These chromosomal aglets are called telomeres and they are made from a form of junk DNA that we have known about for many years, plus complexes of various proteins. The telomeric DNA is formed from repeats of the same six base pairs, TTAGGG, repeated over and over again.{46} These stretch for an average of about 10,000 base pairs in total on each end of every chromosome in the umbilical cord blood of a newborn human baby.{47}
The telomeric DNA is bound by complexes of proteins that help to maintain the structural integrity.[3] The term telomere really refers to the combination of the junk DNA and its associated proteins. A graphic demonstration of the importance of these proteins was shown by some researchers working in mice in 2007. They knocked out expression of one of the proteins by completely inactivating its gene, and found that the resulting mice embryos died early in development.[4]
When the researchers examined the chromosomes in these genetically modified mice, they found that many of them had joined up. The ends had linked up with each other. This was because the DNA repair machinery no longer recognised the telomeres as telomeres. Instead, it reacted as if faced by a whole slew of broken chromosomes and did what it does best. It stuck them together. Unfortunately, by doing so, gene expression became completely disordered. Eventually the chromosomes and cells became so dysfunctional that they triggered a type of cellular suicide,[5] halting development completely.
There is also another feature of the telomeres that is of major interest in biology and human health. Back in the 1960s, researchers were studying how cells divide in the laboratory. They didn’t work with cancer cell lines, as these are derived from cells that have become immortal through abnormal changes. Instead, they studied a kind of cell known as a fibroblast. Fibroblasts are found in a wide range of human tissues. They secrete something called the extracellular matrix, a sort of thick wallpaper paste that holds the cells in position. It’s relatively easy to take a biopsy, for example from skin, and isolate the fibroblasts. These will grow and divide in culture. What the researchers discovered all those years ago was that the cells wouldn’t keep dividing forever. There came a point when they stopped dividing, even when supplied with all the nutrients and oxygen they needed. The cells didn’t die, they just stopped proliferating. This is known as senescence.{48}
Scientists later realised that the telomeres in cells became shorter with each cell division. Every time one of the cells divided, all the DNA in that cell was copied. This ensured that both daughter cells inherited the same 46 chromosomes as the mother cell. But the system that copies the DNA in chromosomes can’t get right to the ends. So, over progressive cycles of cell division, the telomeres became shorter and shorter.{49}
But this didn’t prove that the shortening of the telomeres actually caused cell senescence. It was perfectly possible that the effect on telomere length acted as a kind of marker for cell proliferation, but didn’t have any actual role to play in the changes in cell behaviour.
This is a really important concept in scientific enquiry. There are plenty of situations in which we can see a correlation between two things, but we shouldn’t from that automatically assume there is a causal relationship. Consider the following relationship. There is a strong relationship between developing lung cancer and sucking cough sweets. This doesn’t of course prove that sucking cough sweets gives you lung cancer. One of the first symptoms of lung cancer in many people is the development of a persistent cough, and someone with a cough is likely to try sucking hard sweets to decrease their discomfort.
The confirmation that telomere shortening did indeed lead to senescence came in the 1990s. Scientists demonstrated that if they increased the length of the telomeres in fibroblasts, the cells would bypass senescence and grow indefinitely.{50}
It is now generally accepted that the telomeres act as a molecular clock, counting us down as we age. Not all the details have been established yet, because it’s a difficult area of biology to investigate, for a variety of reasons. One is that in any given cell, the 92 telomeric regions (one at each end of each chromosome) won’t be the same length. This makes it hard to come up with a meaningful measure of telomere length that is applicable throughout a cell, never mind an entire human being.{51} It’s also very difficult for scientists to use their favourite model animal — the mouse — to investigate the relationships between telomere biology and ageing. This is because rodents have extremely long telomeres, much lengthier than in humans. Rodents, of course, are much shorter-lived than humans, suggesting that telomere length is not the only arbiter of ageing, but the accumulated evidence suggests that in humans they are of major importance.
What we do know is that our cells don’t succumb to the ageing process without a fight. They contain mechanisms to try to keep the telomeres long and intact as much as possible. This is achieved in our cells by something called telomerase activity. The telomerase system adds new TTAGGG motifs onto the ends of the chromosomes, basically restoring these important bits of junk DNA that are lost when the cells divide. Telomerase activity requires two components. One part is an enzyme, which adds the repeated sequences back on to the chromosome termini. The other is a piece of RNA, of a defined sequence, which acts as a template so that the enzyme adds the correct bases.
So the ends of our chromosomes rely heavily on junk DNA, genomic material that doesn’t code for proteins. The telomeres themselves are junk, and to maintain them the cell uses the output from a gene that produces RNA, but which is never used as a template for a protein. This RNA itself is a functional molecule, carrying out a vital role.[6],{52}
But if our cells contain a mechanism for maintaining telomere length, through the activity of the telomerase system, why do the telomeres get progressively shorter? What’s wrong with the system, why doesn’t it work properly?
The reason probably stems from the fact that there are few systems in biology that work well if allowed to run unchecked. And telomerase activity is held in very tight check indeed in our cells. The pathological exception to this is in cancer cells. Cancer cells frequently have adapted in such a way that they express high levels of telomerase activity and have elongated telomeres. This contributes to the aggressive growth and proliferation of many tumours. Our cellular systems have probably reached an evolutionary compromise. The telomeres are maintained at sufficient levels that we live long enough to reproduce (anything after that is irrelevant in evolutionary terms). But they aren’t so long that we succumb to cancer too early.
The basic telomere length in an individual is set fairly early in development, at a time when there is an uncharacteristic spike in the telomerase activity.{53} Telomerase activity is also high in germ cells, the cells that give rise to eggs and sperm.{54} This is to ensure that our offspring inherit telomeres of a good length.
Many human tissues contain cells known as stem cells. These are responsible for producing replacement cells when needed. When new cells are needed, a stem cell will copy its DNA and then split it between two daughter cells. Typically, one of these daughter cells will develop into a fully fledged replacement cell. The other will become a new stem cell, which can continue to create replacements in the same way.
4
The gene was called
6
The core enzyme is encoded by the TERT gene and the RNA template is encoded by the TR gene, also known as TERC.