Hypothalamic Programming of Systemic Aging Involving IKKβ/NF-κB and GnRH

By Guo Zhang, Juxue Li, S. Purkayastha, Yizhe Tang, Hai Zhang, Ye Yin, Bo Li, Gang Liu, D. Cai. Nature, 2013

777 citations recorded by the source corpus.

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.

Subfields: Aging, Developmental Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/76f587028b3fe045ee0b88a741d3197c014f5c98

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In Aging

1. J. Campisi
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Citations in the corpus

• Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. (2013, background): “Most recently, it has been shown that hypothalamic NF-kB signaling plays a critical role in the regulation of systemic aging via immune-neuroendocrine integration in mice, implicating the importance of the hypothalamus in systemic aging/longevity control in mammals (Zhang et al., 2013).”
• Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. (2014, background): “Moreover, NF-κB has been shown to drive several aging phenotypes, particularly in the skin, spine, and brain (28,32,33).”
• NF-kappaB Signaling Pathways in Neurological Inflammation: A Mini Review (2015, background): “Recent evidence has shown that activation of NF-κB drives the systemic and brain aging processes in mice (Adler et al., 2007; Zhang et al., 2013).”