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      Gene expression changes with age in skin, adipose tissue, blood and brain

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          Abstract

          Background

          Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age.

          Results

          Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues.

          Conclusions

          Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.

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          Most cited references42

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          Chemokine signaling via the CXCR2 receptor reinforces senescence.

          Cells enter senescence, a state of stable proliferative arrest, in response to a variety of cellular stresses, including telomere erosion, DNA damage, and oncogenic signaling, which acts as a barrier against malignant transformation in vivo. To identify genes controlling senescence, we conducted an unbiased screen for small hairpin RNAs that extend the life span of primary human fibroblasts. Here, we report that knocking down the chemokine receptor CXCR2 (IL8RB) alleviates both replicative and oncogene-induced senescence (OIS) and diminishes the DNA-damage response. Conversely, ectopic expression of CXCR2 results in premature senescence via a p53-dependent mechanism. Cells undergoing OIS secrete multiple CXCR2-binding chemokines in a program that is regulated by the NF-kappaB and C/EBPbeta transcription factors and coordinately induce CXCR2 expression. CXCR2 upregulation is also observed in preneoplastic lesions in vivo. These results suggest that senescent cells activate a self-amplifying secretory network in which CXCR2-binding chemokines reinforce growth arrest.
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            Gene regulation and DNA damage in the ageing human brain.

            The ageing of the human brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease. The time in life when brain ageing begins is undefined. Here we show that transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. This is followed by induction of stress response, antioxidant and DNA repair genes. DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. Moreover, these gene promoters are selectively damaged by oxidative stress in cultured human neurons, and show reduced base-excision DNA repair. Thus, DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a programme of brain ageing that starts early in adult life.
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              Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans.

              The nematode Caenorhabditis elegans is an important model for studying the genetics of ageing, with over 50 life-extension mutations known so far. However, little is known about the pathobiology of ageing in this species, limiting attempts to connect genotype with senescent phenotype. Using ultrastructural analysis and visualization of specific cell types with green fluorescent protein, we examined cell integrity in different tissues as the animal ages. We report remarkable preservation of the nervous system, even in advanced old age, in contrast to a gradual, progressive deterioration of muscle, resembling human sarcopenia. The age-1(hx546) mutation, which extends lifespan by 60-100%, delayed some, but not all, cellular biomarkers of ageing. Strikingly, we found strong evidence that stochastic as well as genetic factors are significant in C. elegans ageing, with extensive variability both among same-age animals and between cells of the same type within individuals.
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                Author and article information

                Contributors
                Journal
                Genome Biol
                Genome Biol
                Genome Biology
                BioMed Central
                1465-6906
                1465-6914
                2013
                26 July 2013
                : 14
                : 7
                : R75
                Affiliations
                [1 ]Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Campus, Westminster Bridge Road, London SE1 7EH, UK
                [2 ]North West London Hospitals NHS Trust, Northwick Park Hospital, Watford Road, Harrow HA1 3UJ, UK
                [3 ]Department of Medical ƒ Molecular Genetics, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK
                [4 ]Wellcome Trust Sanger Institute, HinxtonCB10 1SA,UK
                [5 ]Stanford University, 450 Serra MallStanford, CA 94305, USA
                [6 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
                [7 ]Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet (CMU office 9088), Geneva 1211, Switzerland
                [8 ]St. John's Institute of Dermatology, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK
                [9 ]Oxford Centre for Diabetes, Endocrinology ƒ Metabolism, University of Oxford, Churchill Hospital, Oxford, Headington OX3 7LJ,UK
                Article
                gb-2013-14-7-r75
                10.1186/gb-2013-14-7-r75
                4054017
                23889843
                db89be3e-b36d-43b5-b710-d067e517a27c
                Copyright © 2013 Glass et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 1 November 2012
                : 13 May 2013
                : 26 July 2013
                Categories
                Research

                Genetics
                aging,gene expression,skin,adipose,brain,microarrays
                Genetics
                aging, gene expression, skin, adipose, brain, microarrays

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