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      Age related increase in mTOR activity contributes to the pathological changes in ovarian surface epithelium

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          Abstract

          Ovarian cancer is a disease of older women. However, the molecular mechanisms of ovarian aging and their contribution to the pathogenesis of ovarian cancer are currently unclear. mTOR signalling is a major regulator of aging as suppression of this pathway extends lifespan in model organisms. Overactive mTOR signalling is present in up to 80% of ovarian cancer samples and is associated with poor prognosis. This study examined the role of mTOR signalling in age-associated changes in ovarian surface epithelium (OSE). Histological examination of ovaries from both aged mice and women revealed OSE cell hyperplasia, papillary growth and inclusion cysts. These pathological lesions expressed bonafide markers of ovarian cancer precursor lesions, Pax8 and Stathmin 1, and were presented with elevated mTOR signalling. To understand whether overactive mTOR signalling is responsible for the development of these pathological changes, we analysed ovaries of the Pten trangenic mice and found significant reduction in OSE lesions compared to controls. Furthermore, pharmacological suppression of mTOR signalling significantly decreased OSE hyperplasia in aged mice. Treatment with mTOR inhibitors reduced human ovarian cancer cell viability, proliferation and colony forming ability. Collectively, we have established the role of mTOR signalling in age-related OSE pathologies and initiation of ovarian cancer.

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          Most cited references 34

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          Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

          In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.
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            Rapamycin slows aging in mice.

            Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age-dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in spontaneous activity, occur more slowly in rapamycin-treated mice, suggesting strongly that rapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease. We also note, however, that mice treated with rapamycin starting at 9 months of age have significantly higher incidence of testicular degeneration and cataracts; harmful effects of this kind will guide further studies on timing, dosage, and tissue-specific actions of rapamycin relevant to the development of clinically useful inhibitors of TOR action. © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
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              Ovarian aging: mechanisms and clinical consequences.

              Menopause is the final step in the process referred to as ovarian ageing. The age related decrease in follicle numbers dictates the onset of cycle irregularity and the final cessation of menses. The parallel decay in oocyte quality contributes to the gradual decline in fertility and the final occurrence of natural sterility. Endocrine changes mainly relate to the decline in the negative feedback from ovarian factors at the hypothalamo-pituitary unit. The declining cohort of antral follicles with age first results in gradually elevated FSH levels, followed by subsequent stages of overt cycle irregularity. The gradual decline in the size of the antral follicle cohort is best represented by decreasing levels of anti-Mullerian hormone. The variability of ovarian ageing among women is evident from the large variation in age at menopause. The identification of women who have severely decreased ovarian reserve for their age is clinically relevant. Ovarian reserve tests have appeared to be fairly accurate in predicting response to ovarian stimulation in the assisted reproductive technology (ART) setting. The capacity to predict the chances for spontaneous pregnancy or pregnancy after ART appears very limited. As menopause and the preceding decline in oocyte quality seem to have a fixed time interval, tests that predict the age at menopause may be useful to assess individual reproductive lifespan. Especially genetic studies, both addressing candidate gene and genome wide association, have identified several interesting loci of small genetic variation that may determine fetal follicle pool development and subsequent wastage of his pool over time. Improved knowledge of the ovarian ageing mechanisms may ultimately provide tools for prediction of menopause and manipulation of the early steps of folliculogenesis for the purpose of contraception and fertility lifespan extension.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                12 April 2016
                29 March 2016
                : 7
                : 15
                : 19214-19227
                Affiliations
                1 Gynaecology Oncology Group, School of Biomedical Sciences and Pharmacy, New South Wales, Australia
                2 Hunter Cancer Biobank, New South Wales, Australia
                3 School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia
                4 Division of Gynaecology Oncology, Department of Medical Oncology, Calvary Mater Newcastle, Waratah, New South Wales, Australia
                5 Unit for Laboratory Animal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
                6 Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA
                Author notes
                Correspondence to: Pradeep S. Tanwar, pradeep.tanwar@ 123456newcastle.edu.au
                Article
                8468
                10.18632/oncotarget.8468
                4991377
                27036037
                3008dd97-7dfd-4eb8-8538-bffc428ca44f
                Copyright: © 2016 Bajwa et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Categories
                Research Paper: Gerotarget (Focus on Aging)

                Oncology & Radiotherapy

                ovarian aging, rapamycin, mtor, ovary, ose, gerotarget

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