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Scientific Understanding of Consciousness |
Hypothalamus involved in Systemic Ageing and Lifespan Control
Nature 497, 211–216 (09 May 2013) Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA Institute of Aging, Albert Einstein College of Medicine, Bronx, New York 10461, USA Guo Zhang, Juxue Li, Sudarshana Purkayastha, Yizhe Tang, Hai Zhang, Ye Yin, Bo Li, Gang Liu & Dongsheng Cai [paraphrase] 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. 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. Ageing is characterized by the gradual and overall loss of various physiological functions, leading to the end of lifespan. Although the search for resolution of ageing pathology is continuing, research has shown that certain neurons can mediate environmental influences on ageing in Caenorhabditis elegans and Drosophila, and neural manipulations of insulin or insulin-like growth factor 1 signalling or uncoupling protein 2 were shown to affect lifespan in animals. In this study, we have focused on the hypothalamus, a key brain region that is crucial for the neuroendocrine interaction between the central nervous system and the periphery. We asked whether the hypothalamus may have a fundamental role in ageing development and lifespan control, in addition to its critical involvement in basic life-supporting functions such as growth, reproduction and metabolism. In tackling this bold question, we increasingly appreciated that an atypical collection of hypothalamic inflammatory changes can broadly and causally underlie the development of metabolic syndrome components including being overweight, glucose intolerance and hypertension, and of note, all of these disorders are often related to ageing. Furthermore, we have noted recent literature showing that microglia are involved in neurodegenerative diseases, which aligns with the appreciated connection between systemic immunity and ageing. Here, through targeting hypothalamic immunity/inflammation, we designed to test whether the hypothalamus is fundamentally important for ageing and lifespan control. In this work, we conceived that the hypothalamus, which is known to have fundamental roles in growth, development, reproduction and metabolism, is also responsible for systemic ageing and thus lifespan control. Notably, through activating or inhibiting immune pathway IKK-β and NF-κB in the hypothalamus of mice, we were able to accelerate or decelerate the ageing process, leading to shortened or increased lifespan. Thus, in line with the literature that appreciated the effects of the nervous system on lifespan, our findings provide a proof of principle to the hypothesis that ageing is a life event that is programmed by the hypothalamus. Indeed, brain change is an early ageing manifestation4, and we reasoned that some hypothalamic alterations may act to motivate ageing of the rest parts in the body, and this outreaching role of the hypothalamus aligns with the fact that it is the neuroendocrine ‘headquarters’ in the body. Along this line, we further revealed a direct link between IKK-β and NF-κB activation and GnRH decline, and also importantly, we discovered that GnRH induces adult neurogenesis broadly in the brain, and GnRH therapy can greatly amend ageing disorders. Thus, whereas the inhibition of GnRH by NF-κB may lead to the end of reproductive length—which seems necessary for species’ quality—it initiates systemic ageing at the same time. Questions remain about how hypothalamic IKK-β and NF-κB is activated in this process; speculatively, as deduced from some recent studies about sirtuins and NF-κB, age increase-induced epigenetic changes might be accountable, which calls for future investigations. To summarize, our study using several mouse models demonstrates that the hypothalamus is important for systemic ageing and lifespan control. This hypothalamic role is significantly mediated by IKK-β- and NF-κB-directed hypothalamic innate immunity involving microglia–neuron crosstalk. The underlying basis includes integration between immunity and neuroendocrine of the hypothalamus, and immune inhibition and GnRH restoration in the hypothalamus or the brain represent two potential strategies for combating ageing-related health problems. 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