they aged five years as expected––but didn’t just not shorten as much or hold steady, but actually lengthened in the plant-based lifestyle group. Whereas in a similar study across a similar time frame, there was no difference in telomere length when just giving people the more typical low-fat dairy, skinless chicken breast generic-type healthier dietary advice.

Antioxidant-rich plant foods help maintain telomere length. In contrast, total and saturated fat intake and consumption of refined flour grains, meat and meat products, and soda relate to shorter telomeres. People eating more anti-inflammatory diets tend to have longer telomeres, and the greater the anti-inflammatory potential of the diet over time, the greater potential to significantly slow down the rate of telomere shortening. Those with the most pro-inflammatory diets had almost twice the risk of accelerated telomere shortening.

The most pro-inflammatory food component is saturated fat, found in meat, dairy, eggs, and junk, along with other pro-inflammatory food components like cholesterol and trans fat. Omega-3s tend to be anti-inflammatory, but when put to the test, fish oil supplements failed to have any significant telomere effects.

The most anti-inflammatory food component is fiber. And indeed, if you look at dietary fiber intake and telomere length in a representative sampling of thousands of U.S. adults, even though nobody was eating enough, the more fiber people consumed, the longer their telomeres tended to be. Since there appeared to be a straight-line increase, they could do the math. And it appeared that just a 10 gram increase in fiber per 1,000 calories would equate to four fewer years of biologic aging, whereas, for example, the consumption of soda appeared to increase cell aging by almost two years per daily serving.