One of the ‘busiest’ cell types in the human body is the type of stem cell that gives rise to all the blood cells,[7] including red blood cells and those that we rely on to fight infection. These stem cells proliferate at an incredible rate. This is because we constantly need to replenish the immune cells that fight off the foreign pathogens we encounter every day of our lives. We also need to replace red blood cells, because these only survive for about four months. Incredibly, the human body produces about 2 million red blood cells every second.{55} That requires an awfully active stem cell population, in a pretty much constant state of cell division. These stem cells are enriched for telomerase activity, but eventually even they suffer from telomeres that are too short to do their job properly.{56},{57} This is one reason why the elderly are at greater risk of infection than younger adults. They are essentially running out of immune cells. It’s also one of the reasons why cancer rates rise with age. Our immune system usually does a good job of destroying abnormal cells, but the effectiveness of this surveillance declines as stem cells die off.
Why is the length of our telomeres so important? It’s only junk DNA, so why should it matter if there are only several hundred copies of the non-coding TTAGGG, rather than a few thousand? Much of the problem seems to lie in the relationship between the DNA at the telomeres and the protein complexes that are deposited on this DNA. If the repetitive DNA shrinks below a critical level, the end of the chromosome can’t bind enough of the protective proteins. We’ve already seen one of the consequences of a lack of the relevant proteins in the mice that died before birth.
That was a very extreme example, but it’s undoubtedly the case that it’s vital that the telomeres are long enough to bind lots of the protective protein complexes. We know that this is true in humans as well as mice, because there are people who have inherited mutations in certain key components of the systems for maintaining the telomeres. The effects witnessed aren’t as dramatic as in the genetically modified mice, but that’s because such severely affected foetuses will tend to be lost during pregnancy. But the mutations we know about lead to conditions associated with certain disorders that are normally age-related.
The disorders are predominantly caused by mutations in the telomerase gene, or in the gene that codes for the RNA template, or in genes that encode proteins that protect the telomeres, or help the telomerase system to work effectively.[8]
Essentially, mutations in any of these genes can have similar effects. They basically make it harder for cells to maintain their telomeres. Consequently, the telomeres in patients with these mutations shorten more rapidly than in healthy individuals. This is why they develop symptoms that are suggestive of premature ageing. These disorders are known as human telomere syndromes.{58}
Dyskeratosis congenita is a rare genetic condition, affecting about one in a million individuals. Patients suffer from a whole raft of problems. Their skin contains random dark patches. They develop white patches in their mouth, which can progress to oral cancer, and their fingernails and toenails are thin and weak. They suffer progressive and seemingly irreversible organ failure, triggered initially by bone marrow failure and lung problems. They are also at increased risk of cancer.
Scientists have realised that this condition can be caused by mutations in different genes in different affected families. At least eight mutated genes are known at the moment, and it’s quite possible that there are more.{59} The feature that all the genes have in common is that they are involved in maintaining telomeres. This shows us that no matter how this region of junk DNA gets messed up, the final symptoms tend to be similar.
The lung problems are known as pulmonary fibrosis. Patients suffering from this condition have debilitating symptoms. They suffer shortness of breath and cough a lot, because they can’t move carbon dioxide out of their lungs efficiently or get oxygen into them easily. Looking at their lungs down a microscope, pathologists can see substantial regions where the normal tissue has been replaced by inflammation and fibrous tissue, rather like scar formation.{60}
These clinical and pathological findings in the lungs are ones that are seen quite commonly in respiratory disease, and this prompted scientists to look at samples from patients with a condition known as idiopathic pulmonary fibrosis. Idiopathic just means that there is no obvious reason for the disease. Researchers tested these patients to see if any of them also had defects in the genes whose products protect the telomeres. In all, up to one in six people with a family history of this disease, but no previously identified mutations, were shown to have defects in the relevant genes.{61},{62} Even in patients where there was no apparent family history of pulmonary fibrosis, mutations in telomere-relevant genes were found in between 1 and 3 per cent of cases.{63},{64} There are about 100,000 patients with idiopathic pulmonary fibrosis in the United States, so at a conservative estimate 15,000 of them probably have developed the disease because they cannot maintain their telomeres properly.
Defects in the mechanisms that protect telomeres can also cause a different disease. There’s a condition called aplastic anaemia, in which the bone marrow fails to produce enough blood cells.{65} It’s rare, affecting about one person in half a million. About one in twenty of the people with this condition have mutations in the telomerase enzyme or the accessory RNA template.
What may be happening in some of these patients is that they have both bone marrow defects and lung defects, but one problem becomes clinically apparent before the other. This can lead to unexpected consequences when medically treated. Bone marrow transplants are one of the treatments used for patients with aplastic anaemia. The patients are given drugs to prevent their immune system from rejecting the new bone marrow. Some of these drugs are known to have toxic effects in the lungs. For most patients with aplastic anaemia, this isn’t really a problem. But for those patients who have defects in their telomerase system, these drugs can trigger lung fibrosis that may actually be lethal.{66} The cure becomes the cause of death.
There’s an odd genetic reason why clinicians may not realise that the symptoms they see in a patient are part of an inherited telomere problem. The telomerase complex is usually active in the germ cells, so that parents pass on long telomeres to their children. But in some of the families where there are mutations in the genes encoding the telomerase enzyme or the accessory RNA factor, this isn’t the case. As a consequence, each generation passes on shorter telomeres to its offspring. Because symptoms develop when the telomeres fall below a certain length, each successive generation is born rather nearer to the point where their telomere length falls over the cliff edge.{67}
The effects of this are quite dramatic. A grandparent may have relatively long telomeres and develop pulmonary fibrosis in their 60s. Their child may have intermediate-length telomeres and develop lung symptoms in their 40s. But the third generation may inherit really short telomeres. They may develop aplastic anaemia in childhood.