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      Aging-like Phenotype and Defective Lineage Specification in SIRT1-Deleted Hematopoietic Stem and Progenitor Cells

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          Summary

          Aging hematopoietic stem cells (HSCs) exhibit defective lineage specification that is thought to be central to increased incidence of myeloid malignancies and compromised immune competence in the elderly. Mechanisms underlying these age-related defects remain largely unknown. We show that the deacetylase Sirtuin (SIRT)1 is required for homeostatic HSC maintenance. Differentiation of young SIRT1-deleted HSCs is skewed toward myeloid lineage associated with a significant decline in the lymphoid compartment, anemia, and altered expression of associated genes. Combined with HSC accumulation of damaged DNA and expression patterns of age-linked molecules, these have striking overlaps with aged HSCs. We further show that SIRT1 controls HSC homeostasis via the longevity transcription factor FOXO3. These findings suggest that SIRT1 is essential for HSC homeostasis and lineage specification. They also indicate that SIRT1 might contribute to delaying HSC aging.

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          Highlights

          • SIRT1 deacetylase is essential for homeostatic maintenance of HSCs

          • SIRT1 regulates HSC homeostasis via the longevity factor FOXO3

          • SIRT1 is essential for HSC lineage specification

          • Young SIRT1-deleted HSCs have overlapping features with old HSCs

          Abstract

          SIRT1 deacetylase is essential for homeostatic maintenance of HSCs and for HSC lineage specification. Differentiation of young SIRT1-deleted HSCs is myeloid biased, defective in lymphoid cell production, leads to anemia, and recapitulates the main features of aged HSCs, suggesting that SIRT1 might contribute to delaying HSC aging. The longevity transcription factor FOXO3 mediates the SIRT1 effects on HSC homeostasis.

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          Most cited references46

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          Mammalian sirtuins: biological insights and disease relevance.

          Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.
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            The eosinophil.

            Eosinophils have been considered end-stage cells involved in host protection against parasites. However, numerous lines of evidence have now changed this perspective by showing that eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of diverse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, we summarize the biology of eosinophils, focusing on the growing properties of eosinophil-derived products, including the constituents of their granules as well as the mechanisms by which they release their pleiotropic mediators. We examine new views on the role of eosinophils in homeostatic function, including developmental biology and innate and adaptive immunity (as well as interaction with mast cells and T cells). The molecular steps involved in eosinophil development and trafficking are described, with special attention to the important role of the transcription factor GATA-1, the eosinophil-selective cytokine IL-5, and the eotaxin subfamily of chemokines. We also review the role of eosinophils in disease processes, including infections, asthma, and gastrointestinal disorders, and new data concerning genetically engineered eosinophil-deficient mice. Finally, strategies for targeted therapeutic intervention in eosinophil-mediated mucosal diseases are conceptualized.
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              Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age.

              In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population during aging contribute significantly to the manifestation of these age-associated hematopoietic pathologies. Though the mouse HSC population has been shown to change both quantitatively and functionally with age, changes in the human HSC and progenitor cell populations during aging have been incompletely characterized. To elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated immunophenotypic HSC and other hematopoietic progenitor populations from healthy, hematologically normal young and elderly human bone marrow samples. We found that aged immunophenotypic human HSC increase in frequency, are less quiescent, and exhibit myeloid-biased differentiation potential compared with young HSC. Gene expression profiling revealed that aged immunophenotypic human HSC transcriptionally up-regulate genes associated with cell cycle, myeloid lineage specification, and myeloid malignancies. These age-associated alterations in the frequency, developmental potential, and gene expression profile of human HSC are similar to those changes observed in mouse HSC, suggesting that hematopoietic aging is an evolutionarily conserved process.
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                Author and article information

                Contributors
                Journal
                Stem Cell Reports
                Stem Cell Reports
                Stem Cell Reports
                Elsevier
                2213-6711
                6 June 2014
                6 June 2014
                08 July 2014
                : 3
                : 1
                : 44-59
                Affiliations
                [1 ]Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
                [2 ]Developmental and Stem Cell Biology Multidisciplinary Training Area, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
                [3 ]Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
                [4 ]Department of Experimental Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
                [5 ]Department of Lab Medicine, Children’s Hospital, Boston, MA 02115, USA
                [6 ]Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
                [7 ]Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
                [8 ]Division of Hematology and Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
                [9 ]Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
                Author notes
                []Corresponding author saghi.ghaffari@ 123456mssm.edu
                Article
                S2213-6711(14)00122-2
                10.1016/j.stemcr.2014.04.015
                4110778
                25068121
                987670da-4d20-468a-8905-fd1eddb96331
                © 2014 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                : 6 December 2013
                : 24 April 2014
                : 25 April 2014
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