Telomeres And Their Role In Human Ageing
Telomeres are structures that cap the ends of chromosomes. They are made up of TTAGGG repeats, these repeats can be up to 20kb long (Britt-Compton et al, 2006). The purpose of telomeres is to act as buffers to protect important segments of DNA from being lost due to the inability of DNA polymerase to replicate all the way to the end of the chromosome. This inability was described by Alexei Olovnikov and James Watson as the “end replication problem” in 1971. Chromosomes which are not capped are more likely to undergo recombination, degradation and fusion. Degradation of the chromosome can lead to a loss of genetic information and cellular senescence (Kim, 2002). In addition to an irreversible growth arrest, senescence can also lead to alerted functionality within the cell. (S-h Kim et al, 2002)
The shortening of telomeres to below a critical length has been associated with reduced longevity (Lewin et al, 2003). As we age the length of telomeres in all mitotic tissues decreases, except for in germline tissue. Germline cells implement a TMM (telomere maintenance mechanism) which utilises the enzyme telomerase (Cawthon et al, 2003).
Cawthon et al undertook a study in 2003 to investigate the link between telomere length and the fatality rate, in unrelated individuals aged between 60 and 97 from Utah. The research group used blood samples to obtain data about telomere length. The noted that individuals, who had telomere lengths in the bottom 25% of the data group, were 8 times more likely to die from age related diseases, such as heart disease. Cawthon et al also stated that telomere length may not have a direct impact on mortality, but it may be that telomere dysfunction activates senescence which leads to increased mortality.
Fibroblasts are cells which synthesize the supporting extracellular matrix of many human tissues. These cells are most common in connective tissue. This extracellular matrix is known as the stroma (Jonathan CW Edwards, 2000). When fibroblasts display the senescent phenotype they secrete growth factors, cytokines and enzymes that degrade the framework of the stroma. It is possible that these components lead to the decrease in the integrity and role of the tissue. This is a common sign of human ageing (S-h Kim et al, 2002). Although cellular senescence contributes to ageing it is assumed that it was created through evolution to prevent cancer in mammals. As a result it is commonly used as an example of a possible antagonist to the evolutionary process (S-h Kim et al, 2002).
To truly understand the relationship between telomere’s and human ageing, Blasco et al (1997) analysed telomere length in mice which has disrupted mTR genes. This gene was disrupted in such a way, that no telomerase activity was present in the mice. Initially no abnormalities in the mice were reported and it was assumed that this was due to the sample population of mice having long telomeres. However in later generations, in tissues with high proliferation rate, abnormalities were witnessed. Furthermore mice with disrupted mTR genes showed a similar phenotype to human ageing such as an increased risk in malignancy (Marciniak, 2000).
The cells of Dyskeratosis congenita (DKC) sufferers have lower levels of the enzyme telomerase; shorter telomere lengths are also observed (Marciniak, 2000). It is this fact which makes them ideal models to examine the link between telomeres and ageing. Patients with the autosomal dominant form of DKC are heterozygous for a mutation in the hTERC gene. The hTERC gene is the human RNA component of telomerase (Guilleret, 2002). As a result of this mutation DKC suffers cannot produce sufficient amounts of telomerase. Common symptoms DKC include skin pigmentation, abnormalities in the gut, increased risk of malignancy and progressive bone marrow failure (Royle, 2007). Marciniak, 2000 examined the various phenotypes seen in DKC patients, human ageing and mTR knockout mice. Marciniak created the comparison table shown below:
(Adapted from Trends in Genetics, 16(5), pp. 193-195.)
If the shortening of telomeres was the sole factor that determines the process of ageing, it can be argued as to why DKC patients and mTR knockout mice don’t exhibit a more exact phenotype. It could be that telomere shortening is not the critical factor but rather a host of other factors come into play. Furthermore in mTR knockout mice the phenotype rarely appears in early generation mice, but is much more prevalent in late generation mice. From this observation you can hypothesize that the telomeres in human are at a more decisive length than in mice (Marciniak, 2000).
