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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The proliferation and survival defects in late-generation telomerase-knockout mice are caused by a subset of critically short telomeres rather than by a reduction in mean telomere length.
“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]
Mice carrying a homozygous germline deletion of the telomerase RNA component gene (Terc−/−) exhibit critically short telomeres and premature development of age-related pathologies from the second or third generation.
“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]
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 phenotypes.
“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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“In contrast, recent evidence suggest that restoration of telomerase activity preferentially repaired the shortest telomeres and rescued cellular defects owing to telomere dysfunction (Hemann et al. 2001; Samper et al. 2001).”
BackgroundBlasco, M. A. (2002) · Nature Reviews Cancer · doi:10.1038/nrc862 · Cited by 175 · see citing works
“Reintroduction of telomerase prevents telomere exhaustion and allows viability both in cultured cells and in the context of a telomerase-deficient mous”
BackgroundSelf-citationMice with hyper-long telomeres show less metabolic aging and longer lifespans
Muñoz-Lorente, M. A., Cano-Martin, A. C., & Blasco, M. A. (2019) · Nature Communications · doi:10.1038/s41467-019-12664-x · Cited by 168 · see citing works
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“Indeed, a wild-type telomere length distribution is not restored in mTR / mice (Hemann et al., 2001b; Samper et al., 2001).”
BackgroundSelf-citationSatyanarayana, A., Wiemann, S. U., Buer, J., Lauber, J., Dittmar, K. E. J., Wüstefeld, T., Blasco, M. A., Manns, M. P., & Rudolph, K. L. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg367 · Cited by 158 · see citing works
“In addition, telomere stabilization by telomerase re-expression in G4 mTERC+/± mice, derived from a cross of G3 mTERC±/± mice and mTERC+/± mice (Samper et al., 2001), completely rescued the defective regenerative response following PH, which was present in G4 mTERC±/± littermates (Figure 1D).”
BackgroundSelf-citationHow Telomerase Reaches Its End: Mechanism of Telomerase Regulation by the Telomeric Complex
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“Reintroduction of telomerase activity in laboratory mice lacking the telomerase RNA (TERC) leads to selective elongation of the shortest telomere population (Hemann et al., 2001; Samper et al., 2001).”
BackgroundRevisiting Telomere Shortening in Cancer
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“…collapse due to increased infertility, reduced viability, and a wide spectrum of premature aging pathologies (Blasco et al., 1997; Lee et al., 1998; Rudolph et al., 1999; Herrera et al., 1999a; Herrera et al., 2000; Samper et al., 2002; Leri et al., 2003) (reviewed by Goytisolo and Blasco, 2002).”
BackgroundSelf-citationMice with bad ends: mouse models for the study of telomeres and telomerase in cancer and aging
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“…Journal VOL 24 | NO 6 | 2005 &2005 European Molecular Biology Organization1098 the context of the telomerase-deficient mouse (Bodnar et al, 1998; Hemann et al, 2001b; Samper et al, 2001), demonstrating that short telomeres trigger rapid loss of cell viability unless they are rescued by telomerase.”
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Self-citationFunctional interaction between DNA‐PKcs and telomerase in telomere length maintenance
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Human Cancer Cells Harbor T-Stumps, a Distinct Class of Extremely Short Telomeres
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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).”
BackgroundEvolving views of telomerase and cancer
Blasco, M. (2003) · Trends in Cell Biology · doi:10.1016/s0962-8924(03)00085-0 · Cited by 123 · see citing works
Self-citationReplicating through telomeres: a means to an end
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Self-citationA role for the Rb family of proteins in controlling telomere length
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“Telomerase activity is sufficient to rescue short telomeres and confers an unlimited proliferative capacit”
BackgroundSelf-citationLong noncoding RNAs in aging and age-related diseases
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Telomere and Telomerase Biology
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“Replacement of telomerase by crossing Terc2/2 mice with Terc+/2 mice provided lengthening of the shortened telomeres, and thus it reversed the chromosomal abnormalities mentioned above and prevented the premature aging of the progenies (Samper et al., 2001).”
BackgroundTelomeres and telomerase as therapeutic targets to prevent and treat age-related diseases
Bär, C., & Blasco, M. A. (2016) · F1000Research · doi:10.12688/f1000research.7020.1 · Cited by 115 · see citing works
“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 .”
BackgroundSelf-citationPremature aging in telomerase-deficient zebrafish
Anchelin, M., Alcaraz-Pérez, F., Martínez, C. M., Bernabé-García, M., Mulero, V., & Cayuela, M. L. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.011635 · Cited by 114 · see citing works
“Interestingly, the reintroduction of the tert gene in tertdeficient zebrafish with inherited short telomeres prevented further telomere shortening and organism mortality, as also occurs in mice (Bernardes de Jesus et al., 2012; Jaskelioff et al., 2011; Samper et al., 2001).”
Aging, telomeres, and atherosclerosis
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“[77] demonstrated that critically short telomeres can become fully functional by restoration of telomerase.”
BackgroundLength Regulation and Dynamics of Individual Telomere Tracts in Wild-Type Arabidopsis
Shakirov, E. V., & Shippen, D. E. (2004) · The Plant Cell · doi:10.1105/tpc.104.023093 · Cited by 113 · see citing works
“The Plant Cell, Vol. 16, 1959–1967, August 2004, www.plantcell.orgª 2004 American Society of Plant Biologists binding sites and as a consequence shifts to amore open accessible conformation for telomerase (Shore, 2001; de Lange, 2002; Teixeira et al., 2004).”
BackgroundTelomeres, Telomerase and Ageing
Saretzki, G. C. (2018) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-981-13-2835-0_9 · Cited by 114 · see citing works
Pathology of mouse models of accelerated aging
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“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
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Self-citationLncRNAs Regulatory Networks in Cellular Senescence
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“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 106 · see citing works
“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 108 · see citing works
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Genomic Instability and Epigenetic Changes during Aging
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“Physical inactivity, n (%) 95 (45) 250 (34) .”
Mammalian telomeres and telomerase: why they matter for cancer and aging
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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 · see citing works
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“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 · see citing works
“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 94 · see citing works
“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).”
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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 94 · see citing works
“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 · see citing works
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 94 · see citing works
“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 · see citing works
Autophagy, Cellular Aging and Age-related Human Diseases
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“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 · see citing works
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 · see citing works
“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 90 · see citing works
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 89 · see citing works
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 86 · see citing works
“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 87 · see citing works
Self-citationTelomere repeat binding factors: keeping the ends in check
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“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., Garcı́a, 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 84 · see citing works
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 · see citing works
“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
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“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 · see citing works
Lung alveolar integrity is compromised by telomere shortening in telomerase-null mice
Lee, J., Reddy, R., Barsky, L. W., Scholes, J., Chen, H., Shi, W., & Driscoll, B. (2008) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.90411.2008 · Cited by 76 · see citing works
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 69 · see citing works
“…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 · see citing works
Shared Phenotypes Among Segmental Progeroid Syndromes Suggest Underlying Pathways of Aging
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- 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
- Health Sciences › Medicine › Physiology › 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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