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      Risk stratification by means of biological age-related factors better predicts cancer-specific survival than chronological age in patients with upper tract urothelial carcinoma: a multi-institutional database study

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          Abstract

          Background:

          Chronological age is an important factor in determining the treatment options and clinical response of patients with upper tract urothelial carcinoma (UTUC). Much evidence suggests that chronological age alone is an inadequate indicator to predict the clinical response to radical nephroureterectomy (RNU).

          Patients and methods:

          We retrospectively reviewed the data from 1510 patients with UTUC (Ta-4) treated by surgery. White blood cell (WBC) count, neutrophil-to-lymphocyte ratio, hemoglobin (Hb), platelets, albumin, alkaline phosphatase, lactate dehydrogenase, creatinine, and corrected calcium were tested by the Spearman correlation to indicate the direction of association with chronological age, which yielded significant, negative associations of Hb ( p < 0.001) and WBC ( p = 0.010) with chronological age. For scoring, we assigned points for these categories as follows; point ‘0’ for Hb >14 (reference) and 13–13.9 [odds ratio (OR): 1.533], point ‘1’ for 12–12.9 (OR: 2.391), point ‘2’ for 11–11.9 (OR: 3.015), and point ‘3’ for <11 (OR: 3.584). For WBC, point ‘1’ was assigned for >9200 (OR: 2.541) and ‘0’ was assigned for the rest; 9200–8500 (reference), 8499–6000 (OR: 0.873), 5999–4500 (OR: 0.772), 4499–3200 (OR: 0.486), and <3200 (OR: 1.277).

          Results:

          The 10-year cancer-specific survival (CSS) in the higher risk group with scores of 4 or higher in patients age <60 years was worse than a score of 0, or 1 in age >80 years [mean estimated survival 69.7 months, confidence interval (CI): 33.3–106 versus 103.5. CI: 91–115.9]. The concordance index between biological age scoring and chronological age was 0.704 for CSS and 0.798 for recurrence-free survival. The limitation of the present study is the retrospective nature of the cohort included.

          Conclusions:

          The biological age scoring developed for patients with UTUC undergoing RNU. It was applicable to those with localized disease and performed well in diverse age populations.

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          Most cited references23

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          Biological Age Predictors

          The search for reliable indicators of biological age, rather than chronological age, has been ongoing for over three decades, and until recently, largely without success. Advances in the fields of molecular biology have increased the variety of potential candidate biomarkers that may be considered as biological age predictors. In this review, we summarize current state-of-the-art findings considering six potential types of biological age predictors: epigenetic clocks, telomere length, transcriptomic predictors, proteomic predictors, metabolomics-based predictors, and composite biomarker predictors. Promising developments consider multiple combinations of these various types of predictors, which may shed light on the aging process and provide further understanding of what contributes to healthy aging. Thus far, the most promising, new biological age predictor is the epigenetic clock; however its true value as a biomarker of aging requires longitudinal confirmation.
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            Methylation of the ribosomal RNA gene promoter is associated with aging and age‐related decline

            Summary The transcription of ribosomal RNA genes (rDNA) is subject to epigenetic regulation, as it is abrogated by the methylation of CpG dinucleotides within their promoter region. Here, we investigated, through Sequenom platform, the age‐related methylation status of the CpG island falling into the rDNA promoter in 472 blood samples from 20‐ to 105‐year‐old humans and in different tissues (blood, heart, liver, kidney, and testis) of 15 rats 3–96 weeks old. In humans, we did not find a consistently significant correlation between CpG site methylation and chronological age. Furthermore, the methylation levels of one of the analyzed CpG sites were negatively associated with both cognitive performance and survival chance measured in a 9‐year follow‐up study. We consistently confirmed such result in a replication sample. In rats, the analysis of the homologous region in the tissues revealed the existence of increased methylation in old rats. rRNA expression data, in both humans and rats, were consistent with observed methylation patterns, with a lower expression of rRNA in highly methylated samples. As chronological and biological ages in rats of a given strain are likely to be much closer to each other than in humans, these results seem to provide the first evidence that epigenetic modifications of rDNA change over time according to the aging decline. Thus, the methylation profile of rDNA may represent a potential biomarker of aging.
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              A method for identifying biomarkers of aging and constructing an index of biological age in humans.

              This study was conducted to identify biomarkers of aging and to construct an index of biological age in humans. Healthy adult men (n = 86) who had received an annual health examination from 1992 through 1998 were studied. From 29 physiological variables, five variables (forced expiratory volume in 1 second, systolic blood pressure, hematocrit, albumin, blood urea nitrogen) were selected as candidate biomarkers of aging. Five candidate biomarkers expressed substantial covariance along one principal component. The first principal component obtained from a principal component analysis was used to calculate biological age scores (BAS). Individual BAS showed high longitudinal stability of age-related changes. Age-related changes of BAS are characterized by three components: age, peak functional capacity, and aging rate. A logistic regression analysis suggested that aging rate was influenced by environmental factors, but peak functional capacity was almost independent of environmental factors.
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                Author and article information

                Contributors
                Journal
                Ther Adv Urol
                Ther Adv Urol
                TAU
                sptau
                Therapeutic Advances in Urology
                SAGE Publications (Sage UK: London, England )
                1756-2872
                1756-2880
                11 November 2018
                December 2018
                : 10
                : 12
                : 403-410
                Affiliations
                [1-1756287218811050]Department of Urology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan
                [2-1756287218811050]Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan
                [3-1756287218811050]Department of Urology, Osaka Medical College, Takatsuki, Osaka, Japan
                [4-1756287218811050]Department of Urology, Osaka Medical College, Takatsuki, Osaka, Japan
                [5-1756287218811050]Department of Urology, Nara Medical University, Kashihara, Nara, Japan
                [6-1756287218811050]Department of Urology, Shimane University School of Medicine, Izumo, Shimane, Japan
                [7-1756287218811050]Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan
                [8-1756287218811050]Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan
                [9-1756287218811050]Department of Urology, Nara Medical University, Kashihara, Nara, Japan
                [10-1756287218811050]Department of Urology, Shimane University School of Medicine, Izumo, Shimane, Japan
                [11-1756287218811050]Department of Urology, Osaka Medical College, Takatsuki, Osaka, Japan
                Author notes
                Article
                10.1177_1756287218811050
                10.1177/1756287218811050
                6295779
                8d97651c-9599-4e80-9f95-67724ef2e95c
                © The Author(s), 2018

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 21 September 2018
                : 12 October 2018
                Funding
                Funded by: grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan, ;
                Award ID: 16K11034
                Categories
                Original Research

                age,prognosis,upper tract urothelial carcinoma
                age, prognosis, upper tract urothelial carcinoma

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