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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]
In the citing paper
“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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Citations
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Self-citationTelomeres in cancer and aging: lessons from the mouse
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Self-citationMyocyte proliferation and ventricular remodeling
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Self-citationBiomarkers of Aging and Relevant Evaluation Techniques: A Comprehensive Review
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“…reestablishment of telomerase activity, the researchers crossbred Terc +/- mice with late-stage telomerase-deficient Terc -/- mice that had been reintroduced to telomerase, resulting in offspring with identifiable telomeres and free of chromosomal instability, and unaffected by early aging [33].”
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“Similarly, restoration of telomerase activity in Terc-deficient mice resulted in longer telomeres and absence of premature aging [38], and alleviated the tissue degeneration and activation of DNA damage signaling that are characteristic consequences of telomere loss [39].”
BackgroundEssential roles for Pot1b in HSC self-renewal and survival
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“Previous work had shown that restoration of telomerase activity in mouse zygotes with critically short telomeres, owing to a deficiency in the telomerase RNA component (Terc), rescues critically short telomeres and chromosomal instability in the resulting mice (Samper et al., 2001).”
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Harrington, L. A., & Pucci, F. (2018) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2016.0444 · Cited by 21
Selective pressures for and against genetic instability in cancer: a time-dependent problem
Komarova, N. L., Sadovsky, A. V., & Wan, F. Y. M. (2007) · Journal of The Royal Society Interface · doi:10.1098/rsif.2007.1054 · Cited by 21
“A paper by Rudolph et al. (2001) reports data on intestinal carcinoma in mice and humans which is consistent with a similar model: telomere dysfunction promotes chromosomal instability which drives carcinogenesis at early stages; and telomerase activation restores stability to allow further tumour…”
BackgroundTelomere-length regulation in inter-ecotype crosses of Arabidopsis
Maillet, G., White, C. I., & Gallego, M. E. (2006) · Plant Molecular Biology · doi:10.1007/s11103-006-9061-7 · Cited by 21
“This is in accord with observations that telomerase will extend preferentially the shortest telomeres (Hemann et al. 2001; Samper et al. 2001; Teixeira et al. 2004).”
ResultMaking the most of a little: dosage effects in eukaryotic telomere length maintenance
Harrington, L. A. (2005) · Chromosome Research · doi:10.1007/s10577-005-0994-5 · Cited by 20
“those that lack a detectable telomeric DNA signal), rather than the accumulation of short average telomere lengths per se (Hemann et al. 2001b, Samper et al. 2001, Erdmann et al. 2004).”
BackgroundMurillo-Ortiz, B. O., Albarrán-Tamayo, F., López-Briones, S., Martı́nez-Garza, S., Benı́tez-Bribiesca, L., & Arenas-Aranda, D. J. (2013) · BMC Geriatrics · doi:10.1186/1471-2318-13-99 · Cited by 20
“A previous study showed that restoration of telomerase activity prevented the wide range of degenerative pathologies [36].”
BackgroundEpigenetic Regulation of Telomere Chromatin Integrity in Pluripotent Embryonic Stem Cells
Wong, L. H. (2010) · Epigenomics · doi:10.2217/epi.10.49 · Cited by 23
AKT-dependent signaling of extracellular cues through telomeres impact on tumorigenesis
Sánchez-Vazquez, R., Martínez, P., & Blasco, M. A. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009410 · Cited by 18
Self-citationAging and cancer in transgenic and mutant mice
Anisimov, V. N. (2003) · Frontiers in bioscience · doi:10.2741/1122 · Cited by 19
“Re-introducing telomerase in late generation telomerase-deficient mice, Tert, which have short telomeres and shows severe proliferative defects, restores telomerase activity followed by a rescue of chromosomal instability and premature aging (171).”
Background37 kDa LRP::FLAG enhances telomerase activity and reduces senescent markersin vitro
Otgaar, T. C., Ferreira, E., Malindisa, S. T., Bernert, M., Letsolo, B. T., & Weiss, S. F. T. (2017) · Oncotarget · doi:10.18632/oncotarget.21278 · Cited by 18
“This suggests that the increased telomerase activity following the production of LRP::FLAG is sufficient to maintain telomere length and prevent the accumulation of short telomeres, a characteristic of telomere-dependent senescence [9, 10, 46].”
BackgroundMezníková, M., Erdmann, N., Allsopp, R., & Harrington, L. A. (2009) · Disease Models & Mechanisms · doi:10.1242/dmm.004069 · Cited by 18
“The presence of critically short telomeres, and not of a short average telomere length, correlates with loss of tissue function (Hemann et al., 2001a; Samper et al., 2001; Erdmann et al., 2004).”
InfluentialGenetic and epigenetic trends in telomere research: a novel way in immunoepigenetics
Melicher, D., Buzás, E. I., & Falus, A. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1991-2 · Cited by 17
Preferential extension of short telomeres induced by low extracellular pH
Ge, Y., Wu, S., Xue, Y., Tao, J., Li, F., Chen, Y., Liu, H., Ma, W., Huang, J., & Zhao, Y. B. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw464 · Cited by 17
Mouse models to study the role of telomeres in cancer, aging and DNA repair
Blasco, M. A. (2002) · European Journal of Cancer · doi:10.1016/s0959-8049(02)00450-1 · Cited by 16
Self-citationRenal phenotype of young and old telomerase-deficient mice
Schildhorn, C., Jacobi, C., Weißbrodt, A., Hermstedt, C., Westhoff, J. H., Hömme, M., Bhayadia, R., Gretz, N., Falk, C. S., Schmitt, R., et al. (2015) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2015.08.004 · Cited by 16
Dynamics of telomeric chromatin at the crossroads of aging and cancer
Ye, J., Wu, Y., & Gilson, É. (2010) · Essays in Biochemistry · doi:10.1042/bse0480147 · Cited by 15
“Indeed, excess TERT expression can rescue the renewal capacity of epidermal stem cells [33]; the reintroduction of telomerase TERC in telomerase-defi cient mice with inherited short telomeres prevents further telomere shortening, chromosomal instability and loss of organismal viability [34]; and TERC delivery to mice…”
BackgroundTao, L., Huang, Q., Yang, R. R., Dai, Y., Zeng, Y., Li, C., Li, X., Zeng, J., & Wang, Q. (2019) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-019-01004-0 · Cited by 17
“Murine models have demonstrated that telomerase deficiency and telomere shortening in Terc−/− mice (telomerase-deficient mice) lead to age-related bone loss due to intrinsic osteoblastic defects and increased osteoclastogenesis by inflammatory microenvironment [12] and premature aging [13].”
BackgroundTelomeres, a busy platform for cell signaling.
Gardano, L., Pucci, F., Christian, L., Le Bihan, T., & Harrington, L. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00146 · Cited by 15
“In mice, the extension of telomeres occurs during S-phase and telomerase extends the shortest telomeres preferentially (Hemann and Greider, 1999; Samper et al., 2001; Erdmann et al., 2004; Stern and Bryan, 2008).”
BackgroundCurcuminoid derivatives enhance telomerase activity in an in vitro TRAP assay
Taka, T., Changtam, C., Thaichana, P., Kaewtunjai, N., Suksamrarn, A., Lee, T. R., & Tuntiwechapikul, W. (2014) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2014.09.059 · Cited by 15
Characterization and expression analysis of the tomato telomere-binding protein LeTBP1
Moriguchi, R., Kanahama, K., & Kanayama, Y. (2006) · Plant Science · doi:10.1016/j.plantsci.2006.03.010 · Cited by 14
Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease
Huang, Y., & Wang, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22189867 · Cited by 15
Expression Profiling of mRNAs and Long Non-Coding RNAs in Aged Mouse Olfactory Bulb
Wang, M., Liu, W., Jiao, J., Li, J., Wang, C., & Zhang, L. (2017) · Scientific Reports · doi:10.1038/s41598-017-02329-4 · Cited by 14
Implications of Long Non-Coding RNAs in Age-Altered Proteostasis
Cătană, C.-S., Crișan, C., Opre, D., & Berindan‐Neagoe, I. (2020) · Aging and Disease · doi:10.14336/ad.2019.0814 · Cited by 13
Adult progenitor rejuvenation with embryonic factors
Wang, P., Liu, X., Chen, Y., Jun‐Hao, E. T., Yao, Z., Min‐Wen, J. C., Chua, B. Y.-J., Ma, S., Ma, W., Luo, L., et al. (2023) · Cell Proliferation · doi:10.1111/cpr.13459 · Cited by 13
Haploinsufficiency and telomere length homeostasis
Harrington, L. A. (2011) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2011.11.004 · Cited by 13
TOR Regulates Cell Death Induced by Telomere Dysfunction in Budding Yeast
Qi, H., Chen, Y., Fu, X., Lin, C., Zheng, X.-F., & Liu, L. F. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003520 · Cited by 13
“In mice lacking telomerase activity, progressively shortened telomeres is associated with premature aging [2], while restoration of telomerase activity rescues this phenotype [3].”
BackgroundA genetic and genomic approach to identify longevity genes in mice
de Haan, G., & Williams, R. W. (2004) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2004.09.012 · Cited by 13
D’Souza, Y., Chu, T. W., & Autexier, C. (2013) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-12-0889 · Cited by 12
Zhdanova, N. S., Minina, J. M., & Рубцов, Н. Б. (2012) · Molecular Biology · doi:10.1134/s0026893312040152 · Cited by 11
Prat‐Vidal, C., Crisóstomo, V., Moscoso, I., Báez-Díaz, C., Blanco, V., Gomez‐Mauricio, G., Albericio, G., Aguilar, S., Fernández‐Santos, M. E., Fernández‐Avilés, F., et al. (2021) · Cells · doi:10.3390/cells10102571 · Cited by 10
Whittemore, K., Martínez‐Nevado, E., & Blasco, M. A. (2019) · Aging · doi:10.18632/aging.102430 · Cited by 9
Self-citationLiu, Z., Sun, C. J., Zhang, Z., Jiang, Y., & Zhao, C. (2025) · Biogerontology · doi:10.1007/s10522-025-10228-9 · Cited by 10
“The induction of short telomeres by telomerase is sufficient to restore cellular and organism vitality and genomic stability, as age-related lesions are caused by the transmission of short rather than average telomere length (Samper et al. 2001).”
Heregulin, a new regulator of telomere length in human cells
Menéndez, J. A., Rubio, M. A., Campisi, J., & Lupu, R. (2015) · Oncotarget · doi:10.18632/oncotarget.4964 · Cited by 9
“Whereas telomere attrition due to the absence of telomerase activity (for instance, Terc or Tert knock-out mice) has been shown to suppress tumor growth [52-54], short telomeres have been described to generate chromosome instability, which in turn may lead to an increased risk of developing several cancers [55, 56].”
BackgroundAncestral telomere shortening: A countdown that will increase mean life span?
Hertzog, R. G. (2006) · Medical Hypotheses · doi:10.1016/j.mehy.2006.01.034 · Cited by 9
“The restoration of telomerase activity, in late generation of mice Terc / , with critical short telomeres, has rebuilt the chromosomal stability and rescuing premature aging [20].”
BackgroundChen, J., Bryant, M., Dent, J. J., Sun, Y., Desierto, M. J., & Young, N. S. (2015) · Experimental Gerontology · doi:10.1016/j.exger.2015.10.016 · Cited by 8
“…model is partially supported by previous reports showing that short telomeres induce inflammation while inflammation in turn induces telomeric damage(Jurk et al., 2014), and that re-introduction of telomerase to late generation Trec−/− mice could restore tissue integrity(Samper et al., 2001).”
ResultThe contribution of biogerontology to quality ageing
Bagley, M. C., Davis, T., Latimer, J., & Kipling, D. (2011) · Quality in Ageing and Older Adults · doi:10.5042/qiaoa.2011.0142 · Cited by 8
A mouse model for Li-Fraumeni-Like Syndrome with cardiac angiosarcomas associated to POT1 mutations
Martínez, P., Sánchez-Vazquez, R., Ferrara‐Romeo, I., Serrano, R., Flores, J. M., & Blasco, M. A. (2022) · PLoS Genetics · doi:10.1371/journal.pgen.1010260 · Cited by 8
“Cells were then recovered and metaphases prepared as described [44].”
BackgroundMethodSelf-citationHuang, Y., Lu, H., Zhang, L., Olivier, A. K., Wu, T., Hsu, C., LeGrand, C., Zeng, H., Curran, S., Wang, Q., et al. (2025) · Aging Cell · doi:10.1111/acel.70130 · Cited by 7
“…/ − telomere-humanized mice (telomere length: 16 vs. 10–15 kb in humans) have an older biological age than wild-type mice at the same chronological age (Samper et al. 2001). adaptively mitigate type 2 diabetes, but further research is needed on its protective mechanisms via bacterial metabolites,…”
Fastest Time to Cancer by Loss of Tumor Suppressor Genes
Sanchez‐Tapia, C., & Wan, F. Y. M. (2014) · Bulletin of Mathematical Biology · doi:10.1007/s11538-014-0027-7 · Cited by 7
“The mechanism of telomerase activation and subsequent prevention of CIN is also described in Artandi and DePinho (2000) and Samper et al. (2001).”
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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