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      Aging Hematopoietic Stem Cells Decline in Function and Exhibit Epigenetic Dysregulation

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          Abstract

          Age-related defects in stem cells can limit proper tissue maintenance and hence contribute to a shortened lifespan. Using highly purified hematopoietic stem cells from mice aged 2 to 21 mo, we demonstrate a deficit in function yet an increase in stem cell number with advancing age. Expression analysis of more than 14,000 genes identified 1,500 that were age-induced and 1,600 that were age-repressed. Genes associated with the stress response, inflammation, and protein aggregation dominated the up-regulated expression profile, while the down-regulated profile was marked by genes involved in the preservation of genomic integrity and chromatin remodeling. Many chromosomal regions showed coordinate loss of transcriptional regulation; an overall increase in transcriptional activity with age and inappropriate expression of genes normally regulated by epigenetic mechanisms was also observed. Hematopoietic stem cells from early-aging mice expressing a mutant p53 allele reveal that aging of stem cells can be uncoupled from aging at an organismal level. These studies show that hematopoietic stem cells are not protected from aging. Instead, loss of epigenetic regulation at the chromatin level may drive both functional attenuation of cells, as well as other manifestations of aging, including the increased propensity for neoplastic transformation.

          Author Summary

          Aging is marked by a decline in function of the entire organism. The effect of age on the regenerative capacity of adult stem cells, which should rejuvenate tissues throughout life, is poorly understood. Bone marrow stem cells, also known as hematopoietic stem cells (HSCs), continuously regenerate the cells that comprise the blood, including the immune system, which fails with age. Here, we show that older HSCs were less able to regenerate the blood system than young HSCs. Paradoxically, the HSC number increased concomitantly, leading to no major difference in overall blood production, even though the immune system did exhibit some defects. To determine why these changes occurred, we looked at global patterns of gene expression in young versus old HSC. Stem cells exhibited an elevated inflammatory response and a decline in factors, called chromatin regulators, that orchestrate DNA accessibility and gene expression. Additional evidence supports the idea that loss of overall gene regulation (epigenetic regulation) is a major event during aging. Whereas much of aging research is concentrated on accumulation of mutations in DNA rather than on global regulatory mechanisms, we speculate that these epigenetic changes could drive many of the manifestations of age. This view also may explain the increased incidence of cancer with age.

          Abstract

          In highly purified hematopoietic stem cells from mice aged 2 to 21 months, gene expression analysis indicates a deficit in function yet an increase in stem cell number with advancing age.

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          Most cited references 39

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          Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.

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            Inflamm-aging. An evolutionary perspective on immunosenescence.

            In this paper we extend the "network theory of aging," and we argue that a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are major characteristics of the aging process. This phenomenon, which we will refer to as "inflamm-aging," is provoked by a continuous antigenic load and stress. On the basis of evolutionary studies, we also argue that the immune and the stress responses are equivalent and that antigens are nothing other than particular types of stressors. We also propose to return macrophage to its rightful place as central actor not only in the inflammatory response and immunity, but also in the stress response. The rate of reaching the threshold of proinflammatory status over which diseases/disabilities ensue and the individual capacity to cope with and adapt to stressors are assumed to be complex traits with a genetic component. Finally, we argue that the persistence of inflammatory stimuli over time represents the biologic background (first hit) favoring the susceptibility to age-related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ-specific age-related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes. Following this perspective, several paradoxes of healthy centenarians (increase of plasma levels of inflammatory cytokines, acute phase proteins, and coagulation factors) are illustrated and explained. In conclusion, the beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
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              Cancer epigenetics comes of age.

              The discovery of numerous hypermethylated promoters of tumour-suppressor genes, along with a better understanding of gene-silencing mechanisms, has moved DNA methylation from obscurity to recognition as an alternative mechanism of tumour-suppressor inactivation in cancer. Epigenetic events can also facilitate genetic damage, as illustrated by the increased mutagenicity of 5-methylcytosine and the silencing of the MLH1 mismatch repair gene by DNA methylation in colorectal tumours. We review here current mechanistic understanding of the role of DNA methylation in malignant transformation, and suggest Knudson's two-hit hypothesis should now be expanded to include epigenetic mechanisms of gene inactivation.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Biol
                pbio
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                1544-9173
                1545-7885
                August 2007
                24 July 2007
                : 5
                : 8
                Affiliations
                [1 ] Program for Cell and Molecular Biology , Baylor College of Medicine, Houston, Texas, United States of America
                [2 ] Stem Cells and Regenerative Medicine Center , Baylor College of Medicine, Houston, Texas, United States of America
                [3 ] Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
                [4 ] Department of Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
                [5 ] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
                [6 ] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
                The Salk Institute, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: goodell@ 123456bcm.edu
                Article
                06-PLBI-RA-2319R2 plbi-05-08-05
                10.1371/journal.pbio.0050201
                1925137
                17676974
                Copyright: © 2007 Chambers 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.
                Page count
                Pages: 13
                Categories
                Research Article
                Cell Biology
                Hematology
                Immunology
                Mus (Mouse)
                Custom metadata
                Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, et al. (2007) Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 5(8): e201. doi: 10.1371/journal.pbio.0050201

                Life sciences

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