Telomeres

From Longevity Wiki

A telomere is a region of repetitive nucleotide sequences at the end of linear DNA chromosomes. Together with associated proteins, telomeres protect the terminal regions of chromosomal DNA from degradation and ensure the integrity of chromosomes. Telomere dysfunction has been described as one of the molecular hallmarks of ageing.

History

In the 1930s Barbara McClintock and Herman Muller inferred the existence of unique structures at the end of chromosomes in corn and fruit fly.[1][2] They hypothesised that these structures were essential for chromosome stability and prevention of chromosome fusions. The name “telomere” was coined - from the Greek telos meaning “end” and meros meaning “part". In 1978 Elizabeth Blackburn sequenced telomeric DNA of a protozoan Tetrahymena thermophila and revealed it is composed of tandem repeats of hexanucleotide sequences. [3] In 1982, together with Jack Szostak, she experimentally confirmed the protective role of telomeres. [4] In 1985 Blackburn and Carol Greider discovered a novel enzyme, telomerase, capable of extending telomere length. [5] Blackburn, Szostak and Greider were awarded a Nobel Prize in Physiology or Medicine in 2009 “for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase”.[6]

Telomere function and structure

Telomeres are DNA fragments that cap the ends of linear chromosomes and protect them from erosion and end-to-end fusions.[7] The terminal ends of linear chromosomes cannot be fully replicated, and as a result telomeres shorten at each mitotic cycle. As telomeres reach a critical length, they cannot longer fully maintain their protective functions, which triggers a DNA damage response and arrests cell proliferation.[8] As DNA breaks in telomeres are irreparable, cell senescence can be triggered even when telomere lenght is not critically short. [9]

Telomeric DNA is made of tandem repeats of nucleotide sequences, and does not code for proteins. Sequence of telomeres is well-conserved among humans and other vertebrates and consists of “TTAGGG” repeats.[10][11] As opposed to the sequence, telomere length varies widely among and within species, within an organism, and even between chromosomes.[11] In humans, telomere length has been shown to vary between 5 and 15 thousand base pairs.[12] The telomere is cloaked in a specialised six-protein complex, called shelterin, which ensures protection of chromosome ends and distinguishes telomeres from sites of DNA damage.[13]

Telomerase

Telomerase is an enzyme that elongates telomeres. It consists of an RNA subunit (TERC) and a protein subunit, telomerase reverse transcriptase (TERT). TERT is able to bind the end part of the chromosome’s telomeric sequence and synthesise new telomeric repeats using TERC as a template. Telomerase is abundantly present in germ cells, stem cells and most cancer cells. Differentiated (non-dividing) cells show modest or undetectable expression levels of telomerase. [14]

GV1001

GV1001 is a small peptide containing 16 amino acids that mimics a fragment of the active catalytic site of human telomerase reverse transcriptase (hTERT).[15] GV1001 peptide can be recognized by the immune system that reacts by killing the telomerase-active cells.[16][17] GV1001 has antioxidant and neuroprotective effects in neural stem cells, which appear to be mediated by scavenging free radicals, increasing survival signals and decreasing death signals.[18]

GV1001 was used for the treatment of Alzheimer's disease patients with moderate to severe dementia and confirmed that, compared to those in the placebo, GV1001 significantly improved the Alzheimer's disease patient’s cognitive function.[19] According to the hypothesis (Park H. et al., 2024) GV1001 binds to GnRHRs and activates downstream signaling pathways, increasing cAMP levels. This pathway might affect the degradation of Aβ peptides, reduction of p-tau, modulation of neuroinflammation (i.e., reducing pro-inflammatory and increasing anti-inflammatory microglia and astrocytes), and suppression of neuronal loss.[20]

Telomeres in aging and age-related diseases

Telomere dysfunction has been described as one of the 9 Hallmarks of Aging, as shortening ("attrition") of telomeres in general progresses with age in all proliferating tissues.[21][22]

The rate of telomere attrition changes throughout the lifetime, and is much faster in the first two years of life than during later life.[23] On average, telomere length in human leukocytes was found to shorten by 30-35 base pairs per year, reaching about 6 thousand base pairs in people over 60 years old.[24] Telomeric length of 5 thousand base pairs has been suggested to be a "telomeric brink" denoting a high risk of imminent death.[25] Although most people do not reach the telomeric brink in their lifetime, further extension of human longevity might be increasingly constrained by telomere length.

Accelerated telomere shortening and dysfunction has been linked to several age-related diseases, such as chronic obstructive pulmonary disease, metabolic syndrome, liver cirrhosis, atherosclerosis, osteoporosis, chronic kidney disease.[26] However, associations between telomere length and age-dependent conditions are often inconsistent and the molecular understanding of these associations is still lacking.[22] There is currently insufficient clinical evidence to use telomere length or shortening rate as biomarkers for human aging, but research in this area is ongoing.[27]

Telomeres and telomerase in cancer and other diseases

Increased levels of telomerase have been found in the vast majority of human cancers, whereas mutations decreasing telomerase function cause a range of genetic disorders, such as dyskeratosis congenita, idiopathic pulmonary fibrosis and bone marrow failure.[28] Longer telomere lenghts have been associated with higher risk of melanoma, lung cancer, prostate cancer, and chronic lymphocytic leukemia. [25]

Telomeres and telomerase in anti-aging therapies

Age-reversing telomerase mRNA therapeutics

A dogma arose in the 1990s that telomerase causes cancer. This is wrong and set back the field by decades. The reality is that permanent telomerase supports cancer, whereas healthy stem cells frequently turn on telomerase transiently throughout our lives to stave off the devastating effects of short telomeres.[29] A single dose of telomerase mRNA delivered in vivo using lipid nanoparticles reverses years of telomere shortening in hours.[30]

Mice

Mice engineered with much longer telomeres than those of the natural species showed improved mitochondrial function, improved metabolic parameters, decreased cancer, and increased longevity (12.75% increase in median longevity). [31][32] Due to concerns related to the association between telomerase expression and cancer, this was an important finding that suggests that telomere length per se does not increase cancer risk in mice.[31]

Gene therapies delivering telomerase gene have been studied in mice. In a 2012 study by Bernardes de Jesus and colleagues, treatment of adult and old mice with a single injection of an adeno-associated virus expressing mouse TERT had beneficial effects on health, fitness, and longevity.[33] Mice treated at 1 year of age had an increase of median lifespan of 24%, while mice treated at 2 years of age had a lifespan increase of 13%.

In a 2022 study by Jaijyan and colleagues, monthly treatment of mice with a cytomegalovirus vector expressing mouse TERT extended median lifespan by 41.4%.[34][35] Both intranasal and injectable preparations of the vector were tested, and performed equally well in delivering gene therapy to multiple organs, without increasing cancer or unwanted side effects. The sample size was small, with a total of 16 mice across the 2 delivery groups. However, the extent of lifespan extension was striking and requires further testing, such as in different mice strains and with larger sample sizes. The observed extension of lifespan also suggests that telomerase may actually decrease cancer risk, consistent with a younger phenotype by influencing aging.[31][34]

References

  1. ↑ Creighton, H. B., & McClintock, B. (1931). A correlation of cytological and genetical crossing-over in Zea mays. Proceedings of the National Academy of Sciences, 17(8), 492-497.
  2. ↑ MULLER, H. J. (1938). The remaking of chromosomes. Collecting net, 13, 181-198.
  3. ↑ Blackburn, E. H., & Gall, J. G. (1978). A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. Journal of molecular biology, 120(1), 33-53.
  4. ↑ Szostak, J. W., & Blackburn, E. H. (1982). Cloning yeast telomeres on linear plasmid vectors. Cell, 29(1), 245-255.
  5. ↑ Greider, C. W., & Blackburn, E. H. (1985). Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. cell, 43(2), 405-413.
  6. ↑ Summary. NobelPrize.org. Nobel Prize Outreach AB 2022. Mon. 25 Jul 2022. <https://www.nobelprize.org/prizes/medicine/2009/press-release/>
  7. ↑ de Lange, Titia. ”How Telomeres Solve the End-Protection Problem”. Science, vol. 326, nr 5955, november 2009, s. 948–52. DOI.org (Crossref), https://doi.org/10.1126/science.1170633.
  8. ↑ Cesare, Anthony J., och Jan Karlseder. ”A Three-State Model of Telomere Control over Human Proliferative Boundaries”. Current Opinion in Cell Biology, vol. 24, nr 6, december 2012, s. 731–38. DOI.org (Crossref), https://doi.org/10.1016/j.ceb.2012.08.007.
  9. ↑ Fumagalli, M., Rossiello, F., Clerici, M., Barozzi, S., Cittaro, D., Kaplunov, J. M., ... & d’Adda di Fagagna, F. (2012). Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nature cell biology, 14(4), 355-365.
  10. ↑ Meyne, J., m.fl. ”Conservation of the Human Telomere Sequence (TTAGGG)n among Vertebrates.” Proceedings of the National Academy of Sciences, vol. 86, nr 18, september 1989, s. 7049–53. DOI.org (Crossref), https://doi.org/10.1073/pnas.86.18.7049.
  11. ↑ 11.0 11.1 Oeseburg, Hisko, m.fl. ”Telomere Biology in Healthy Aging and Disease”. Pflügers Archiv - European Journal of Physiology, vol. 459, nr 2, januari 2010, s. 259–68. DOI.org (Crossref), https://doi.org/10.1007/s00424-009-0728-1.
  12. ↑ Takubo, Kaiyo, m.fl. ”Telomere Lengths Are Characteristic in Each Human Individual”. Experimental Gerontology, vol. 37, nr 4, april 2002, s. 523–31. DOI.org (Crossref), https://doi.org/10.1016/S0531-5565(01)00218-2.
  13. ↑ de Lange, Titia. ”Shelterin: The Protein Complex That Shapes and Safeguards Human Telomeres”. Genes & Development, vol. 19, nr 18, september 2005, s. 2100–10. DOI.org (Crossref), https://doi.org/10.1101/gad.1346005.
  14. ↑ Cong, Yu-Sheng, m.fl. ”Human Telomerase and Its Regulation”. Microbiology and Molecular Biology Reviews, vol. 66, nr 3, september 2002, s. 407–25. DOI.org (Crossref), https://doi.org/10.1128/MMBR.66.3.407-425.2002.
  15. ↑ Park, H. H., Lee, K. Y., Kim, S., Lee, J. W., Choi, N. Y., Lee, E. H., ... & Koh, S. H. (2014). The novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase. Neurobiology of aging, 35(6), 1255-1274. PMID: 24439482 DOI: 10.1016/j.neurobiolaging.2013.12.015
  16. ↑ Tian, X., Chen, B., & Liu, X. (2010). Telomere and telomerase as targets for cancer therapy. Applied biochemistry and biotechnology, 160(5), 1460-1472. PMID: 19412578 DOI: 10.1007/s12010-009-8633-9
  17. ↑ Inderberg-Suso, E. M., Trachsel, S., Lislerud, K., Rasmussen, A. M., & Gaudernack, G. (2012). Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001. Oncoimmunology, 1(5), 670-686. PMID: 22934259 PMC3429571 DOI: 10.4161/onci.20426
  18. ↑ Park, H. H., Yu, H. J., Kim, S., Kim, G., Choi, N. Y., Lee, E. H., ... & Koh, S. H. (2016). Neural stem cells injured by oxidative stress can be rejuvenated by GV1001, a novel peptide, through scavenging free radicals and enhancing survival signals. Neurotoxicology, 55, 131-141. PMID: 27265016 DOI: 10.1016/j.neuro.2016.05.022
  19. ↑ Koh, S. H., Kwon, H. S., Choi, S. H., Jeong, J. H., Na, H. R., Lee, C. N., ... & Lee, K. Y. (2021). Efficacy and safety of GV1001 in patients with moderate-to-severe Alzheimer’s disease already receiving donepezil: A phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. Alzheimer's research & therapy, 13, 1-11. PMID: 33771205 PMC7995588 DOI: 10.1186/s13195-021-00803-w
  20. ↑ Park, H., Kwon, H. S., Lee, K. Y., Kim, Y. E., Son, J. W., Choi, N. Y., ... & Koh, S. H. (2024). GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer’s disease mouse model. Brain, Behavior, and Immunity, 115, 295-307. PMID: 37884161 DOI: 10.1016/j.bbi.2023.10.021
  21. ↑ Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., ... & Pierce, B. L. (2020). Determinants of telomere length across human tissues. Science, 369(6509), eaaz6876.
  22. ↑ 22.0 22.1 Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. Frontiers in Genetics, 11, 630186.
  23. ↑ Frenck Jr, R. W., Blackburn, E. H., & Shannon, K. M. (1998). The rate of telomere sequence loss in human leukocytes varies with age. Proceedings of the National Academy of Sciences, 95(10), 5607-5610.
  24. ↑ Calado, R. T., & Dumitriu, B. (2013, April). Telomere dynamics in mice and humans. In Seminars in hematology (Vol. 50, No. 2, pp. 165-174). WB Saunders.
  25. ↑ 25.0 25.1 Steenstrup, T., Kark, J. D., Verhulst, S., Thinggaard, M., Hjelmborg, J. V., Dalgård, C., ... & Aviv, A. (2017). Telomeres and the natural lifespan limit in humans. Aging (Albany NY), 9(4), 1130.
  26. ↑ Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F. (2022). Telomere dysfunction in ageing and age-related diseases. Nature cell biology, 24(2), 135-147.
  27. ↑ Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. Frontiers in Genetics, 11, 630186.
  28. ↑ Roake, C. M., & Artandi, S. E. (2020). Regulation of human telomerase in homeostasis and disease. Nature reviews Molecular cell biology, 21(7), 384-397.
  29. ↑ Rejuvenation Technologies is targeting longevity and age-related disease with telomerase-based mRNA therapies
  30. ↑ Rejuvenation Technologies exits stealth with $10.6m for age-reversing mRNA therapeutics
  31. ↑ 31.0 31.1 31.2 Muñoz-Lorente, M. A., Cano-Martin, A. C., & Blasco, M. A. (2019). Mice with hyper-long telomeres show less metabolic aging and longer lifespans. Nature communications, 10(1), 1-14.
  32. ↑ CNIO researchers obtain the first mice born with hyper-long telomeres and show that it is possible to extend life without any genetic modification - CNIO, accessed 05 Aug 2022
  33. ↑ 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 molecular medicine, 4(8), 691-704.
  34. ↑ 34.0 34.1 Jaijyan, D. K., Selariu, A., Cruz-Cosme, R., Tong, M., Yang, S., Stefa, A., ... & Zhu, H. (2022). New intranasal and injectable gene therapy for healthy life extension. Proceedings of the National Academy of Sciences, 119(20), e2121499119.
  35. ↑ https://www.chemistryworld.com/news/gene-therapy-showcases-technique-to-extend-life-in-mice/4015718.article?utm_campaign=cw_shared&utm_medium=post&utm_source=navigator accessed 05 Aug 2022
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