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

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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.

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Figure 1: Ageing-dependent hypothalamic NF-κB activation.
Figure 2: Ageing manipulations by hypothalamic IKK-β and NF-κB.
Figure 3: Role of hypothalamic microglia in ageing.
Figure 4: Genetic longevity by brain-specific IKK-β knockout.
Figure 5: Inhibition of GnRH by IKK-β and NF-κB.
Figure 6: Central and systemic actions of GnRH in counteracting ageing.

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Acknowledgements

We thank other Cai laboratory members for technical assistance, and L. Farhana, D. Stocco, L. Eckhardt, T. Ohshima, A. Lin and D. Tantin for reagents. This study was supported by National Institutes of Health (NIH) grants R01 AG 031774, R01 DK078750, and American Diabetes Association grant 1-12-BS-20 (all to D.C.). D.C. is a recipient of Irma T. Hirschl Scholarship.

Author information

D.C. conceived project and designed the study; G.Z., J.L., S.P., Y.T., H.Z. and Y.Y. performed experiments with assistance from B.L. and G.L. All authors carried out data analyses and interpretations; D.C. organized experimentation and wrote the paper.

Correspondence to Dongsheng Cai.

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The authors declare no competing financial interests.

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Zhang, G., Li, J., Purkayastha, S. et al. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 497, 211–216 (2013). https://doi.org/10.1038/nature12143

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