Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice

Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 01/2011; 469(7328):102-6. DOI: 10.1038/nature09603
Source: PubMed


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 vivo. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses. 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 interneurons, 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 risk 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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    • "As senescent cells seem to persist and accumulate with age in different tissues (Campisi & Sedivy, 2009), their altered functional profile including a pro-inflammatory secretory phenotype changes the tissue microenvironment in ways that can promote both cancer and aging phenotypes (Krtolica & Campisi, 2002). This view is supported by the findings that removal of senescent cells (Baker et al., 2011) or re-elongation of telomeres (Jaskelioff et al., 2011) in transgenic mice can delay the onset of age-related pathologies. These functions of senescence have recently been summarized as the 'four faces' of senescence (Rodier & Campisi, 2011). "

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    • "Telomeres are also shorter with age in neuronal stem cells of mouse subventricular area (Ferrón et al., 2009). Importantly, late generation telomerase-deficient mice showed neuronal loss in the hippocampal region and frontal cortex associated with short-term memory deficits (Rolyan et al., 2011), impaired olfaction (Jaskelioff et al., 2011), and anxiety-like behaviors (Lee et al., 2010), while telomerase reactivation in adult mice is able to delay and reverse many aging-related phenotypes, including cognitive performances (Jaskelioff et al., 2011). Overall these observations suggest that telomere stability and maintenance are required for brain functions . "
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    • "Whether natural aging features are reversible is unknown. Our finding that some aging features are reversible provides new insight and is consistent with recent evidence that some aging features caused by telomere dysfunction are partially reversible (Jaskelioff et al., 2011). Thus, some age-associated tissue dysfunction due to loss of cell proliferation might be ameliorated, if proliferation can be enhanced. "
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