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      Hypothalamic stem cells control aging speed partly through exosomal miRNAs

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          SUMMARY

          Hypothalamic control of aging was recently proposed, but the responsible mechanisms still remain unclear. Here, following the observation that aging of mice started with a substantial loss of hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1, we developed several mouse models with ablation of these hypothalamic cells, each of them consistently displaying an acceleration in aging-like physiological changes or shortening in lifespan. Conversely, aging retardation and lifespan extension were achieved in mid-aged mice when locally implanted with healthy hypothalamic stem/progenitor cells that were genetically engineered to survive from aging-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells greatly contributed to exosomal miRNAs in the cerebrospinal fluid which declined over aging, while central treatment with healthy hypothalamic stem/progenitor cells-secreted exosomes led to slowdown of aging. In conclusion, aging speed is controlled significantly by hypothalamic stem cells partially through release of exosomal miRNAs.

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          Object recognition test in mice.

          Marianne Leger, Anne Quiedeville, Valentine Bouet … (2013)
          The object recognition test is now among the most commonly used behavioral tests for mice. A mouse is presented with two similar objects during the first session, and then one of the two objects is replaced by a new object during a second session. The amount of time taken to explore the new object provides an index of recognition memory. As more groups have used the protocol, the variability of the procedures used in the object recognition test has increased steadily. This protocol provides a necessary standardization of the procedure. This protocol reduces inter-individual variability with the use of a selection criterion based on a minimal time of exploration for both objects during each session. In this protocol, we describe the three most commonly used variants, containing long (3 d), short (1 d) or no habituation phases. Thus, with a short intersession interval (e.g., 6 h), this procedure can be performed in 4, 2 or 1 d, respectively, according to the duration of the habituation phase. This protocol should allow for the comparison of results from different studies, while permitting adaption of the protocol to the constraints of the experimenter.
          Article 0 comments Cited 435 times – based on 0 reviews     Review now
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            A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration.

            Thorsten Buch, Frank Heppner, Christine Tertilt … (2005)
            A new system for lineage ablation is based on transgenic expression of a diphtheria toxin receptor (DTR) in mouse cells and application of diphtheria toxin (DT). To streamline this approach, we generated Cre-inducible DTR transgenic mice (iDTR) in which Cre-mediated excision of a STOP cassette renders cells sensitive to DT. We tested the iDTR strain by crossing to the T cell- and B cell-specific CD4-Cre and CD19-Cre strains, respectively, and observed efficient ablation of T and B cells after exposure to DT. In MOGi-Cre/iDTR double transgenic mice expressing Cre recombinase in oligodendrocytes, we observed myelin loss after intraperitoneal DT injections. Thus, DT crosses the blood-brain barrier and promotes cell ablation in the central nervous system. Notably, we show that the developing DT-specific antibody response is weak and not neutralizing, and thus does not impede the efficacy of DT. Our results validate the use of iDTR mice as a tool for cell ablation in vivo.
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              Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH.

              Akiko Satoh, Cynthia S. Brace, Nick Rensing … (2013)
              The mammalian Sir2 ortholog Sirt1 plays an important role in metabolic regulation. However, the role of Sirt1 in the regulation of aging and longevity is still controversial. Here we demonstrate that brain-specific Sirt1-overexpressing (BRASTO) transgenic mice show significant life span extension in both males and females, and aged BRASTO mice exhibit phenotypes consistent with a delay in aging. These phenotypes are mediated by enhanced neural activity specifically in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), through increased orexin type 2 receptor (Ox2r) expression. We identified Nk2 homeobox 1 (Nkx2-1) as a partner of Sirt1 that upregulates Ox2r transcription and colocalizes with Sirt1 in the DMH and LH. DMH/LH-specific knockdown of Sirt1, Nkx2-1, or Ox2r and DMH-specific Sirt1 overexpression further support the role of Sirt1/Nkx2-1/Ox2r-mediated signaling for longevity-associated phenotypes. Our findings indicate the importance of DMH/LH-predominant Sirt1 activity in the regulation of aging and longevity in mammals. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 0410462
                Journal ID (pubmed-jr-id): 6011
                Journal ID (nlm-ta): Nature
                Journal ID (iso-abbrev): Nature
                Title: Nature
                ISSN (Print): 0028-0836
                ISSN (Electronic): 1476-4687
                Publication date Nihms-submitted: 15 July 2017
                Publication date (Electronic): 26 July 2017
                Publication date (Print): 03 August 2017
                Publication date PMC-release: 13 June 2018
                Volume: 548
                Issue: 7665
                Pages: 52-57
                Affiliations
                [1 ]Department of Molecular Pharmacology, Diabetes Research Center, Institute of Aging, Albert Einstein College of Medicine, Bronx, NY 10461
                Author notes
                Correspondence should be addressed to D.C. ( dongsheng.cai@ 123456einstein.yu.edu ), Phone: 718-430-2426, Fax: 718-430-8922, dongsheng.cai@ 123456einstein.yu.edu
                [2]

                These authors equally contributed to this work.

                Article
                Manuscript ID: NIHMS884456
                DOI: 10.1038/nature23282
                PMC ID: 5999038
                PubMed ID: 28746310
                SO-VID: 8bdea0a1-997a-40f2-8b7b-25e18c1e89e9
                License:

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                Subject: Article

                ScienceOpen disciplines: Uncategorized
                Keywords: aging,hypothalamus,neural stem cell,mirna,exosome
                Data availability:
                ScienceOpen disciplines: Uncategorized
                Keywords: aging, hypothalamus, neural stem cell, mirna, exosome

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