CHAPTER TWELVE

Pregnancy: Cellular Aging Begins in the Womb

When I (Liz) found out I was pregnant, I instantly felt protective toward my tiny unborn baby. On getting back the test results, I immediately stopped smoking. Luckily, I had been smoking only lightly, a few cigarettes a day at most. I found the transition easy to make—especially because I was so concerned about the baby’s wellbeing. I have never smoked again. I also became very interested in what to eat. Listening to my obstetrician and her team, I paid attention to getting nutrients from foods (like fish, chicken, and leafy greens). I also took the micronutrient supplements for iron and vitamins they recommended.

Now, many years later, we have a much deeper understanding of how a mother’s nutrition and health status affects her developing baby. We are also learning what happens to a baby’s telomeres in the womb. Little did I suspect, all those years ago, that my decisions may have helped to protect my baby’s telomeres. Or, more spectacular, that the choices I made—and the events that had happened to me years before the baby was born—might even have affected the starting point of my son’s telomeres.

Telomeres continue to be shaped throughout adulthood. Our choices can make our telomeres healthier, or they can hasten their shortening. But long before we’re old enough to make decisions about what to eat or how much to exercise, and before chronic stress starts to threaten our DNA base pairs, we begin life with an initial telomere setting. Some of us arrive in this world with shorter telomeres. Some of us are lucky to have longer ones.

As you can imagine, telomere length at birth is influenced by genetics, but that is not the whole story. We are learning astonishing things about how parents can shape their children’s telomeres—before those children are even born. And this matters—the telomere length at birth and early childhood is a major predictor of what we have left as we become adults.1 The nutrients that a pregnant mother consumes, and the level of stress she experiences, can influence her baby’s telomere length. It is even possible that parents’ life histories can affect telomere length in the next generation. In a sentence: Aging begins in utero.

PARENTS CAN PASS THEIR SHORTENED TELOMERES TO THEIR CHILDREN

Chloe, now age nineteen, became pregnant two years ago. Without much support or understanding from her parents, she left home and moved in with a friend. To help pay her share of the rent, she dropped out of high school and began working a minimum-wage retail job. Despite her difficult circumstances, Chloe has been determined to give her baby a good start in life. While she was pregnant, she did her best to get prenatal care. She took the prenatal vitamins she was prescribed, even though she says they made her sick. When her son was born, Chloe pledged that he would always, always feel loved.

Chloe is determined to give her child what she didn’t have—better health and greater satisfaction—and to help lift him as part of the next generation. But there is shocking evidence that Chloe’s low education level could have indirectly shaped her baby’s telomeres—while he was still in the womb. Babies whose mothers never completed high school have shorter telomeres in their cord blood compared to those whose moms had a high school diploma—meaning that they have shorter telomeres from the first day of their lives.² Older children whose parents have lower levels of education also have shorter telomeres.3 These findings are based on studies that controlled for other factors that could have influenced the results, such as, in the baby study, whether their babies had a low birth weight.

Let this sink in for a moment, because the implications, if borne out in subsequent studies, are revolutionary. How could a parent’s education level affect the telomeres of her developing baby?

The answer is that telomeres are transgenerational. Parents can, of course, hand down genes that affect telomere length. But the really profound message is that parents have a second way of transmitting telomere length, known as direct transmission. Because of direct transmission, both parents’ telomeres—at whatever length they are at the time of conception in the egg and sperm—are passed to the developing baby (a form of epigenetics).

Direct transmission of telomere length was discovered when researchers were investigating telomere syndromes. Telomere syndromes, as you’ll remember, are genetic disorders that lead to hyperaccelerated aging. Their victims have extremely short telomeres. People with telomere syndromes—think of Robin in an earlier chapter—often watch their hair turn gray while still in their teens. Their bones can become fragile, or their lungs can stop working properly, or they can develop certain cancers. In other words, they make an early and tragically dramatic entrance into the diseasespan. Telomere syndromes are inherited, caused when parents pass a single mutated telomere-related gene down to their children.

But there was a mystery. Some children in these families are lucky enough not to inherit the bad gene that causes the telomere syndrome. You’d think these children would escape premature cellular aging, right? Yet some children without the bad gene still showed mild to moderate signs of early aging—not as severe as what you might find in a full-blown telomere syndrome, but beyond what is normal, such as very early graying. Researchers decided to measure these children’s telomeres and found that their telomeres were, in fact, unusually short. The children had escaped the gene that causes inherited telomere syndrome, but somehow they had still been born with short telomeres that persisted in being short. These children had received short telomeres from their parents—but not through inheritance of a bad gene. Although the children were growing up with normal telomere maintenance genes, because their telomeres had started off so short, the telomeres simply could not be replenished fast enough to catch up and attain normal lengths.4

How can this be? How can children receive short telomeres from their parents, if not through genes? The answer, once you know it, is immediately obvious. It turns out that parents can directly transmit their telomere length to the child in the womb. Here’s how it happens: A baby begins with a mother’s egg, fertilized by the father’s sperm. That egg contains chromosomes. Those chromosomes contain genetic material, of course. That’s how genetic material is passed down to the baby. But the material of the chromosomes of the fertilized egg also includes the telomeres at their ends. Because the baby is made from the egg, the baby receives those telomeres directly—of whatever length they are at that time. If the mother’s telomeres are short throughout her body (including those in the egg) when she contributes the egg, the baby’s telomeres will be short, too. They’ll be short from the moment the baby starts developing. That’s how children without the bad gene received shorter telomeres. And this suggests that if the mother has been exposed to life factors that have shortened her telomeres, she can pass those shortened telomeres directly to her baby. On the other hand, a mother who has been able to keep her telomeres robust will pass her stable, healthy telomeres to the growing child.

What does Dad contribute? Upon fertilization of the egg, the chromosomes that come in from the dad via the sperm join the chromosomes from the mother. The sperm, like the egg, also bears its own telomeres that are directly transmitted to the developing baby. The research to date suggests a father can directly transmit short telomeres, but just not to the extent that a mother with very short telomeres would. In a new study of 490 newborns and parents, babies’ cord blood telomeres were more related to their moms’ telomere length than their dads’, but they are both clearly influential.5

So far, there have been only a few studies that look at direct transmission of telomere length in humans. That would involve measuring both the genetics for telomeres, and the telomeres themselves, so we can separate out the effects of genetics from life experience. Those studies have all been focused on families with telomere syndromes.⁶ But we and other researchers suspect that it happens in the normal population, too.⁷ As you’re about to see, the science of direct transmission suggests a way that poverty and disadvantage may have effects that echo through the generations.

CAN SOCIAL DISADVANTAGE BE PASSED DOWN THROUGH THE GENERATIONS?

Did your parents suffer from prolonged, extreme stress before you were born? Were they poor, or did they live in a dangerous neighborhood? You already know that the way that your parents lived before you were conceived probably affected their telomeres. It may have also affected yours. If your parents’ telomeres were shortened by chronic stress, poverty, unsafe neighborhoods, chemical exposures, or other factors, they may have passed their shortened telomeres to you through direct transmission in the womb. There is even the possibility that you, in turn, could pass those shortened telomeres to your own children.

Direct transmission has strong and chilling implications for all of us who care about future generations. It raises a controversial idea. In our view, the evidence from telomere syndrome families suggests that it is possible for the effects of social disadvantage to accumulate over the generations. We can already see the pattern in large epidemiological studies: Social disadvantage is associated with poverty, worse health—and shorter telomeres. Parents whose telomeres are shortened by this disadvantage may directly transmit those shorter telomeres to their babies in utero. Those children will be born a step behind, or base pairs behind, with telomeres shortened by their parents’ life circumstances. Now imagine that as these children grow up, they are also exposed to poverty and stress. Their telomeres, already shortened, will erode even further. In a downward spiral, each generation directly transmits its ever-shortening telomeres to the next. And each new baby could be born further and further behind, with cells that are more and more vulnerable to premature aging and an early diseasespan. This pattern is exactly what happens in the rare telomere syndrome families: With each successive generation, the progressively shorter and shorter telomeres cause earlier and worse disease impacts than in the generation before.

From the first moments of life, telomeres may be a measure of social and health inequalities. They may help explain the disparity among different postal codes in the United States. People living in certain ZIP codes that represent wealthier areas have life expectancies up to ten years longer than people in other ZIP codes that cover poorer areas. This difference has often been explained by risky behaviors or exposure to violence. But the actual biology of babies born into these neighborhoods may also be different. Tragically, a neighborhood’s health challenges may be compounded from generation to generation. But biology is not destiny; there are many things we can do to maintain our telomeres through our own lifetime.

Figure 26: Aging at Birth? “Mom, what happened to the level playing field?” Babies are born with short telomeres depending on their mothers’ genes but also their mothers’ biological health, level of stress, and, possibly, level of education.

NUTRITION IN PREGNANCY: FEEDING A BABY’S TELOMERES

“You’re eating for two now.” Pregnant women hear this advice all the time. It’s true: A developing baby gets its calories and nutrition from the food the mother eats (and it’s not true the mom needs to eat twice as much). Now it appears that what a pregnant woman eats can also affect her baby’s telomeres. Here, we’ll look at the nutrients that have been connected to telomere length in utero.

Protein

Animal research suggests that modest protein deprivation in pregnancy causes accelerated telomere shortening in the offspring in a number of tissues, including the reproductive tract, and can lead to earlier mortality.8 When a mother rat is fed a low-protein diet during pregnancy, her daughters have shorter telomeres in their ovaries. They also have more oxidative stress and higher mitochondria copy numbers, suggesting that the cells are under high stress and to cope they are rapidly producing more mitochondria.⁹

The damage can even travel to the third generation. When the researchers looked at the granddaughter rats, they found that their ovaries had undergone accelerated tissue aging. They had more oxidative stress, higher mitochondria copy numbers, and shorter telomeres in their ovaries. The granddaughters were victims of early cellular aging, all as a result of a low-protein diet two generations earlier.¹⁰

Co-enzyme Q

There is strong evidence in humans and animal models that maternal malnourishment during pregnancy leads to increased risk of heart disease in the offspring. If a pregnant mother doesn’t get enough to eat, or isn’t adequately nourished, her child may be born at a low birth weight. Often, there’s a rebound effect, with the underweight baby playing a game of catch-up that eventually leads to overeating and obesity. Babies born at a low birth weight carry an increased risk for cardiovascular disease as they get older, and babies who experience this postnatal rebound of rapid weight gain have a risk that’s even higher.

As we said, this scenario links maternal malnourishment to heart disease—and one of the links in the chain may be telomere shortening. Rat pups that are born to mothers who don’t get enough protein tend, like their human counterparts, to have a low birth weight. And just like human babies, they often experience a later rebound of weight gain. Susan Ozanne at the University of Cambridge has found that these rat pups have shorter telomeres in the cells of several organs, including the heart aorta. They also have lower levels of an enzyme known as CoQ (ubiquinone). CoQ is a natural antioxidant that is found mostly in our mitochondria, which play a role in energy production. A CoQ deficit has been associated with faster aging of the cardiovascular system. But when the pups’ diets were supplemented with CoQ, the negative effects of protein deprivation were wiped out, including the effects on telomeres.11 Ozanne and her colleagues concluded that “early intervention with CoQ in at-risk individuals may be a cost-effective and safe way of reducing the global burden of [cardiovascular diseases].”

Of course, it’s a long leap from rat to human. What’s good for one may not be good for another. Even in rats, we don’t know whether the benefits are restricted to pups whose mothers were deprived of protein. CoQ should be put on the list of nutrients for further study of their potentially positive effects on telomeres. If those benefits exist, they could be harnessed for babies of mothers who had inadequate nutrition during pregnancy, or even for adults who are at risk for heart disease. Note that no studies we are aware of have used CoQ during pregnancy, or examined the safety, and thus we are not recommending it.

Folate

Folate, a B vitamin, is another crucial nutrient during pregnancy. You probably know that folate decreases the risk of spina bifida, a birth defect, but it also prevents DNA damage by shielding the regions of chromosomes known as the centromere (all the way in the middle of the chromosome) and the subtelomere (the chromosome region just inside and next to the telomere). When folate levels drop too low, the DNA becomes hypomethylated (losing its epigenetic marks), and the telomeres become too short—or, in a few cases, abnormally elongated.12 Low folate levels also cause an unstable chemical, uracil, to be incorporated into the DNA, and possibly into the telomere itself, perhaps causing temporary elongation.

Babies of mothers who have inadequate folate during pregnancy have shorter telomeres, further pointing to folate as vital for optimal telomere maintenance.¹³ And gene variants that make it harder for the body to use folate are associated with shorter telomeres in some studies.¹⁴

The U.S. Department of Health and Human Services recommends that pregnant women get between 400 and 800 micrograms of folate daily.¹⁵ Just don’t assume that getting even more folate is better. At least one study hints that a mom overdoing vitamin supplementation of folate may decrease her baby’s telomere length.¹⁶ To repeat a theme of this book: moderation and balance are essential!

BABY’S TELOMERES ARE LISTENING TO MOM’S STRESS

A mother’s psychological stress may affect her developing baby’s telomere length. Our colleagues Pathik Wadhwa and Sonja Entringer from the University of California, Irvine, asked if we would collaborate on a study of prenatal stress and telomeres, and we were delighted to join them and study the start of life. The study was small, but it showed that when mothers experience severe stress and anxiety during pregnancy, their babies tend to have shorter telomeres in their cord blood.17 A baby’s telomeres can suffer from prenatal stress. A recent study extended this finding by examining stressful life experiences. Researchers added up the stressful events that happened in the year before giving birth. The mothers with the highest number of stressful life events had babies with telomeres that were shorter by 1,760 base pairs at birth.¹⁸

Sonja and Pathik wanted to know how long the effect of prenatal stress on the baby might last. They recruited a group of adult men and women and asked if their mothers had experienced any extremely stressful events while they were pregnant. (The volunteers interviewed their mothers about major events, such as the death of a loved one or a divorce.) As adults, the volunteers who had been exposed to prenatal stress were different in a several ways—even after controlling for factors that might influence their current health. They had more insulin resistance. They were more likely to be overweight or obese. When they underwent a lab-stressor test, they released more cortisol. When their immune cells were stimulated, they responded with higher levels of proinflammatory cytokines.¹⁹ Finally, they had shorter telomeres.²⁰ A pregnant mother’s severe psychological stress appears to have echoes into the next generation, affecting the trajectory of telomere length for decades of the child’s life.

We’re speaking of very serious stress here. Almost all pregnant mothers experience some mild to moderate stress—not necessarily because they are pregnant but because they are human. At this point, there is no reason to believe that these lower levels of stress are harmful to a baby’s telomeres.

The main player that has been examined in pregnancy stress is cortisol. This hormone is released from the mother’s adrenal glands and can cross the placenta to affect the fetus.21 In birds, cortisol from a stressed pregnant bird will make its way into the egg to affect the offspring. Either injecting cortisol into the egg or stressing out the mother can lead to shorter telomeres in chicks. These studies suggest the possibility that a human mother’s stress could be passed on to her baby in the form of short telomeres. Again, what can happen in birds may not happen in humans—but we know enough about chronic stress and telomeres to state that pregnant women must be protected from life’s harshest stressors. These include any kind of emotional or physical abuse, violence, war, chemical exposures, food insecurity, and grinding poverty. At the very least, we can support local efforts to provide services and support that buffer pregnant women from survival threats like hunger and violence from the earliest days of pregnancy.

Figure 27: Telomere Transmission. There are at least three paths for telomere transmission from a parent to a grandchild. If a mother has short telomeres in her eggs, those short telomeres can be transmitted directly to the baby (this is known as germline transmission). All the baby’s telomeres would then be shorter, including his or her own germline cells (sperm or eggs). During fetal development, maternal stress or poor health can lead to telomere loss in the baby, thanks to excessive cortisol exposure and other biochemical factors. Postnatally, the child’s life experiences can shorten his or her telomeres. This child’s short telomeres in germline can then be transmitted to his or her future offspring. Mark Haussman and Britt Heidinger have described such transmission pathways in animals and humans.22

It’s clear that parents, especially mothers, influence the telomere health of their babies. And as you’re about to see, telomere health is also heavily determined by the way we raise our children and teenagers.

While the health of future generations is important to all societies, it is not, in reality, often paid attention to. Our investment in our most vulnerable young citizens can now be thought of in terms of also investing in base pairs of telomeres, for our collective future of robust health and extended healthspans.

TELOMERE TIPS

Some transmission of telomere length is out of our control. This includes genetics and direct transmission from eggs and sperm. Telomere transmission to children can happen when a parent has very short telomeres, regardless of genetics. It is a real possibility that we could be unknowingly transmitting disparities in health through this direct telomere transmission.

Some of what we transmit is under our control. A mother’s severe stress during pregnancy, smoking, and intake of certain nutrients, such as folate, are related to her baby’s telomere length.

The transmission of severe social disadvantage through telomeres can likely be blocked through policies that protect the health of women of childbearing age, and especially pregnant women, from toxic stressors and food insecurity.