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      Aging and Gene Expression in the Primate Brain

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          Abstract

          It is well established that gene expression levels in many organisms change during the aging process, and the advent of DNA microarrays has allowed genome-wide patterns of transcriptional changes associated with aging to be studied in both model organisms and various human tissues. Understanding the effects of aging on gene expression in the human brain is of particular interest, because of its relation to both normal and pathological neurodegeneration. Here we show that human cerebral cortex, human cerebellum, and chimpanzee cortex each undergo different patterns of age-related gene expression alterations. In humans, many more genes undergo consistent expression changes in the cortex than in the cerebellum; in chimpanzees, many genes change expression with age in cortex, but the pattern of changes in expression bears almost no resemblance to that of human cortex. These results demonstrate the diversity of aging patterns present within the human brain, as well as how rapidly genome-wide patterns of aging can evolve between species; they may also have implications for the oxidative free radical theory of aging, and help to improve our understanding of human neurodegenerative diseases.

          Abstract

          Transcriptional profiles in human and chimpanzee reveal a diversity of aging patterns present within the human brain, as well as how rapidly genome-wide patterns of aging can evolve between species.

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          The free radical theory of aging matures.

          K Beckman, B N AMES (1998)
          The free radical theory of aging, conceived in 1956, has turned 40 and is rapidly attracting the interest of the mainstream of biological research. From its origins in radiation biology, through a decade or so of dormancy and two decades of steady phenomenological research, it has attracted an increasing number of scientists from an expanding circle of fields. During the past decade, several lines of evidence have convinced a number of scientists that oxidants play an important role in aging. (For the sake of simplicity, we use the term oxidant to refer to all "reactive oxygen species," including O2-., H2O2, and .OH, even though the former often acts as a reductant and produces oxidants indirectly.) The pace and scope of research in the last few years have been particularly impressive and diverse. The only disadvantage of the current intellectual ferment is the difficulty in digesting the literature. Therefore, we have systematically reviewed the status of the free radical theory, by categorizing the literature in terms of the various types of experiments that have been performed. These include phenomenological measurements of age-associated oxidative stress, interspecies comparisons, dietary restriction, the manipulation of metabolic activity and oxygen tension, treatment with dietary and pharmacological antioxidants, in vitro senescence, classical and population genetics, molecular genetics, transgenic organisms, the study of human diseases of aging, epidemiological studies, and the ongoing elucidation of the role of active oxygen in biology.
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            Gene regulation and DNA damage in the ageing human brain.

            Tao Lu, Ying Pan, Shyan-Yuan Kao … (2004)
            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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              Intra- and interspecific variation in primate gene expression patterns.

              Wolfgang Enard, Philipp Khaitovich, Joachim Klose … (2002)
              Although humans and their closest evolutionary relatives, the chimpanzees, are 98.7% identical in their genomic DNA sequences, they differ in many morphological, behavioral, and cognitive aspects. The underlying genetic basis of many of these differences may be altered gene expression. We have compared the transcriptome in blood leukocytes, liver, and brain of humans, chimpanzees, orangutans, and macaques using microarrays, as well as protein expression patterns of humans and chimpanzees using two-dimensional gel electrophoresis. We also studied three mouse species that are approximately as related to each other as are humans, chimpanzees, and orangutans. We identified species-specific gene expression patterns indicating that changes in protein and gene expression have been particularly pronounced in the human brain.
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                Author and article information

                Contributors
                : Role: Academic Editor
                Journal
                Journal ID (nlm-ta): PLoS Biol
                Journal ID (publisher-id): pbio
                Title: PLoS Biology
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Print): 1544-9173
                ISSN (Electronic): 1545-7885
                Publication date (Print): September 2005
                Publication date (Electronic): 2 August 2005
                Volume: 3
                Issue: 9
                Electronic Location Identifier: e274
                Affiliations
                [1] 1 Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America,
                [2] 2Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany,
                [3] 3Society of Fellows, Harvard University, Cambridge, Massachusetts, United States of America,
                [4] 4Genome Sciences Department, Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America
                University of Newcastle upon Tyne United Kingdom
                Article
                DOI: 10.1371/journal.pbio.0030274
                PMC ID: 1181540
                PubMed ID: 16048372
                SO-VID: 03ecc21c-f148-4515-942f-097f0839f710
                Copyright © Copyright: © 2005 Fraser 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 work is properly cited.
                History
                Date received : 18 February 2005
                Date accepted : 7 June 2005
                Related
                Gene Expression in the Aging Brain
                Categories
                Subject: Research Article
                Subject: Bioinformatics/Computational Biology
                Subject: Neuroscience
                Subject: Primates
                Subject: Homo (Human)

                ScienceOpen disciplines: Life sciences
                Data availability:
                ScienceOpen disciplines: Life sciences

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