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Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH.

Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D - Nature (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

ABSTRACT
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.

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Aging-dependent hypothalamic NF-κB activation57BL/6 mice (chow-fed males) were analyzed at young (3–4 months) age (Y), middle-old (11–13 months) age (M), and old (22–24 months) age (O). a&b. Hypothalami were analyzed via Western blots. b: Intensity of p-RelA normalized by RelA (au: arbitrary unit). c&d. Mice received MBH injections of lentiviral GFP controlled by NF-κB response element (NF-κB/RE), and following ~3-week recovery, brain sections were made to reveal GFP and NeuN stainining. DAPI staining shows entire cell populations. Bar = 25 µm. d: Percentages of cells co-expressing GFP and NeuN (GFP+NeuN+) among NeuN-expressing cells (NeuN+) in the MBH. **P < 0.01, ***P < 0.001; n = 6 (b) and 3 (d) per group. Error bars reflect mean ± SEM.
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Figure 1: Aging-dependent hypothalamic NF-κB activation57BL/6 mice (chow-fed males) were analyzed at young (3–4 months) age (Y), middle-old (11–13 months) age (M), and old (22–24 months) age (O). a&b. Hypothalami were analyzed via Western blots. b: Intensity of p-RelA normalized by RelA (au: arbitrary unit). c&d. Mice received MBH injections of lentiviral GFP controlled by NF-κB response element (NF-κB/RE), and following ~3-week recovery, brain sections were made to reveal GFP and NeuN stainining. DAPI staining shows entire cell populations. Bar = 25 µm. d: Percentages of cells co-expressing GFP and NeuN (GFP+NeuN+) among NeuN-expressing cells (NeuN+) in the MBH. **P < 0.01, ***P < 0.001; n = 6 (b) and 3 (d) per group. Error bars reflect mean ± SEM.

Mentions: In studying the potential role of the hypothalamus in aging, we developed a strategy of targeting hypothalamic immunity, and as shown in our recent work12–15, infection-unrelated inflammatory changes in the mediobasal hypothalamus (MBH) underlies the development of various metabolic syndrome components, and the molecular basis is mediated critically by NF-κB and its upstream IκB kinase-β (IKKβ). Indeed, using NF-κB subunit RelA phosphorylation to report NF-κB activation, we observed that while hypothalamic NF-κB was barely active in young mice, it was activated in the hypothalamus of mice at middle-old ages, and the activities further increased when mice became older (Fig. 1a&b). Agreeing with this observation, mRNA levels of many cytokines and immune regulators increased in the hypothalamus of old mice compared to young group (data not shown). To directly visualize NF-κB activity in the MBH, we employed NF-κB reporter which induces GFP upon the binding of NF-κB to its transcriptional response element in a lentiviral vector (Fig. 1c). After in vitro assessment of this approach ( suppl. Fig. 1a & b), we performed animal experiments by delivering this lentiviral NF-κB reporter into the MBH of mice at young, middle-old, and old ages. A prolonged recovery period was used to minimize the procedure-related non-specific effects on NF-κB. We found that GFP was negligible in the MBH of young mice (Fig. 1c), but was evident in the MBH of middle-old mice and became more profound in old mice (Fig. 1c&d), confirming that aging is associated with hypothalamic NF-κB activation. We also injected this lentiviral NF-κB reporter into various other brain regions, and comparatively, the MBH was most sensitive to aging-related NF-κB activation (suppl. Fig. 1c – e). Of interest, immunostaining with Neuronal marker NeuN revealed that NF-κB activation in neurons was relatively modest under middle-old aging, but became prominent when age further increased (Fig. 1c&d). Thus, aging development is characterized by chronic activation of NF-κB-directed innate immune pathway predominantly in the hypothalamus.


Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH.

Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D - Nature (2013)

Aging-dependent hypothalamic NF-κB activation57BL/6 mice (chow-fed males) were analyzed at young (3–4 months) age (Y), middle-old (11–13 months) age (M), and old (22–24 months) age (O). a&b. Hypothalami were analyzed via Western blots. b: Intensity of p-RelA normalized by RelA (au: arbitrary unit). c&d. Mice received MBH injections of lentiviral GFP controlled by NF-κB response element (NF-κB/RE), and following ~3-week recovery, brain sections were made to reveal GFP and NeuN stainining. DAPI staining shows entire cell populations. Bar = 25 µm. d: Percentages of cells co-expressing GFP and NeuN (GFP+NeuN+) among NeuN-expressing cells (NeuN+) in the MBH. **P < 0.01, ***P < 0.001; n = 6 (b) and 3 (d) per group. Error bars reflect mean ± SEM.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3756938&req=5

Figure 1: Aging-dependent hypothalamic NF-κB activation57BL/6 mice (chow-fed males) were analyzed at young (3–4 months) age (Y), middle-old (11–13 months) age (M), and old (22–24 months) age (O). a&b. Hypothalami were analyzed via Western blots. b: Intensity of p-RelA normalized by RelA (au: arbitrary unit). c&d. Mice received MBH injections of lentiviral GFP controlled by NF-κB response element (NF-κB/RE), and following ~3-week recovery, brain sections were made to reveal GFP and NeuN stainining. DAPI staining shows entire cell populations. Bar = 25 µm. d: Percentages of cells co-expressing GFP and NeuN (GFP+NeuN+) among NeuN-expressing cells (NeuN+) in the MBH. **P < 0.01, ***P < 0.001; n = 6 (b) and 3 (d) per group. Error bars reflect mean ± SEM.
Mentions: In studying the potential role of the hypothalamus in aging, we developed a strategy of targeting hypothalamic immunity, and as shown in our recent work12–15, infection-unrelated inflammatory changes in the mediobasal hypothalamus (MBH) underlies the development of various metabolic syndrome components, and the molecular basis is mediated critically by NF-κB and its upstream IκB kinase-β (IKKβ). Indeed, using NF-κB subunit RelA phosphorylation to report NF-κB activation, we observed that while hypothalamic NF-κB was barely active in young mice, it was activated in the hypothalamus of mice at middle-old ages, and the activities further increased when mice became older (Fig. 1a&b). Agreeing with this observation, mRNA levels of many cytokines and immune regulators increased in the hypothalamus of old mice compared to young group (data not shown). To directly visualize NF-κB activity in the MBH, we employed NF-κB reporter which induces GFP upon the binding of NF-κB to its transcriptional response element in a lentiviral vector (Fig. 1c). After in vitro assessment of this approach ( suppl. Fig. 1a & b), we performed animal experiments by delivering this lentiviral NF-κB reporter into the MBH of mice at young, middle-old, and old ages. A prolonged recovery period was used to minimize the procedure-related non-specific effects on NF-κB. We found that GFP was negligible in the MBH of young mice (Fig. 1c), but was evident in the MBH of middle-old mice and became more profound in old mice (Fig. 1c&d), confirming that aging is associated with hypothalamic NF-κB activation. We also injected this lentiviral NF-κB reporter into various other brain regions, and comparatively, the MBH was most sensitive to aging-related NF-κB activation (suppl. Fig. 1c – e). Of interest, immunostaining with Neuronal marker NeuN revealed that NF-κB activation in neurons was relatively modest under middle-old aging, but became prominent when age further increased (Fig. 1c&d). Thus, aging development is characterized by chronic activation of NF-κB-directed innate immune pathway predominantly in the hypothalamus.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus