OPINION | GENE THERAPY |
presumably to protect the genetic information they contain. However, most normal human somatic cells have very low levels of telomerase, which means that shortening of the telomeres is not repaired and they become progressively shorter as the cells age.
Cancer risks If we suppose for a moment that the loss of telomeres does indeed contribute to the ageing process, it would be reasonable to expect that increasing the availability of the telomerase enzyme would slow the progression of ageing, and this is, in principle, what the Spanish researchers have shown. Unfortunately, there is a potential
decline in bodily function of one sort or
another. As the function of one body system declines, there are knock-on effects on other systems, the cumulative effect of which is to produce the signs and symptoms of ageing. One obvious potential culprit is the immune system, the gradual decline of which can lead to problems in other physiological systems going unchecked. Another likely candidate is the
endocrine system. It is known that the production of certain hormones declines with age, a process that is associated with diseases that tend to be more prevalent in older people, such as type II diabetes. It has also been suggested that the
Ô biological clockÕ, if one exists, resides in the hypothalamus, which links the nervous system to the endocrine system via the pituitary gland.
Telomeres Among adherents to the genetic cellular theory, attention has focused on the telomeres ® repetitive nucleotide sequences that occur at the ends of a chromosome and protect them from damage, rather like the aglet of a shoelace. When a cell divides, the DNA polymerase enzyme that replicates the DNA sequence starts at one end of the chromosome and works its way along, copying each base pair in turn. However, it is not able to reach all the way to the end of the chromosome. This means that a small amount of genetic information would be lost in every cell cycle were it not for the presence of the telomeres. What the telomeres do, in effect, is allow the enzyme to reach the end of the coding region of the
60 ❚
chromosome: they themselves do not encode any genetic information. Telomeres comprise repeating
sequences of six base pairs ® TTAGGG on one DNA strand and the complementary AATCCC on the other. During cell division, a small amount of the telomere is lost, so that gradually the telomeres become shortened. In human blood cells, for example, the telomeres comprise approximately 8000 base pairs at birth, falling to around 3000 base pairs in mid-life, and only 1500 base pairs in elderly people. This shortening of the
telomeres has been linked to the ageing process. In humans and other species, a healthy lifespan shows a positive correlation with longer telomeres, and patients with premature ageing or age-related disorders tend to have shorter telomeres than healthy individuals. In addition, cells with damaged telomeres have been shown to collect in certain tissues of elderly mice and some non-human primates. However, whether shorter telomeres
In humans and other
problem with this approach. Removing a mechanism that ensures that cells have a finite lifespan risks making them immortal (which is another way of saying cancerous), and the shortening of the telomeres may well have evolved as a tumour-suppressing mechanism designed to prevent precancerous cells from proliferating indefinitely. That risk may be more
species, a healthy lifespan
shows a positive correlation with longer telomeres, and patients with premature ageing or age-related disorders tend to have shorter telomeres than healthy individuals.
than theoretical. As cancer cells divide more frequently than normal cells, their telomeres shorten relatively rapidly, and shortened telomeres have been reported in a number of types of human cancer, including bone, prostate, bladder, lung, and head and neck cancers. If the telomeres become too short, the cells will die, and
are merely a sign of ageing, like grey hair, or whether they in some way cause ageing, is still hotly debated. In some cells, the loss of the telomeres
is counteracted by the action of telomerase, a ribonucleoprotein DNA polymerase complex that comprises the protein telomerase reverse transcriptase (TERT) and a catalytic RNA. Some human cells, such as stem and progenitor cells, have relatively high levels of telomerase,
July/August 2012 |
prime-journal.com
some cancers have been found to increase the production of telomerase, presumably as a defence against this process. Cancer-prone animals that have been genetically modified to over-express the telomerase enzyme have been found to develop cancers earlier in life than normal animals of the same species. In fact, the measurement of telomerase
levels has been suggested as a diagnostic test for cancer. Conversely, a number of groups have investigated whether inhibiting telomerase might be a way of attacking cancer. No product based on this approach has reached the market as yet, although some are in development. Meanwhile, despite the cancer risk, the prospect of extending lifespan by
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