A telomere is a region of repetitive DNA sequences at the end of a chromosome. Telomeres protect the ends of chromosomes from becoming frayed or tangled. Each time a cell divides, the telomeres become slightly shorter. Eventually, they become so short that the cell can no longer divide successfully, and the cell dies.

Telomere. A chromosome is essentially a long, long piece of DNA that has really wrapped up and compacted on itself until it looks like the structure you probably picture when I say chromosome. The problem is that the long piece of DNA has two ends, and they're just hanging out there loose. A lot of things could go wrong if those ends aren't protected. They could get cut off, or they could join onto other loose DNA ends, which would be a problem for the cell. Telomeres are how cells protect chromosome ends. The telomere itself is a long stretch of a specific short DNA sequence repeated over and over hundreds of times. At the very end of the telomere is a sort of knot not called the "T-loop," which keeps the chromosome ends from all sticking together. Every time a cell divides, some of those telomere repeats get cut off. So in certain cell types that divide a lot, an enzyme called "telomerase" adds those repeats back so the telomere doesn't get too short.

Lisa H. Chadwick, Ph.D., Program Director, Division of Genome Sciences

Many scientists speculate that another contributor to the aging process is the accumulation of cellular retirees. After cells divide about 50 times, they quit the hard work of dividing and enter a phase in which they no longer behave as they did in their youth.

Damage to each person’s genome, often called the “Book of Life,” accumulates with time. Such DNA mutations arise from errors in the DNA copying process, as well as from external sources, such as sunlight and cigarette smoke. DNA mutations are known to cause cancer and also may contribute to cellular aging.

How do our cells know when to retire? Do cellular clocks have a big hand and a little hand and go, “Tick, tock?” Not exactly. It turns out that each cell has 92 internal clocks—one at each end of its 46 chromosomes. Before a cell divides, it copies its chromosomes so that each daughter cell will get a complete set. But because of how the copying is done, the very ends of our long, slender chromosomes don’t get copied. It’s as if a photocopier cut off the first and last lines of each page.

As a result, our chromosomes shorten with each cell division. Fortunately, the regions at the ends of our chromosomes—called telomeres— spell out the genetic equivalent of gibberish, so no harm comes from leaving parts of them behind. But once a cell’s telomeres shrink to a critical minimum size, the cell takes notice and stops dividing.

In 1985, scientists discovered telomerase. This enzyme extends telomeres, rebuilding them to their former lengths. In most of our cells, the enzyme is turned off before we’re born and stays inactive throughout our lives. But theoretically, if turned back on, telomerase could pull cellular retirees back into the workforce. Using genetic engineering, scientists reactivated the enzyme in human cells grown in the laboratory. As hoped, the cells multiplied with abandon, continuing well beyond the time when their telomerase-lacking counterparts had stopped.

Aging in Fast-Forward: Werner Syndrome

Mary was diagnosed with Werner syndrome at age 26, when she was referred to an ophthal­mologist for cataracts in both eyes, a condition most commonly found in the elderly. She had developed normally until she’d reached her teens, at which point she failed to undergo the growth spurt typical of adolescents. She remem­bers being of normal height in elementary school, but reports having been the shortest person in her high school graduating class, and she had slender limbs relative to the size of her trunk. In her early 20s, she noticed her hair graying and falling out, and her skin became unusually wrinkled for someone her age. Soon after the diagnosis, she developed diabetes.

Although hypothetical, Mary’s case is a classic example of Werner syndrome, a rare inherited disease that in many respects resembles premature aging. People with Werner syndrome are particularly prone to cancer, cardiovascular disease, and diabetes, and they die at a young age—typically in their 40s. At a genetic level, their DNA is marked by many mutations. These characteristics support the theory that accumulating DNA mutations is a significant factor in normal human aging. At age 15, this Japanese-American woman looked healthy, but by age 48, she had clearly developed symptoms of Werner syndrome. The gene involved in Werner syndrome was identified in 1996 and was found to encode what appears to be an enzyme involved in DNA repair. This suggests that people with Werner syndrome accumulate excessive DNA mutations because this repair enzyme is either missing or not working properly. A few years after the discovery of the human Werner syndrome gene, scientists identified a corresponding gene in yeast. Deleting the gene from yeast cells shortened their lifespan and led to other signs of accelerated aging. This supports a link between this gene and aging, and it provides scientists a model with which to study Werner syndrome and aging in general.

At age 15, this Japanese-American woman looked healthy, but by age 48, she had clearly developed symptoms of Werner syndrome.

The gene involved in Werner syndrome was identified in 1996 and was found to encode what appears to be an enzyme involved in DNA repair. This suggests that people with Werner syndrome accumulate excessive DNA mutations because this repair enzyme is either missing or not working properly.

A few years after the discovery of the human Werner syndrome gene, scientists identified a corresponding gene in yeast. Deleting the gene from yeast cells shortened their lifespan and led to other signs of accelerated aging. This supports a link between this gene and aging, and it provides scientists a model with which to study Werner syndrome and aging in general.

The ends of linear chromosomes are maintained by the action of the telomerase enzyme.

Telomerase is typically found to be active in germ cells, adult stem cells, and some cancer cells. For her discovery of telomerase and its action, Elizabeth Blackburn received the Nobel Prize for Medicine and Physiology in 2009. Later research using HeLa cells (obtained from Henrietta Lacks) confirmed that telomerase is present in human cells. And in 2001, researchers including Diane L. Wright found that telomerase is necessary for cells in human embryos to rapidly proliferate.

Summary

The ends of eukaryotic chromosomes pose a problem, as polymerase is unable to extend them without a primer. Telomerase, an enzyme with an inbuilt RNA template, extends the ends by copying the RNA template and extending one end of the chromosome. DNA polymerase can then extend the DNA using the primer. In this way, the ends of the chromosomes are protected. Cells have mechanisms for repairing DNA when it becomes damaged or errors are made in replication. These mechanisms include mismatch repair to replace nucleotides that are paired with a non-complementary base and nucleotide excision repair, which removes bases that are damaged such as thymine dimers.

Telomerase is an enzyme that contains a catalytic part and an inbuilt RNA template; it functions to maintain telomeres at chromosome ends.

Cells that undergo cell division continue to have their telomeres shortened because most somatic cells do not make telomerase. This essentially means that telomere shortening is associated with aging. With the advent of modern medicine, preventative health care, and healthier lifestyles, the human life span has increased, and there is an increasing demand for people to look younger and have a better quality of life as they grow older.

In 2010, scientists found that telomerase can reverse some age-related conditions in mice. This may have potential in regenerative medicine. Telomerase-deficient mice were used in these studies; these mice have tissue atrophy, stem cell depletion, organ system failure, and impaired tissue injury responses. Telomerase reactivation in these mice caused extension of telomeres, reduced DNA damage, reversed neurodegeneration, and improved the function of the testes, spleen, and intestines. Thus, telomere reactivation may have potential for treating age-related diseases in humans.

Cancer is characterized by uncontrolled cell division of abnormal cells. The cells accumulate mutations, proliferate uncontrollably, and can migrate to different parts of the body through a process called metastasis. Scientists have observed that cancerous cells have considerably shortened telomeres and that telomerase is active in these cells. Interestingly, only after the telomeres were shortened in the cancer cells did the telomerase become active. If the action of telomerase in these cells can be inhibited by drugs during cancer therapy, then the cancerous cells could potentially be stopped from further division.

Normal Function

The TERT gene provides instructions for making one component of an enzyme called telomerase. Telomerase maintains structures called telomeres, which are composed of repeated segments of DNA found at the ends of chromosomes. Telomeres protect chromosomes from abnormally sticking together or breaking down (degrading). In most cells, telomeres become progressively shorter as the cell divides. After a certain number of cell divisions, the telomeres become so short that they trigger the cell to stop dividing or to self-destruct (undergo apoptosis). Telomerase counteracts the shortening of telomeres by adding small repeated segments of DNA to the ends of chromosomes each time the cell divides.

In most types of cells, telomerase is either undetectable or active at very low levels. However, telomerase is highly active in cells that divide rapidly, such as cells that line the lungs and gastrointestinal tract, cells in bone marrow, and cells of the developing fetus. Telomerase allows these cells to divide many times without becoming damaged or undergoing apoptosis. Telomerase is also abnormally active in most cancer cells, which grow and divide without control or order.

The telomerase enzyme consists of two major components that work together. The component produced from the TERT gene is known as hTERT. The other component is produced from a gene called TERC and is known as hTR. The hTR component provides a template for creating the repeated sequence of DNA that telomerase adds to the ends of chromosomes. The hTERT component then adds the new DNA segment to chromosome ends.

Health Conditions Related to Genetic Changes

Dyskeratosis congenita

At least 40 mutations in the TERT gene have been identified in people with dyskeratosis congenita. This disorder is characterized by changes in skin coloring (pigmentation), white patches inside the mouth (oral leukoplakia), and abnormally formed fingernails and toenails (nail dystrophy). People with dyskeratosis congenita have an increased risk of developing several life-threatening conditions, including cancer and a progressive lung disease called pulmonary fibrosis. Many affected individuals also develop a serious condition called aplastic anemia, also known as bone marrow failure, which occurs when the bone marrow does not produce enough new blood cells.

Most of the TERT gene mutations that cause dyskeratosis congenita change single protein building blocks (amino acids) in the hTERT protein, causing it to be unstable or dysfunctional. The mutations interfere with telomerase function, leading to impaired maintenance of telomeres and reduced telomere length. Cells that divide rapidly are especially vulnerable to the effects of shortened telomeres. As a result, people with dyskeratosis congenita may experience a variety of problems affecting quickly dividing cells in the body such as cells of the nail beds, hair follicles, skin, lining of the mouth (oral mucosa), and bone marrow.

Breakage and instability of chromosomes resulting from inadequate telomere maintenance may lead to genetic changes that allow cells to divide in an uncontrolled way, resulting in the development of cancer in some people with dyskeratosis congenita.

Idiopathic pulmonary fibrosis

At least 70 mutations in the TERT gene have been identified in people with the progressive lung disease idiopathic pulmonary fibrosis. This condition causes scar tissue (fibrosis) to build up in the lungs, which makes the lungs unable to transport oxygen into the bloodstream effectively. Mutations in the TERT gene have been found in cases that run in families (familial pulmonary fibrosis) and, less commonly, in isolated (sporadic) cases. Some individuals with idiopathic pulmonary fibrosis due to TERT gene mutations have family members with other features of dyskeratosis congenita (described above), such as aplastic anemia or cancer.

Mutations in the TERT gene reduce or eliminate the function of telomerase, which allows telomeres to become abnormally short as cells divide. The shortened telomeres likely trigger cells that divide rapidly, such as cells that line the inside of the lungs, to stop dividing or to die prematurely. In people with idiopathic pulmonary fibrosis, shorter telomeres are associated with a more severe disease and a quicker decline in lung function. Additional research is needed to confirm how shortened telomeres contribute to the progressive scarring and lung damage characteristic of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a complex disease that is probably caused by a combination of genetic and environmental factors. Studies suggest that many affected people with TERT gene mutations may have also been exposed to environmental risk factors, such as cigarette smoke or certain kinds of dust or fumes. It is possible that mutations in the TERT gene increase a person's risk of developing idiopathic pulmonary fibrosis, and then exposure to certain environmental factors can trigger the disease.

Breast cancer

MedlinePlus Genetics provides information about Breast cancer

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Melanoma

Mutations in the TERT gene have been associated with an increased risk of a type of skin cancer called melanoma. Researchers suggest that these mutations may impair telomere maintenance and result in DNA damage. Damage to genes that help control the growth and development of cells can cause uncontrolled cell growth and lead to development of cancer.

Cancers

Mutations in the TERT gene have also been associated with an increased risk of a form of blood cancer called acute myeloid leukemia. As in melanoma (described above), researchers think changes in the TERT gene may impair telomere maintenance, which leads to DNA damage. Damage to genes that help control the growth and development of blood cells can cause uncontrolled cell growth and promote the development of leukemia.

Other disorders

TERT gene mutations have also been found in people with isolated aplastic anemia, a form of bone marrow failure that occurs without the other physical features of dyskeratosis congenita (described above). Researchers suggest that mutations affecting different parts of the telomerase enzyme may account for the absence of these features. Some believe that isolated aplastic anemia caused by TERT gene mutations may actually represent a late-onset form of dyskeratosis congenita in which physical features such as nail dystrophy are mild and may not be noticeable.

Other Names for This Gene

• EST2
• hEST2
• TCS1
• telomerase catalytic subunit
• telomerase-associated protein 2
• TERT_HUMAN
• TP2
• TRT

Genomic Location

Made of DNA, telomeres resemble shoelace tips and serve a similar function. Telomeres are tiny pieces of DNA capping the very ends of our chromosomes. As cells divide normally throughout our lives, each DNA-containing chromosome must be copied, and the tips of stringy chromosomes are particularly vulnerable to damage, much like an actual shoestring can be physically damaged by dragging across the ground.

Thus, telomeres protect our genes by taking a hit themselves — they are known to become frayed and shorter as our cells divide many times throughout life. Scientists are learning that shorter telomeres also show up along with certain diseases, like atherosclerosis and some types of cancer. They suspect that shorter telomeres also compromise the health of cells in blood vessels, which may set the stage for clots to form, stick, and block blood flow.

As reported in a 2011 study, scientists conducting the Cardiovascular Health Study learned that certain telomere-associated molecular changes were linked with higher risk of death from cardiovascular disease in Caucasian women. These findings suggest that short telomeres might be a tool for predicting or monitoring heart disease in some women.