БИОХИМИЯ, 2021, том 86, вып. 12, с. 1766–1781
УДК 577.24
Существуют ли доказательства в пользу субтеломерно-теломерной теории старения?
Обзор
1 Member of the Italian Society for Evolutionary Biology (SIBE), 14100 Asti, Italy
2 Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy
3 ФГБУН Институт биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова РАН, 117997 Москва, Россия
4 Department of Medicine and Health Sciences, University of Molise, 86100 Campobasso, Italy
5 Italian Society of Gerontology and Geriatrics (SIGG), 50129 Firenze, Italy
6 Istituti Clinici Scientifici Maugeri SPA – Società Benefit, IRCCS, 82037 Telese Terme (BN), Italy
Поступила в редакцию 16.06.2021
После доработки 30.07.2021
Принята к публикации 02.09.2021
DOI: 10.31857/S0320972521120022
КЛЮЧЕВЫЕ СЛОВА: старение, феноптоз, теломера, субтеломера, эпигенетические изменения, постепенное клеточное старение, клеточное старение, теломерный гетерохроматиновый кэп.
Аннотация
Теломерная теория описывает механизм клеточного старения, согласно которому старение происходит в основном за счет укорочения теломер при каждой дупликации клеток. Субтеломерно-теломерная теория лишена ряда недостатков первой теории и постулирует значительную роль субтеломерной ДНК в механизмах старения. В настоящей работе проведен углубленный анализ соответствия между положениями и следствиями субтеломерно-теломерной теории и результатами экспериментов. В частности, проанализированы данные касательно взаимосвязи между старением и i) эпигенетическими модификациями; ii) окислением и воспалением; iii) защитой теломеры; iv) теломерным гетерохроматиновым кэпом; v) постепенным клеточным старением; vi) клеточным старением; vii) угасанием организма по мере укорочения теломер. В целом, приведенные в работе данные свидетельствуют в пользу субтеломерно-теломерной теории или, по крайней мере, ей не противоречат. Вкратце, феномен клеточного старения, которое через различные пути в конечном итоге обусловливает старение всего организма, в значительной степени зависит от эпигенетических модификаций, регулируемых системой субтеломера–теломера–теломерный кэп–теломераза. Процессы, опосредующие клеточное старение, по-видимому, не являются случайными, неизбежными и необратимыми, а, скорее, вызываются и регулируются генетически предопределенными механизмами, соответственно, они подвержены изменениям и могут быть обратимы соответствующими способами. В целом, приведенные данные поддерживают тезис о том, что старение является генетически запрограммированным и регулируемым феноптотическим явлением и свидетельствуют против предположения, что старение вызвано случайным и неизбежным действием дегенеративных факторов.
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Список литературы
1. Libertini, G., Ferrara, N., Rengo, G., and Corbi, G. (2018) Elimination of senescent cells: prospects according to the subtelomere–telomere theory, Biochemistry (Moscow), 83, 1477-1488, doi: 10.1134/S0006297918120064.
2. Libertini, G., Corbi, G., and Ferrara, N. (2020) Importance and meaning of TERRA sequences for aging mechanisms, Biochemistry (Moscow), 85, 1505-1517, doi: 10.1134/S0006297920120044.
3. Libertini, G., Corbi, G., Conti, V., Shubernetskaya, O., and Ferrara, N. (2021) Evolutionary Gerontology and geriatrics – why and how we age, Advances in Studies of Aging and Health, 2, Switzerland, Springer, doi: 10.1007/978-3-030-73774-0.
4. Skulachev, V. P. (1997) Aging is a specific biological function rather than the result of a disorder in complex living systems: biochemical evidence in support of Weismann’s hypothesis, Biochemistry (Moscow), 62, 1191-1195.
5. Libertini, G. (2012) Classification of phenoptotic phenomena, Biochem (Moscow), 77, 707-715, doi: 10.1134/S0006297912070024.
6. Slijepcevic, P., and Hande, M. P. (1999) Chinese hamster telomeres are comparable in size to mouse telomeres, Cytogenet. Cell Genet., 85, 196-199, doi: 10.1159/000015292.
7. Gorbunova, V., Bozzella, M. J., and Seluanov, A. (2008) Rodents for comparative aging studies: from mice to beavers, Age (Dordr.), 30, 111-119, doi: 10.1007/s11357-008-9053-4.
8. Kubota, C., Yamakuchi, H., Todoroki, J., Mizoshita, K., Tabara, N., et al. (2000) Six cloned calves produced from adult fibroblast cells after long-term culture, Proc. Natl. Acad. Sci. USA, 97, 990-995, doi: 10.1073/pnas.97.3.990.
9. Lanza, R. P., Cibelli, J. B., Faber, D., Sweeney, R. W., Henderson, B., et al. (2001) Cloned cattle can be healthy and normal, Science, 294, 1893-1894, doi: 10.1126/science.1063440.
10. Fossel, M. B. (2004) Cells, aging and Human Disease, Oxford University Press, New York.
11. Blackburn, E. H. (2000) Telomere states and cell fates, Nature, 408, 53-56, doi: 10.1038/35040500.
12. Pontèn, J., Stein, W. D., and Shall, S. (1983) A quantitative analysis of the aging of human glial cells in culture, J. Cell Phys., 117, 342-352, doi: 10.1002/jcp.1041170309.
13. Jones, R. B., Whitney, R. G., and Smith, J. R. (1985) Intramitotic variation in proliferative potential: stochastic events in cellular aging, Mech. Ageing Dev., 29, 143-149, doi: 10.1016/0047-6374(85)90014-4.
14. Londoño-Vallejo, J. A., DerSarkissian, H., Cazes, L., and Thomas, G. (2001) Differences in telomere length between homologous chromosomes in humans, Nucleic Acids Res., 29, 3164-3171, doi: 10.1093/nar/29.15.3164.
15. Graakjaer, J., Bischoff, C., Korsholm, L., Holstebroe, S., Vach, W., et al. (2003) The pattern of chromosome-specific variations in telomere length in humans is determined by inherited, telomere-near factors and is maintained throughout life, Mech. Aging Dev., 124, 629-640, doi: 10.1016/s0047-6374(03)00081-2.
16. Hjelmborg, J. B., Dalgård, C., Möller, S., Steenstrup, T., Kimura, M., et al. (2015) The heritability of leucocyte telomere length dynamics, J. Med. Genet., 52, 297-302, doi: 10.1136/jmedgenet-2014-102736.
17. Brown, W. R., MacKinnon, P. J., Villasanté, A., Spurr, N., Buckle, V. J., and Dobson, M. J. (1990) Structure and polymorphism of human telomere-associated DNA, Cell, 63, 119-132, doi: 10.1016/0092-8674(90)90293-n.
18. Nergadze, S. G., Farnung, B. O., Wischnewski, H., Khoriauli, L., Vitelli, V., et al. (2009) CpG-island promoters drive transcription of human telomeres, RNA, 15, 2186-2194, doi: 10.1261/rna.1748309.
19. Diman, A., and Decottignies, A. (2018) Genomic origin and nuclear localization of TERRA telomeric repeat-containing RNA: from Darkness to Dawn, FEBS J., 285, 1389-1398, doi: 10.1111/febs.14363.
20. Chu, H.-P., Cifuentes-Rojas, C., Kesner, B., Aeby, E., Lee, H.-G., et al. (2017) TERRA RNA antagonizes ATRX and protects telomeres, Cell, 170, 86-101, doi: 10.1016/j.cell.2017.06.017.
21. Chu, H.-P., Froberg, J. E., Kesner, B., Oh, H. J., Ji, F., et al. (2017) PAR-TERRA directs homologous sex chromosome pairing, Nat. Struct. Mol. Biol., 24, 620-631, doi: 10.1038/nsmb.3432.
22. Ben-Porath, I., and Weinberg, R. (2005) The signals and pathways activating cellular senescence, Int. J. Biochem. Cell Biol., 37, 961-976, doi: 10.1016/j.biocel.2004.10.013.
23. Coppé, J.-P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., et al. (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic Russian Academy of Sciences and the p53 tumor suppressor, PLoS Biol., 6, 2853-2868, doi: 10.1371/journal.pbio.0060301.
24. Cristofalo, V. J., and Pignolo, R. J. (1993) Replicative senescence of human fibroblast-like cells in culture, Physiol. Rev., 73, 617-638, doi: 10.1152/physrev.1993.73.3.617.
25. Wang, E. (1995) Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved, Cancer Res., 55, 2284-2292.
26. Kirkland, J. L., and Tchkonia, T. (2017) Cellular senescence: a translational perspective, EBioMedicine, 21, 21-28, doi: 10.1016/j.ebiom.2017.04.013.
27. Libertini, G., and Ferrara, N. (2016) Aging of perennial cells and organ parts according to the programmed aging paradigm, Age (Dordr.), 38, 35, doi: 10.1007/s11357-016-9895-0.
28. Horvath, S. (2013) DNA methylation age of human tissues and cell types, Gen. Biol., 14, R115, doi: 10.1186/gb-2013-14-10-r115.
29. Mammalian Methylation Consortium (2021) Universal DNA methylation age across mammalian tissues, bioRxiv, doi: 10.1101/2021.01.18.426733.
30. Bernstein, B. E., Stamatoyannopoulos, J. A., Costello, J. F., Ren, B., Milosavljevic, A., et al. (2010) The NIH roadmap epigenomics mapping consortium, Nat. Biotechnol., 28, 1045-1048, doi: 10.1038/nbt1010-1045.
31. Illingworth, R., Kerr, A., Desousa, D., Jørgensen, H., Ellis, P., et al. (2008) A novel CpG island set identifies tissue-specific methylation at developmental gene loci, PLoS Biol., 6, e22, doi: 10.1371/journal.pbio.0060022.
32. Christensen, B. C., Houseman, E. A., Marsit, C. J., Zheng, S., Wrensch, M. R., et al. (2009) Aging and environmental exposures alter tissue specific DNA methylation dependent upon CpG island context, PLoS Genet., 5, e1000602, doi: 10.1371/journal.pgen.1000602.
33. Thompson, R. F., Atzmon, G., Gheorghe, C., Liang, H. Q., Lowes, C., et al. (2010) Tissue-specific dysregulation of DNA methylation in aging, Aging Cell, 9, 506-518, doi: 10.1111/j.1474-9726.2010.00577.x.
34. Bollati, V., Schwartz, J., Wright, R., Litonjua, A., Tarantini, L., et al. (2009) Decline in genomic DNA methylation through aging in a cohort of elderly subjects, Mech. Ageing Dev., 130, 234-239, doi: 10.1016/j.mad.2008.12.003.
35. Bell, J. T., Tsai, P. C., Yang, T. P., Pidsley, R., Nisbet, J., et al. (2012) Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population, PLoS Genet., 8, e1002629, doi: 10.1371/journal.pgen.1002629.
36. Horvath, S., Zhang, Y., Langfelder, P., Kahn, R., Boks, M., et al. (2012) Aging effects on DNA methylation modules in human brain and blood tissue, Genome Biol., 13, R97, doi: 10.1186/gb-2012-13-10-r97.
37. Rakyan, V. K., Down, T. A., Maslau, S., Andrew, T., Yang, T. P., et al. (2010) Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains, Genome Res., 20, 434-439, doi: 10.1101/gr.103101.109.
38. Teschendorff, A. E., Menon, U., Gentry-Maharaj, A., Ramus, S. J., Weisenberger, D. J., et al. (2010) Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer, Genome Res., 20, 440-446, doi: 10.1101/gr.103606.109.
39. Hernandez, D. G., Nalls, M. A., Gibbs, J. R., Arepalli, S., van der Brug, M., et al. (2011) Distinct DNA methylation changes highly correlated with chronological age in the human brain, Hum. Mol. Genet., 20, 1164-1172, doi: 10.1093/hmg/ddq561.
40. Koch, C. M., and Wagner, W. (2011) Epigenetic-aging-signature to determine age in different tissues, Aging (Albany NY), 10, 1018-1027, doi: 10.18632/aging.100395.
41. Bocklandt, S., Lin, W., Sehl, M. E., Sánchez, F. J., Sinsheimer, J. S., et al. (2011) Epigenetic predictor of age, PLoS One, 6, e14821, doi: 10.1371/journal.pone.0014821.
42. Booth, L. N., and Brunet, A. (2016) The aging epigenome, Mol. Cell, 62, 728-744, doi: 10.1016/j.molcel.2016.05.013.
43. Kane, A. E., and Sinclair, D. A. (2019) Epigenetic changes during aging and their reprogramming potential, Crit. Rev. Biochem. Mol. Biol., 54, 61-83, doi: 10.1080/10409238.2019.1570075.
44. Greer, E. L., and Shi, Y. (2012) Histone methylation: a dynamic mark in health, disease and inheritance, Nat. Rev. Genet., 13, 343-357, doi: 10.1038/nrg3173.
45. McCauley, B. S., and Dang, W. (2014) Histone methylation and aging: lessons learned from model systems, Biochim. Biophys. Acta, 1839, 1454-1462, doi: 10.1016/j.bbagrm.2014.05.008.
46. Pal, S., and Tyler, J. K. (2016) Epigenetics and aging, Sci. Adv., 2, e1600584, doi: 10.1126/sciadv.1600584.
47. Ashapkin, V. V., Kutueva, L. I., and Vanyushin, B. F. (2017) Aging as an epigenetic phenomenon, Curr. Genomics, 18, 385-407, doi: 10.2174/1389202918666170412112130.
48. Bird, A. (2002) DNA methylation patterns and epigenetic memory, Genes Dev., 16, 6-21, doi: 10.1101/gad.947102.
49. Stein, R., Razin, A., and Cedar, H. (1982) In vitro methylation of the hamster adenine phosphoribosyltransferase gene inhibits its expression in mouse L cells, Proc. Natl. Acad. Sci. USA, 79, 3418-3422, doi: 10.1073/pnas.79.11.3418.
50. Hansen, R. S., and Gartler, S. M. (1990) 5-Azacytidine-induced reactivation of the human X chromosome-linked PGK1 gene is associated with a large region of cytosine demethylation in the 5′ CpG island, Proc. Natl. Acad. Sci. USA, 87, 4174-4178, doi: 10.1073/pnas.87.11.4174.
51. Benetti, R., Garcнa-Cao, M., and Blasco, M. A. (2007) Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres, Nat. Genet., 39, 243-250, doi: 10.1038/ng1952.
52. Maeda, T., Guan, J. Z., Higuchi, Y., Oyama, J., and Makino, N. (2009) Aging-related alterations of subtelomeric methylation in sarcoidosis patients, J. Gerontol. A Biol. Sci. Med. Sci., 64, 752-760, doi: 10.1093/gerona/glp049.
53. Blasco, M. A. (2007) The epigenetic regulation of mammalian telomeres, Nat. Rev. Genet., 8, 299-309, doi: 10.1038/nrg2047.
54. Buxton, J. L., Suderman, M., Pappas, J. J., Borghol, N., McArdle, W., et al. (2014) Human leukocyte telomere length is associated with DNA methylation levels in multiple subtelomeric and imprinted loci, Sci. Rep., 4, 4954, doi: 10.1038/srep04954.
55. Schellenberg, A., Lin, Q., Schüler, H., Koch, C. M., Joussen, S., et al. (2011) Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks, Aging (Albany NY), 3, 873-888, doi: 10.18632/aging.100391.
56. Zhou, X., Hong, Y., Zhang, H., and Li, X. (2020) Mesenchymal stem cell senescence and rejuvenation: current status and challenges, Front. Cell. Dev. Biol., 8, 364, doi: 10.3389/fcell.2020.00364.
57. Harman, D. (1956) Aging: a theory based on free radical and radiation chemistry, J. Gerontol., 11, 298-300, doi: 10.1093/geronj/11.3.298.
58. Höhn, A., Weber, D., Jung, T., Ott, C., Hugo, M., et al. (2017) Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence, Redox Biol., 11, 482-501, doi: 10.1016/j.redox.2016.12.001.
59. Liguori, I., Russo, G., Curcio, F., Bulli, G., Aran, L., et al. (2018) Oxidative stress, aging, and diseases, Clin. Interv. Aging, 13, 757-772, doi: 10.2147/CIA.S158513.
60. Reeg, S., and Grune, T. (2015) Protein oxidation in aging: does it play a role in aging progression? Antioxid. Redox Signal., 23, 239-255, doi: 10.1089/ars.2014.6062.
61. Barnes, R. P., Fouquerel, E., and Opresko, P. L. (2019) The impact of oxidative DNA damage and stress on telomere homeostasis, Mech. Ageing Dev., 177, 37-45, doi: 10.1016/j.mad.2018.03.013.
62. Zuo, L., Prather, E. R., Stetskiv, M., Garrison, D. E., Meade, J. R., et al. (2019) Inflammaging and oxidative stress in human diseases: from molecular mechanisms to novel treatments, Int. J. Mol. Sci., 20, 4472, doi: 10.3390/ijms20184472.
63. Beckman, K. B., and Ames, B. N. (1998) The free radical theory of aging matures, Physiol. Rev., 78, 547-581, doi: 10.1152/physrev.1998.78.2.547.
64. Oliveira, B. F., Nogueira-Machado, J.-A., and Chaves, M. M. (2010) The role of oxidative stress in the aging process, ScientificWorldJournal, 10, 1121-1128, doi: 10.1100/tsw.2010.94.
65. Sanz, A., and Stefanatos, R. K. (2008) The mitochondrial free radical theory of aging: a critical view, Curr. Aging Sci., 1, 10-21, doi: 10.2174/1874609810801010010.
66. Skulachev, V. P. (2009) New data on biochemical mechanism of programmed senescence of organisms and antioxidant defense of mitochondria, Biochemistry (Moscow), 74, 1400-1403, doi: 10.1134/s0006297909120165.
67. Bohr, V. A., and Anson, R. M. (1995) DNA damage, mutation and fine structure DNA repair in aging, Mutat. Res., 338, 25-34, doi: 10.1016/0921-8734(95)00008-t.
68. Weinert, B. T., and Timiras, P. S. (2003) Invited review: theories of aging, J. Appl. Physiol., 95, 1706-1716, doi: 10.1152/japplphysiol.00288.2003.
69. Franceschi, C., Bonafè, M., Valensin, S., Olivieri, F., De Luca, M., et al. (2000) Inflamm-aging. An evolutionary perspective on immunosenescence, Ann. NY Acad. Sci., 908, 244-254, doi: 10.1111/j.1749-6632.2000.tb06651.x.
70. Fülöp, T. (2017) Immunosenescence and inflammaging: an intricate connection, Innov. Aging, 1 (Suppl 1), 961, doi: 10.1093/geroni/igx004.3465.
71. Libertini, G. (2015) Non-programmed versus programmed aging paradigm, Curr. Aging Sci., 8, 56-68, doi: 10.2174/1874609808666150422111623.
72. Wilmut, I., Schnieke, A. E., McWhir, J., Kind, A. J., and Campbell, K. H. (1997) Viable offspring derived from fetal and adult mammalian cells, Nature, 385, 810-813, doi: 10.1038/385810a0.
73. Cowan, C. A., Atienza, J., Melton, D. A., and Eggan, K. (2005) Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells, Science, 309, 1369-1373, doi: 10.1126/science.1116447.
74. Takahashi, K., and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors, Cell, 126, 663-676, doi: 10.1016/j.cell.2006.07.024.
75. D’Autrйaux, B., and Toledano, M. B. (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis, Nat. Rev. Mol. Cell Biol., 8, 813-824, doi: 10.1038/nrm2256.
76. Schieber, M., and Chandel, N. S. (2014) ROS function in redox signaling and oxidative stress, Curr. Biol., 24, R453-462, doi: 10.1016/j.cub.2014.03.034.
77. Bettin, N., Oss Pegorar, C., and Cusanelli, E. (2019) The emerging roles of TERRA in telomere maintenance and genome stability, Cells, 8, 246, doi: 10.3390/cells8030246.
78. Montero, J. J., Lopez de Silanes, I., Grana, O., and Blasco, M. A. (2016) Telomeric RNAs are essential to maintain telomeres, Nat. Commun., 7, 12534, doi: 10.1038/ncomms12534.
79. Libertini, G., and Ferrara, N. (2016) Possible interventions to modify aging, Biochemistry (Moscow), 81, 1413-1428, doi: 10.1134/S0006297916120038.
80. Stewart, J. A., Chaiken, M. F., Wang, F., and Price, C. M. (2012) Maintaining the end: roles of telomere proteins in end-protection, telomere replication and length regulation, Mutat. Res., 730, 12-19, doi: 10.1016/j.mrfmmm.2011.08.011.
81. Jones, M., Bisht, K., Savage, S. A., Nandakumar, J., Keegan, C. E., and Maillard, I. (2016) The shelterin complex and hematopoiesis, J. Clin. Invest., 126, 1621-1629, doi: 10.1172/JCI84547.
82. Takai, K. K., Hooper, S., Blackwood, S., Gandhi, R., and de Lange, T. (2010) In vivo stoichiometry of shelterin components, J. Biol. Chem., 285, 1457-1467, doi: 10.1074/jbc.M109.038026.
83. Li, J. S. Z., Fusté, J. M., Simavorian, T., Bartocci, C., Tsai, J., et al. (2017) TZAP: A telomere-associated protein involved in telomere length control, Science, 355, 638-641, doi: 10.1126/science.aah6752.
84. De Lange, T. (2005) Shelterin: the protein complex that shapes and safeguards human telomeres, Genes Dev., 19, 2100-2110, doi: 10.1101/gad.1346005.
85. Aksenova, A. Y., and Mirkin, S. M. (2019) At the beginning of the end and in the middle of the beginning: structure and maintenance of telomeric DNA repeats and interstitial telomeric sequences, Genes, 10, 118, doi: 10.3390/genes10020118.
86. Simonet, T., Zaragosi, L.-E., Philippe, C., Lebrigand, K., Schouteden, C., et al. (2011) The human TTAGGG repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats, Cell Res., 21, 1028-1038, doi: 10.1038/cr.2011.40.
87. Kwon, S. M., Hong, S. M., Lee, Y. K., Min, S., and Yoon, G. (2019) Metabolic features and regulation in cell senescence, BMB Rep., 52, 5-12, doi: 10.5483/BMBRep.2019.52.1.291.
88. D’Mello, N. P., and Jazwinski, S. M. (1991) Telomere length constancy during aging of Saccharomyces cerevisiae, J. Bacteriol., 173, 6709-6713, doi: 10.1128/jb.173.21.6709-6713.1991.
89. Laun, P., Pichova, A., Madeo, F., Fuchs, J., Ellinger, A., et al. (2001) Aged mother cells of Saccharomyces cerevisiae show markers of oxidative stress and apoptosis, Mol. Microbiol., 39, 1166-1173, doi: 10.1111/j.1365-2958.2001.02317.x.
90. Herker, E., Jungwirth, H., Lehmann, K. A., Maldener, C., Fröhlich, K. U., et al. (2004) Chronological aging leads to apoptosis in yeast, J. Cell Biol., 164, 501-507, doi: 10.1083/jcb.200310014.
91. Lesur, I., and Campbell, J. L. (2004) The transcriptome of prematurely aging yeast cells is similar to that of telomerase-deficient cells, MBC Online, 15, 1297-1312, doi: 10.1091/mbc.e03-10-0742.
92. Libertini, G. (2009) The role of telomere-telomerase system in age-related fitness decline, a tameable process, in Telomeres: Function, Shortening and Lengthening (Mancini, L., ed.) Nova Science Publ., New York, pp. 77-132.
93. Koch, C. M. (2012) Monitoring of cellular senescence by DNA-methylation at specific CpG sites, Aging Cell, 11, 366-369, doi: 10.1111/j.1474-9726.2011.00784.x.
94. Schellenberg, A. (2014) Proof of principle: quality control of therapeutic cell preparations using senescence-associated DNA-methylation changes, BMC Res. Notes, 7, 254, doi: 10.1186/1756-0500-7-254.
95. Fernandez-Rebollo, E. (2020) Senescence-associated metabolomic phenotype in primary and iPSC-derived mesenchymal stromal cells, Stem Cell Rep., 14, 201-209, doi: 10.1016/j.stemcr.2019.12.012.
96. Wagner, W., Horn, P., Castoldi, M., Diehlmann, A., Bork, S., et al. (2008) Replicative senescence of mesenchymal stem cells: a continuous and organized process, PLoS One, 3, e2213, doi: 10.1371/journal.pone.0002213.
97. Spitzhorn, L. S. (2019) Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature, Stem Cell Res. Ther., 10, 100, doi: 10.1186/s13287-019-1209-x.
98. Hynes, K. (2013) Mesenchymal stem cells from iPS cells facilitate periodontal regeneration, J. Dent. Res., 92, 833-839, doi: 10.1177/0022034513498258.
99. Robin, J. D., Ludlow, A. T., Batten, K., Magdinier, F., Stadler, G., et al. (2014) Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances, Genes Dev., 28, 2464-2476, doi: 10.1101/gad.251041.114.
100. Takubo, K., Aida, J., Izumiyama-Shimomura, N., Ishikawa, N., Sawabe, M., et al. (2010) Changes of telomere length with aging, Geriatr. Gerontol. Int., 10, S197-S206, doi: 10.1111/j.1447-0594.2010.00605.x.
101. Daniali, L., Benetos, A., Susser, E., Kark, J. D., Labat, C., et al. (2013) Telomeres shorten at equivalent rates in somatic tissues of adults, Nat. Commun., 4, 1597, doi: 10.1038/ncomms2602.
102. Okuda, K., Bardeguez, A., Gardner, J. P., Rodriguez, P., Ganesh, V., et al. (2002) Telomere length in the newborn, Pediatr. Res., 52, 377-381, doi: 10.1203/00006450-200209000-00012.
103. Libertini, G. (2014) Programmed aging paradigm: how we get old, Biochemistry (Moscow), 79, 1004-1016, doi: 10.1134/S0006297914100034.
104. Moraes, F., and Góes, A. (2016) A decade of human genome project conclusion: Scientific diffusion about our genome knowledge, Biochem. Mol. Biol. Educ., 44, 215-223, doi: 10.1002/bmb.20952.