Telomerase reactivation reverses tissue degeneration in aged telomerase deficient mice

By M. Jaskelioff, F. Muller, J. Paik, Emily Thomas, Shan Jiang, A. Adams, Ergun Sahin, M. Kost-Alimova, A. Protopopov, J. Cadiñanos and 3 more. Nature, 2010

829 citations recorded by the source corpus.

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.

Subfields: Aging, Endocrine and Autonomic Systems, Physiology

View Paper: https://www.semanticscholar.org/paper/e8979f16fd203e2da6b0b4ab00099b85b2df9b18

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Citations in the corpus

Ageing as a risk factor for disease. (2012, background): “Telomerase expression is high in neuronal stem cells and is important for brain development [92]; it decreases in differentiated neurons, but can be reactivated in response to stress, where it may play a protective role, because inhibiting telomerase increases neurons’ susceptibility to apoptosis [9”
Senescence and aging: Causes, consequences, and therapeutic avenues (2018, background): “Cells isolated from these mice proliferate normally in vitro, and deterioration in multiple tissues is reduced (Jaskelioff et al., 2011).”
The hallmarks of aging. (2013, background): “In particular, the premature aging of telomerase-deficient mice can be reverted when telomerase is genetically reactivated in these agedmice (Jaskelioff et al., 2011).”
Telomere length in early life predicts lifespan (2012, background): “Progressive telomere shortening has been linked to both normal aging and to various degenerative diseases in a wide range of studies mainly in humans and mice (2), and telomere lengthening has been shown to have a restorative effect (11).”
Rejuvenation of regeneration in the aging central nervous system (2012, background): “Recent data suggest that age-associated defects in neural stem cells can be reversed by reactivation of telomerase (Jaskelioff et al., 2011), suggesting that aged OPCs might, in principle, remain competent for efficient remyelination.”