Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappa B and GnRH | |
Article | |
关键词: TUMOR-NECROSIS-FACTOR; EXTENDS LIFE-SPAN; MOUSE MODEL; NEURONS; MICROGLIA; LONGEVITY; OBESITY; MICE; INFLAMMATION; NEUROGENESIS; | |
DOI : 10.1038/nature12143 | |
来源: SCIE |
【 摘 要 】
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 kappa B kinase-beta (IKK-beta), nuclear factor kappa B (NF-kappa B) and related microglianeuron 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-beta and NF-kappa B activation. Mechanistic studies further revealed that IKK-beta and NF-kappa 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.
【 授权许可】
Free