Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice.
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.
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.
Mariela
M
Jaskelioff
Florian L
FL
Muller
Ji-Hye
JH
Paik
Emily
E
Thomas
Shan
S
Jiang
Andrew C
AC
Adams
Ergun
E
Sahin
Maria
M
Kost-Alimova
Alexei
A
Protopopov
Juan
J
Cadiñanos
James W
JW
Horner
Eleftheria
E
Maratos-Flier
Ronald A
RA
Depinho
D000375:Aging / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D000089662:Doublecortin Protein; D004789:Enzyme Activation / Q000187:drug effects; D004793:Enzyme Reactivators / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009186:Myelin Sheath / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010641:Phenotype; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D044968:Regenerative Medicine; D012903:Smell / Q000187:drug effects / Q000502:physiology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D019098:Telomerase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D004793:Enzyme Reactivators; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; C016601:afimoxifene; D019098:Telomerase; C509187:Tert protein, mouse