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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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Genetic longevity by brain-specific IKKβ knockoutN/IKKβlox/lox mice (N/IKKβl/l) and littermate WT in males were maintained on a chow since weaning. a&b. Young (3 months) vs. old age (18–20 months) mice were tested for cognition (a) and muscle endurance (b). MWM data included time in target northwest (NW) vs. off-target northeast (NE), southwest (SW) and southeast (SE) quadrants in probe trials. c–h. Young (3–4 months) vs. old (20–24 months) mice were scarified for assessing muscle (quadriceps) fiber size (c), dermal thickness (d–f), bone mass (g), and tail tendon breaking time (h). i. Lifespan follow-up (n = 20 in WT and n = 25 in N/IKKβl/l). *P < 0.05, **P < 0.01; young WT: n = 10 (b), 3 (c&e), 5 (f), 6 (g) and 8 (h); young N/IKKβl/l: n = 14 (b), 3 (c,e,f), 6 (g) and 8 (h); old WT: n = 10 (a), 7 (b), 3 (c&e), 5 (f&g), and 6 (h); old N/IKKβl/l n = 10 (a), 7 (b), 3 (c,e,f), and 6 (g&h). Error bars reflect mean ± SEM.
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Figure 4: Genetic longevity by brain-specific IKKβ knockoutN/IKKβlox/lox mice (N/IKKβl/l) and littermate WT in males were maintained on a chow since weaning. a&b. Young (3 months) vs. old age (18–20 months) mice were tested for cognition (a) and muscle endurance (b). MWM data included time in target northwest (NW) vs. off-target northeast (NE), southwest (SW) and southeast (SE) quadrants in probe trials. c–h. Young (3–4 months) vs. old (20–24 months) mice were scarified for assessing muscle (quadriceps) fiber size (c), dermal thickness (d–f), bone mass (g), and tail tendon breaking time (h). i. Lifespan follow-up (n = 20 in WT and n = 25 in N/IKKβl/l). *P < 0.05, **P < 0.01; young WT: n = 10 (b), 3 (c&e), 5 (f), 6 (g) and 8 (h); young N/IKKβl/l: n = 14 (b), 3 (c,e,f), 6 (g) and 8 (h); old WT: n = 10 (a), 7 (b), 3 (c&e), 5 (f&g), and 6 (h); old N/IKKβl/l n = 10 (a), 7 (b), 3 (c,e,f), and 6 (g&h). Error bars reflect mean ± SEM.

Mentions: We further resorted to a genetic model of brain-specific IKKβ knockout mice, N/IKKβlox/lox mice which we generated by breeding Nestin-Cre with IKKβlox/lox mice as we described previously13. Compared to littermate wildtype (WT) with matched IKKβlox/lox background, these knockout mice were indeed developmentally indistinguishable in terms of brain size and gross morphology (suppl. Fig. 6). We also compared IKKβlox/lox mice to additional types of controls, and confirmed that all these mice were similar across a spectrum of aging-related physiological and histological changes (suppl. Fig. 7). In this context, we profiled aging-related physiology and pathology in N/IKKβlox/lox mice and littermate WT. At an old age, after technical assessment (suppl. Fig. 8a – c), we subjected mice to Morris Water Maze (MWM), and found that N/IKKβlox/lox mice outperformed WT (Fig. 4a). This cognitive improvement was specific to aging, since young N/IKKβlox/lox mice and WT performed similarly (suppl. Fig. 8d – h). Thus, although NF-κB appears to have a role in the development of hippocampal synaptic plasticity31–33, the net effect from suppressing brain IKKβ/NF-κB under aging paradigm is cognitively beneficial. Using grip test, we further found that compared to WT, N/IKKβlox/lox mice had a reduced extent of aging-related muscle weakness (Fig. 4b). Also, as shown in Fig. 4c–h, N/IKKβlox/lox mice were protected against aging-induced muscle and skin atrophy, bone loss, and collagen cross-linking. In addition to males, female N/IKKβlox/lox mice were studied, and the findings were consistent (suppl. Fig. 9). Also importantly, we did lifespan analysis through following a cohort of male N/IKKβlox/lox mice and littermate WT. As shown in Fig. 4i, WT had a typical pattern of median and maximal lifespan; in contrast, N/IKKβlox/lox mice showed a pronounced phenotype of longevity, with median lifespan 23% longer (P = 0.0002) and maximal lifespan 20% longer (p < 0.05) than WT. We recognize that the longevity phenotype of this genetic model could be a result of IKKβ inhibition jointly in neurons and glia, since Nestin-Cre is known to target neural stem/progenitor cells and derived neurons and glia. To summarize, longevity in this genetic model significantly recapitulates aging retardation from hypothalamic IKKβ/NF-κB inhibition, and technologically, aging retardation can be achieved via IKKβ/NF-κB inhibition across the brain without evident side effects or compromised efficacy.


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)

Genetic longevity by brain-specific IKKβ knockoutN/IKKβlox/lox mice (N/IKKβl/l) and littermate WT in males were maintained on a chow since weaning. a&b. Young (3 months) vs. old age (18–20 months) mice were tested for cognition (a) and muscle endurance (b). MWM data included time in target northwest (NW) vs. off-target northeast (NE), southwest (SW) and southeast (SE) quadrants in probe trials. c–h. Young (3–4 months) vs. old (20–24 months) mice were scarified for assessing muscle (quadriceps) fiber size (c), dermal thickness (d–f), bone mass (g), and tail tendon breaking time (h). i. Lifespan follow-up (n = 20 in WT and n = 25 in N/IKKβl/l). *P < 0.05, **P < 0.01; young WT: n = 10 (b), 3 (c&e), 5 (f), 6 (g) and 8 (h); young N/IKKβl/l: n = 14 (b), 3 (c,e,f), 6 (g) and 8 (h); old WT: n = 10 (a), 7 (b), 3 (c&e), 5 (f&g), and 6 (h); old N/IKKβl/l n = 10 (a), 7 (b), 3 (c,e,f), and 6 (g&h). Error bars reflect mean ± SEM.
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Related In: Results  -  Collection

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Figure 4: Genetic longevity by brain-specific IKKβ knockoutN/IKKβlox/lox mice (N/IKKβl/l) and littermate WT in males were maintained on a chow since weaning. a&b. Young (3 months) vs. old age (18–20 months) mice were tested for cognition (a) and muscle endurance (b). MWM data included time in target northwest (NW) vs. off-target northeast (NE), southwest (SW) and southeast (SE) quadrants in probe trials. c–h. Young (3–4 months) vs. old (20–24 months) mice were scarified for assessing muscle (quadriceps) fiber size (c), dermal thickness (d–f), bone mass (g), and tail tendon breaking time (h). i. Lifespan follow-up (n = 20 in WT and n = 25 in N/IKKβl/l). *P < 0.05, **P < 0.01; young WT: n = 10 (b), 3 (c&e), 5 (f), 6 (g) and 8 (h); young N/IKKβl/l: n = 14 (b), 3 (c,e,f), 6 (g) and 8 (h); old WT: n = 10 (a), 7 (b), 3 (c&e), 5 (f&g), and 6 (h); old N/IKKβl/l n = 10 (a), 7 (b), 3 (c,e,f), and 6 (g&h). Error bars reflect mean ± SEM.
Mentions: We further resorted to a genetic model of brain-specific IKKβ knockout mice, N/IKKβlox/lox mice which we generated by breeding Nestin-Cre with IKKβlox/lox mice as we described previously13. Compared to littermate wildtype (WT) with matched IKKβlox/lox background, these knockout mice were indeed developmentally indistinguishable in terms of brain size and gross morphology (suppl. Fig. 6). We also compared IKKβlox/lox mice to additional types of controls, and confirmed that all these mice were similar across a spectrum of aging-related physiological and histological changes (suppl. Fig. 7). In this context, we profiled aging-related physiology and pathology in N/IKKβlox/lox mice and littermate WT. At an old age, after technical assessment (suppl. Fig. 8a – c), we subjected mice to Morris Water Maze (MWM), and found that N/IKKβlox/lox mice outperformed WT (Fig. 4a). This cognitive improvement was specific to aging, since young N/IKKβlox/lox mice and WT performed similarly (suppl. Fig. 8d – h). Thus, although NF-κB appears to have a role in the development of hippocampal synaptic plasticity31–33, the net effect from suppressing brain IKKβ/NF-κB under aging paradigm is cognitively beneficial. Using grip test, we further found that compared to WT, N/IKKβlox/lox mice had a reduced extent of aging-related muscle weakness (Fig. 4b). Also, as shown in Fig. 4c–h, N/IKKβlox/lox mice were protected against aging-induced muscle and skin atrophy, bone loss, and collagen cross-linking. In addition to males, female N/IKKβlox/lox mice were studied, and the findings were consistent (suppl. Fig. 9). Also importantly, we did lifespan analysis through following a cohort of male N/IKKβlox/lox mice and littermate WT. As shown in Fig. 4i, WT had a typical pattern of median and maximal lifespan; in contrast, N/IKKβlox/lox mice showed a pronounced phenotype of longevity, with median lifespan 23% longer (P = 0.0002) and maximal lifespan 20% longer (p < 0.05) than WT. We recognize that the longevity phenotype of this genetic model could be a result of IKKβ inhibition jointly in neurons and glia, since Nestin-Cre is known to target neural stem/progenitor cells and derived neurons and glia. To summarize, longevity in this genetic model significantly recapitulates aging retardation from hypothalamic IKKβ/NF-κB inhibition, and technologically, aging retardation can be achieved via IKKβ/NF-κB inhibition across the brain without evident side effects or compromised efficacy.

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