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Each time a cell divides, not all the DNA is copied so over time, there is progressive reduction in the number of tandem repeat sequences leading to telomere shortening in somatic cells. It is thought that in humans the cells replicate about 50 times before it is too short which is known as Hayflicks' limit (ref). (http://longevity.about.com/od/researchandmedicine/p/telomeres.htm). Eventually a point will be reached whereby cell division will cease at the shortest length compatible with stability is reach, a state termed replicative (mitotic) senescence' (Kappei, et al, 2007). This process stems from the fact that DNA polymerase is no longer capable of replicating the linear template. The overall effect is that the cell may malfunction and can encounter eventual death. Currently researchers are trying to better understand the mechanism involve with telomeres and its consequential impact on ageing and cancer. http://www.precisionnutrition.com/wordpress/wp-content/uploads/2008/12/telomerase-copy.jpg
Telomeres and telomerase (175)
http://www.precisionnutrition.com/wordpress/wp-content/uploads/2008/12/telomerase-copy.jpgGerm cells do not undergo telomeric shortening, attributed to the fact that telomerase an enzyme-RNA complex is present (ref) thus having an unlimited capacity to replicate never reaching replicative senescence; (ref). This complex is absent in somatic cells. Telomerase helps to compensate for the shortening of telomeres during cell replication and division. This function is carried out with the addition of telomere repeat sequences to the 3' end of the DNA strands (template strand). Through this, the DNA polymerase is able to complete its job in the completion of the 'incomplete ends' of the opposite strand (lagging strand). The activity of telomerase is regulated by certain proteins. If telomerase is constantly active, cells can grow indefinitely without the occurrence of senescence.If some telomerase is present then cell senescence would be delayed. If less telomerase is present then the processed of senescence would occur sooner.
Telomeres and cellular ageing (500)
The process of ageing is accompanied by the shortening of telomeres (Kappei, et al, 2007). This is also true for premature ageing syndromes and age-related disease which have an association with shortened telomeres. Both observations are central to the hypothesis that the length of telomeres in replicating cells is inversely correlated with age and thus telomere lengths have a direct influence on longevity (Kappei, et al, 2007). Cellular ageing is representative of biological ageing. Regarding age-related disorders, there are difficulties in determining whether shortened telomeres are a cause or consequence of the disorders.
There is a well known case of 'Dolly' a cloned sheep who developed arthritis in its left rear leg, this was thought to be an indication of premature ageing which isn't surprising as it was developed from somatic cells of a 6 year old sheep. Never mind the fact that the cells had before hand undergone extensive cell proliferation in vivo in the absence of the telomerase enzyme (ref). Consequently, Dolly the sheep suffered from immense erosion as well as shortened telomere was present in the somatic cells. This experimentation is just one of many that are minute indications of the correlation between ageing and shortened telomeres.
Additionally, there is an age related disease called progeria whereby young children age so rapidly they suffer and eventually from many symptoms associate with old age in their teens. When the cells of this disease was analysed, it was found that many of the cells had short telomeres which suggested that the shortening process of the telomeres contributed to the pathology of the disease and thus is in support of the hypothesis that such shortening contributes to cellular ageing.
Furthermore researchers used laboratory mouse models who also have the same telomerase repeat sequence of human (TTAGGG) n, and who also had defective telomerase. Through selective breeding, it was found that successive generations had signs of premature ageing as well as life spans that were shortened. From this, further evidence is provided in support of role of telomerase and thus telomeres in ageing.
Although researchers make known that ageing process in its entirety cannot be explain just by telomere shortening. It is also pointed out that there is no obvious relationship between the starting length of telomeres and a species' lifespan. This is attributing to the fact that although mice for example have a much longer telomere than humans, they only live for duration of about 2 years. In addition, there are other factors which have an impact on cellular ageing such as oxidative damage caused by free radicals; faults in the DNA damage and its repair systems and mitochondrial ageing whereby antioxidants are produced.
Telomeres and cancer (500)
The activity of telomerase can sometimes perform a negative function and aids in the provision of tumour cells with unlimited growth potential (ref). 90% of human tumours reactivate telomerase which displays hyperactivity in the replacement of telomere parts of lost during cell division (ref). As well as continuous elongation and maintenance of telomeres, its presence promotes cancer cells to be more cancerous. It is detail than typically a cancer cell undergoes about 80 doublings before a tumour mass is big enough to be detected (ref). If telomerase is withdrawn from a cancer cell that has been thriving on its activity for quite a long time, there becomes a change as cancer cells ceases to multiply as much, it becomes less invasive an less malignant. Therefore it can be said that telomerase prompts cancer cells to have a more malignant phenotype in addition to the ability to keep them immortal as they maintain the ends of chromosomes.
Conversely, the shortening of telomeres contributes to the genomic instability which can trigger cancer. Evidence in support of short telomeres being a risk factor for cancer in humans is growing; one being that short telomeres is partly responsible for early stages of certain cancers and can push cancer to a more progressive state. Researchers from John Hopkins University School of Medicine carried out an experimentation using cells taken from prostate cancer patients. A discovery was made in those telomeres taken from precancerous lesion and reveal to be up to four times shorter than cells of the surrounding tissue which was normal.
Because of the enhanced activity of telomerase in cancer cells they can be used as a diagnostic tool for early cancer so treatment can be put into place before the cancer spreads and the condition worsen. Moreover if the telomerase is made inactive, then the telomere would shorten and replicative senescence could be reached stooping the high amount of proliferation associate with cancer.