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    • A well known trigger of

    2018-10-25

    A well-known trigger of cellular senescence, closely related to inflammaging, is telomere length shortening. However, while considerable evidence shows that circulating inflammatory markers are predictors of mortality in community-living elderly individuals (), there are conflicting results on the role of telomere length (). in this issue of demonstrate with a cross-sectional approach that telomere length, measured in the DNA extracted from whole blood of centenarian offspring, centenarians and (semi-)supercentenarians displays a superior maintenance compared to the one measured in community-living elderly subjects. Indeed, telomere length of centenarian offspring is maintained for more than 20years at a length corresponding to 60years of age in the general population. Interestingly, the authors observed that while long telomeres might be a prerequisite for exceptional lifespan in humans, they did not predict mortality. Conversely, Arai et al. confirmed that a multibiomarker score of systemic inflammation, which included anti-cytomegalovirus IgG, IL-6, TNF-α and C-reactive protein levels, was associated with an increased risk of mortality, loss of cognitive function and physical function decline, in normal aging and at extreme old age (up to 110years). These data demonstrate that a multiple biomarker index may represent a more powerful predictor of mortality in older adults than a single inflammatory mediator, as also recently shown through a combined measure of interleukin 6 (IL-6) and soluble TNF receptor 1 (sTNFR1) ().
    Introduction Extra-uterine high-grade serous Müllerian carcinomas, which include cancers originating in either the fallopian tubes or endosalpingiosis (Dubeau, 2008; Dubeau and Drapkin, 2013), are the most lethal gynecological cancers while carcinomas of the breast are the most common cancer in women (Boyle et al., 2008). There is considerable overlap in the risk factors associated with both diseases. For example, menstrual ubiquitin conjugating enzyme activity is the most important risk factor for the sporadic forms of both diseases while germline BRCA1 or BRCA2 mutations are the most important cause of the familial forms (Whittemore et al., 1992; Brose et al., 2002; Pike et al., 2004). An understanding of the underlying mechanisms mediating cancer risk for both diseases could have a significant impact on their morbidity and mortality by leading to the development of preventive strategies targeting these mechanisms specifically. Existing mouse models for serous extra-uterine Müllerian (previously referred to as serous ovarian) carcinomas (Dubeau, 2008; Dubeau and Drapkin, 2013), are based on forced expression of selected oncogenes, often combined with homozygous knockouts of BRCA1 or BRCA2 or other relevant tumor suppressor genes in a tissue-specific manner (Miyoshi et al., 2002; Orsulic et al., 2002; Connolly et al., 2003; Flesken-Nikitin et al., 2003; Dinulescu et al., 2005; Clark-Knowles et al., 2007; Szabova et al., 2012; Perets et al., 2013). None of these models, to our knowledge, are associated with predisposition to both reproductive and mammary cancers. These models have led to significant progress in establishing the role of the targeted genes or pathways in cancer development and elucidating their intracellular activity, but were not designed to investigate the interplay between environmental/hormonal and genetic factors. In addition, although heterozygous germline BRCA1/2 mutations are strongly associated with cancer predisposition in both organs in human, the current models are invariably based on homozygous inactivation of these genes, a condition that is never present in the human germline. Even when restricted to specific organs, such homozygous lesions may lead to development defects in these organs (Xu et al., 1999; Kim et al., 2006), diminishing their relevance to human. The higher penetrance of homozygous mutations may also override the influence of environmental or systemic hormonal factors, thus complicating studies of their interaction with genetic factors. Finally, there is strong evidence, both from animal and human studies (Chodankar et al., 2005; Hong et al., 2010; Widschwendter et al., 2013), that BRCA1 mutations lead to cancer predisposition not only via cell-autonomous mechanisms, but also via alterations in hormone producing cells that influence, from a distance, the cells from which ovarian and breast cancers develop. This conclusion is strengthened by the fact that menstrual cycle activity has a strong influence on risk of breast and extra-uterine Müllerian carcinoma, even in individuals with strong genetic predisposition such as Brca1 mutation carriers (Narod et al., 1998). Current animal models based on inactivation of Brca1 to induce the development of invasive cancers do not recapitulate such cell-nonautonomous mechanisms.