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Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres
Open accessAbstract
Reconstitution of telomerase activity is proposed as a potential gene therapy to prevent, or rescue, age-related diseases produced by critical telomere shortening. However, it is not known whether or not short telomeres are irreversibly damaged. We addressed this by re-introducing telomerase in late generation telomerase-deficient mice, Terc-/-, which have short telomeres and show severe proliferative defects. For this, we have crossed these mice with Terc+/- mice and analyzed telomere length, chromosomal instability and premature aging of the progeny. The Terc-/- progeny had one set of chromosomes with normal telomeres, whereas the other set remained with critically short telomeres; these mice presented chromosomal instability and premature aging. In contrast, Terc+/- progeny showed all chromosomes with detectable telomeres, and did not show chromosomal instability or premature aging. These results prove that critically short telomeres can be rescued by telomerase, and become fully functional, thus rescuing premature aging. This has important implications for the future design of telomerase-based gene therapy of age-related diseases.
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“In particular, mice carrying a homozygous germline deletion of the telomerase RNA component gene (Terc−/−) exhibit critically short telomeres and a premature development of age-related pathologies from the second or third generation [8, 18–20, 51, 70, 72, 101, 103]”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [101]
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“in turn responsible for chromosomal aberrations (Hemann et al, 2001; Samper et al, 2001).”
From Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer (2012) · cites this paper as Samper et al, 2001
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“The defects in proliferation and survival seen in late-generation telomerase-knockout mice appear to be caused by a subset of critically short telomeres, rather than a reduction in mean telomere length.”
From Telomeres and telomerase in cancer (2010) · cites this paper as [67]
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“The most persuasive evidence for a causal role comes from in vitro and in vivo manipulation of telomerase activity which impacts on TL and has been shown to enhance or reverse senescence and ageing-associated phenotypes35–39.”
From Identification of seven loci affecting mean telomere length and their association with disease (2013) · cites this paper as [38]
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Cited by
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“Research in the M.A.B. laboratory is funded by the Spanish Ministry of Economy and Competitiveness Projects (SAF2013-45111-R and SAF2015-72455-EXP), the Comunidad de Madrid Project (S2017/BMD-3770), the World Cancer Research Project (16-1177), and the Fundación Botín (Spain).”
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“It has been demonstrated in budding yeast and mouse that the shortest telomeres are elongated preferentially by telomerase (Zhu et al., 1998; Hemann et al., 2001; Samper et al., 2001; Teixeira et al., 2004).”
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“Importantly, restoration of TERC expression in mice with inherited critically short telomeres is sufficient to prevent the phenotypes associated with short telomeres in these mice, including aplastic anemia, intestinal atrophy, and infertility, among others 108,109 .”
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Aging, telomeres, and atherosclerosis
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BackgroundLength Regulation and Dynamics of Individual Telomere Tracts in Wild-Type Arabidopsis
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Pathology of mouse models of accelerated aging
Harkema, L., Youssef, S. A., & de Bruin, A. (2016) · Veterinary Pathology · doi:10.1177/0300985815625169 · Cited by 105
“Few reports briefly mention the presence of testicular degeneration and/or atrophy and lipofuscin accumulation.(41,43,128,146,165) Even fewer reports mention changes in the ovaries, such as the absence of primary oocytes and follicles.”
Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice
González-Suárez, E., Geserick, C., Flores, J. M., & Blasco, M. A. (2005) · Oncogene · doi:10.1038/sj.onc.1208413 · Cited by 109
Self-citationLncRNAs Regulatory Networks in Cellular Senescence
Pavan Kumar, P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112615 · Cited by 109
“premature senescence and aging in murine models [48], whereas abnormal expression of TERRA induces premature senescence in fibroblasts due to suppression of telomere elongation [49].”
BackgroundBeyond average: potential for measurement of short telomeres
Vera, E., & Blasco, M. A. (2012) · Aging · doi:10.18632/aging.100462 · Cited by 112
“15 kb of telomeric repeats and therefore, that could be considered as critically short, a determination which is very important for aging studies as critically short/uncapped telomeres are the ones associated to induction of a DDR, chromosome end-to-end fusions, and the occurrence of aging phenotypes in the context of…”
BackgroundSelf-citationMyocardial Aging and Senescence: Where Have the Stem Cells Gone?
Sussman, M. A., & Anversa, P. (2004) · Annual Review of Physiology · doi:10.1146/annurev.physiol.66.032102.140723 · Cited by 105
Erdmann, N., Liu, Y., & Harrington, L. A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401580101 · Cited by 110
Genomic Instability and Epigenetic Changes during Aging
López-Gil, L., Pascual‐Ahuir, A., & Proft, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241814279 · Cited by 130
Hoen, P. W., de Jonge, P., Na, B. Y., Farzaneh-Far, R., Epel, E., Lin, J., Blackburn, E., & Whooley, M. A. (2011) · Psychosomatic Medicine · doi:10.1097/psy.0b013e31821b1f6e · Cited by 106
“Physical inactivity, n (%) 95 (45) 250 (34) .”
Mammalian telomeres and telomerase: why they matter for cancer and aging
Blasco, M. A. (2003) · European Journal of Cell Biology · doi:10.1078/0171-9335-00335 · Cited by 106
Self-citationThe effect of TERC haploinsufficiency on the inheritance of telomere length
Goldman, F., Bouarich, R., Kulkarni, S., FREEMAN, S., Du, H., Harrington, L. A., Mason, P. J., Londoño‐Vallejo, A., & Bessler, M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505318102 · Cited by 105
Mozgová, I., Mokroš, P., & Fajkus, J. (2010) · The Plant Cell · doi:10.1105/tpc.110.076182 · Cited by 105
“Telomerase has been shown to preferentially act on shorter telomeres (Hemann et al., 2001; Samper et al., 2001; Shakirov and Shippen, 2004; Teixeira et al., 2004; Chang et al., 2007), and telomere length is specific and stable in each Arabidopsis ecotype (Riha et al., 2001, 2002; Shakirov and…”
Telomerase Protects Werner Syndrome Lineage-Specific Stem Cells from Premature Aging
Cheung, H.-H., Liu, X., Canterel-Thouennon, L., Li, L., Edmonson, C., & Rennert, O. M. (2014) · Stem Cell Reports · doi:10.1016/j.stemcr.2014.02.006 · Cited by 102
“2 j 534–546 j April 8, 2014 j a2014 The Author rase rescues telomere dysfunction is not clear; however, telomerase was reported to extend telomeres and rescue premature aging and reverse tissue degeneration in aged Terc / mice with shortened telomeres (Jaskelioff et al., 2011; Samper et al., 2001).”
Many ways to telomere dysfunction: in vivo studies using mouse models
Goytisolo, F. A., & Blasco, M. A. (2002) · Oncogene · doi:10.1038/sj.onc.1205085 · Cited by 96
“It has been demonstrated recently that telomerase is able to recognize critically short telomeres in the context of a mouse and elongate them to di erent lengths, thus preventing endto-end chromosomal fusions (Samper et al., 2001b).”
BackgroundMethodResultInfluentialSelf-citationStarr, J. M., Shiels, P. G., Harris, S. E., Pattie, A., Pearce, M. S., Relton, C. L., & Deary, I. J. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.09.020 · Cited by 96
González‐Suárez, E., Flores, J. M., & Blasco, M. A. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.20.7291-7301.2002 · Cited by 98
“This is supported by the fact that telomerase reintroduction through the germ line is able to elongate critically short telomeres and prevent chromosomal aberrations in the context of the telomerase-deficient mouse model (3, 15, 18, 26).”
BackgroundSelf-citationMassive Telomere Loss Is an Early Event of DNA Damage-induced Apoptosis
Ramı́rez, R., Carracedo, J., Jiménez, R., Canela, A., Herrera, E., Aljama, P., & Blasco, M. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m206818200 · Cited by 94
Self-citationThe relationship between aging and carcinogenesis: a critical appraisal
Anisimov, V. N. (2003) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(02)00121-x · Cited by 99
“telomerase in late generation telomerase-deficient mice, Tert / , which have short telomeres and shows severe proliferative defects, restores of telomerase activity followed by a rescue chromosomal instability and premature aging [205].”
BackgroundPreferential maintenance of critically short telomeres in mammalian cells heterozygous for mTert
Liu, Y., Kha, H. T., Ungrin, M., Robinson, M. O., & Harrington, L. A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.062549199 · Cited by 94
Autophagy, Cellular Aging and Age-related Human Diseases
Cheon, S. Y., Kim, H. J., Rubinsztein, D. C., & Lee, J. E. (2019) · Experimental Neurobiology · doi:10.5607/en.2019.28.6.643 · Cited by 95
Zhao, Y. B., Abreu, E. B., Kim, J., Stadler, G., Eskiocak, U., Terns, M. P., Terns, R. M., Shay, J. W., & Wright, W. E. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.03.020 · Cited by 92
“Under nonequilibrium conditions in which telomere length has been experimentally manipulated, there is a general consensus that telomerase preferentially extends the shortest telomere (Hemann et al., 2001; Ouellette et al., 2000; Samper et al., 2001).”
BackgroundCheng, H., Fan, X., Lawson, W. E., Paueksakon, P., & Harris, R. C. (2015) · Kidney International · doi:10.1038/ki.2015.69 · Cited by 89
Canela, A., Martín-Caballero, J., Flores, J. M., & Blasco, M. A. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.10.4275-4293.2004 · Cited by 90
“a consequence of telomerase overexpression, since telomerase has been reported to act preferentially on critically short telomeres (19, 25).”
BackgroundMethodInfluentialSelf-citationNoncoding RNA control of cellular senescence
Abdelmohsen, K., & Gorospe, M. (2015) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1297 · Cited by 92
Varela, E., Schneider, R. P., Ortega, S., & Blasco, M. A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105414108 · Cited by 94
Self-citationRole of lncRNAs in aging and age‐related diseases
He, J., Tu, C., & Liu, Y. (2018) · Aging Medicine · doi:10.1002/agm2.12030 · Cited by 88
“to rescue premature aging phenotypes by restoring functional telomerase.(115) Apart from that, TERC could affect angiogenesis and metastasis‐related genes’ expression without affecting telomere length.”
BackgroundChromatin regulation and non-coding RNAs at mammalian telomeres
Schoeftner, S., & Blasco, M. A. (2009) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2009.09.015 · Cited by 96
Self-citationTelomere repeat binding factors: keeping the ends in check
Karlseder, J. (2003) · Cancer Letters · doi:10.1016/s0304-3835(02)00706-1 · Cited by 88
“This model is supported by the finding that cells that lack detectable telomeric DNA sequences preferentially take part in telomere fusions [41,42].”
BackgroundModulation of telomere protection by the PI3K/AKT pathway
Méndez‐Pertuz, M., Martínez, P., Blanco‐Aparicio, C., Gómez‐Casero, E., García, A. B., Martinez-Torrecuadrada, J. L., Palafox, M., Cortés, J., Serra, V., Pastor, J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01329-2 · Cited by 88
Self-citationRole of Mammalian Rad54 in Telomere Length Maintenance
Jaco, I., Muñoz, P., Goytisolo, F. A., Wesoły, J., Bailey, S. M., Taccioli, G. E., & Blasco, M. A. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.16.5572-5580.2003 · Cited by 85
“This finding can be explained by the fact that these cells have proficient telomerase activity (see below), which in turn has been shown to preferentially elongate short telomeres, thus preventing critical telomere loss (16, 31).”
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Long-term molecular and cellular stability of human neural stem cell lines
Villa, A., Navarro‐Galve, B., Bueno, C., Franco, S., Blasco, M. A., & Martı́nez-Serrano, A. (2004) · Experimental Cell Research · doi:10.1016/j.yexcr.2003.11.025 · Cited by 84
Self-citationMajumder, M., House, R. P., Palanisamy, N., Qie, S., Day, T. A., Neskey, D. M., Diehl, J. A., & Palanisamy, V. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1006306 · Cited by 82
“In support of this function, TERC-deficient mice displayed short telomeres, chromosomal instability, and premature aging [41].”
BackgroundLong Non-Coding RNAs in Neuronal Aging
Fernandes, D. P., Bitar, M., Jacobs, F. M. J., & Barry, G. (2018) · Non-Coding RNA · doi:10.3390/ncrna4020012 · Cited by 75
Lung alveolar integrity is compromised by telomere shortening in telomerase-null mice
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McNees, C. J., Tejera, Á. M., Martínez, P., Murga, M., Mulero, F., Fernández-Capetillo, Ó., & Blasco, M. A. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.200908136 · Cited by 71
“…to have a shorter mean telomere length than other mouse chromosomes in several independent mouse strains (Zijlmans et al., 1997; Hande et al., 1999; Samper et al., 2001a), whereas chromosome 11 was chosen because it is homologous to human chromosome 17, which was also reported to have relatively…”
InfluentialSelf-citationMechanisms of chromosome-end protection
Cervantes, R. B., & Lundblad, V. (2002) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(02)00325-3 · Cited by 71
Shared Phenotypes Among Segmental Progeroid Syndromes Suggest Underlying Pathways of Aging
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Metadata
- Authors
- Samper, E., Flores, J. M., & Blasco, M. A.
- Affiliations
- Centro Nacional de Biotecnología (ES)
- Universidad Complutense de Madrid (ES)
- ORCID
- Flores, Juana M
- Venue
- The EMBO Reports
- Published
- 2001-09-01
- Volume
- 2
- Issue
- 9
- Pages
- 800-807
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC1084029
- OpenAlex
- W1984552013
- Cited by
- 263
- References
- 31
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 6 · 2020: 7 · 2019: 16 · 2018: 10 · 2017: 12 · 2016: 14 · 2015: 16 · 2014: 8 · 2013: 12 · 2012: 11
- FWCI
- 9.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- EMBO Reports (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Swiss Bridge Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- telomerase, telomerase reconstitution, telomere shortening, chromosomal instability, premature aging, telomere length, gene therapy, age-related diseases
- MeSH terms
- Aging, Animals, Bone Marrow, Bone Marrow Cells, Chromosome Aberrations, Chromosomes, Crosses, Genetic, Genotype, Intestine, Small, Male, Mice, Transgenic, Phenotype, Testis, Y Chromosome, Telomere, In Situ Hybridization, Fluorescence, Telomerase, Mice
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