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The epigenetics of aging: What the body’s hands of time tell us

We’ve all met older adults who seem younger, whose bodies and brains seem decades nimbler than their actual ages, and wondered, “What makes them different?” Despite the wide range of supplements and related products that claim, without scientific evidence, that they can turn back the years, the key to foiling Father Time may lie in the field of epigenetics.

What is epigenetics?

The word “epigenetics” is derived from the Greek word “epi”, meaning “over” or “above,” and in this case, over or above the genome. This area of research involves the study of how our behaviors and environment can cause changes that affect the way our genes work. Genes are made of a chemical called DNA.

Segment of DNA represented by 3-D animated threads that twist and wrap around in a round pattern on a black background.Epigenetic changes are vital to normal biological functioning and can affect natural cycles of cellular death, renewal, and senescence. Different lifestyle and behavioral factors such as diet, sleep, exercise, smoking, and drinking alcohol can also affect the composition and location of the chemical groups that bind to our DNA. Environmental factors such as stress and trauma or even neighborhoods or zip codes may also have an impact.

As part of NIA’s work to increase health span — the part of a person’s life during which he or she is generally in good health — several NIA-funded researchers are accelerating understanding of these epigenetic markers and mechanisms of aging.

Payel Sen, Ph.D., a Stadtman investigator with the NIA Intramural Research Program, leads a team using epigenetic techniques to study the repair of aging or damaged cells. Her lab is currently focused on whether liver tissue and cells can be restored to a younger state to heal the damage from aging, disease, or injury.

The first step to better understanding epigenetics, Sen said, is understanding the intricate way long strands of DNA are packaged inside our cells. Inside the nuclei of cells from all living things, each of those tightly coiled, very long DNA strands contain a set of instructions to build that organism.

“If you drew out the DNA that's wound up inside of just one cell nucleus, it would be six feet long,” she added.

DNA inside the cell nucleus is highly organized and specifically structured, wound around proteins called histones, which are proteins found in cell nuclei that impact the packing and formation of DNA, into structures known as nucleosomes. Similar to clothespins arranged in intricate three-dimensional patterns on a winding clothesline, nucleosomes can be spaced tightly or far apart. Their spacing and organization is affected by exposure to various chemicals, both those that are found naturally inside our bodies as well as those that originate from our environment including food, drugs, and toxins.

As DNA’s spacing and organization changes, different genes become accessible to other parts of our bodies’ genetic machinery that “read” genes and turn them on. This is called gene expression, which starts the process to create the proteins that are the building blocks of the cell activity and growth connected to that gene. Conversely, other chemicals in the body, especially compounds called methyl groups, at certain positions on histones, can alter the spacing and organization of genes. This, in effect, turns them “off” so they won’t be read. This process is known as gene regulation.

A variety of other biological interactions are involved, but in general, epigenetics provides an additional layer of instructions that can affect where and when our genes are expressed that doesn’t change the genetic code itself.

“Our epigenetic processes are under exquisite control in our bodies, but they are also extremely influenced by the environment,” Sen said. “Let’s say you go to the beach and you get exposed to a lot of ultraviolet rays. Certain regions of your skin cells’ genomes are going to react to that and produce byproducts that may not be good for our skin.”

On the other hand, Sen points out that mild levels of environmental stress can be beneficial. “Exercise, being exposed to changes in temperature by not just being in an air-conditioned room all the time, and so on, these kinds of things might make us more resilient,” she added.

Epigenetics: An accurate cellular clock

Epigenetics can also mark accurate chronological time versus biological time. Our chronological age is based on our birthdate, but biological age means the true age that our cells, tissues, and organ systems appear to be, based on biochemistry. Our epigenome is affected by our environment and experiences over time, similar to how rings on the inside of a tree can tell us the tree’s age and mark where it had encountered damage or stress.

3-D round numbered clock that has images of small clocks and timepieces coming out of the top.

Steve Horvath, Ph.D., Sc.D., of the University of California, Los Angeles, along with his twin brother and their friends and collaborators, have been interested in longevity since they were teenagers.

“We were complete amateurs, but at some point, we realized that extending healthy lifespan is a prerequisite for addressing many other grand challenges of our civilization,” Horvath said.

Horvath went on to discover an epigenetic clock that allows us to measure the age of all human tissues. Past models of biological versus chronological age were based on an analysis of telomeres. These are structures at the end of chromosomes that keep them from tangling with each other and play an important role in DNA replication during cell division.

Horvath zeroed in on a natural epigenetic process known as DNA methylation, through which methyl groups attach to cytosines, one of the four main building blocks of our genetic code. By studying changes and patterns in DNA methylation over time in various body tissues, he perfected a molecular clock. More recent human clocks have been developed as estimators of mortality risk. Horvath and his team have since analyzed the DNA methylation clocks from 174 different mammalian species, including exceptionally long-living animals such as the naked mole rats, bats, and bowhead whales. This work resulted in a universal biological aging clock for all mammalian species.

As Horvath has refined this work, it has informed projects seeking epigenetic mechanisms with therapeutic potential. He currently is participating in the expansion of a small, preliminary human study to see if a treatment to change the methylation of sites on one’s DNA could help restore youthful function to the thymus gland. The goal is to prevent the natural age-related degradation of our immune system’s ability to ward off disease and infection.

Like much of the epigenetic field, many obstacles remain for translating animal and cellular lab models to human trials, but the potential is intriguing. Horvath hopes that continued studies, and eventually, rigorous human trials, will someday unlock new ways to slow biologic aging and extend human lifespan.

“That’s kind of the Holy Grail in my lab, to identify and validate anti-aging interventions,” he said.

Epigenetics and our environments

Multiple scientists are researching how to use epigenetics to help heal the body. Others seek to determine how physical or emotional scars from one’s environment or early years, along with our lifestyle and habits, can affect our biological age and outcomes as we grow older.

For example, NIA-funded Researcher Morgan Levine, Ph.D., of the Yale University Department of Pathology, has made major strides in applying modern computational analysis to finding biomarkers that connect to differences between calendar and biological age. Biomarkers are signatures in the body that can help measure natural processes or disease, infections, or toxin exposure. Levine used a machine learning approach to find patterns in big longitudinal studies like the CDC’s National Health and Nutrition Examination Survey to identify a set of nine biomarkers that were accurate predictors of future disease risk, functioning, and mortality when combined with participants’ calendar ages.

A lot of times we’ll define biological age in one dimension, but we know aging itself is multidimensional, so we want to better understand personal aging, not just the rate but the diversity of experiences, plus different risk factors based on lifestyle or background.

— Morgan Levine, Ph.D.

Levine’s research has shown evidence of big differences in healthy aging outcomes between socioeconomic groups. For example, accelerated aging among African Americans makes their biological age about three years greater than white peers of the same chronological age. “We see huge disparities between racial and ethnic groups,” Levine said. “We don’t think those are innate genetic differences but more about what different groups experience and encounter over their lives.”

Terrie Moffitt, Ph.D., of Duke University, another NIA-supported researcher this field, studies how behavioral and social factors in early life may influence long-term differences in biological age, mortality, and health outcomes. Her team tracks early life adversity, chronic stress, childhood health, personality, and intelligence along with less measurable but vital puzzle pieces such as social connectedness, isolation, and a sense of purpose throughout our lives.

Moffitt and her team study data from longitudinal studies like New Zealand’s Dunedin Multidisciplinary Health and Development Study that has been tracking and testing participants since the early 1970s. One study revealed a surprising factor connected to our biological age: intelligence levels measured earlier in life. Dunedin participants who had higher IQ test scores as children consistently had younger biological age measures as adults than fellow participants with lower childhood intelligence.

There are many possible explanations. It could be that kids with higher IQs grow up into adults who tend to have indoor, white collar jobs that are less physically taxing and require less exposure to the stressors, thus not accumulating years of extra biological age. Perhaps higher intelligence means a stronger family support network, access to resources, and an understanding of the importance of healthy diet and exercise.

But Moffitt sees the lifelong connection between aging rate and intelligence as a puzzle that needs further study. She says it could underscore the importance of working to close gaps in education, nutrition, and health care for at-risk children across the world.

“There's the possibility that childhood intelligence is sort of like a canary in the coal mine,” she said. “The brain is our hungriest organ and uses the most resources of all the body. So, it could be that if there's anything wrong anywhere in the body with physical health, that it shows up first in the functions of the brain. So even though children often look pretty darn healthy, if you give them IQ tests you can find some variation that gives you a clue for who's going to end up aging fast or slow.”

Multiple studies have shown that racial and ethnic minorities tend to have lower socioeconomic status and education levels, which tend to co-occur with higher levels of adversity, trauma, obesity, addiction, depression, and stress. These all need to be accounted for, along with biology, if we are truly going to get an accurate picture of human aging and the different rates at which we age, and the variations in resilience to obstacles. Research on these types of health disparities remain a strategic priority for NIA.

Nobel Prize-winning epigenetic research

One of the most promising, Nobel Prize-winning epigenetic techniques uses a harmless virus to introduce special genes called Yamanaka factors (after the researcher who discovered them) to undo the epigenetic programming of mature cells. This process transforms the mature cells back into their younger stem cell form. Having those younger cells in place has been shown to regenerate some function lost to age, illness, or injury.

3-D blue-colored cells with pink centers from a microscope camera.

Recently, NIA-supported researchers led by David Sinclair, Ph.D., A.O., of Harvard University, also came up with a novel technique using Yamanaka factors in an experiment in lab mice that shows great promise for future paths toward treating age-related vision problems. Working in lab cell cultures, the team was able to reverse damage to vision-related neural cells and later made progress restoring some vision loss in a mouse model of glaucoma, a leading cause of age-related human blindness.

Yamanaka factors also feature prominently in the work of another NIA-supported researcher in this field, Thomas Rando, M.D., Ph.D., of Stanford University. Rando is working to uncover whether there is a way to keep our muscle cells young and vital. Another focus of his work is in identifying therapeutic interventions that may be able to mimic the natural benefits of diet and exercise.

“We started pursuing this idea that aging is at least in part an epigenetic phenomenon and that the age of a cell can be modified and modulated,” said Rando. “We want to find out what’s responding to these external stimuli at a molecular level that’s actually making an old cell young. What is that reprogramming process and what is the state of young versus old?”

Today, his team pursues research on combining Yamanaka factors with different body tissues to revitalize and repair them. Rando likens it to the popular comic book character Wolverine who has a mutation giving him a super-fast healing factor that regenerates injured tissue and protects him from toxins.

“We see this in a movie, and we all say, ‘Yeah right,’ but that’s exactly what we do biologically, but we just do it more slowly,” he said.

Rando hopes to someday find safe, effective techniques for stem cell-based, targeted treatments for everything from sports injuries to muscular dystrophy to broken hips. The idea is to get injured tissues or diseased organs to heal faster like they did in their younger days. While modern science is still very far away from such a proven intervention, Rando is optimistic. “Say you break a bone. If you’re 70 years old and break a bone, you’d like to apply a therapy to make that bone heal like a 20- or 30-year-old,” he said.

Next steps for epigenetics research

The science of epigenetics offers intriguing windows into how and why we age at different rates. It also holds both great promise and potential peril for unethical or inequitable use. While this field is growing fast, it is still evolving, and many of the technologies are still only used in animal models and have not yet been approved for humans. Be skeptical and cautious when considering any anti-aging interventions, especially if something seems too good to be true.

While it’s nice to imagine how epigenetics could someday be manipulated to heal or restore, common sense advice on healthy aging remains: eat right, exercise, get enough sleep, moderate unhealthy habits, and stay socially connected.

“There’ve been a lot of books and movies about how people want to extend their lifespans through technology, but I think we're already there in a sense, through medical technology, whether it’s hip replacements, cataract surgery, or heart pumps that extend our years of life,” Duke University’s Moffitt surmised. “But what we all would really like is to have a longer health expectancy: to still be healthy, active, happy and well into our golden years.”