By Sreenidhi Venkatesh
Looped around at the end of chromosomes, sit the incredibly essential telomeres that influence aging, cancer, cell health and much more. These repetitive sequences of DNA, which are commonly found as ‘TTAGGG’ in humans, occur thousands of times. They behave like a cap by protecting the ends of chromosomes from being degraded, fusing with other chromosomes, or the cells’ DNA repair mechanism (Mestrovic, 2019).
The shortening of telomeres is a very fascinating concept that has come to the forefront of research due to the associations found between it and numerous diseases. As primers are unable to attach themselves to the very end of the chromosome, the Okazaki fragment cannot be synthesised causing the DNA to look damaged. With every replication, the telomere continues to shorten due to this phenomenon until it reaches the ‘Hayflick limit’. This concept explains cellular aging, where after 40-60 replications, cells are unable to divide any further and go through apoptosis. The telomeres shorten to an extent that they are unable to protect the actual chromosome from shortening, thereby triggering DNA repair mechanisms such as checkpoint arrest (Bartlett, 2014).
The single-stranded overhangs in telomeres occur on the lagging strand where there is incomplete end replication. These overhangs often loop back onto a complementary repeat to form a double-stranded DNA protective loop, which prevents the activation of the DNA damage response. In order for telomeres to be protected, they are also capped by telomere binding proteins, however these proteins only function when the G-tails and the duplex telomeric DNA (formed from the loops) are maintained (Mestrovic, 2019).
In 1984, Elizabeth Blackburn co-discovered the enzyme telomerase. This RNA-dependent DNA polymerase synthesises DNA using an RNA template, which is a special RNA molecule with a sequence that is complementary to the telomeric sequence. Prior to DNA replication, the telomerase extends the single stranded overhang so that any shortening of the telomere that takes place, does not have serious implications and has taken place on the extended region (Blackburn, 2009).
While they have their own repair mechanisms, telomeres are subject to a variety of other threats in the human body. A condition that we experience on a regular basis, and struggle to avoid, is stress. Stress manifests itself through a variety of factors that include anxiety, depression, and other psychological disorders (Webb, Yu, & Zakian, 2013). Stress is defined as when ‘environmental demands require physiologic or behavioural changes to maintain balance and homeostasis’ (Lee et al. 2016). Stress and its responses are unique to every individual. As a response to stress, the body releases a variety of biomolecules which contributes to the allostatic load, a side-effect of which could be the shortening of telomeres. The constant changes in endocrine and neural feedback experienced due to the stress that an individual is feeling has negative implications, also known as allostatic load (Law et al., 2016).
In humans and mice, it has been identified that one consequence of chronic stress is the production of reactive oxygen species (ROS). These are factors which are unstable and are responsible for the majority of DNA damage that occurs. The production of ROS, due to psychological stress, tends to take place in the brain where superoxide ions or hydroxide radicals, O2 or HO, are produced which then lead to the production of hydrogen peroxide. The formation of these species leads to DNA damage such as bases being oxidised, sugars being modified, or breakage of DNA strands. When these ROS accumulate in large amounts, it causes excessive DNA damage therefore leading cells to experience premature senescence, also known as cell cycle arrest (Mathur, Epel, & Khazeni, 2016; Kudielka & Kirschbaum, 2001). Telomeres are especially susceptible to this due to their heterochromatin state, which prevents them from being repaired efficiently if they are damaged. Most commonly, the guanine in telomeres undergoes oxidation, due to the high level of ‘G’ in the sequence. This form of lesion is known as 8-oxoguanine (Florido, Tchkonia, & Kirkland, 2011; Pinak, 2006).
In a study conducted to assess the effect of oxidative stress on DNA replication, it was identified that in the presence of H2O2, S-phase of the cell cycle was hindered. The study further did a chromosome orientation fluorescence in situ hybridisation (CO-FISH), to determine specifically at what point of DNA replication the block was taking place. Probes were used to identify the G and C rich sequences in the telomeres, and it was found that there were significantly fewer replicated telomeres in the samples treated with peroxide than the controls (Coluzzi, Leone, & Sgura, 2019). A previous study conducted by the same team demonstrated that persistent treatment with hydrogen peroxide led to the formation of 8-oxoguanine which is associated with the shortening of telomeres. While these tests were not conducted in humans, they did indicate that the presence of ROS is associated with DNA damage that contributes to the shortening of telomeres (Coluzzi et al., 2018).
While the above studies do not explicitly suggest that psychological stress contributes to the shortening of telomeres, a variety of psychological disorders such as anxiety, depression, and schizophrenia have shown to contribute to the production of ROS. In a study conducted on rats, it was shown that after inducing varying degrees of emotional stress on the rat, oxidative stress in cells was observed (Hamilton, Walsh, & Van Remmen, 2012).
In a study conducted to determine the length of telomeres in patients who had experienced depression, a significant reduction in telomere length was observed. This was further supported by a study which stated that the biological age of their patients with depression was 10 years older than their chronological age (Vakonaki et al., 2018). As shortening of telomeres has been shown to have associations with aging, this study suggests that depression could lead to shorter telomeres. While there are studies indicating the contrary, the causality between depression and telomere length has not been established due to the numerous uncontrolled factors that influence them, including triggers of depression, and effects of anti-depressants and other medication (Vakonaki et al., 2018).
Schizophrenia is another condition that has been researched with regards to telomeres. While it is not directly related to stress and the exact causes are unknown, it is said that a particularly stressful or emotional experience in an individual’s life could trigger this disorder. The oxidative stress noted in other stress related disorders is also present in schizophrenia patients, and the side effects are seen to affect processes such as mitochondrial signalling and neuronal excitability which are associated with the pathology of schizophrenia. When telomere lengths were measured in schizophrenia patients, they were observed to be shorter. Contrastingly, patients who had been administered anti-psychotics had longer telomeres in comparison. This could suggest the anti-psychotic medication acts as protection against the oxidative side effects produced in schizophrenic patients. However, as with depression studies, this relationship has not been consistent and has not been explicitly established (Vakonaki et al., 2018).
Understanding the connection between shortening telomeres and psychological disorders is especially interesting because conditions such as anxiety and depression are quite prevalent in society. While it is easy to identify more prominent consequences of ill mental health, it is important to recognise that it could be affecting us at a genetic level which leads to poor cell health and premature biological aging. Studying the effects of external stress and psychological disorders is challenging due to the unrestricted variables that affect every individual, however it is necessary to understand how our body responds to chronic stress that surrounds us, so we not only learn how to respond to it better, but to also develop treatments that are able to target the damage done by stress.
Bartlett, Z. (2014) Hayflick Limit. Available from: https://embryo.asu.edu/pages/hayflick-limit#:~:text=The%20Hayflick%20Limit%20is%20a,programmed%20cell%20death%20or%20apoptosis [Accessed 15th October 2020]
Blackburn, E. (2009) Nobel Prize. Available from: https://www.nobelprize.org/womenwhochangedscience/stories/elizabeth-blackburn [Accessed 16th October 2020]
Coluzzi, E., Colamartino, M., Cozzi, R., Leone, S., Meneghini, C., O’Callaghan, N. & Sgura, A. (2018) Oxidative stress induces persistent telomeric DNA damage responsible for nuclear morphology change in mammalian cells. PLoS One. 9(10). Available from: https://pubmed.ncbi.nlm.nih.gov/25354277/ [Accessed 18th October 2020]
Coluzzi, E., Leone, S. & Sgura, A. (2019) Oxidative Stress Induces Telomere Dysfunction and Senescence by Replication Fork Arrest. Cells. 8(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356380/ [Accessed 18th October 2020]
Florido, R., Tchkonia, T. & Kirkland, J. (2011) Aging and Adipose Tissue. Handbook of the Biology of Aging. Available from: https://www.sciencedirect.com/science/article/pii/B9780123786388000051 [Accessed 17th October 2020]
Hamilton, RT., Walsh, ME. & Van Remmen, H. (2012) Mouse Models of Oxidative Stress Indicate a Role for Modulating Healthy Aging. Journal of Experimental and Clinical Pathology. 4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188441/ [Accessed 18th October 2020]
Kudielka, BM. & Kirschbaum, C. (2001) Stress and Health Research. International Encyclopedia of the Social and Behavioural Sciences. 15170-15175. Available from: https://www.sciencedirect.com/science/article/pii/B0080430767038183 [Accessed 17th October 2020]
Law, E., Girgis, A., Sylvie, L., Levesque, J. & Pickett, H. (2016) Telomeres and Stress: Promising Avenues for Research in Psycho-Oncology. Asia-Pacific Journal of Oncology Nursing. 3(2). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123495/#__ffn_sectitle [Accessed 16th October 2020]
Mathur, M., Epel, E. & Khazeni, N. (2016) Perceived Stress and Telomere Length: A Systematic Review, Meta-Analysis, and Methodologic Considerations for Advancing the Field. Brain Behaviour Immunology. 158-169. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590630/ [Accessed 17th October 2020]
Mestrovic, T. (2019) Telomere Function. Available from: https://www.news-medical.net/life-sciences/Telomere-Function.aspx [Accessed from 15th October 2020]
Pinak, M. (2006) Enzymatic recognition of radiation-produced oxidative DNA lesion. Molecular dynamics approach. Modern Methods for Theoretical Physical Chemistry of Biopolymers. 191-210. Available from: https://www.sciencedirect.com/science/article/pii/B9780444522207500745 [Accessed 17th October 2020]
Salim, S. (2014) Oxidative Stress and Psychological Disorders. Current Neuropharmacology. 12(2). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964745/#:~:text=Oxidative%20stress%20is%20an%20imbalance,oxidative%20stress%20or%20redox%20imbalances [Accessed 17th October 2020]
Vakonaki, E., Tsiminikaki, K., Plaitis, S., Fragkiadaki, P., Tsoukalas, D., Katsikantami, I., Vaki, G., Tzatzarakis, M. N., Spandidos, D. A. & Tsatsakis, A. M. (2018) Common mental disorders and association with telomere length. Biomedical Reports. 2018. Available from: https://www.spandidos-publications.com/10.3892/br.2018.1040#b23-br-0-0-1040 [Accessed 18th October 2020]
Webb, CJ., Wu, Y. & Zakian, VA. (2013) DNA Repair at Telomeres: Keeping the ends intact. Cold Spring Harbour Perspectives Biology. 5(6). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660827/ [Accessed 16th October 2020]