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Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice

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.

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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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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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The authors declare no competing financial interests.

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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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