Telomeres are the repeating nucleotide sequences (ATCG) of DNA, which are located at the ends of chromosomes. They are partially erased or damaged after each cell division by mitosis . They have a significant function of preventing DNA damage and fusion of neighbouring chromosomes during mitosis, which would lead to genetic changes and potentially cell apoptosis, contributing to an increasing rate of ageing. Cells with extremely short telomeres are no longer able to divide and damaged tissues require regeneration via use of stem cells. When the cell is no longer able to divide, it reaches senescence. This normally happens after 50-70 divisions depending on the cell type. With age, the number of senescent cells accumulate, which compromises their function, and metabolic activities are carried out less efficiently. As a result, the organism starts to age.
In Vivo Experiments
Data collected via in vivo can be more easily applied to humans, as reactions to specific alterations can be predicted. Some in vivo experiments have successfully shown that telomere length can be significantly increased over 75 generations of cell division by changing its sequence of base pairs. [2, p. 337-365.]
Single Telomere Length Analysis (STELA)
It targets the amplification of telomeric DNA from a single chromosomal end using primers specific to subtelomeric sequences of single chromosomes. This method cannot register critically short telomeres (approximately 100 base pairs long in comparison to normal telomere length of 8,000 base pairs) . However, it is suitable for detection of telomeres in a low concentration of DNA, otherwise a smear is seen.
Terminal Restriction Fragment (TRF)
TRF is the first telomere length measurement technique to be developed, hence it is seen as the gold standard, used for accurate comparisons between different studies. It is based on frequent cutting restriction enzymes which do not have recognition sites in telomeric and subtelomeric regions, therefore they frequently cut the DNA material, leaving the telomere regions intact, which can then be viewed through gel electrophoresis and their amounts quantified. The gel electrophoresis will show telomere smears, whose position will display the length of telomeres. This method also provides an overestimation of telomere length, as it takes into account subtelomeric regions and different laboratories may use different restriction enzymes, which means that the length of the cut regions may vary, with a variation coefficient of 1.74% . Therefore, average telomere size may be overestimated.
Research and Evaluation
In a research project at Spanish National Cancer Research Centre, stem cells were allowed to divide in a petri dish in a process, which lead to formation of extra-long telomeres. Using these stem cells, scientists generated mice which had extra-long telomeres . This has successfully led to an increase in average lifespan of mice. Hence, showing that there is a positive correlation between lifespan and telomere length. Results have shown a significant improvement in longevity, as median lifespan of mice has extended by 12.74% . The study has also shown that no adverse effects on mice health have been recorded. They had no cognitive defects and had suppressed susceptibility to cancer compared to control mice with normal telomere length .
The improvement seen from altering the length of telomere is quite significant as it targets the areas that are most vulnerable to degeneration in the human lifetime (e.g. mitochondrial activity, metabolic exchanges, cholesterol build-up), which in turn means that we can postpone or minimise the onset of 1,6,7th (i.e cardiovascular disease, cancer and diabetes) most common disease to cause death, hence potentially increasing the longevity, as those people would have less susceptible bodies and metabolic systems . However, some cancers are caused by viral infections, such as human hepatitis B and C, in which case telomere lengthening treatment would not be applicable .
Additionally, it is proven that ageing is a fundamental factor for cancer development, as it is believed that risk factors accumulate over the years leading to dramatic increase in incidence of cancer development . It is also associated with decreased ability of stem cells to repair damage in the organism, as the effectiveness of this system decreases with age due to limiting ability to divide, from telomere attrition and cellular senescence. Therefore, over time, the rate of damage intake overthrows the rate of repair, leading to damage accumulation and susceptibility to cancers.
Over 50% of deaths in low-income countries were caused by communicable diseases, such as conditions caused by pregnancy, childbirth or malnutrition . These are the conditions that are not caused by body degeneration due to ageing and accumulation of genetically damaged senescent cells, hence, telomere elongation would not be helpful in postponing the onset of those conditions.
Furthermore, the death rates from non-communicable diseases, such as cardiovascular diseases, are higher in middle- and low-income countries, as overall global data suggests that these regions account for 78% of NCD deaths . However, assuming that telomere lengthening is a realistic solution for early onset of these diseases, it is an expensive procedure. This means that it is not necessarily available for those who require it the most, hence average global rate of ageing may not be significantly affected. Furthermore, only 18% of in vivo studies reach human trials, which means that it is questionable how realistic it is that telomere elongation would be available for the general public .
In conclusion, the mechanism of telomere alteration and its effects on factors mentioned above are not entirely known, hence although the procedure has a great potential of reducing rate of ageing, currently it requires further research.
References1. Genetic Science Learning Center (2016, March 1) ‘Are Telomeres the Key to Aging and Cancer’. – URL: https://learn.genetics.utah.edu/content/basics/telomeres/
2. Greider, C. ‘Telomere length regulation’ Annual Review of Biochemistry. (1996) 65: p 337-365. – URL: https://www.annualreviews.org/doi/abs/10.1146/annurev.bi.65.070196.002005?src=recsys
3. Johnson, Stephen (2019, October 22) ‘Scientists extended mice lifespan 12% by tweaking telomeres’. – URL: https://bigthink.com/surprising-science/telomere-aging
4. Ringelhan, M., McKeating, J. A., & Protzer, U. (2017) ‘Viral hepatitis and liver cancer’. – URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597741/
5. Scarborough, Ri, (2017, August 29) ‘Of mice and men: why animal trial results don’t always translate to humans’. – URL: https://theconversation.com/of-mice-and-men-why-animal-trial-results-dont-always-translate-to-humans-73354
6. World Health Organisation (2018, May 24) ‘The top 10 causes of death’. URL: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
7. Xu Z, et al. (2013) ‘The length of the shortest telomere as the major determinant of the onset of replicative senescence’. – URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730915/