Hypothalamic programming of systemic ageing involving IKK-?, NF-?B and GnRH.

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 I?B kinase-? (IKK-?), nuclear factor ?B (NF-?B) 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-? and NF-?B activation. Mechanistic studies further revealed that IKK-? and NF-?B 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.

SUBMITTER: Zhang G 

PROVIDER: S-EPMC3756938 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature