Telomeres

Telomeres are sequences at the ends of chromosomes. Though they are written in the 'alphabet' of the genes, telomeres do not contain the codes for proteins. So telomeres are not themselves genes, but neither are they meaningless junk. Instead these repetitive sequences protect the ends of the chromosome from damage, and prevent the chromosomes from fusing into rings, or binding haphazardly to other DNA in the cell nucleus.

When a cell divides, the chromosomes are copied by enzyme molecules. These molecules faithfully transcribe the genetic information on each chromosome, producing mirror images of both of the two original strands (which themselves were mirror images of each other). But the enzyme molecules that do the duplicating are unable to completely reproduce the tips of the chromosomes, much as a tape recorder can not play the last few centimeters of tape in a cassette. As a result, the duplicate chromosome is necessarily slightly shorter than the original, lacking a small amount of the original telomere sequence. The missing DNA does not measurably affect cellular functioning until enough cell divisions have occurred that the telomeres on at least one of the chromosomes in the cell become critically short.

Cells with critically short telomeres alter their character by transcribing a partly distinct set of genes. They also become unresponsive to triggers that would normally stimulate them to divide. Though these growth arrested cells can live on in the body for years, once they have reached this state, they do not under normal circumstances, replicate themselves. They are said to have reached their Hayflick limit (named for the discoverer of the arrested state).

Telomerase

Because sperm and egg cells are themselves descended from progenitor cells, if there were no mechanism for replacing lost telomere, then all organisms with linier chromosomes (eukaryotes) would be condemned to quick extinction due to Hayflick limits in their reproductive tissues. Clearly, that's not the case. Instead, there are a number of mechanisms in nature that counteract the natural tendency of telomeres to erode over time. Vertebrates, including mammals, use a remarkable enzyme dubbed 'telomerase'. This hybrid molecule, part protein, part RNA, is capable of slowing telomere erosion, halting erosion altogether, or lengthening telomeres beyond those in the parent cell. The genes that produce telomerase are found in every potentially replicating cell in the body, including cells at their Hayflick limits, but the genes that produce telomerase are inactive in the great majority of our cells, for the vast bulk of our lives. Those genes are active across the body only in early fetal development. After that point, telomerase is only found in a few special tissues such as antibody producing immune cells, cells that replenish the gut lining, and sperm producing cells.

The telomere theory of animal aging

From the age that reproduction typically begins in a species, individual animals decline in overall efficiency, and their vulnerability to injury and illness increases. The technical term for this decline is 'senescence', though in common parlance the process is less precisely termed 'aging'.

Though the connection is still controversial, many biologists believe that the senescent decline observed in mammals is the result of an ever increasing percentage of cells across the body reaching their Hayflick limits. Clearly, if an ever larger percentage of the body's cells are unable to reproduce, then defense, maintenance and repair of the body would become increasingly difficult tasks. Thus, telomere erosion and Hayflick limits could account for most of the decline in efficiency, and increases in vulnerability that characterizes the aging of sexually mature mammals.

The evidence supporting this perspective has grown substantially in the last few years of research. Further, the discovery that several diseases that produce syndromes of apparently accelerated aging in humans (e.g. Hutchinson-Gilford progeria and Werner's syndrome) have now been linked to telomere-system defects, strongly suggest that this mechanism is fundamental to the explanation of aging in humans.

Telomeres and cancer

The obvious question is this:

If senescence is caused or exacerbated by the erosion of telomeres that accompanies cell division, and if every cell is capable of producing an enzyme that can halt or reverse that process, why is that gene turned off in most tissues for most of life? Could everlasting youth be as simple as turning that gene back on all over the body?

A number of people have advanced exactly that interpretation. Unfortunately, there is a very good reason to think that turning telomerase back on across the body would be a disastrous mistake. Telomeres and telomerase, it turns out, are important players in another active area of study: cancer.

Science has learned much about cancer since the so called 'War on Cancer' began. One of the most striking discoveries has been that cancer is rarely if ever the result of a single mutation. Generally, several complimentary mutations must occur in the same cell to produce an ever growing tumor, which then experiences further changes, producing a cancer. One of the most striking features that distinguishes the vast majority of tumors and cancers from the normal tissue from which they arose is the presence of the enzyme telomerase. The logical connection being that, without telomerase, the cells in a tumor would quickly divide so many times that their telomeres would become critically short, cell division would be arrested as all the cells ran up against their Hayflick limits, and the small growth would likely go unnoticed. Over time, the cells in this 'proto-tumor would be lost through the normal processes that eliminate cells from the body and they would not be replaced. If that happens regularly in the body, as it seems that it must, it has not yet captured the attention of medical science.

When science investigates a particular tumor, it is because the tumor has followed another course. Medically important tumors have, almost by definition, become large enough to disrupt normal bodily function in some way. In order to grow large enough to capture our attention, some particular cell must have at least two mutations, each of those mutation amazingly improbable on its own. First, a cell must be genetically damaged such that it becomes insensitive to the signals that would normally tell it to stop dividing. When that mutation has run its course, the product will be a small colony of growth arrested cells, each of which contain that first mutation. In other words, all of the cells that descended from that first reproduction-committed mutant will also be reproduction-committed. They will, after all, have each inherited the mutation that set the needless cell division in motion. But, in spite of being prone to reproduce endlessly, these cells will be dormant because their newly short telomeres will have arrested the machinery of cell division. And that is where the process will end, unless one of those cells is unlucky enough to receive further genetic damage, this time in the area of the telomerase gene. If the a gene required to prevent telomerase from being produced is damaged such that telomerase is suddenly available, then the reproductively-prone, previously growth-arrested cell, will resume the growth juggernaut. But this time, there are no built in limits to be reached. With a propensity to grow, and telomerase maintaining the telomeres, a dangerous cascade is well under way. This is the beginning of a tumor.

Infinite youth vs. cure for cancer: Natural selection and modern medicine in the same bind

Now we can begin to understand the complexity of the problem we face. If telomerase activating mutations are a prerequisite to cancer, then why hasn't natural selection eliminated this land mine from our cells? If short telomeres are the reason we grow old, then why not activate telomerase across the body and stay young? As should be clear at this point, there is a built in trade-off that we have no means of escaping.

Increasing resistance to cancer necessarily comes at the cost of accelerating our decline with age. Slowing the aging process would necessarily expose us to increased propensity for cancer.

At any given moment the body of an adult human is composed of roughly 10 trillion cells. Nearly all of those cells could spawn a deadly tumor with the right mutations. The system of finite, eroding telomeres provides us that ability to repair and maintain our tissues for a substantial period, during which time the runaway cells that would otherwise become deadly tumors are rained in by the Hayflick failsafe. The cost of this system is that we are condemned to grow old. As bad as that may seem, however, it is the lesser of two evils. If our telomeres did not erode, and therefore did not provide a failsafe mechanism to catch runaway mutants, then we would likely be overrun by tumors before we ever got the chance to reproduce.

Want to learn more?

The above description is a sketch of a scientific theory. Because that theory is presented here in a less technical context, this explanation can only provide a broad outline of the various details. A much more complete description of the theory, including a review of the existing evidence, can be found in this paper.

More information is also available at Telomere.org.

If there are questions that you would like to see addressed here, feel free to pass them along.