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

Guo Zhang, Juxue Li, Sudarshana Purkayastha, Yizhe Tang, Hai Zhang, Ye Yin, Bo Li, Gang Liu and Dongsheng Cai ()
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Guo Zhang: Albert Einstein College of Medicine
Juxue Li: Albert Einstein College of Medicine
Sudarshana Purkayastha: Albert Einstein College of Medicine
Yizhe Tang: Albert Einstein College of Medicine
Hai Zhang: Albert Einstein College of Medicine
Ye Yin: Albert Einstein College of Medicine
Bo Li: Albert Einstein College of Medicine
Gang Liu: Albert Einstein College of Medicine
Dongsheng Cai: Albert Einstein College of Medicine

Nature, 2013, vol. 497, issue 7448, 211-216

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature12143

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