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Do the Caps of Your Chromosomes Hold the Secret to More Years?

After 40 years, leading scientists in the field of telomere research are getting closer to finding therapeutics that could treat diseases of aging, if not aging itself.

By Kristen French

Illustration by Victor Mosquera

July, Outside magazine ran a profile of a woman named Elizabeth Parrish. “Liz Parrish Wants to Live Forever,” the headline shouted. A few years earlier, in 2015, Parrish had become the first human guinea pig in an experiment intended to reverse aging through gene therapy. She, and the scientists who designed the therapy, were optimistic. They thought they might have found a formula that would, essentially, stop time.

Conducted in a private clinic in Bogota, Colombia, Parrish’s treatment was aimed at lengthening her cells’ telomeres, the caps of DNA at the ends of our chromosomes. Telomeres function like our bodies’ internal clocks, determining the rate at which we age. They shorten over time, as our cells divide, and when they become short enough, the chromosomes can no longer replicate and the cells that house them typically stop dividing and undergo senescence, or else die. This shortening is associated with a number of age-related conditions, such as diabetes, hypertension, Alzheimer’s disease, and cancer, as well as idiopathic pulmonary fibrosis, bone marrow failure, and cryptogenic liver cirrhosis.

In 2016, Parrish’s company BioViva announced some good news: a lab in Houston had determined that the gene therapy she received in Colombia had extended the telomeres in her white blood cells — as measured by counting DNA base pairs — by 9 percent. According to the press release, this was equivalent to 20 years of aging. (Newborns have telomeres that are about 8,000–13,000 DNA letters long, and they are thought to decline by about 20–40 base pairs each year.) But BioViva did not publish a formal research paper to go with the findings, rendering them useless to most scientists.

Today, Parrish looks pretty much the same as she did in 2015, and no further findings about her health or rate of aging have emerged. But plenty of other promising telomere research has. Some scientists have even characterized the current state of telomere research as nothing short of a “revolution.”

What Are Telomeres?
Telomeres are like nubs protecting the ends of our chromosomes from damage, much in the way a thimble protects the thumb of a seamstress. The term telomere comes from the Greek: telos, which translates as “end,” and meros, which means “part.” Composed of DNA and specialized proteins, telomeres form protective loops that prevent the chromosome ends from being recognized as sites of DNA damage, which could attract unnecessary and even harmful “repairs.”

The longer one’s telomeres are, the better they protect the ends of one’s chromosomes. But not all people start life with equally long telomeres, and the length of your telomeres is at least partly genetic, says Jerry Shay, a professor of Cell Biology at the University of Texas, Southwestern Medical Center in Dallas, who has been studying telomeres for decades. Likewise, not all telomeres shorten at the same rate because not all cells renew at the same rate, says Shay.

Cells in the intestinal tract, for instance, turn over every seven days. Cells in the lung turn over every six months. But in a span of minutes, tens of millions of new blood cells will be created in the average human. Anything that causes damage can shorten a cell’s telomeres. Smoking, for example, can severely shorten telomeres in lung cells — as well as increase the risk of lung cancer.

“But not all people start life with equally long telomeres, and the length of your telomeres is at least partly genetic.”
Today, some companies, such as TeloYears, purport to measure your telomeres and spit out a longevity score. But this is difficult to do accurately. What matters for both disease and aging is not the average length of your telomeres, but rather the length of your shortest telomeres, according to Shay. It is the critically short telomeres that lead to either cell death or to activation of telomerase, an enzyme that adds nucleotides to telomeres, lengthening them, and that is highly active in cancer cells. (More on telomerase and cancer below.) Measuring the shortest telomeres is much harder to do than taking an average.

Telomere Caps (U.S. Department of Energy Human Genome Program)
Where Did Telomere Research Begin?
The role that telomeres and telomerase play in protecting chromosomes was first discovered in the late 1970s and early 1980s by Jack Szostak, Elizabeth Blackburn, and her then-graduate student Carol Greider. Together they showed that certain nucleotide repeats found protecting the ends of chromosomes in single-celled protozoan also were found performing the same function in yeast cells, which suggested something basic to all living organisms was at work. Blackburn and Greider then were able to identify telomerase, the enzyme that makes telomere DNA.

“When we started we just said well this is a long shot experiment that’s worth a try. Now it’s become a whole field in itself because it’s so relevant to aging and cancer.”
Telomerase — which is composed of an RNA subunit, and a catalytic protein subunit called TERT, or telomere reverse transcriptase — is naturally found in fetal tissues, adult germ cells, and is otherwise primarily active during development. Its purpose is to allow stem cells to replicate themselves and develop into more specialized cells in embryos and fetuses. But it is also found in tumor cells, where it is 10–20 times more active than in resting adult stems cells. “When we started we just said well this is a long shot experiment that’s worth a try,” Szostak said about their earliest investigations into telomeres.

That turned out to be quite an understatement. “Now it’s become a whole field in itself because it’s so relevant to aging and cancer,” he said. In 2009, the trio won a Nobel Prize for their work. Almost forty years after their discovery, scientists are still puzzling out the precise function, structure, and role of telomeres and telomerase in both aging and cancer.

The real hurdle now is how to deliver telomere targeting treatments to human cells, says Szostak, who is no longer doing telomere research, but still watches the field closely. “Really targeted delivery is the general problem that tons of people are working on,” he said. He is skeptical that this problem of delivery will be resolved any time soon.

What Is the Link Between Short Telomeres and Cancer?
The biggest obstacle to successfully arresting aging via telomere tinkering is the cancer risk. “When telomeres get really short, they send off a DNA damage signal and it makes the cell stop dividing,” said Shay. With short telomeres, you get oncogenic changes, tumor suppressor losses, and all of a sudden you have such short telomeres that the cells start fusing their ends together. “There’s all kinds of DNA damage, and the way a cancer cell survives is by up-regulating telomerase,” he said.

Because most of the cells in our bodies do not regularly use telomerase, they age, but when telomerase is activated in a cell, the cell can become immortal, dividing forever, and with other changes, become cancerous. Telomerase gets shut off during development, and it stays shut off unless you get cancer.

As it turns out, telomerase goes silent because it’s right by a telomere and the TERT gene, said Shay. When telomeres get long enough they loop over and turn off the telomerase gene. When the telomeres get short this telomerase gene is no longer protected and can be turned back on. That’s why it’s turned on in 85 or 90 percent of all cancers.

“There’s all kinds of DNA damage, and the way a cancer cell survives is by up-regulating telomerase.”
But so far, telomerase inhibitors have not been shown in clinical trials to successfully treat cancer, according to Ronald DePinho, another giant in the field of telomere research. “Those trials have not progressed as quickly as I would have liked to see them progress,” said DePinho.

Recent Advances in Telomere Research
Several major breakthrough findings have advanced the field of telomerase research over the past decade. DePinho, who initially studied telomeres at Harvard University’s Dana-Farber Cancer Institute, was able to link telomeres to the three major theories of aging — DNA damage, mitochondrial dysfunction and free-radical accumulation — in one elegant formulation.

His work in mouse models showed that telomere dysfunction activates a gene called p53, which suppresses a protein called PGC, which normally promotes expression of genes that make mitochondria work well and protects us from free-radicals. Then in a 2010 study, his lab showed that turning on the telomerase gene in lab-engineered artificially-aged mice caused a dramatic return of youthfulness — new growth of the brain and testes, heightened fertility, and restored cognitive function.

Two years later, Spanish telomere researcher Maria Blasco showed that lengthening the telomeres of normal mice using a viral vector called AAV9 to deliver a gene therapy called TERT increased their healthspans, without causing cancer. More recently, Blasco was able to show that the same therapy did not cause cancer even in cancer-prone mice. “We still do not know whether in humans, with a much longer survival, telomerase may favor or not tumorigenesis,” wrote Blasco in an email, “but our results certainly indicate that telomerase overexpression per se is not acting as an oncogene.”

Blasco has further shown that AAV9-TERT can improve the symptoms of pulmonary fibrosis, a fatal lung disease associated with shortened telomeres, as well as aplastic anemia, a rare blood disorder caused by failure of the bone marrow to make enough new blood cells. She is working on developing mouse models that demonstrate that short telomeres can lead to cognitive impairment, in order to better understand whether TERT therapies could be used to treat diseases such as Alzheimer’s.

Are We Close To Telomere Therapies?
In the meantime, a race seems to be on to get human clinical trials going for telomerase therapies that target specific diseases of aging and premature aging. Leading telomere researcher Helen Blau of Stanford University, together with former colleague John Ramunas, founded Rejuvenation Technologies, which has already received funding for preclinical studies to prepare human trials for a modified messenger RNA therapy that would be used to treat diseases associated with premature aging. Blau predicts these human clinical trials could be run under an accelerated FDA track because of the severity of the diseases and a lack of treatments that address the underlying telomere defect.

Blau and Ramunas, who previously worked in Blau’s lab, published research in 2015 that showed their modified mRNA therapy can temporarily extend telomeres in human cells. The modified mRNA sticks around for just 48 hours, which means that the treated cells don’t go on to divide indefinitely, reducing cancer risk. And yet those 48 hours were enough to extend the telomeres in human muscle and skin cells by about an entire kilobase, the equivalent of ten years of lifespan.

The findings have huge implications for diseases that have been found to be associated with short telomeres, such as dyskeratosis congenita, duchenne muscular dystrophy, liver cirrhosis and even heart disease and heart failure. “We’re focusing on specific diseases involving short telomeres initially,” says Ramunas. “We’re at a very early stage still.”

The biggest challenge is delivery because each individual cell type requires a slightly different mechanism — viral vectors work for certain kinds of cells, but not others. Blau was tight-lipped about the kinds of alternative delivery mechanisms her lab is testing but said they are making progress toward a clinically applicable solution.

“We’re focusing on specific diseases involving short telomeres initially. We’re at a very early stage still.”
Jerry Shay, meanwhile, is currently focused on lengthening the healthspan of centenarians. He recently studied a group of centenarians, some of whom were in robust health and others who were suffering from age-related disease, and found important genetic differences as well as differences in the lengths of telomeres in their T-cells, immune cells found in the blood. Shay would like to design a therapy that would allow him to extend the T-cell telomeres of those individuals who are genetically predisposed to the greatest decline in old age.

A key difference from other treatments targeted at live humans is that he would work ex-vivo. That means that Shay and his team would remove the T-cells from patients, transfect these cells with purified telomerase, then study these modified T-cells to be sure they hadn’t introduced cancer or mutations or defects, and infuse the T-cells back into the patients’ blood. Helen Blau, the director of the Baxter Laboratory for Stem Cell Biology at Stanford University, has pointed out that extending the telomeres of T-cells is risky because they divide so frequently and are predisposed to cancer, but Shay says that’s why his group would examine the cells closely before they injected them back into the body. Regardless, FDA approval could take time, said Shay.

It’s Too Soon for Miracle Drugs
Elizabeth Parrish’s former partner Bill Andrews thinks he has the answer to the difficult riddle of targeted delivery of telomere therapy. A leading expert on telomeres, Andrews initially supported Parrish’s experiment in Colombia, but later disavowed the results, saying he wasn’t sure Parrish had used a legitimate protocol and that the study didn’t produce enough data. Andrews is now conducting his own clinical trial in Colombia using a similar telomere targeting gene therapy, though details are sparse.

Some of Andrews colleagues in the field caution that it’s too soon for such testing in humans — that the cancer risk is too high. For this reason, and because the FDA doesn’t treat aging as a disease, it would be difficult to get approval to do these clinical trials in the U.S.

But others are cautiously optimistic about his work. “All power to Bill Andrews for sticking to it and searching far and wide for a better drug,” said John Ramunas, a telomere researcher from the Stanford lab of Helen Blau, which has made a number of critical findings. “In principle, it would reverse the aging process to extend telomeres in all of our cell types,” said Ramunas. “I think that’s worth aiming for.”

Finding the right gene therapy mechanism that would safely activate telomerase in every single human cell type is likely many years off, however — different cell types require different approaches.

“In principle, it would reverse the aging process to extend telomeres in all of our cell types. I think that’s worth aiming for.”
Aubrey de Grey, a leading and sometimes provocative figure in the field of longevity research, was more brash. “At the end of the day, what I suspect, is that we’re only going to get real answers to this question as it relates to humans, by studying humans. By actually observing what happens to the crazy people who are actually supplementing the telomerase into cells via medical tourism.”

It’s obviously not ideal that these experiments are open-label and are neither randomized, double-blinded nor controlled, said De Grey — if you’re paying proper money to get a risky life-extending gene therapy you don’t want to be a control.

But if the follow up on patients is thorough enough, then we should be able to at least get some “tentative answers,” he said.

An article of https://endpoints.elysiumhealth.com/what-are-telomere-therapies-for-aging-4becbf10485e

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