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Telomeres and Telomerase infoaging guides BIOLOGY OF AGING TELOMERES AND TELOMERASE An introduction to aging science brought to you by the American Federation for Aging Research WHAT ARE TELOMERES? 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 chromosomes, 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 cell’s reproductive life carry our genes. 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 cell division. 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 chromosome 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 telomere 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 humans, 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 senescence 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 Leonard Hayflick 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 human 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 j oining, 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 enzyme 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 progeria, 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. protein 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 Selective breeding 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 apoptosis. 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 cancer 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 mutations 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 genome 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 cancers. 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 l imits 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 (germline 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 immortality upon these cells.
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