Neuro Primer: Telomeres

By Marta Garo-Pascual

Telomeres are the “shoelace caps” of linear chromosomes and, as shoelace caps protect shoelaces, telomeres serve a protective role for chromosomes. Barbara McClintock and Hermann Muller described them in the 1930s and coined the term telomere from the Greek telos (“end”) and meros (“part”). These end parts of the chromosomes consist of repeats of DNA sequences associated with proteins. The proteins associated with telomeres prevent chromosomes from attaching to each other (Sfeir & de Lange, 2012). If such a thing happened, it would be almost impossible for the genetic material to be evenly separated during cell division. These proteins also prevent the cell from mistaking the ends of chromosomes with DNA strand breaks (de Lange, 2005).

The cell biology of telomeres is fascinating. For the cell to divide, the DNA of the cells must replicate itself. The machinery responsible for replication does reliable work on copying the original genetic material; however, due to a quirk of nature, this machinery is unable to replicate the DNA strand to its very end (Olovnikov, 1972; Watson, 1972). This results in the shortening of the chromosomes with each cell division. It sounds terrible that parts of chromosomes are lost every time the cell divides but, thankfully, these parts are the telomeres. It is not by coincidence that the repetitive sequence of telomeres lacks information for protein synthesis. Thus, telomeres protect the genes that are located in more internal regions of the chromosomes.

Much like the rings in a tree trunk, telomere length can reflect the number of divisions of a cell. In fact, human cells grown in vitro have a limit of 50-60 replication cycles (Hayflick, 1965), a limitation that is thought to be imposed by telomere length. When telomere length is too short, the integrity of genes is compromised, and the cell enters what is called the “senescence program” and no longer divides. This reduction in the number of cells that can divide accompanies ageing and may explain part of the functional decline of most body organs (Blasco, 2007). For this reason, telomere attrition is considered a hallmark of ageing (Lopez-Otin et al., 2013).

However, telomere length cannot be explained by ageing alone. It also depends on lifestyle factors and genetic inheritance. Smoking and high body weight can accelerate telomere shortening, whereas the Mediterranean diet and exercise can slow it down (Canudas et al., 2020; Shammas, 2011; Song et al., 2010; Valdes et al., 2005). The most important predictor of telomere length is genetics. Telomere length has an estimated heritability of 70% according to several family-based studies (Broer et al., 2013). This means that if you inherited long telomeres from your parents, you are likely to have long telomeres throughout your life despite an unhealthy lifestyle.

Decades after telomeres were first identified, it was thought that they could only be shortened. This is not true. The discovery in the 1980s of telomerase, the enzyme that can extend telomeres, was such a breakthrough that it merited the Nobel Prize in Medicine and Physiology in 2009 (Nobel Prize, 2009). This prize was awarded to Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak for their contribution to the discovery of this previously unknown enzyme. Telomerase can extend the DNA sequence of telomeres and provide the necessary template to fully copy chromosomes without shortening (Greider & Blackburn, 1989; Szostak & Blackburn, 1982). Telomerase is largely inactive in human somatic cells, which means that telomere shortening is an inevitable reality for most cells (Hiyama & Hiyama, 2007). However, the discovery of telomerase highlights the possibility to manipulate telomere length for therapeutic purposes.

The most direct application of telomerase modulation would probably be in neurodegenerative diseases, where the ageing process of the brain is accelerated and highly dysfunctional. In the two most common neurodegenerative diseases, Alzheimer’s and Parkinson’s, observations point to telomere dysregulation. Many studies investigating telomere length in patients with Alzheimer’s disease have found that telomeres are shorter than those found in their healthy peers (Forero et al., 2016). In Parkinson’s disease, there is still no evidence of telomere length changes in patients, however, mice with extremely short telomeres express some of the same motor problems that characterise Parkinson’s (Rossiello et al., 2022).

Can we delay neurodegenerative diseases by switching on telomerase? In animal models, activating telomerase can reverse ageing effects (Jaskelioff et al., 2011) without increasing the incidence of cancer (Bernardes de Jesus et al., 2012). You heard right! Interestingly, cancer and ageing can be seen as two sides of the same coin. While a hallmark of ageing is telomere shortening, telomerase is active in most cancers such that long telomeres make some cancer cells immortal (Chakravarti et al., 2021). Thus, telomerase modulation can not only help fight premature ageing or degenerative diseases, but also cancer. For example, telomerase activators could treat degenerative diseases, while telomerase inhibitors could treat cancer (Chakravarti et al., 2021).

Overall, telomere length is a measure of cellular division and is determined by the genetic inheritance, the ageing process, and the lifestyle of an individual. This is an interesting measure when we study conditions such as cancer or neurodegenerative diseases, where a combination of these three components –genetics, ageing, and lifestyle– are considered causal factors. More studies need to be conducted to fully understand why telomere length is modulated by these factors. The time is now. We now know from laboratory experiments that telomere length can be modulated by activating or inhibiting telomerase in animal models and in vitro preparations. We can therefore start dreaming of therapies that modulate telomeres to their optimal length because too long or too short can be harmful, but telomeres at the right length can protect us.

~~~

Written by Marta Garo-Pascual

Illustrated by Vidya Saravanapandian

Edited by Honoreé Brewton and Mary Cooper

~~~

Become a Patron!

References

Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med, 4(8), 691-704. https://doi.org/10.1002/emmm.201200245

Blasco, M. A. (2007). Telomere length, stem cells and aging. Nat Chem Biol, 3(10), 640-649. https://doi.org/10.1038/nchembio.2007.38

Broer, L., Codd, V., Nyholt, D. R., Deelen, J., Mangino, M., Willemsen, G., . . . Boomsma, D. I. (2013). Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect. Eur J Hum Genet, 21(10), 1163-1168. https://doi.org/10.1038/ejhg.2012.303

Canudas, S., Becerra-Tomas, N., Hernandez-Alonso, P., Galie, S., Leung, C., Crous-Bou, M., . . . Salas-Salvado, J. (2020). Mediterranean Diet and Telomere Length: A Systematic Review and Meta-Analysis. Adv Nutr, 11(6), 1544-1554. https://doi.org/10.1093/advances/nmaa079

Chakravarti, D., LaBella, K. A., & DePinho, R. A. (2021). Telomeres: history, health, and hallmarks of aging. Cell, 184(2), 306-322. https://doi.org/10.1016/j.cell.2020.12.028

de Lange, T. (2005). Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev, 19(18), 2100-2110. https://doi.org/10.1101/gad.1346005

Forero, D. A., Gonzalez-Giraldo, Y., Lopez-Quintero, C., Castro-Vega, L. J., Barreto, G. E., & Perry, G. (2016). Meta-analysis of Telomere Length in Alzheimer’s Disease. J Gerontol A Biol Sci Med Sci, 71(8), 1069-1073. https://doi.org/10.1093/gerona/glw053

Greider, C. W., & Blackburn, E. H. (1989). A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature, 337(6205), 331-337. https://doi.org/10.1038/337331a0

Hayflick, L. (1965). The Limited in Vitro Lifetime of Human Diploid Cell Strains. Exp Cell Res, 37, 614-636. https://doi.org/10.1016/0014-4827(65)90211-9

Hiyama, E., & Hiyama, K. (2007). Telomere and telomerase in stem cells. Br J Cancer, 96(7), 1020-1024. https://doi.org/10.1038/sj.bjc.6603671

Jaskelioff, M., Muller, F. L., Paik, J. H., Thomas, E., Jiang, S., Adams, A. C., . . . Depinho, R. A. (2011). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature, 469(7328), 102-106. https://doi.org/10.1038/nature09603

Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217. https://doi.org/10.1016/j.cell.2013.05.039

Nobel Prize. (2009). The Nobel Prize in Physiology or Medicine 2009. Retrieved 26/10/2022 from https://www.nobelprize.org/prizes/medicine/2009/press-release/

Olovnikov, A. M. (1972). A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol, 41(1), 181-190. https://doi.org/10.1016/0022-5193(73)90198-7

Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F. (2022). Telomere dysfunction in ageing and age-related diseases. Nat Cell Biol, 24(2), 135-147. https://doi.org/10.1038/s41556-022-00842-x

Sfeir, A., & de Lange, T. (2012). Removal of shelterin reveals the telomere end-protection problem. Science, 336(6081), 593-597. https://doi.org/10.1126/science.1218498

Shammas, M. A. (2011). Telomeres, lifestyle, cancer, and aging. Curr Opin Clin Nutr Metab Care, 14(1), 28-34. https://doi.org/10.1097/MCO.0b013e32834121b1

Song, Z., von Figura, G., Liu, Y., Kraus, J. M., Torrice, C., Dillon, P., . . . Lenhard Rudolph, K. (2010). Lifestyle impacts on the aging-associated expression of biomarkers of DNA damage and telomere dysfunction in human blood. Aging Cell, 9(4), 607-615. https://doi.org/10.1111/j.1474-9726.2010.00583.x

Szostak, J. W., & Blackburn, E. H. (1982). Cloning yeast telomeres on linear plasmid vectors. Cell, 29(1), 245-255. https://doi.org/10.1016/0092-8674(82)90109-x

Valdes, A. M., Andrew, T., Gardner, J. P., Kimura, M., Oelsner, E., Cherkas, L. F., . . . Spector, T. D. (2005). Obesity, cigarette smoking, and telomere length in women. Lancet, 366(9486), 662-664. https://doi.org/10.1016/S0140-6736(05)66630-5

Watson, J. D. (1972). Origin of concatemeric T7 DNA. Nat New Biol, 239(94), 197-201. https://doi.org/10.1038/newbio239197a0