Microglia have taken center stage in Alzheimer’s disease (AD) research recently. Not only have genetics studies pinpointed variants in the microglial receptor TREM2 as major risk factors for AD (see ARF related news story), but tuning down microglial cytokines has been shown to reduce plaque buildup (see ARF related news story), and a new network analysis links microglial dysfunction with AD pathology (see upcoming ARF Webinar). Could microglia also accelerate aging, the strongest risk factor for AD? In the May 1 Nature, Dongsheng Cai and scientists at the Albert Einstein College of Medicine, Bronx, New York, report that microglial inflammation in the hypothalamus of mice caused overall senescence, shortened lifespan, and weakened cognition. Conversely, quelling glial activation slowed aging and raised performance on cognitive tests. This study could have implications for the treatment of age-associated disorders, such neurodegeneration, cardiovascular disease, and diabetes, wrote the authors.

"This work places microglia at the epicenter of the aging process,” wrote Terrence Town, University of Southern California, Los Angeles, in an e-mail to Alzforum. "This neuroinflammatory pathway has obvious implications for AD,” he added.

Almond sized, the human hypothalamus releases hormones for growth, reproduction, and metabolism. Cai’s group previously showed that inflammation in the hypothalamus contributes to the development of obesity, glucose intolerance, and hypertension—all metabolic syndrome components associated with aging and Alzheimer's disease. These disorders came about upon activation of a central regulator of immunity—a proinflammatory transcription factor called nuclear factor κB (NF-κB), and its upstream IκB kinase-β (IKK-β (see Li et al., 2012; Zhang et al., 2008; and Purkayastha et al., 2011). NF-κB is elevated in the brains of those who died with AD (see Terai et al., 1996) and has been reported to exacerbate Aβ pathology under pathological conditions (see Chami et al., 2012). Cai and colleagues wondered if NF-κB signaling might be tied to aging.

To probe that question, co-first authors Guo Zhang, Juxue Li, Sudarshana Purkayastha, Yizhe Tang, and Hai Zhang first looked at how hypothalamic NF-κB activity changed over the mouse lifespan. They found little of the transcription factor in the hypothalamus of young mice, but it rose as the animals aged. The researchers then chronically activated NF-κB in the hypothalamus of middle- to old-age mice, using a lentiviral vector that carried IKK-β. This shortened lifespan reduced bone mass, wasted muscle, and left the animals with thinner skin. NF-κB activation also worsened cognitive performance on the Morris water maze. On the other hand, blocking hypothalamic NF-κB lengthened lifespan relative to controls, elevated performance on cognitive tests, and improved age-related biomarker profiles.

Microglia appeared to be initial players in this aging process. The number of microglia with activated NF-κB grew with age in the hypothalamus, and they overproduced inflammatory cytokines such as tumor necrosis factor-α. TNF-α is both induced by and activates NF-κB in a feed-forward loop. TNF-α also activates IKK-β. Nearby hypothalamic neurons later upped their own NF-κB and TNF-α production, implying that the microglial output led to inflammatory neuron changes.

Could reining in microglia control aging? When the researchers knocked out IKK-β in hypothalamic microglia of middle-aged mice, microglia numbers held steady with age, while TNF-α remained low. When they got older, these knockouts outperformed wild-type controls on the Morris water maze test and retained more muscle strength, bone mass, and skin thickness. Their maximum lifespan stretched to about 1,100 days, around 10 percent longer than the wild-type. Together, the results suggest that microglial IKK-β accelerates aging.

How does microglial NF-κB signaling reduce lifespan? Looking for the downstream effects, the researchers found that gonadotropin-releasing hormone (GnRH), which regulates sex hormones and reproduction, was diminished. Does its reduction accelerate aging? Levels of the hormone fell in the hypothalamus with age—a decline prevented by inhibition of IKK-β and NF-κB, and enhanced by their activation. GnRH replacement therapy seemed to turn back the clock. Both wild-type and IKK-β knockout mice injected subcutaneously with GnRH for up to eight weeks showed fewer signs of age and performed better on cognitive tests than untreated controls. This youthening may be related to neurogenesis, which declines with age. When injected into the hypothalamus of old mice, GnRH seemed to promote differentiation of new neurons—indicated by BrdU labeling. This is the first time GnRH has been tied to neurogenesis, Cai said. The new cells would have to be tested with appropriate markers to be sure it was true neurogenesis, wrote Gerd Kempermann, Center for Regenerative Therapies, Dresden, Germany, to Alzforum in an e-mail.

Treatments that target GnRH could translate to humans if scientists find a safe, efficacious method, said Cai. Such therapies might help prevent age-related disorders, including diabetes, cardiovascular disease, and neurodegenerative disease. “People tend to think about aging as a passive, chaotic deterioration of tissues,” Cai told Alzforum. “We provide a new view—it includes a brain-controlled process.”

The suggestion that the aging process is driven by the integration of immune and hormonal responses is a new paradigm, wrote Dana Gabuzda and Bruce Yankner of Harvard Medical School, Boston, in an accompanying editorial. It “raises the intriguing possibility that hypothalamic regulation could be therapeutically manipulated to have broad effects on the aging process.”

In addition to the reported effects on aging, the hypothalamus coordinates energy metabolism and stress responses, wrote Mark Mattson, National Institute on Aging, Baltimore, Maryland, to Alzforum in an e-mail (see full comment below). It would be interesting to explore how these pathways influence each other, he added. Metabolic syndrome and stress are both potential risk factors for AD (see ARF related news series).

This study provides some of the first evidence in a mammalian system that one entity centrally regulates the aging process. “I think the brain is going to turn out to be more important than any other tissue for mammalian aging,” said Leonard Guarente, Massachusetts Institute of Technology, Cambridge. He and colleagues recently reported that length of circadian periods, which are regulated by a portion of the hypothalamus, determine lifespan in mice (see Libert et al., 2012). “Maybe we’ve underestimated the importance of the hypothalamus,” he said.—Gwyneth Dickey Zakaib

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  1. <strong>A Hypothalamus-Centric Inflammation-Mediated View of Aging. What About Energy Metabolism?</strong><br />

    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).

    <p>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.

    </p><p>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.

  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.

    View all comments by Michael Heneka

References

News Citations

  1. Enter the New Alzheimer’s Gene: TREM2 Variant Triples Risk
  2. Soothing Neuroinflammation Quells Plaques in Mice

Webinar Citations

  1. Can Network Analysis Identify Pathological Pathways in Alzheimer’s

Paper Citations

  1. . IKKβ/NF-κB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Nat Cell Biol. 2012 Oct;14(10):999-1012. PubMed.
  2. . Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell. 2008 Oct 3;135(1):61-73. PubMed.
  3. . Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nat Med. 2011 Jul;17(7):883-7. PubMed.
  4. . Enhancement of immunoreactivity for NF-kappa B in the hippocampal formation and cerebral cortex of Alzheimer's disease. Brain Res. 1996 Sep 30;735(1):159-68. PubMed.
  5. . Nuclear factor-κB regulates βAPP and β- and γ-secretases differently at physiological and supraphysiological Aβ concentrations. J Biol Chem. 2012 Jul 13;287(29):24573-84. PubMed.
  6. . Deviation of innate circadian period from 24 h reduces longevity in mice. Aging Cell. 2012 Oct;11(5):794-800. PubMed.

Other Citations

  1. ARF related news series

Further Reading

Papers

  1. . IKKβ/NF-κB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Nat Cell Biol. 2012 Oct;14(10):999-1012. PubMed.
  2. . Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell. 2008 Oct 3;135(1):61-73. PubMed.
  3. . Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nat Med. 2011 Jul;17(7):883-7. PubMed.
  4. . Neuroinflammation in overnutrition-induced diseases. Vitam Horm. 2013;91:195-218. PubMed.
  5. . Role of the hypothalamus in mediating protective effects of dietary restriction during aging. Front Neuroendocrinol. 2012 Dec 20; PubMed.
  6. . Metabolic syndrome and cognitive decline in early Alzheimer's disease and healthy older adults. J Alzheimers Dis. 2013 Jan 1;35(2):253-65. PubMed.
  7. . NF-κB in Aging and Disease. Aging Dis. 2011 Dec;2(6):449-65. PubMed.
  8. . NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest. 2001 Feb;107(3):247-54. PubMed.
  9. . Inflammation and NF-kappaB in Alzheimer's disease and diabetes. J Alzheimers Dis. 2009;16(4):809-21. PubMed.

Primary Papers

  1. . Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature. 2013 May 1; PubMed.
  2. . Physiology: Inflammation links ageing to the brain. Nature. 2013 May 1; PubMed.