Dementia and Neurocognitive Disorders (대한치매학회지)

Korean Dementia Association (대한치매학회)
권호 표지
DOI QR코드

DOI QR Code

Is Telomere Length Shortening a Risk Factor for Neurodegenerative Disorders?

  • Hyun-Jung Yu (Department of Neurology, Bundang Jesaeng General Hospital) ;
  • Seong-Ho Koh (Department of Neurology, Hanyang University College of Medicine)
  • Received : 2022.06.15
  • Accepted : 2022.06.30
  • Published : 2022.07.31
Download PDF
⟨ Previous Next ⟩

Abstract

Telomeres are located at the end of chromosomes. They are known to protect chromosomes and prevent cellular senescence. Telomere length shortening has been considered an important marker of aging. Many studies have reported this concept in connection with neurodegenerative disorders. Considering the role of telomeres, it seems that longer telomeres are beneficial while shorter telomeres are detrimental in preventing neurodegenerative disorders. However, several studies have shown that people with longer telomeres might also be vulnerable to neurodegenerative disorders. Before these conflicting results can be explained through large-scale longitudinal clinical studies on the role of telomere length in neurodegenerative disorders, it would be beneficial to simultaneously review these opposing results. Understanding these conflicting results might help us plan future studies to reveal the role of telomere length in neurodegenerative disorders. In this review, these contradictory findings are thoroughly discussed, with the aim to better understand the role of telomere length in neurodegenerative disorders.

Keywords

Acknowledgement

This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea (grant numbers: HI20C0253, HU21C0113, and HU21C0007) and the Medical Research Center (2017R1A5A2015395).

References

  1. Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG, Croteau DL, et al. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 2019;15:565-581.
  2. Azam S, Haque ME, Balakrishnan R, Kim IS, Choi DK. The ageing brain: molecular and cellular basis of neurodegeneration. Front Cell Dev Biol 2021;9:683459.
  3. Bernadotte A, Mikhelson VM, Spivak IM. Markers of cellular senescence. Telomere shortening as a marker of cellular senescence. Aging (Albany NY) 2016;8:3-11.
  4. Wright WE, Tesmer VM, Huffman KE, Levene SD, Shay JW. Normal human chromosomes have long G-rich telomeric overhangs at one end. Genes Dev 1997;11:2801-2809.
  5. McEachern MJ, Krauskopf A, Blackburn EH. Telomeres and their control. Annu Rev Genet 2000;34:331-358.
  6. Sarek G, Kotsantis P, Ruis P, Van Ly D, Margalef P, Borel V, et al. CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle. Nature 2019;575:523-527.
  7. Koh SH, Choi SH, Jeong JH, Jang JW, Park KW, Kim EJ, et al. Telomere shortening reflecting physical aging is associated with cognitive decline and dementia conversion in mild cognitive impairment due to Alzheimer's disease. Aging (Albany NY) 2020;12:4407-4423.
  8. Wang J, Liu Y, Xia Q, Xia Q, Wang B, Yang C, et al. Potential roles of telomeres and telomerase in neurodegenerative diseases. Int J Biol Macromol 2020;163:1060-1078.
  9. Kim EJ, Koh SH, Ha J, Na DL, Seo SW, Kim HJ, et al. Increased telomere length in patients with frontotemporal dementia syndrome. J Neurol Sci 2021;428:117565.
  10. Fani L, Hilal S, Sedaghat S, Broer L, Licher S, Arp PP, et al. Telomere length and the risk of Alzheimer's disease: the Rotterdam Study. J Alzheimers Dis 2020;73:707-714.
  11. Chow HM, Herrup K. Genomic integrity and the ageing brain. Nat Rev Neurosci 2015;16:672-684.
  12. Moller P. Genotoxicity of environmental agents assessed by the alkaline comet assay. Basic Clin Pharmacol Toxicol 2005;96 Suppl 1:1-42.
  13. Jeppesen DK, Bohr VA, Stevnsner T. DNA repair deficiency in neurodegeneration. Prog Neurobiol 2011;94:166-200.
  14. McKinnon PJ. Maintaining genome stability in the nervous system. Nat Neurosci 2013;16:1523-1529.
  15. Hwang JY, Aromolaran KA, Zukin RS. The emerging field of epigenetics in neurodegeneration and neuroprotection. Nat Rev Neurosci 2017;18:347-361.
  16. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013;153:1194-1217.
  17. Johri A, Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther 2012;342:619-630.
  18. Keogh MJ, Chinnery PF. Mitochondrial DNA mutations in neurodegeneration. Biochim Biophys Acta 2015;1847:1401-1411.
  19. Kultz D. Molecular and evolutionary basis of the cellular stress response. Annu Rev Physiol 2005;67:225-257.
  20. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev 2010;24:2463-2479.
  21. Narita M, Young AR, Arakawa S, Samarajiwa SA, Nakashima T, Yoshida S, et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 2011;332:966-970.
  22. Oh J, Lee YD, Wagers AJ. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med 2014;20:870-880.
  23. Currais A. Ageing and inflammation - A central role for mitochondria in brain health and disease. Ageing Res Rev 2015;21:30-42.
  24. Shin JS, Hong A, Solomon MJ, Lee CS. The role of telomeres and telomerase in the pathology of human cancer and aging. Pathology 2006;38:103-113.
  25. van Steensel B, Smogorzewska A, de Lange T. TRF2 protects human telomeres from end-to-end fusions. Cell 1998;92:401-413.
  26. Takubo K, Nakamura K, Izumiyama N, Furugori E, Sawabe M, Arai T, et al. Telomere shortening with aging in human liver. J Gerontol A Biol Sci Med Sci 2000;55:B533-B536.
  27. Herrmann M, Pusceddu I, Marz W, Herrmann W. Telomere biology and age-related diseases. Clin Chem Lab Med 2018;56:1210-1222.
  28. Cawthon RM, Smith KR, O'Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003;361:393-395.
  29. Lukens JN, Van Deerlin V, Clark CM, Xie SX, Johnson FB. Comparisons of telomere lengths in peripheral blood and cerebellum in Alzheimer's disease. Alzheimers Dement 2009;5:463-469.
  30. Panossian LA, Porter VR, Valenzuela HF, Zhu X, Reback E, Masterman D, et al. Telomere shortening in T cells correlates with Alzheimer's disease status. Neurobiol Aging 2003;24:77-84.
  31. Scarabino D, Broggio E, Gambina G, Corbo RM. Leukocyte telomere length in mild cognitive impairment and Alzheimer's disease patients. Exp Gerontol 2017;98:143-147.
  32. Lee EH, Han MH, Ha J, Park HH, Koh SH, Choi SH, et al. Relationship between telomere shortening and age in Korean individuals with mild cognitive impairment and Alzheimer's disease compared to that in healthy controls. Aging (Albany NY) 2020;13:2089-2100.
  33. Liu M, Huo YR, Wang J, Wang C, Liu S, Liu S, et al. Telomere shortening in Alzheimer's disease patients. Ann Clin Lab Sci 2016;46:260-265.
  34. Hackenhaar FS, Josefsson M, Adolfsson AN, Landfors M, Kauppi K, Hultdin M, et al. Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers. Alzheimers Res Ther 2021;13:130.
  35. Palmos AB, Duarte RR, Smeeth DM, Hedges EC, Nixon DF, Thuret S, et al. Telomere length and human hippocampal neurogenesis. Neuropsychopharmacology 2020;45:2239-2247.
  36. Ashrafi A, Cosentino S, Kang MS, Lee JH, Schupf N, Andersen SL, et al. Leukocyte telomere length is unrelated to cognitive performance among non-demented and demented persons: an examination of long life family study participants. J Int Neuropsychol Soc 2020;26:906-917.
  37. Zekry D, Herrmann FR, Irminger-Finger I, Ortolan L, Genet C, Vitale AM, et al. Telomere length is not predictive of dementia or MCI conversion in the oldest old. Neurobiol Aging 2010;31:719-720.
  38. Rolyan H, Scheffold A, Heinrich A, Begus-Nahrmann Y, Langkopf BH, Holter SM, et al. Telomere shortening reduces Alzheimer's disease amyloid pathology in mice. Brain 2011;134:2044-2056.
  39. Lee A, Gilbert RM. Epidemiology of Parkinson disease. Neurol Clin 2016;34:955-965.
  40. Simon DK, Tanner CM, Brundin P. Parkinson disease epidemiology, pathology, genetics, and pathophysiology. Clin Geriatr Med 2020;36:1-12.
  41. Martin-Ruiz C, Williams-Gray CH, Yarnall AJ, Boucher JJ, Lawson RA, Wijeyekoon RS, et al. Senescence and inflammatory markers for predicting clinical progression in Parkinson's disease: the ICICLE-PD study. J Parkinsons Dis 2020;10:193-206.
  42. Wu Y, Pei Y, Yang Z, Li K, Lou X, Cui W. Accelerated telomere shortening independent of LRRK2 variants in Chinese patients with Parkinson's disease. Aging (Albany NY) 2020;12:20483-20492.
  43. Levstek T, Redensek S, Trost M, Dolzan V, Podkrajsek KT. Assessment of the telomere length and its effect on the symptomatology of Parkinson's disease. Antioxidants 2021;10:137.
  44. Degerman S, Domellof M, Landfors M, Linder J, Lundin M, Haraldsson S, et al. Long leukocyte telomere length at diagnosis is a risk factor for dementia progression in idiopathic parkinsonism. PLoS One 2014;9:e113387.
  45. Schurks M, Buring J, Dushkes R, Gaziano JM, Zee RY, Kurth T. Telomere length and Parkinson's disease in men: a nested case-control study. Eur J Neurol 2014;21:93-99.
  46. Wang H, Chen H, Gao X, McGrath M, Deer D, De Vivo I, et al. Telomere length and risk of Parkinson's disease. Mov Disord 2008;23:302-305.
  47. Hudson G, Faini D, Stutt A, Eccles M, Robinson L, Burn DJ, et al. No evidence of substantia nigra telomere shortening in Parkinson's disease. Neurobiol Aging 2011;32:2107.e3-2107.e5.
  48. Forero DA, Gonzalez-Giraldo Y, Lopez-Quintero C, Castro-Vega LJ, Barreto GE, Perry G. Telomere length in Parkinson's disease: a meta-analysis. Exp Gerontol 2016;75:53-55.
  49. Khan BK, Yokoyama JS, Takada LT, Sha SJ, Rutherford NJ, Fong JC, et al. Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. J Neurol Neurosurg Psychiatry 2012;83:358-364.
  50. Strong MJ, Abrahams S, Goldstein LH, Woolley S, Mclaughlin P, Snowden J, et al. Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener 2017;18:153-174.
  51. Linkus B, Wiesner D, Messner M, Karabatsiakis A, Scheffold A, Rudolph KL, et al. Telomere shortening leads to earlier age of onset in ALS mice. Aging (Albany NY) 2016;8:382-393.
  52. De Felice B, Annunziata A, Fiorentino G, Manfellotto F, D'Alessandro R, Marino R, et al. Telomerase expression in amyotrophic lateral sclerosis (ALS) patients. J Hum Genet 2014;59:555-561.
  53. Al Khleifat A, Iacoangeli A, Shatunov A, Fang T, Sproviero W, Jones AR, et al. Telomere length is greater in ALS than in controls: a whole genome sequencing study. Amyotroph Lateral Scler Frontotemporal Degener 2019;20:229-234.
  54. Xia K, Zhang L, Zhang G, Wang Y, Huang T, Fan D. Leukocyte telomere length and amyotrophic lateral sclerosis: a Mendelian randomization study. Orphanet J Rare Dis 2021;16:508.