Dromes closely recapitulate the phenotypes of previously generated mouse models for

May 9, 2024

Dromes closely recapitulate the phenotypes of previously generated mouse models for telomerase deficiency. In particular, mice genetically deficient for telomerase or a number of the telomere-binding proteins present a plethora of pathologies commonly characterized by the loss of tissue regeneration and organ function 32, 74. In addition to the defects inside the very proliferative tissues for instance the bone marrow or the skin, mice and humans with telomerase deficiency also present pathologies in more quiescent tissues, for instance cardiomyopathy, insulin resistance, and lung and liver fibrosis 75, 76. To date it remains unknown how telomerase deficiency also leads to quick telomeres in tissues with a decrease proliferative prospective 77, 78. In this regard, mitochondrial dysfunction has been lately reported in quiescent tissues (including the heart and liver) inside the context of telomerase deficiency in mice. Numerous reports described that mt-TERT (TERT that localizes at mitochondria) improves mitochondrial function and protects from oxidative stress 79-81. In specific, telomerase deficient mice which have been bred for quite a few generations and have an elevated abundance of brief telomeres present a marked mitochondrial compromise triggered by the suppression from the peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC1 and PGC1) networks which manage, amongst other processes, mitochondrial function and oxidative defense 82. Interestingly, this connection in between telomere dysfunction and mitochondrial dysfunction is mediated by p53, a prevalent checkpoint to telomere syndromes 83. In addition, mitochondrial dysfunction in quiescent tissues of telomerase-deficient mice might be initiated by pathways independent of p53 83. Of note, mitochondrial defects have been described in the initial generation of TERT KO mice (G1) 82, when telomere length is still conserved, demonstrating that mitochondrial dysfunction could, at least partially, precede or parallel telomere shortening. It has also been not too long ago demonstrated that mitochondrial dysfunction is connected with physiological mouse aging, and reverted by telomerase activation 15, 82. With all the aim of dissecting the part of telomerase activity and telomere length in cancer and aging, numerous mouse models for telomerase over-expression happen to be generated (table 1). Transgenic mice that carry the mouse TERT gene beneath the handle from the keratin five promoter (K5-mTERT referred hereafter as TgTERT) show improved tissue fitness, nonetheless, owing to an increased incidence of spontaneous tumors, these mice don’t show an extended median lifespan 84. To unmask the possible anti-aging role of telomerase, TgTERT mice had been crossed with mice carrying extra copies with the tumor suppressors p53, p16 and Arf (Sp16/ SArf/Sp53 mice), which were previously reported to be cancer resistant 14.Apoptolidin Apoptosis In this context, TgTERT/Sp16/SArf/Sp53 showed enhanced health span plus a 40 enhance in median longevity in comparison with wild-type controls, or 26 comparing together with the long-lived and healthful Sp16/SArf/Sp53 mice, demonstrating the anti-aging activity of telomerase.AQC Protocol A similarEurope PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsTrends Genet.PMID:30125989 Author manuscript; obtainable in PMC 2014 January 21.de Jesus and BlascoPagescenario occurred when telomerase overexpression was combined with other cancerprotective situations, including by subjecting mice to caloric restriction (CR). Within this setting, telomeras.