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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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Inhibition of GnRH by IKKβ/NF-κBa–c Hypothalamic GnRH mRNA of indicated mice. d–g. GT1–7 cells were transfected with CAIKKβ, RelA or DNIκBα vs. control (Con) plasmid (d,e,g), co-transfected with GnRH-promoter luciferase plasmid (e&f), or together with RelA shRNA (sh-RelA) vs. control shRNA (sh-Con) plasmid (f), and were measure for GnRH release (d), GnRH promoter (e&f), and c-Fos, c-Jun, PKCα and PKCδ mRNA levels (g). h. GnRH promoter activities were measured for GT1–7 cells transfected with GnRH-promoter luciferase plasmid, co-transfected with c-Jun or c-Fos plasmid vs. control plasmid (Con), or treated with TPA vs. vehicle (Veh). i. GnRH promoter activities were measured for GT1–7 cells transfected with GnRH-promoter luciferase plasmid, co-transfected with CAIKKβ vs. control (Con) plasmid, and with c-Fos/c-Jun shRNA plasmids (sh-c-Fos/sh-c-Jun) vs. scramble shRNA control (sh-Con). j. Summarized schematic model. *P < 0.05, **P < 0.01, ***P < 0.001; n = 12 (a&e) and 3 (f–i) per group, and n = 6 (b), 8 (c) and 4 (d) in Con, n = 8 (b) and 6 (d) in IKKβ, and n = 8 (c) and 6 (d) in IκBα. Error bars reflect mean ± SEM.
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Figure 5: Inhibition of GnRH by IKKβ/NF-κBa–c Hypothalamic GnRH mRNA of indicated mice. d–g. GT1–7 cells were transfected with CAIKKβ, RelA or DNIκBα vs. control (Con) plasmid (d,e,g), co-transfected with GnRH-promoter luciferase plasmid (e&f), or together with RelA shRNA (sh-RelA) vs. control shRNA (sh-Con) plasmid (f), and were measure for GnRH release (d), GnRH promoter (e&f), and c-Fos, c-Jun, PKCα and PKCδ mRNA levels (g). h. GnRH promoter activities were measured for GT1–7 cells transfected with GnRH-promoter luciferase plasmid, co-transfected with c-Jun or c-Fos plasmid vs. control plasmid (Con), or treated with TPA vs. vehicle (Veh). i. GnRH promoter activities were measured for GT1–7 cells transfected with GnRH-promoter luciferase plasmid, co-transfected with CAIKKβ vs. control (Con) plasmid, and with c-Fos/c-Jun shRNA plasmids (sh-c-Fos/sh-c-Jun) vs. scramble shRNA control (sh-Con). j. Summarized schematic model. *P < 0.05, **P < 0.01, ***P < 0.001; n = 12 (a&e) and 3 (f–i) per group, and n = 6 (b), 8 (c) and 4 (d) in Con, n = 8 (b) and 6 (d) in IKKβ, and n = 8 (c) and 6 (d) in IκBα. Error bars reflect mean ± SEM.

Mentions: To better depict the hypothalamic control of aging, we focused on neuroendocrine pathways of the hypothalamus, and identified that IKKβ/NF-κB negatively regulated gonadotropin-releasing hormone (GnRH). The classical action of GnRH is to regulate sex hormones and reproduction, but it has yet to be studied regarding if GnRH is important for whole-body aging. We found that aging was associated with reduced hypothalamic GnRH mRNA, and this change was reversed by IKKβ/NF-κB inhibition but enhanced by IKKβ/NF-κB activation (Fig. 5a–c, suppl. Fig. 10a). Using GT1–7 cells, a cell line of GnRH neurons, we confirmed that GnRH release from these cells decreased upon IKKβ/NF-κB activation but increased by IKKβ/NF-κB inhibition (Fig. 5d). To study if NF-κB might inhibit GnRH gene, we introduced GnRH promoter-driven luciferase into GT1–7 cells, and simultaneously activated or inhibited IKKβ/NF-κB in these cells. Results showed that GnRH promoter activity reduced ~50% upon IKKβ/NF-κB activation but increased 4–5 folds by IKKβ/NF-κB inhibition (Fig. 5e&f). Moreover, IKKβ/NF-κB activation increased c-Fos, c-Jun, PKCα and PKCδ mRNA levels (Fig. 5g), and this finding was meaningful, because c-Fos/c-Jun overexpression and PKC activation were both able to inhibit GnRH promoter (Fig. 5h). Further, IKKβ/NF-κB’s inhibition on GnRH promoter was attenuated by blocking c-Fos/c-Jun (Fig. 5i) or by suppressing PKC pathway (suppl. Fig. 10b). Altogether, c-Fos/c-Jun and PKC pathways can work together to mediate the inhibitory effect of IKKβ/NF-κB on GnRH (Fig. 5j), and in conjunction with relevant literature34, transcriptional integration of NF-κB and c-Jun seems to account for down-regulation of GnRH 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)

Inhibition of GnRH by IKKβ/NF-κBa–c Hypothalamic GnRH mRNA of indicated mice. d–g. GT1–7 cells were transfected with CAIKKβ, RelA or DNIκBα vs. control (Con) plasmid (d,e,g), co-transfected with GnRH-promoter luciferase plasmid (e&f), or together with RelA shRNA (sh-RelA) vs. control shRNA (sh-Con) plasmid (f), and were measure for GnRH release (d), GnRH promoter (e&f), and c-Fos, c-Jun, PKCα and PKCδ mRNA levels (g). h. GnRH promoter activities were measured for GT1–7 cells transfected with GnRH-promoter luciferase plasmid, co-transfected with c-Jun or c-Fos plasmid vs. control plasmid (Con), or treated with TPA vs. vehicle (Veh). i. GnRH promoter activities were measured for GT1–7 cells transfected with GnRH-promoter luciferase plasmid, co-transfected with CAIKKβ vs. control (Con) plasmid, and with c-Fos/c-Jun shRNA plasmids (sh-c-Fos/sh-c-Jun) vs. scramble shRNA control (sh-Con). j. Summarized schematic model. *P < 0.05, **P < 0.01, ***P < 0.001; n = 12 (a&e) and 3 (f–i) per group, and n = 6 (b), 8 (c) and 4 (d) in Con, n = 8 (b) and 6 (d) in IKKβ, and n = 8 (c) and 6 (d) in IκBα. Error bars reflect mean ± SEM.
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Figure 5: Inhibition of GnRH by IKKβ/NF-κBa–c Hypothalamic GnRH mRNA of indicated mice. d–g. GT1–7 cells were transfected with CAIKKβ, RelA or DNIκBα vs. control (Con) plasmid (d,e,g), co-transfected with GnRH-promoter luciferase plasmid (e&f), or together with RelA shRNA (sh-RelA) vs. control shRNA (sh-Con) plasmid (f), and were measure for GnRH release (d), GnRH promoter (e&f), and c-Fos, c-Jun, PKCα and PKCδ mRNA levels (g). h. GnRH promoter activities were measured for GT1–7 cells transfected with GnRH-promoter luciferase plasmid, co-transfected with c-Jun or c-Fos plasmid vs. control plasmid (Con), or treated with TPA vs. vehicle (Veh). i. GnRH promoter activities were measured for GT1–7 cells transfected with GnRH-promoter luciferase plasmid, co-transfected with CAIKKβ vs. control (Con) plasmid, and with c-Fos/c-Jun shRNA plasmids (sh-c-Fos/sh-c-Jun) vs. scramble shRNA control (sh-Con). j. Summarized schematic model. *P < 0.05, **P < 0.01, ***P < 0.001; n = 12 (a&e) and 3 (f–i) per group, and n = 6 (b), 8 (c) and 4 (d) in Con, n = 8 (b) and 6 (d) in IKKβ, and n = 8 (c) and 6 (d) in IκBα. Error bars reflect mean ± SEM.
Mentions: To better depict the hypothalamic control of aging, we focused on neuroendocrine pathways of the hypothalamus, and identified that IKKβ/NF-κB negatively regulated gonadotropin-releasing hormone (GnRH). The classical action of GnRH is to regulate sex hormones and reproduction, but it has yet to be studied regarding if GnRH is important for whole-body aging. We found that aging was associated with reduced hypothalamic GnRH mRNA, and this change was reversed by IKKβ/NF-κB inhibition but enhanced by IKKβ/NF-κB activation (Fig. 5a–c, suppl. Fig. 10a). Using GT1–7 cells, a cell line of GnRH neurons, we confirmed that GnRH release from these cells decreased upon IKKβ/NF-κB activation but increased by IKKβ/NF-κB inhibition (Fig. 5d). To study if NF-κB might inhibit GnRH gene, we introduced GnRH promoter-driven luciferase into GT1–7 cells, and simultaneously activated or inhibited IKKβ/NF-κB in these cells. Results showed that GnRH promoter activity reduced ~50% upon IKKβ/NF-κB activation but increased 4–5 folds by IKKβ/NF-κB inhibition (Fig. 5e&f). Moreover, IKKβ/NF-κB activation increased c-Fos, c-Jun, PKCα and PKCδ mRNA levels (Fig. 5g), and this finding was meaningful, because c-Fos/c-Jun overexpression and PKC activation were both able to inhibit GnRH promoter (Fig. 5h). Further, IKKβ/NF-κB’s inhibition on GnRH promoter was attenuated by blocking c-Fos/c-Jun (Fig. 5i) or by suppressing PKC pathway (suppl. Fig. 10b). Altogether, c-Fos/c-Jun and PKC pathways can work together to mediate the inhibitory effect of IKKβ/NF-κB on GnRH (Fig. 5j), and in conjunction with relevant literature34, transcriptional integration of NF-κB and c-Jun seems to account for down-regulation of GnRH 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