Telomerase: The Fountain of Youth?

At the end of last month, an amazing and promising discovery was made: an enzyme called telomerase could, in mice, reverse tissue degeneration, one of the critical features of aging.

Telomerase is actually involved in many important biological functions, from cancer formation to the aging of our cells. While it was long thought that telomerase is involved in controlling the age of our cells, this recent study reported that it might also play an important role in the aging process of an entire organism, not just their individual cells.

The implications are huge; not only may we better understand premature aging, but we may even be able to better control, and possibly reverse, the negative effects of aging in humans.

Telomerase has been studied for decades, and to understand what telomerase is and does, it’s easiest to go back to the early 1970s. It was at this time that researchers found out that whenever a cell divides into two new cells, a tiny bit of the DNA at the ends of its chromosomes is lost. (Chromosomes are organized, string-like packages that store our DNA; people usually have 23 chromosome pairs in each cell.) Cells don’t perfectly copy their DNA. Although it’s a very small amount of DNA that’s lost each division, it adds up over time and could eventually cause the loss of vital genetic information.

Telomeres to the rescue: By the late 1970s, it was discovered how cells solve the problem of this lost DNA. When our cells divide, instead of losing valuable genes at the ends of our chromosomes, we just lose pieces of telomeres. A telomere isn’t a gene (it doesn’t have instructions for making anything in the cell), but is just a long piece of disposable DNA. (Specifically, telomeres are made up of a defined DNA sequence, TTAGGG, that is repeated several thousand times.) In this way, telomeres serve as a protective “cap” on the chromosome ends; when a cell divides, the telomeres are slowly shortened over time, keeping valuable genes from getting destroyed.

Telomerase: But even with these protective chromosome “caps,” animals couldn’t live for several generations with their telomeres continually shortening, especially if their shortened DNA was passed on to their offspring. About 50 to 200 base pairs of DNA are lost with each cell division, a process that clearly can’t go on forever. Amazingly, life somehow finds a way to reverse this shortening: Newborn babies have telomeres that are about 15-20 thousand DNA base-pairs long, much longer than the telomeres of their parents.

This biological puzzle long perplexed researchers, until 1984 when Elizabeth Blackburn and Carol Greider (her PhD student at the time) at the University of California, Berkeley, discovered an enzyme called telomerase. What does telomerase do? Telomerase is able to add telomere DNA back onto the ends of chromosomes, and consequently can preserve the integrity of the chromosomes over time.

But in humans only a few types of cells make telomerase: sperm and eggs (“germ” cells needed for reproduction), stem cells, and cells in regenerating tissues. These cell types must have a longer lifespan to pass genes onto a new generation, and to replace old or damaged cells over time.

The discoveries of telomeres and telomerase were such a breakthrough that Blackburn, Greider, and Jack Szostak (at Harvard Medical School) were awarded the Nobel Prize in Physiology or Medicine in 2009 for it. Blackburn also collaborated with Eduardo Orias, a professor at the University of California, Santa Barbara, in the 1980s while investigating the genetics of Tetrahymena, a single-celled ciliated organism that Blackburn first discovered telomerase in. Orias recently celebrated his 50th anniversary of working at UCSB, and continues to investigate Tetrahymena genetics.

A biological clock: In addition to protecting the ends of chromosomes, telomeres are also thought to function as a kind of clock for the cell, measuring how many times the cell has divided into two cells. When a cell has divided many, many times, and its telomeres have become very short, the cell detects this and stops itself from dividing ever again. It ceases to multiply and “senesces.”

Cancer: What purpose would there be to stopping old cells from continuing to multiply? The answer is thought to be related to cancer; this telomere countdown may be an innate anti-cancer mechanism. To become cancerous, a cell needs to gain several mutations, and this process usually takes a long time to happen. Ideally, an old cell will die before its DNA has gained enough random mutations to make it cancerous, and it’ll be replaced by a new cell.

But sometimes an old cell gets too many mutations before it can be eliminated (whether by chance or though exposure to carcinogens) and it becomes cancerous. Telomeres, telomerase, and cancer are intimately related, though, as with much in the field of cancer, we’re still trying to figure a lot of these connections out. Cancer cells usually have short telomeres, probably because they were “old” cells that just barely escaped self-destruction. But the cancer cells have figured out how to get around the problem of having short telomeres; unlike most of the normal tissues in the body, cancers make telomerase. This allows the cancer cells to maintain their telomere length and keep proliferating. They no longer have a self-destruct clock.

Consequently, there have been anti-cancer drugs developed that specifically block telomerase activity. Such drugs are in preclinical and clinical trials for treating prostate, lung, breast, pancreatic, and other cancers and have encouraging results. One such anti-telomerase drug, Imetelstat (GRN163L), developed by the biopharmaceuticals company Geron, showed promising results in preclinical trials against a wide variety of tumors, and has moved on to clinical trials testing the efficacy of this drug against non-small-cell lung cancer, breast cancer, and other cancers.

Telomerase and aging: But while telomerase plays a deleterious role in creating cancers, it plays a beneficial role in preventing and possibly even reversing, aging. When telomeres are lost, tissues progressively atrophy, the body’s supply of stem cells becomes depleted, healing is impaired, organs can fail. Age-related diseases, such as atherosclerosis, Alzheimer’s disease, and others, are associated with shortened telomeres. People born with shorter telomeres usually have a shortened lifespan. There are often other medical complications associated with shorter telemeres but it’s difficult to say, ultimately, whether the shortened telomeres are the cause of such conditions, or an effect. Also unclear is whether damage caused by shortened telomeres from aging can be reversed, or simply halted.

In the laboratory, it’s been shown that human cells can have increased life spans if they’re forced to make telomerase. These senescent-resistant cells also appear to be “normal”; they’re not cancerous. This goes along with the thought that cancer cells’ production of telomerase is an effect of these cells becoming cancerous, not the primary cause. However, while telomerase makes cells in a petri dish live longer, many scientists are skeptical as to whether increased telomerase production can make an entire animal live longer or be youthful.

But the recent study in mice may have skeptics rethinking their stances.

The Fountain of Youth, at least for mice: Two weeks ago, a study published by Ronald DePinho and his postdoctoral fellow Mariela Jaskelioff at the Harvard Medical School in the journal Nature showed that degeneration in mice can be reversed by activating telomerase.

The researchers created mice that lack telomerase, and consequently have short, dysfunctional telomeres. These adult mice had severe tissue degeneration, similar to premature aging, due to this mutation. To see whether telomerase could halt or reverse this degeneration, the researchers reactivated telomerase activity in these adult mice. The telomerase lengthened the short telomeres, caused cells to grow that had stopped growing, and eliminated the degeneration that had been previously seen in several organs, including some neurodegeneration. The telomerase didn’t just stop more damage from occurring; it reversed the damage that had already been done.

The future of telomerase: The exciting recent finding that telomerase may actually be able to reverse tissue damage in degenerative, adult mice has many implications. This finding may raise questions about using anti-telomerase drugs to fight cancer. At the same time, telomerase may be further investigated for possible use in reversing aging in people, although much work must be done before this is feasible; telomerase in mice and humans may function in different ways. But while further research will need to be conducted, this finding highlights the importance of telomerase, and how it may help us better understand and “treat” aging.

For more on telomerase and telomeres, see Leonard Guarente, Linda Partridge, and Douglas Wallace’s book “Molecular Biology of Aging,” Catherine Brady’s book “Elizabeth Blackburn and the Story of Telomeres,” the recent article reporting that the addition of telomerase in mice reverses tissue degeneration, or Wikipedia’s articles on the “Telomere” or “Telomerase.”

Biology Bytes author Teisha Rowland is a science writer, blogger at All Things Stem Cell, and graduate student in molecular, cellular, and developmental biology at UCSB, where she studies stem cells. Send any ideas for future columns to her at science@independent.com.