Hypothalamic Programming of Systemic Ageing Involving IKK-β, NF-κB and GnRH

Nature. 2013 May 9;497(7448):211-6. doi: 10.1038/nature12143. Epub 2013 May 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Aging / genetics
  • Aging / physiology*
  • Animals
  • Brain / drug effects
  • Brain / physiology
  • Cognition / drug effects
  • Female
  • Gonadotropin-Releasing Hormone / antagonists & inhibitors
  • Gonadotropin-Releasing Hormone / metabolism*
  • Gonadotropin-Releasing Hormone / pharmacology
  • Hypothalamus / cytology
  • Hypothalamus / drug effects
  • Hypothalamus / enzymology
  • Hypothalamus / physiology*
  • I-kappa B Kinase / deficiency
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Longevity / drug effects
  • Longevity / genetics
  • Longevity / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / enzymology
  • Microglia / physiology
  • NF-kappa B / metabolism*
  • Neurogenesis
  • Reproduction / physiology

Substances

  • NF-kappa B
  • Gonadotropin-Releasing Hormone
  • I-kappa B Kinase