title: P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan.
abstract: Oxidative stress and telomere attrition are considered the driving factors of aging. As oxidative damage to telomeric DNA favors the erosion of chromosome ends and, in turn, telomere shortening increases the sensitivity to pro-oxidants, these two factors may trigger a detrimental vicious cycle. To check whether limiting oxidative stress slows down telomere shortening and related progeria, we have investigated the effect of p66SHC deletion, which has been shown to reduce oxidative stress and mitochondrial apoptosis, on late-generation TERC (telomerase RNA component)-deficient mice having short telomeres and reduced lifespan. Double mutant (TERC(-/-) p66SHC(-/-) ) mice were generated, and their telomere length, fertility, and lifespan investigated in different generations. Results revealed that p66SHC deletion partially rescues sterility and weight loss, as well as organ atrophy, of TERC-deficient mice, but not their short lifespan and telomere erosion. Therefore, our data suggest that p66SHC-mediated oxidative stress and telomere shortening synergize in some tissues (including testes) to accelerate aging; however, early mortality of late-generation mice seems to be independent of any link between p66SHC-mediated oxidative stress and telomere attrition.
authors.affiliation: Experimental Oncology Department, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgio
authors.affiliation: Experimental Oncology Department, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Stendardo
authors.affiliation: Experimental Oncology Department, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Migliaccio
authors.affiliation: Experimental Oncology Department, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
mesh_terms: D000818:Animals; D004249:DNA Damage; D005298:Fertility / Q000235:genetics*; D017353:Gene Deletion; D005838:Genotype; D008136:Longevity; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010641:Phenotype; D011371:Progeria / Q000235:genetics* / Q000473:pathology*; D012313:RNA / Q000378:metabolism; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000172:deficiency / Q000378:metabolism*; D016019:Survival Analysis; D019098:Telomerase / Q000172:deficiency* / Q000378:metabolism; D059506:Telomere Shortening; D015431:Weight Loss
chemical_list: C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase
keywords: fertility; lifespan; oxidative DNA damage; telo-meres