. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature. 2013 May 1; PubMed.


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  1. Zhang and colleagues conducted experiments to prove a connection among hypothalamic function, innate immune activation, and systemic aging. In their experiments, they assessed systemic aging by overall lifespan, muscle endurance, muscle size, bone mass, tail tendon collagen crosslinking, and dermal thickness. While activation of NF-κB in hypothalamic neurons by IκB kinase-β (IκK-β) reduced lifespan and accelerated signs of systemic aging, delivery of IkKB-α, which inhibits the NF-κB signaling pathway, showed a protective effect. An increasing number of microglial cells expressing tumor necrosis factor α was found in the hypothalamus of aging mice. The authors, however, leave open which aging-dependent stimulus is responsible for this obviously sterile type of innate immune activation. Instead, they suggested that microglial TNF-α accounts for the activation of NF-κB in neighboring hypothalamic neurons. However, this is far from being proven, since inflammatory microglia usually generate other inflammatory mediators, including interleukin-1β and nitric oxide synthase (Wynn et al., 2013), of which many could account for the observed effects. In the absence of data showing that an anti-TNF-α directed strategy blocks neuronal NF-κB activation, the suggested microglial-neuronal crosstalk remains hypothetical.

    Interestingly, inhibiting microglial NF-κB activation by ablation of IκK-β abolished the age-induced increase of hypothalamic microglia and also prevented microglial TNF-α expression, age-related cognitive decline, muscle weakness, and tail collagen crosslinking. The authors confirmed this using a nestin-Cre approach, which targeted IκK-β in neurons and, presumably, glia. One would have been interested to learn whether astrocytes may represent a third aging-relevant component in hypothalamic inflammation.

    Since NF-κB activation decreased, and its inhibition increased, gonadotropin-releasing hormone (GnRH) promoter activity, GnRH mRNA, and tissue GnRH levels, Zhang and colleagues further studied the role of this neuroendocrine factor in mediating the observed systemic effects. In independent experiments, they showed that direct delivery of GnRH into the third ventricle of aged mice improved neurogenesis. Since the authors observed that GnRH promoted neurogenesis in the hypothalamus and hippocampus, they hypothesized that "GnRH travels within the brain to promote neurogenesis." This is unproven. Injecting a substance into the third ventricle makes it surely accessible to a variety of brain areas including the ones reported. A guided "travel" or systematic transport within the brain can only be tested when the site of application and of detection are not connected to the CSF, which will naturally distribute it. In a further set of experiments, mice received GnRH subcutaneously, which led to improved muscle endurance, muscle fiber size, and better performance in the Morris water maze. Despite an intriguing connection to the inflammatory pathways, and in particular to GnRH suppression, a causal link between these and NF-kB remains unproven.


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