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. Activation of IKK-β and NF-κB in the hypothalamus of mice is shown to accelerate the ageing process, leading to shortened lifespan; inhibition of hypothalamic or brain IKK-β and NF-κB delays ageing and increases lifespan, and NF-κB activation results in a reduction of GnRH levels, whereas NF-κB inhibition leads to GnRH-induced neurogenesis to mediate ageing retardation. Ageing is closely associated with both nutrition and inflammation, and certain neurons can mediate environmental influences on ageing in Caenorhabditis elegans and Drosophila. This study focuses on the hypothalamus, a brain region that is critical for the neuroendocrine interaction between the central nervous system and the periphery. Guo Zhang et al. show that activation of IKK-β and NF-κB in the hypothalamus of mice accelerates the ageing process and shortens lifespan. Inhibition of IKK-β and NF-κB, mediators of metabolic inflammation, delays ageing and extends lifespan. NF-κB activation results in a decline of gonadotropin-releasing hormone (GnRH) levels and suppresses neurogenesis. GnRH treatment amends ageing-impaired neurogenesis and decelerates ageing. These results suggest that NF-κB-mediated inhibition of GnRH may shut down reproduction and ensure the quality of the species, but it initiates systemic ageing at the same time.

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