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      Manipulating the exposome to enable better ageing

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          Abstract

          The sum total of life course exposures creates an exposome that has a significant impact on age-related health. Understanding the interplay between exposome factors and the (epi) genome, offers pertinent insights into the ageing process and its relationship with the accumulation of allostatic load. We propose to exploit this to develop a biomimetic approach that will provide insight into how evolution through natural selection in other species has solved many age related human health issues. In particular, we will emphasise the need to reconnect a more mechanistic approach to medical science with a broader natural sciences approach, using biomimetics to mitigate the global burden of age related ill health. In particular, we will discuss how such an approach indicates leverage of the activities of the Nrf 2 gene to enhance health span via reintroduction of the classical ‘Food as Medicine’ concept, including modulation of the microbiome and the creation of more salutogenic and biophilic environments. Additionally, we will discuss how this approach integrates with novel and developing senotherapies.

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          Most cited references81

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          The Hallmarks of Aging

          Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.
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            A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010

            The Lancet, 380(9859), 2224-2260
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              DNA methylation age of human tissues and cell types

              Background It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. Results I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance. Conclusions I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.
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                Author and article information

                Journal
                Biochem J
                Biochem J
                BCJ
                Biochemical Journal
                Portland Press Ltd.
                0264-6021
                1470-8728
                30 July 2021
                28 July 2021
                : 478
                : 14
                : 2889-2898
                Affiliations
                [1 ]Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, U.K.
                [2 ]Research Institute of Wildlife Ecology, Department of Interdisciplinary Life Sciences, University of Veterinary Medicine, Savoyenstreet 1, 1160 Vienna, Austria
                [3 ]Department of Human Evolutionary Biology, UCLA Division of Cardiology, Co-Director, Evolutionary Medicine Program at UCLA, Harvard University, California, U.S.A
                [4 ]Division of Renal Diseases, University of Colorado Anschutz Medical Campus, Aurora, Colorado, U.S.A
                [5 ]CRONICAS Centre of Excellence in Chronic Diseases, Universidad Peruana Cayetano Heredia, Lima, Peru
                [6 ]Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Campus Flemingsberg, Stockholm, Sweden
                Author notes
                Correspondence: Peter Stenvinkel ( Paul.Shiels@ 123456glasgow.ac.uk )
                Author information
                http://orcid.org/0000-0002-7577-9843
                http://orcid.org/0000-0002-8785-4820
                Article
                BCJ-478-2889
                10.1042/BCJ20200958
                8331090
                34319404
                b0d25618-b49e-407e-a244-81354b532637
                © 2021 The Author(s)

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND).

                History
                : 5 May 2021
                : 3 July 2021
                : 7 July 2021
                Categories
                Aging
                Ecology & Environmental Biochemistry
                Epigenetics
                Immunology & Inflammation
                Therapeutics & Molecular Medicine
                Translational Science
                Review Articles

                Biochemistry
                ageing,allostatic load,biomimetics,exposome,microbiome,nrf2
                Biochemistry
                ageing, allostatic load, biomimetics, exposome, microbiome, nrf2

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