P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

Abstract

SummaryOxidative 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.

p66Shc Contributes to Liver Fibrosis through the Regulation of Mitochondrial Reactive Oxygen Species

“…p66Shc is crucially involved in the intracellular redox balance and oxidative stress levels. The reported protection achieved by p66Shc deletion is primarily due to the reduction in intracellular free radicals 17, 19, 41. In this study, our data suggest that p66Shc silencing protected mice from liver fibrosis by blunting the production of free radicals and that the ROS mediator p66Shc is a crucial trigger for liver fibrosis.…”

Arginase-II Deficiency Extends Lifespan in Mice

“…First, lifespan of mice kept in SPF conditions shall be analyzed, although the experimental condition in conventional laboratories resembles more human living conditions. For example, mice deficient in p66 Shc reveal extended lifespan under SPF conditions (Migliaccio et al, 1999 ), but shortened lifespan under conventional conditions (Giorgio et al, 2016 ). Second, it is interesting to analyze the causes of death in our mice models, which requires long-term investigation.…”

“…Accordingly, inhibition of mTOR/S6K1 pathway in model organisms including invertebrate animals and rodent mice extends lifespan (Selman et al, 2008 ; Harrison et al, 2009 ; Bitto et al, 2016 ; Pan and Finkel, 2017 ). In addition, the mitochondrial redox enzyme p66 Shc that plays an important role in mitochondrial reactive oxygen species (ROS) generation, is implicated in the acceleration of aging and age-associated diseases (Camici et al, 2015 ; Giorgio et al, 2016 ). Interestingly, cellular senescence accumulates in aged organisms and elimination of p16 INK4a expressing senescent cells in mice mitigates tissue degeneration and has been shown to extend healthy lifespan (Baker et al, 2016 ).…”

Modulation of Obesity and Insulin Resistance by the Redox Enzyme and Adaptor Protein p66Shc

“…TERC −/− mice have a decreased average lifespan, and it was observed that the concomitant deletion of p66 Shc was unable to restore this defect, while it was able to ameliorate other aspects, like sterility, weight loss, and multi-organ atrophy. To date, the exact phenotype of these mice has not been fully investigated [ 37 ]. In summary, it is possible that p66 Shc does not truly regulate life expectancy, but it is involved in the determination of health-span, which has a very strong translational impact to human pathology.…”