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Nature. 2013 May 9;497(7448):211-6. doi: 10.1038/nature12143. Epub 2013 May 1.

Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH.

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  • 1Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

Abstract

Ageing is a result of gradual and overall functional deteriorations across the body; however, it is unknown whether an individual tissue primarily works to mediate the ageing progress and control lifespan. Here we show that the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by IκB kinase-β (IKK-β), nuclear factor κB (NF-κB) and related microglia-neuron immune crosstalk. Several interventional models were developed showing that ageing retardation and lifespan extension are achieved in mice by preventing ageing-related hypothalamic or brain IKK-β and NF-κB activation. Mechanistic studies further revealed that IKK-β and NF-κB inhibit gonadotropin-releasing hormone (GnRH) to mediate ageing-related hypothalamic GnRH decline, and GnRH treatment amends ageing-impaired neurogenesis and decelerates ageing. In conclusion, the hypothalamus has a programmatic role in ageing development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating ageing-related health problems.

PMID:
23636330
[PubMed - indexed for MEDLINE]
PMCID:
PMC3756938
Free PMC Article
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