Chromosomes, DNA, genes, telomeres, telomerase, etc. these are some among the terms that are constantly used by different scientists in medicine in their attempt to explain the complexity of the building of cells. It is with the discovery of these components of cells that we have came to the understanding of the role played by some of them in the aging process. This article, however, will focus on an enzyme which is essential for the repair of one of these components which is vital for the cell’s survival. The aim is to share an understanding of the role of telomerase and senescent cells in antiaging.

What is a telomere?

For simplicity, a telomere is like a plastic cap of the end of your shoelaces. It’s important for the long-lasting function of the shoelaces, without it, the shoe laces would quickly unwind and lose their ability to hold our shoes where we want them. For those interested in the actual definition of a telomere, it’s enough to note that a telomere is a structure at the end of a linear chromosome. It consists of a repeat of nitrogenous base sequence of TTAGGG and a protein called shelterin. These parts of a chromosome protect it against damage, degradation and in so doing protects the cell against the untimely death. Unfortunately with constant cellular devisions the telomeres shorten and eventually lose their protective function, this is called “end replication problem”. This together with oxidative injury happen continuously as we age hence the length of telomeres is a good measure of our biological age.

There is more to the function of telomeres and the results of their damage. One that is worth mentioning is the fact that, it is not only the length of the telomeres that is important but also the integrity of their structures, such as capping, which prevents the signalling of DNA damage.

What protects these telomeres from shortening?

The body has a wonderful tool to repair these telomeres; it is called Telomerase reverse transcriptase. Like the name implies, it is an enzyme that is responsible for the replication of the telomeric regions of a chromosomal DNA. It counteracts the process of telomeric shortening which acts as a signal for the replicative senescence of the somatic cells. With understanding the function of this enzyme we can deduce that the length of a telomere and the activity of a telomerase reflect the ability of a cell to divide and make copies of itself. However, many somatic cells in human bodies do not actively express telomerase and its important to know where to look when trying to estimate the person’s telomerase activity.

Which cells have high activity of telomerase?

Many studies have sought to understand the funtion and the limitations of this enzyme and for that reason they had to find ways to isolate and study this enzyme. Telomarase activity is high in stem, sex and tumor cells and to some extant in the cells lining the inner wall of the human gut, the lymphocytes and the thymus. A process called Telomerase repeat amplification protocol (TRAP) is a common method used in determining the activity of telomerase in human and other mammalian cells. Futher details on the hows are not added in this article. Other ways this activity could be measured, could be using processes like Telomere Restriction Fragment (TRF) and Telomere Dysfuction Induced Foci (TIF).

Telomerase vs aging

By now you should have a clear basic understanding of how important it is for scientists to know as much as possible about the activity of telomerase in order to prevent or delay the process of telomere shortening. Nowerdays, one of the main focuses of medical researches in aging is the attempt to exploit this benefit of telomerase in haulting or reducing the pace of cellular senescence which in a nutshell is when the cell stops dividing and undergoes curtain changes that includes chromatin and secretome changes, together with tumer suppressor activation. This process was first descibed by Hayflick and Moorhead when they were explaining the irriversible ceasation of growth of human diploid cell strains after extensive serial passaging in culture.

So there are several drugs that have been studied which activate or increase the activity of this enzyme. Such drugs include drugs like Cycloastragenol (TA-65), which has been sold as a food supplement since 2013 and works by activating telomerase. This in actual fact leads us to the discussion of mechanisms of enhancing the enzymatic activity of telomerase for antiaging.

These mechanisms include:

  • Classical gene therapy with transfection of telomerase sequences. A process that can be used for tissue engineering and for the treatment of chronic diseases in humans, provided that the duration of the function of the induced telomerase is time-limited in order to avoid unnecessary and possibly fatal consequences.
  • Reexpression of silanced telomerase. The cells usually downregulate telomerase after cell differentiation using epigenetic alterations. However, to some extent, this process can be reversed with drugs that inhibit histone deacetylase (e.g., Belinostat, Panobinostat, Valproate, etc) and estrogen receptor agonists.
  • Activation of residual enzymatic activity. This process is possible in cells like stem cells of regenerative tissues and lymphocytes. The telomerase activity is activated by enzymatic phosphorylation which then leads to nuclear translocation. However, this function of lymphocytes is gradually lost with aging and leads to a decrease in immune memory cells, hence the decrease in the function of the immune system in aging organisms.
  • Modulation of the intracellular location. Telomerase can be translocated between the nucleus of the cell and the cytoplasm of the cell and drugs which can ulter this process can lead to an increase in its acivity.

So, in a nutshell drugs which can safely increase the activity of Telomerase can hault or decrease the pace of the aging process and hence increase the health span (the number of years a person spends in good health). Reaserch has shown that there are cells in the human body which have unusually short telemores. This is true for Human Peritoneal Mesothelial Cells (HPMCs). This has somehow proved right the theory that ‘telomeres don’t shorten due to aging but due to a decline in the activity of Telomerase’, is correct. The HPMC aging is said to be associated with dysfunction of mitochondria, which leads to the increased production of reactive oxygen species and subsequent cell injury. This indicates that premature aging is associated with oxydative stress.

The role of cellular senescence in aging

Many scietists believe that cellular senescence contibute to age related tissue and organ dysfunction and eventually leading to different chronic diseases that are related to aging. This is thought to be a complex process with several mechanisms. There are 3 mechanisms which are worth mentioning, by which the senescent cells are thought to be promoting tissue dysfunctions. These mechanisms include:

  • p38 MARK (Mitogen-Activated Protein Kinase) which are reactive to stressors like UV radiation, heat shock, cytokines, etc and are involed in cell apoptosis, autophagy, cell differentiation and inevertably affect the tissue funtion. Persistant activity of this kinase results in impaired cellular regeneration.
  • DSBs (DNA double strand breaks). These processes are rare but are very dangerous when they occur because they can cause cell death or cancer causing mutations in the DNA.
  • Senescence-associated Beta-galactosidase activity. This is practically evident in the cells which are cultured and studied outside the body and the results of which help differentiate between the replicatively senescent state of a cell and the simply quiscent state of a cell during growth arrest.

Conclusion

The study of an ageing cell and how we can slow it and hopefully finally stop it is a complex one. Not only is antiaging scietifically challanging, but it is also ethically challanging as the discovery of the wonder drug and the achievement of human immortality could lead to other adverse effects like overpopulation and severe resource shortages. This article however hopes to have made the reader aware that there is a scientific hope in the usage of enhancers of telomerase activity in increasing longevity. I also hope that I have made you aware that ageing is not only about shortening of telomeres but a wide rage of damages to the living cell.

References

White RR, Vijg J.. Do DNA Double-Strand Breaks Drive Aging?. Mol Cell. 2016 Sep 1;63(5):729-38.
Telomerase and telomeres in aging theory and chronographic aging theory. Mayya P. Razgonova, Alexander M. Zakharenko, Kirill S. Golokhvast, Maria Thanasoula, Evangelia Sarandi, Konstantinos Nikolouzakis, Persefoni Fragkiadaki, Dimitris Tsoukalas, Demetrios A. Spandidos, Aristidis Tsatsakis Mol Med Rep. 2020 Sep; 22(3): 1679–1694. Published online 2020 Jun 25.
Springer Nature Singapore Pte Ltd. 2018 221J. R. Harris, V. I. Korolchuk (eds.), Biochemistry and Cell Biology of Ageing. Part I Biomedical Science, Subcellular Biochemistry 90.
Van Deursen, Jan M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439–446.
Harris, J. Robin; Korolchuk, Viktor I. (2018). [Subcellular Biochemistry] Biochemistry and Cell Biology of Ageing. Part I Biomedical Science Volume 90: Telomeres, Telomerase and Ageing. 10.1007, 221–308.
Telomerase Repeated Amplification Protocol (TRAP), Ilgen Mender, Jerry W. Shay Bio Protoc. Author manuscript; available in PMC 2016 May 11. Published in final edited form as: Bio Protoc. 2015 Nov 20.
Therapeutic Targeting of Telomerase. Kathrin Jäger, Michael Walter Genes (Basel) 2016 Jul; 7(7): 39. Published online 2016 Jul 21.
Pasyukova EG, Vaiserman AM. HDAC inhibitors: A new promising drug class in anti-aging research. Mech Ageing Dev. 2017 Sep;166:6-15.