infoaging guides

BIOLOGY OF AGING

TELOMERES AND An introduction to aging brought to you by the American Federation for Aging Research WHAT ARE ? our cells would be unable to telomeres. Research published in reproduce at all. the January 21, 2003, issue of the Inside the nucleus of ­virtually all Proceedings of the National Acad- of our cells are 46 , Telomeres also play an important emy of Sciences suggests that the thread-like packages that protective role in our cells. Their the end of a ’s reproductive life carry our . At the tips of presence prevents important may actually be triggered when these chromosomes, like the hard ­genetic material from being lost this loop unravels, either due to ends of shoelaces, are structures during . They also DNA damage or to telomeres that called telomeres. While they do serve as a “cap” on the ends have become excessively short. not ­contain genes, telomeres of chromosomes, protecting are important for replication or ends from appear- Telomeres tend to get shorter ­duplication of the chromosomes ing broken. This is an important over time. Two researchers, Alexei during cell division. They are function, because broken chromo- Olovnikov and James D. Watson, made up of approximately 1,000 somes trigger unwanted biological independently recognized that to 2,500 copies of a repeated DNA ­responses. DNA replication machinery cannot sequence (the order of ­chemical copy chromosome ends com- building blocks in a stretch of HOW TELOMERES WORK pletely. Watson named this the DNA), TTAGGG. “end replication problem.” Each Telomeres are composed of dou- time a normal cell divides, the Why do we need telomeres? When ble strands of deoxyribonucleic ends don’t get completely copied, we are born, we don’t have every acid (DNA), except for the very and the telomeres become just a cell our bodies will ever need. As ends, called overhangs, bit shorter. Eventually, telomeres we grow, we need new skin, bone, which have single-strands. Many are so short that the chromosome blood, and many other kinds of telomeres, including those from reaches a critical length, and no cells. Even as adults, we need to , appear to form t-loops— further cell division can occur. make new cells. For example, special folded structures where the skin cells and those cells that single-stranded tail of the telomere This cellular aging phenomenon is line our intestines are constantly is tucked into the more internal known as replicative ­ replaced. All of these reproducing double-stranded part. T-loops are or the Halyflick limit (discovered cells need their telomeres for cell thought to be important for the by in 1961). division. Without their telomeres, protective-capping function of ­Telomere shortening is a ­major

Telomeres are located at the tips of these chromosomes, where they act like the hard ends of shoelaces.

2 | Infoaging Guide to Telomeres and Telomerase factor limiting cell division. While however, it can have devastating laboratory, most cells can some have likened this to a consequences. only divide 30 to 80 times before ­genetic biological clock, others they stop reproducing. Cells taken have described the telomere as If two different chromosomes are from older persons and persons a fuse that becomes shorter and fused by way of telomere end with premature aging syndromes shorter, until it sets off a kind of j­oining, they cannot ­separate undergo even fewer divisions cellular time bomb that wreaks properly during replication. ­During before reaching ­senescence. havoc on the cell’s internal work- cell division, a tug of war ­between Scientists know senescence is ings. Today, researchers continue the two daughter cells over the related to telomere length ­because to probe the telomeric “timepiece,” fused chromosome usually ­results adding telomerase, an hoping to better understand the in it being broken into two ­uneven that lengthens telomeres, to aging process and fight diseases. pieces. Each daughter cell then cells allows them to reproduce inherits a chromosome with ­indefinitely. WHEN TELOMERES missing or extra DNA and has MALFUNCTION one (newly broken) end ­missing One group of researchers looked a telomere. That end is free to at the cells of people with As mentioned above, telomeres potentially cause another round of ­, a disease that ages serve as protective caps on the chromosome fusion and ­breakage. young children so rapidly that they ends of chromosomes. From Through this mechanism, die in their teens with many of the time to time, defects in this ­uncapped telomeres can wreak symptoms of old age. Their cells’ ­capping function can occur, and havoc, killing cells and ­rendering chromosomes have exceptionally may be ­related to the end loops those that survive genetically short telomeres, suggesting that ­unraveling. abnormal. the disease is causing rapid cell turnover. The cells are using up The capping function can be lost if In addition to causing DNA ­repair their ability to reproduce, which the telomere becomes too short or in the form of recombination or in turn may contribute to their is deleted entirely, or if a telomere end joining, broken DNA ends or ­premature aging. is missing or mutated. uncapped telomeres can ­trigger The body perceives ­uncapped other cellular responses. ­Because Researchers have also ­developed ­chromosomes as broken DNA broken chromosomes are a ­severe a type of laboratory mouse ends. In most cells, broken DNA form of DNA damage, cells are that has defective telomerase. ends spark one of two repair often exquisitely sensitive to ­ of these mice mechanisms. their presence. Unrepaired bro- produced successive generations ken DNA ends will often ­trigger with signs of premature aging and The first is called homologous cellular growth arrest, thereby shortened life spans, ­providing ­recombination (HR), in which ­preventing any cell division as further evidence of the role of a broken DNA end is fixed by long as the broken ends persist. ­telomeres and telomerase in aging. ­copying the sequence from a In some ­human cells, broken DNA similar, unbroken DNA molecule. ends can trigger cellular suicide, a The entire aging process ­cannot In some situations, recombination ­process known as . be explained solely by ­telomere between malfunctioning telomeres shortening. To date, evidence can be frequent enough to keep Because short telomeres are more ­supporting the relevance of cells alive and keep telomeres common in older cells, telomere ­replicative senescence and very long. capping problems may be related telomere biology to is to the development of cancer and rather strong; however, the direct In a second mechanism, the other age-related diseases. ­evidence ­linking replicative senes- broken ends of two chromosomes cence and ­human aging remains with telomere failure simply fuse TELOMERES AND AGING controversial and is of continued together. This is called non- interest and ­effort of study. Some homologous end joining (NHEJ). Once a cell’s telomeres have point out that no relationship Under most circumstances, this reached a critically short length, ­exists between initial telomere end joining is an effective and that cell can no longer divide. Its length and a species’ life span. useful DNA repair process. With structure and function begins to Mice, for example, have much malfunctioning human telomeres, fail. Some cells even die. In the longer telomeres than humans,

Infoaging Guide to Telomeres and Telomerase | 3 and live only two years or so. This accumulated. Therefore, leads to the question ­concerning they remain pre-malignant and do the role of replicative aging not develop cancer. among different organisms and whether mice or humans represent However, telomere shortening itself the more ­common mammalian may be an active contributor to the ­paradigm. genetic abnormalities that ­trigger cancer because dysfunctional TELOMERES AND OTHER ­telomeres drive ­instability. AGE-RELATED DISEASES In fact, there is ­growing ­evidence AND CONDITIONS of an association ­between ­shortened telomeres and a greater The shortening of telomeres has risk of cancer ­development in been associated with a number humans. In addition, ­laboratory of diseases, many of them age- evidence has shown that shorter related. Shortened telomeres telomeres may contribute ­directly have been identified in aging Telomere shortening may to the ­progression of the ­earliest skin, blood, and ­cardiovascular be an active contributor to stages of certain . In an cells. And the cells of people the genetic abnormalities experiment involving cells taken with a variety of diseases—from from prostate cancer patients, ­atherosclerosis to hepatitis to that trigger cancer because ­researchers from the Johns blood disorders—have been found ­dysfunctional telomeres drive ­Hopkins University School of to have shortened telomeres. genome instability. ­Medicine found that telomeres in cells from precancerous ­lesions THE RELATIONSHIP BETWEEN were four times shorter than TELOMERES AND CANCER of telomeres (ALT) for telomere telomeres in cells taken from ­surrounding ­normal tissue. If telomeres give our cells finite maintenance. Telomerase is an life spans, how is it that cancer enzyme that “rewinds” our cellular clocks. It lengthens our shortened THE ROLE OF TELOMERASE cells seem to possess infinite life IN CANCER spans? How can they reproduce telomeres, replacing bits of DNA and spread infinitely? How do lost in ordinary cell division. If Telomerase is the enzyme that ­cancer cells get around the l­imits telomerase stops telomere short- replenishes shortened telomeres that telomeres impose on our ening, then in theory, those cells and allows cells to reproduce healthy cells, thereby becoming with telomerase can live forever. indefinitely. Found in only a few immortal? Since most cancer cells contain normal human cell types ( telomerase, researchers believe cells, proliferating stem cells, and In many non-human organisms, it is a critical factor in conferring some immune cells), telomerase is telomerase is always active when ­ upon these cells. present in as many as 90 percent cells are dividing. This makes up of human cancers. This makes for gradual telomere shortening Inactivation of telomerase and the resulting telomere shorten- telomerase an attractive candidate from replication and cell division. for highly selective cancer drugs. This activity, regulated by certain ing likely evolved in humans to , keeps telomere length ­reduce the incidence of cancer. By The evidence that activation more or less constant. causing replicative senescence, of telomerase is necessary for telomere shortening acts as a most cancers to thrive is strong. Human cells are different. In most road block to the abnormally high ­Indeed, some scientists believe of them, telomerase is turned off. amount of proliferation associated that telomerase activation is the This means telomeres shorten as with the development of cancer. main ­pathway by which cancer cells continue to divide. However, It takes many divisions for cells cells become immortal, that is, almost 90 percent of all cancer to ­accumulate enough mutations able to reproduce forever without cells possess telomerase, while to become malignant. Cells that limits. Cancer cells generally need the remaining employ a mecha- exhaust their replicative life span to acquire four-to-six mutations to nism called alternative lengthening become senescent with only a few become malignant. On average,

4 | Infoaging Guide to Telomeres and Telomerase a cell with a would need • Gonadal toxicity. Some normal cells would require so many divi- to expand to at least a ­million telomerase activity is seen sions to cause a relapse that their cells (20 doublings) before it had a in the cells of the ovary and ­telomeres would become too short chance for another rare ­mutation testes. Thus, some researchers in the absence of telomerase. to occur. If a cell can ­divide 30 speculate that anti-telomerase to 80 times, pre-malignant cells drugs could potentially inter- Diagnostics can only acquire one-to-three fere with fertility. The fact that telomerase is active ­mutations before they stop in up to 90 percent of all cancer ­dividing. Replicative aging is thus One drawback to the use of cells suggests that telomerase a barrier against the formation of ­anti-telomerase drugs in ­treating activity may help to diagnose malignant cancer cells. Thus, say cancer is the length of time early cancers so they can be researchers, telomerase activation ­needed for such drugs to have treated quickly, before the ­cancer is necessary for most, but not all, any effects. If tumor telomeres spreads. Theoretically, ­biopsies, cancers to grow. are long enough, it might take tissue scrapings, and ­biological many cell ­divisions of ­telomerase fluids such as blood may ­provide A number of researchers have ­inhibition before they’re short ­adequate cell samples for suggested that if telomerase is enough to kill the tumor cell. ­detecting telomerase activity. At required for so many cancers to Even if ­anti-telomerase drugs a practical level, however, today’s flourish, perhaps anti-telomerase were ­developed in the near fu- tests do not yet compare favorably drugs could be developed as ture, they would need to be used with other tests, so their clinical cancer-fighting agents. Some have in ­conjunction with faster-acting ­application has been limited. suggested that such a drug would anti-cancer drugs. The hope is have minimal side effects, since that very rare surviving cancer so few normal cells have active telomerase. Others caution that some side effects are possible be- cause some normal cells, among them dividing germ-line lineages, stem cells, and some cells in the skin, blood, and gasterointestial track, do have telomerase activity. Potential side effects include:

• Blood toxicity. Some popula- tions of stem cells, which are the parents of mature blood cells, do use telomerase. ­Anti-telomerase drugs could, therefore, suppress the pro- duction of vital blood cells.

• Immune toxicity. Some ­infection-fighting cells use telomerase normally, so ­anti-telomerase drugs could, theoretically, weaken our ability to fight infection.

• Skin toxicity. While most of our skin cells have little telomerase activity, the skin stem cells that repair wounds do have some. Anti-telomerase drugs might Some scientists believe that telomerase activation is cause delayed wound healing. the main pathway­ by which cancer cells—such as this breast — become immortal. Prognostics Telomerase biology may also help to identify cancer survivors who might benefit from ­supplemental therapies after surgery. In a ­recent study, the expression of ­telomerase was a strong predictor of long-term outcome. In breast cancer survivors without lymph node involvement, 98 percent of those with the lowest levels of telomerase expression ­survived more than 12 years. Among ­patients with the highest levels of telomerase, there were no ­survivors after 12 years.

THE FUTURE OF TELOMERE AND TELOMERASE RESEARCH

At the leading edge of cancer research, scientists are ­currently looking at ways to help the ­ identify and target malignant cells by way of their telomerase expression, ­leaving normal cells unharmed. In one clinical trial, 12 patients with advanced prostate cancer were vaccinated with immune cells that could do just that. All patients with detectable levels of circulating tumor cells showed declines ranging from six to a thousand fold. Limited clinical trials are now ­underway to test this approach with other types of cancer.

Another approach uses ­oncolytic viruses to attack telomerase- expressing cells. These are ­genetically engineered viruses that specifically infect and destroy cancer cells by penetrating their membranes and replicating inside them. The replication is triggered by the presence of telomerase.

TISSUE Scientists are currently looking at ways to help the immune system identify and target malignant cells by way of their If low telomerase is related to the shortened telomeres that mark telomerase expression, leaving normal cells unharmed. an aging cell, perhaps we can “turn on” the expression of this

6 | Infoaging Guide to Telomeres and Telomerase to lengthen the lifespan While cell therapy offers example, might hTERT-modified of a cell or organ. One goal of ­tremendous promise in ­clinical cells be more dangerous if muta- ­ is to overcome medicine, the safety issue tional changes months or years ­organ failure by infusing cells with ­dominates the future ­acceptability after transplantation cause the ­telomerase. A patient donates and widespread use. ­Researchers ­activation of ? Also, is cells that are modified in culture are grappling with certain any potential risk of hTERT gene by the ­introduction of telomerase. ­questions such as: What is the therapy acceptable—even when The cells are then returned to the likelihood for long-term change given to save lives? ­patient to correct a deficiency. that might trigger abnormal tissue Thus far, 17 different cell types growth? Specifically, what is the Future research must also ­unravel have been used to engineer 22 risk of cancer? the phenomenon of cellular different kinds of tissues. The ­aging even in newly engineered limitations of this technology are The results of a study at Duke ­tissues. In the smooth muscle cells considerable, however, emphasiz- University suggest that telomerase ­described above, for example, ing our limited understanding of is not independently capable of ­age-related changes to cells were the complexity of aging cells. inducing tumor formation. http:// not reversed by transplantation of www.ncbi.nlm.nih.gov/pmc/ar- cells modified with telomerase. In The use of a donor’s own cells to ticles/PMC1413782/ fact, collagen synthesis ­decreases build new tissue has its ­limitations and consequently reduces because of the limited ­lifespan The over expression of telomerase­ the strength of even robustly of most cells—especially cells activity in cultured cells failed to ­engineered vessels. from older patients. This ­inability result in malignant change in a to ­proliferate, however, can be number of cell types The results Research into telomeres and overcome if the donor’s cells of various analyses of this Duke telomerase is still in its early are infused with a specific gene, study thus far, suggest no evidence­ ­phases, but scientists have called hTERT, that switches of tumor­ formation of either the learned much in these last few on ­telomerase ­expression. hTERT cells or the control cells. years. The knowledge they have ­Telomerase then ­restores length to Another laboratory at the UT amassed and continue to ­pursue shortened telomeres. Southwestern Medical Center has offers enormous potential for also reported that long-term effect ­understanding and perhaps In one proposed form of therapy, of telomerase immortalized human ­controlling the diseases of old age. cells with shortened telomeres are fibroblast does not show cancer- donated by a patient. Telomere associated changes. http://www. length is restored in culture with an ncbi.nlm.nih.gov/pubmed/9916803 infusion of hTERT. Cells are then reintroduced in the patient’s body While cell therapy appears to restore tissue function. One to be an exciting field with application, for example, might be ­tremendous promise, future in arterial bypass grafting in aging research ­endeavors involving cardiac patients. hTERT cell therapy need to care- fully explore long-term risks. For

American Federation for Aging Research (AFAR) Websites: 55 West 39th Street, 16th Floor www.afar.org New York, NY 10018 www.afar.org/infoaging

Phone: (212) 703-9977 Facebook and Twitter: Toll-free: (888) 582-2327 AFARorg Fax: (212) 997-0330 Email: [email protected]

© 2016 American Federation for Aging Research. All rights reserved.