End Game

Mail-order telomere testing is here. But what can that tell you about aging and disease risk?
Fall 2019
Fouquerel (left) and Opresko answer questions consumers may have about new tests promising answers about health and longevity.
Editor’s Note: In our last Tough Questions, we asked the University of Pittsburgh’s Mylynda Massart and Jeremy Berg, What can genetics reports from consumer companies like 23andMe really tell you about your health? 
Some companies now offer tests to measure the tips of chromosomes, called telomeres, so that you learn more about how you’re aging. What do these tests really mean? For answers, we tapped into the expertise of two telomere researchers— Pitt’s Patricia Opresko, professor of environmental and occupational health in the Graduate School of Public Health, and Thomas Jefferson University’s Elise Fouquerel (Fel ’18). Fouquerel, now an assistant professor, completed a postdoc in Opresko’s lab. 
This article was adapted from The Conversation, with permission.
We are molecular biologists studying how chemicals, agents from the environment, and metabolism damage telomeres and affect their lengths and function. We’re also interested in how damaged telomeres affect the health of our cells and genome. The idea of offering telomere length as part of a genetic test is intriguing since telomeres protect our genetic material. But equating telomere length with something as complex as aging struck us as tricky and overly simplistic.
We thought it would be helpful to probe: What exactly are telomeres? What are telomere tests? And what are companies claiming they can tell you? What’s meant by age based on your birthday versus your “telomere age”?
Telomeres play a big role in keeping our chromosomes and bodies healthy even though they make up only a tiny fraction of our total DNA. The Greek origins of the word telomere describewhere to find them. “Telo” means “end” while “mere” means “part.” Telomeres cap both ends of all 46 chromosomes in each cell and protect chromosomes from losing genetic material. They are often compared to the plastic tips at the ends of shoelaces that prevent fraying.
What’s the link between telomere length and human disease?
Telomeres are important for human health; and despite their protective function, they are not indestructible. Telomeres shorten every time a cell divides and shorten progressively as we age.
When telomeres become too short or lost, the chromosome tips are left unprotected and become sticky. This can cause chromosomes to fuse. To prevent further chromosome shortening and fusions, the cells enter senescence, a state in which they can no longer divide. Although they lose the ability to rejuvenate tissues, senescent cells can still promote inflammation and secrete factors that favor growth of nearby precancerous or cancerous cells.
Unfortunately, our lifestyle can actually accelerate the shortening. Environmental exposures such as sunlight, air pollution, cigarette smoke, and even inflammation or poor diet can damage cell components, including DNA. They do this by generating unstable oxygen molecules, or free radicals. Telomeres are particularly susceptible to damage by free radicals. 
In collaboration with chemist Marcel Bruchez, at Carnegie Mellon University, we developed a new tool that damages only the telomeres. Using this tool, we discovered that oxidative damage to telomeres is sufficient to not only accelerate their shortening but also to cause telomere loss.
In previous laboratory experiments, scientists found that eliminating senescent cells from mice led to the delay or prevention of diseases and conditions associated with aging, including heart disease, diabetes, osteoporosis, and lung fibrosis. This has led to the pursuit of new drugs called senolytics that could eliminate senescent cells in humans.
Is longer better?
Since short telomeres cause cells to senesce, this makes them interesting targets for healthy, disease-free aging. Also, since telomeres shorten with age, regardless of exposure to toxins, this led to the notion that telomere length may provide information about a person’s “true” biological age. 
Commercial tests typically measure telomere lengths or amounts of telomeric DNA in a blood sample. Companies compare your telomeres to telomeres from people of similar age to try to determine the biological age of your blood cells. 
However, just as individuals of the same age vary in height and weight, so do telomeres. If a child falls in the 40th percentile for height, this means compared to 100 girls her age, she is taller than 40. Charts similar to growth charts for children have been generated for telomeres. 
People with telomere lengths below the first percentile are at risk for developing specific diseases including anemia, immunodeficiency, and pulmonary fibrosis, likely due to a gene mutation that impairs telomere maintenance.
At the other extreme, individuals with gene mutations that lead to very long telomeres, above the 99th percentile, are at greater risk for developing inherited forms of melanoma and brain cancers. Longer telomeres allow a cell to divide more times, and with every division there is a chance that an error during genome duplication produces a mutation that promotes cancer. 
In a way, telomeres follow the Goldilocks principle. Too short or too long is not optimal.
Can telomere length predict health outcomes?
But what about telomere lengths in between the extremes? Studies involving hundreds to thousands of participants show general associations of shorter telomeres with increased risk for some diseases of aging, including heart disease, whereas longer telomeres are associated with increased risk for some types of cancers. 
But translating these population studies to predictions about individual life spans and health is difficult. Some people with shorter telomeres do not develop heart disease in these population studies. More studies are needed to fully understand what an individual’s telomere length means for their health and aging. 
Large population studies show a healthy diet is associated with longer telomeres. Yet, claims about specific supplements for telomere health lack scientific backing. 
If such a product could extend telomeres, would it be safe? Or would it increase your risk for developing cancer (because of longer telomeres)? Can protecting telomeres or slowing their shortening promote disease-free aging? We do not have the answers to these questions yet.
So, considering the uncertainties, should you have your telomeres measured? 
Maybe, if the results would motivate healthy lifestyle changes. For now, a better investment for healthy aging would be to spend the money on exercise programs and nutritious foods instead.

The chromosomes here with two pink spots have joined. They are doomed.

They Blew the Caps Off

Scientists have long observed a correlation between telomere damage and cellular aging, but for the first time ever, researchers have demonstrated a cause-and-effect link between the two.
Research—led by Patty Opresko, professor of environmental and occupational health at the Graduate School of Public Health and coleader of the Genome Stability Program at the UPMC Hillman Cancer Center—shows how oxidative stress attacks telomeres, removing the lid on our chromosomes and allowing them to fuse to other, unwilling chromosomes.
“When the cell goes to divide, the chromosomes are now stuck together, so now you have a chromosome being pulled in a tug-of-war between two new daughter cells,” says Opresko. “The forces of that tug-of-war cause the chromosome to break.”
Scientists already knew that where you find oxidative stress—both smoking and air pollution can lead to this—you also find short telomeres. But according to Bennett Van Houten, the other leader of the Genome Stability Project and a professor of pharmacology and chemical biology, they didn’t know precisely what caused telomere shortening. The literature suggests oxidative DNA damage at the telomere, but no one could precisely show cause and effect.  One major source of oxidative stress in the cell generally is dysfunctional mitochondria.
To figure out what was going on, they decided to, as Van Houten says,  “go in with a laser beam and hit” just the telomeres then just the mitochondria.
The studies were possible thanks to Marcel Bruchez, director of the Molecular Biosensors and Imaging Center at Carnegie Mellon University. Using Bruchez’s FAP (short for fluorogen-activating protein) tool, Opresko says they “attached a catcher’s mitt,” which was specially designed to receive light, to the telomeres. When they fired a laser at the mitt, it created oxygen molecules that harmed the telomeres and no other part of the chromosome.
They recorded this event, live on camera, with the help of Simon Watkins, Distinguished Professor of Cell Biology who directs Pitt Med’s Center for Biologic Imaging. A high-definition video shows a laser beam ripping the lid off of the DNA packages and disturbing the cell. Elise Fouquerel, former Opresko postdoc who’s now at Thomas Jefferson University, was the first author on a Molecular Cell paper describing this.
And when Van Houten’s team targeted mitochondria with Bruchez’s tool, they found that sick mitochondria caused increased amounts of oxidative stress, which directly caused telomere damage. That work is described in an August Proceedings of the National Academy of Sciences.
“Pittsburgh is the city of bridges, and none of this would have been possible without collaboration—the bridges built between these different labs,” says Opresko.   —Evan Bowen-Gaddy 
Images: Courtesy Opresko Lab  
Portraits: Courtesy Opresko and Fouquerel    
Photo illustration: Elena Gialamas Cerri