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

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  1. A Hypothalamus-Centric Inflammation-Mediated View of Aging. What About Energy Metabolism?
    Zhang et al. (1) report three remarkable findings that transcend the fields of aging, neuroscience, and immunology. First, by selectively manipulating the activation state of the transcription factor NF-κB in cells of the mediobasal hypothalamus (MBH), they show that the lifespan of mice can be extended by reducing NF-κB activity and shortened by elevating NF-κB activity. Second, they provide evidence that a local microglia-mediated inflammatory process in the MBH drives aging of mice. Third, their data suggest that a local inflammation-mediated reduction in gonadotropin-releasing hormone (GnRH) is an important determinant of lifespan. As indicated in the title of their article, the authors’ overall conclusion from their findings is that inflammation-related processes in the hypothalamus program or coordinate the aging process throughout the entire animal. The notion that aging is a "programmed" process has been the subject of much debate in the aging field during the past half-century, with the current balance of evidence tipped in favor of aging not being programmed in most species, including mammals (2).

    The hypothalamus clearly regulates the responses of many different organ systems to environmental conditions including energy (food) availability, stressors, and the presence of a potential mate. Among the functions of the hypothalamus, the one which would seem to be most likely to impact on the aging process is the regulation of energy metabolism. There is a strong rationale for the latter statement because of the extensive evidence that lifespan can be extended by reducing energy intake in a wide range of species, including mice, and the results of numerous studies in which signaling pathways are genetically manipulated point to pathways involved in cellular energy metabolism (e.g., insulin signaling and mTOR) in the aging process (3,4). Two unanswered questions, therefore, are if, and to what extent, the apparent effects of NF-κB and/or GnRH signaling on aging (1) are mediated by changes in the regulation of energy metabolism. In this regard, it is of interest to note that: 1) NF-κB regulates energy homeostasis (5); 2) GnRH neurons are regulated by glucose (6); and 3) obesity and type 2 diabetes (which shorten lifespan) inhibit GnRH production (7). It is, therefore, of great importance to rigorously evaluate energy metabolism in mice in which MBH NF-κB is manipulated.

    Another major function of the hypothalamus is to coordinate adaptive responses of the organism to stress. NF-κB and TNF-α signaling play fundamental roles in cellular responses to local tissue injury/stress, and so it is reasonable that these stress-responsive proteins might also be involved in hypothalamus-mediated organismal stress responses. NF-κB and TNF-α signaling normally play important beneficial roles in developmental and synaptic plasticity, and in neuroprotection (8,9). Thus, TNF-α-NF-κB signaling induces the expression of the neurotrophic factor BDNF, the anti-apoptotic protein Bcl-2, the mitochondrial antioxidant enzyme Mn-SOD, and glutamate receptor subunits. During aging, and much more so in chronic inflammatory conditions, there occurs a dysregulation of TNF-α expression and NF-κB activity that adversely affects cellular functions, and may spread to cells and tissues beyond local sites where dysregulated inflammation is initiated. A general feature of aging that likely contributes greatly to cellular aging and associated diseases is a progressive impairment of adaptive cellular stress response mechanisms (10). For example, the ability of intermittent fasting (an "anti-aging" intervention) to induce the expression of neurotrophic factors, protein chaperones, and antioxidant enzymes in the brain is impaired during aging, and this is associated with dysregulated/chronic inflammation (11). It might, therefore, be the case that during aging the beneficial actions of NF-κB signaling are compromised, which then precipitates dysregulated inflammation. GnRH may normally enhance adaptive cellular stress responses, and a reduction in GnRH signaling during aging might, therefore, render cells more prone to oxidative stress and inflammation. Clearly, the intriguing findings of Zhang et al. raise many new questions regarding the interrelationships among inflammation, energy metabolism, and neuroendocrine signaling in the contexts of normal aging and age-related diseases.

    References:

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

    . On the programmed/non-programmed nature of ageing within the life history. Curr Biol. 2011 Sep 27;21(18):R701-7. PubMed.

    . Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Ageing Res Rev. 2006 Aug;5(3):332-53. PubMed.

    . Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest. 2013 Mar 1;123(3):980-9. PubMed.

    . The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation. Trends Cell Biol. 2012 Nov;22(11):557-66. PubMed.

    . Regulation of gonadotropin-releasing hormone neurons by glucose. Trends Endocrinol Metab. 2011 Nov;22(11):443-9. PubMed.

    . Hypothesis: kisspeptin mediates male hypogonadism in obesity and type 2 diabetes. Neuroendocrinology. 2010;91(4):302-7. PubMed.

    . Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ. 2006 May;13(5):852-60. PubMed.

    . Preconditioning and neurotrophins: a model for brain adaptation to seizures, ischemia and other stressful stimuli. Amino Acids. 2007;32(3):299-304. PubMed.

    . Recruiting adaptive cellular stress responses for successful brain ageing. Nat Rev Neurosci. 2012 Mar;13(3):209-16. PubMed.

    . Age and energy intake interact to modify cell stress pathways and stroke outcome. Ann Neurol. 2010 Jan;67(1):41-52. PubMed.

    View all comments by Mark Mattson
  2. 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.

    References:

    . Macrophage biology in development, homeostasis and disease. Nature. 2013 Apr 25;496(7446):445-55. PubMed.