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Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice

Nature volume 469, pages 102–106 (2011)Cite this article

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Abstract

An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo1. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses1. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2+ neural progenitors, Dcx+ newborn neurons, and Olig2+ oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons2, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk1,3 and the marked reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.

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Figure 1: 4-OHT-dependent induction of telomerase activity in TERT-ER cells.
Figure 2: Telomerase activation in adult TERT-ER mice.
Figure 3: Neural stem cell function following telomerase reactivation in vitro.
Figure 4: NSC proliferation and differentiation following telomerase reactivation in vivo.
Figure 5: Brain size, myelination, and olfactory function following telomerase reactivation.

References

  1. Sahin, E. & Depinho, R. A. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464, 520–528 (2010)

    Article  ADS  CAS  Google Scholar 

  2. Whitman, M. C. & Greer, C. A. Adult neurogenesis and the olfactory system. Prog. Neurobiol. 89, 162–175 (2009)

    Article  Google Scholar 

  3. Sharpless, N. E. & DePinho, R. A. How stem cells age and why this makes us grow old. Nature Rev. Mol. Cell Biol. 8, 703–713 (2007)

    Article  CAS  Google Scholar 

  4. Ju, Z. & Lenhard Rudolph, K. Telomere dysfunction and stem cell ageing. Biochimie 90, 24–32 (2008)

    Article  CAS  Google Scholar 

  5. Hoeijmakers, J. H. DNA damage, aging, and cancer. N. Engl. J. Med. 361, 1475–1485 (2009)

    Article  CAS  Google Scholar 

  6. Ferrón, S. et al. Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells. Development 131, 4059–4070 (2004)

    Article  Google Scholar 

  7. Cawthon, R. M. et al. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361, 393–395 (2003)

    Article  CAS  Google Scholar 

  8. Wyllie, F. S. et al. Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts. Nature Genet. 24, 16–17 (2000)

    Article  CAS  Google Scholar 

  9. Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998)

    Article  ADS  CAS  Google Scholar 

  10. Tomás-Loba, A. et al. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135, 609–622 (2008)

    Article  Google Scholar 

  11. Samper, E., Flores, J. M. & Blasco, M. A. Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres. EMBO Rep. 2, 800–807 (2001)

    Article  CAS  Google Scholar 

  12. Metzger, D. et al. Conditional site-specific recombination in mammalian cells using a ligand-dependent chimeric Cre recombinase. Proc. Natl Acad. Sci. USA 92, 6991–6995 (1995)

    Article  ADS  CAS  Google Scholar 

  13. Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997)

    Article  CAS  Google Scholar 

  14. Wong, K. K. et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003)

    Article  ADS  CAS  Google Scholar 

  15. Choudhury, A. R. et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nature Genet. 39, 99–105 (2006)

    Article  Google Scholar 

  16. Best, B. P. Nuclear DNA damage as a direct cause of aging. Rejuvenation Res. 12, 199–208 (2009)

    Article  CAS  Google Scholar 

  17. Drapeau, E. & Nora Abrous, D. Stem cell review series: role of neurogenesis in age-related memory disorders. Aging Cell 7, 569–589 (2008)

    Article  CAS  Google Scholar 

  18. Ferrón, S. R. et al. Telomere shortening in neural stem cells disrupts neuronal differentiation and neuritogenesis. J. Neurosci. 29, 14394–14407 (2009)

    Article  Google Scholar 

  19. Enwere, E. et al. Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J. Neurosci. 24, 8354–8365 (2004)

    Article  CAS  Google Scholar 

  20. Lafreniere, D. & Mann, N. Anosmia: loss of smell in the elderly. Otolaryngol. Clin. North Am. 42, 123–131 (2009)

    Article  Google Scholar 

  21. Ma, D. K. et al. Activity-dependent extrinsic regulation of adult olfactory bulb and hippocampal neurogenesis. Ann. NY Acad. Sci. 1170, 664–673 (2009)

    Article  ADS  Google Scholar 

  22. Kobayakawa, K. et al. Innate versus learned odour processing in the mouse olfactory bulb. Nature 450, 503–508 (2007)

    Article  ADS  CAS  Google Scholar 

  23. Caporaso, G. L. et al. Telomerase activity in the subventricular zone of adult mice. Mol. Cell. Neurosci. 23, 693–702 (2003)

    Article  CAS  Google Scholar 

  24. Artandi, S. E. & DePinho, R. A. Telomeres and telomerase in cancer. Carcinogenesis 31, 9–18 (2010)

    Article  CAS  Google Scholar 

  25. Zhang, P., Dilley, C. & Mattson, M. P. DNA damage responses in neural cells: focus on the telomere. Neuroscience 145, 1439–1448 (2007)

    Article  CAS  Google Scholar 

  26. Lee, J. et al. Telomerase deficiency affects normal brain functions in mice. Neurochem. Res. 35, 211–218 (2010)

    Article  CAS  Google Scholar 

  27. Breton-Provencher, V. et al. Interneurons produced in adulthood are required for the normal functioning of the olfactory bulb network and for the execution of selected olfactory behaviors. J. Neurosci. 29, 15245–15257 (2009)

    Article  CAS  Google Scholar 

  28. Maser, R. S. et al. DNA-dependent protein kinase catalytic subunit is not required for dysfunctional telomere fusion and checkpoint response in the telomerase-deficient mouse. Mol. Cell. Biol. 27, 2253–2265 (2007)

    Article  CAS  Google Scholar 

  29. Abramoff, M. D., Magelhaes, P. J. & Ram, S. J. Image Processing with ImageJ. Biophotonics Int. 11, 36–42 (2001)

    Google Scholar 

  30. Potzner, M. R. et al. Prolonged Sox4 expression in oligodendrocytes interferes with normal myelination in the central nervous system. Mol. Cell. Biol. 27, 5316–5326 (2007)

    Article  CAS  Google Scholar 

  31. Shao, C. et al. Mitotic recombination produces the majority of recessive fibroblast variants in heterozygous mice. Proc. Natl Acad. Sci. USA 96, 9230–9235 (1999)

    Article  ADS  CAS  Google Scholar 

  32. Paik, J. H. et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5, 540–553 (2009)

    Article  CAS  Google Scholar 

  33. Mahoney, J. E. et al. Quantification of telomere length by FISH and laser scanning cytometry. Proc. SPIE 6859, 1–9 (2008)

    Google Scholar 

  34. Gorczyca, W. et al. Analysis of human tumors by laser scanning cytometry. Methods Cell Biol. 64, 421–443 (2001)

    Article  CAS  Google Scholar 

  35. Spink, A. J. et al. The EthoVision video tracking system–a tool for behavioral phenotyping of transgenic mice. Physiol. Behav. 73, 731–744 (2001)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank R. Segal for critical comments, R. Bronson, K. Ligon and C. Maire for histological advice, S. S. Chae for assistance with neurosphere measurement studies and L. Cameron for time-lapse microscopy studies. M.J. was supported in part by a Susan G. Komen for the Cure fellowship (PDF060881). F.L.M. was supported by ACS fellowship PF-08-261-01-TBE. This work and R.A.D. was supported by R01CA84628 and U01CA141508 grants from the NIH National Cancer Institute and the Belfer Foundation. R.A.D. was supported by an American Cancer Society Research Professorship.

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Authors and Affiliations

  1. Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Mariela Jaskelioff, Florian L. Muller, Ji-Hye Paik, Emily Thomas, Shan Jiang, Ergun Sahin, Maria Kost-Alimova, Alexei Protopopov, Juan Cadiñanos, James W. Horner & Ronald A. DePinho

  2. Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Andrew C. Adams & Eleftheria Maratos-Flier

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  1. Mariela Jaskelioff
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Contributions

M.J. and R.A.D. designed and guided the research; M.J., F.L.M., J.-H.P., E.S., E.T., S.J. and M.K.-A. performed research. J.C. and J.W.H. generated the TERT-ER mouse. M.J., F.L.M., A.C.A., A.P., E.M.-F. and R.A.D. analysed data. M.J. and R.A.D. wrote the manuscript.

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Correspondence to Ronald A. DePinho.

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Jaskelioff, M., Muller, F., Paik, JH. et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469, 102–106 (2011). https://doi.org/10.1038/nature09603

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