Telomeres and Telomerase Possible Roles in Aging and Cancer Biology Diagrams Telomere uncapping with advancing age might lead to P53/P21-induced senescence and subsequent inflammation in arteries. Although age-related telomere uncapping has not been assessed in noncultured human tissues, telomere shortening has been shown to occur over time in most human somatic tissues (23, 30, 47), including arteries (12, 41, 44). 4.1. Sex differences in telomere uncapping and senescence. We have previously demonstrated in arteries that telomere uncapping increases with advancing age in a combined group of women and men (Morgan et al., 2013). In the present study, we demonstrate that arterial telomere uncapping was significantly greater with age in women, but not men.
Environmental stressors such as bacterial toxins and radiation can cause premature aging and fibrosis. Wang et al. reveal that in mice exposed to radiation or the bacterial toxin bleomycin, the tumor suppressor protein FBW7 marks the telomere protein TPP1 for degradation, triggering telomere uncapping and shortening, cancer or stem cell aging, and pulmonary fibrosis. Targeting FBW7 by an 8-mer
related telomere uncapping is associated with cellular senescence ... Biology Diagrams
Since then, great advances have been made in the understanding of how telomeres are able to signal the senescence arrest. These mechanisms are of particular importance in the field of ageing, since cellular senescence, driven by telomere dysfunction, has been shown to be a causal driver of ageing and age-related pathology (van Deursen, 2014). 1.1. In this review, we describe how telomere uncapping potentially leads to age-related vascular dysfunction and increased cellular senescence, oxidative stress, and inflammation. Importantly, we present evidence to argue that telomere uncapping is more biologically relevant than telomere shortening and a better marker of vascular aging and target However, it is important to remember that telomere uncapping and cellular senescence have critical physiological roles. Recapping telomeres has never been demonstrated experimentally and may lead to the division of cells with damaged DNA. In contrast, age-related telomere uncapping may result directly from a dysfunctional shelterin complex, in
Here, we report that in response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligase FBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7 binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitination and accelerates degradation, triggering telomere uncapping and DNA
FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping Biology Diagrams
Interestingly, unlike telomere length, telomere uncapping was found to strongly correlate to markers of p53/p21-associated senescence in arteries from healthy young and old individuals. 21 Furthermore, in comparison with healthy old controls, age-matched hypertensive individuals have greater p53/p21-dependent senescence and telomere uncapping
