Link between long telomeres and longevity is a tall tale, study finds
The story, as so often in science, sounded so appealing. Cells have a molecular clock that determines how long they live. If you can just stop the clock, cells can live indefinitely. And the same should apply to humans, who are made up of cells, after all. Stop cell clocks and you can stay youthful.
The clocks are shaped like caps at the ends of chromosomes — the long, twisted strands of DNA that carry cells’ genes. The caps on chromosomes, called telomeres, are chains of short, repeating segments of DNA. Each time a cell divides, its telomeres get a little shorter, eventually getting so short that the cell dies.
“Short telomeres were considered bad — people with premature aging syndrome had short telomeres — so long telomeres were considered good,” said Dr. Mary Armanios, Professor of Oncology at Johns Hopkins University School of Medicine and Director of the Telomere Center at the School of Medicine’s Sidney Kimmel Comprehensive Cancer Center. “And the longer the better.”
But of course nothing in biology is that simple. And an article published Thursday in the New England Journal of Medicine detailing the results of a study conducted by Dr. Armanio’s study shows that the telomere story is no exception. While short telomeres lead to health problems, long telomeres lead to their own health problems. Far from prolonging life, long telomeres appear to cause cancer and a blood disorder known as CHIP, a condition that increases the risk of blood cancer and heart disease.
dr Elizabeth Blackburn, a professor emeritus at the University of California, San Francisco, who received the Nobel Prize for her discovery of telomeres and was not involved with the study, said it was a “beautiful paper” that went beyond correlations to a direct connection between long telomeres and disease. She added that the research “clarifies this whole trade-off.”
for dr Armanios it is the culmination of the work she started 20 years ago.
When scientists first began studying telomeres, they found that young people had longer telomeres than older people. When cells are grown in the lab, their telomeres act as a kind of ticking clock, determining how long they have to live.
Telomeres were soon touted as the secret to aging – companies touted that they could determine your biological age by measuring the length of your telomeres. Others said you could extend your life by preserving your telomeres with supplements.
But dr Armanios and other researchers had noticed that telomere lengths appeared to be constrained to a narrow range, indicating that there is a price to be paid for having very long or very short telomeres.
Population studies of several groups seemed to support this idea. They found correlations — not cause and effect — with increased disease risks at both ends of the normal telomere spectrum.
Individuals with shorter-than-average telomeres appeared to be at increased risk of immune system problems and a variety of degenerative diseases, as well as pulmonary fibrosis, a lung disease. Those with longer-than-average telomeres appeared to have a slightly increased risk of cancer.
However, there was some confusion.
“Some organisms have insanely long telomeres, like mice,” said Dr. Benjamin Ebert, Chair of Medical Oncology at the Dana-Farber Cancer Institute. “And mice don’t live that long.”
As a human geneticist, Dr. Armanios that the way to get answers is to study people. “There are things that you just can’t tell from studying cells,” she said.
She suspected, she said, that “you just can’t lengthen telomeres without a price,” and began looking at people with very long telomeres to see what that price might be.
She decided to look for people with a common genetic mutation, POT1, that can result in long telomeres. It was known to increase the risk of cancer, but most researchers thought it was for reasons other than telomere lengthening.
She ended up with 17 people from five families. They ranged in age from 7 to 83 years and had exceptionally long telomeres.
They also had tumors ranging from benign ones like goiter and uterine fibroids to malignant ones like melanoma and blood cancer. During the two-year study, four patients died from various types of cancer.
Harriet Brown, 73, of Frederick, Md., is one of the study participants with very long telomeres. She had benign tumors called paragangliomas in her neck and throat, thyroid cancer, and two melanomas. She also has CHIP, the blood disorder linked to heart disease and blood cancer.
She has frequent scans and exams, but, she said, “there’s really not much I can do at this point” because there’s no way to prevent more tumors from developing.
The impact of long telomeres on people like Ms. Brown makes perfect sense, said Dr. Norman Sharpless, professor of cancer policy and innovation at the University of North Carolina School of Medicine and former director of the National Cancer Institute.
“It doesn’t take long for telomeres to grow cells,” he said. “It’s that they don’t have the brakes to stop them from growing.” And because the telomeres of people with POT1 mutations don’t get shorter with each cell division, the cells hang around and divide regularly. The longer they divide in the body, the more time they have to accumulate random mutations, some of which stimulate tumor growth.
This is especially true in the blood, where cells are constantly being produced. POT1 mutations in some of these blood cells can give them time to accumulate other mutations that give them a selective growth advantage. Soon, some of these mutated blood cells pretty much take over a person’s bone marrow. The result is CHIP.
This is a new view of CHIP. The thought was that CHIP itself causes cancer because people with CHIP have an increased risk of blood cancer.
Instead, said Dr. Armanios, long telomeres both generate CHIP and independently give cells time to develop cancer-causing mutations.
“The biology of aging is much more complicated than we had hoped,” said Dr. Sharpless.
Or, like Dr. Blackburn noted: Long telomeres are not the secret to eternal youth.
“There’s no free lunch,” she said.