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Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH
Open accessAbstract
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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“inflammatory and stress responses activate NF-κB in the hypothalamus and induce a signaling pathway that results in reduced production of gonadotropin-releasing hormone (GnRH) by neurons”
From The Hallmarks of Aging (2013) · cites this paper as Zhang et al., 2013
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“This GnRH decline can contribute to numerous aging-related changes such as bone fragility, muscle weakness, skin atrophy and reduced neurogenesis.”
From The Hallmarks of Aging (2013) · cites this paper as Zhang et al., 2013
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“GnRH treatment prevents aging-impaired neurogenesis and decelerates aging development in mice”
From The Hallmarks of Aging (2013) · cites this paper as Zhang et al., 2013
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“Gonadotropin-releasing hormone ameliorates neurogenesis and decelerates the ageing process in mice.463”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [463]
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Rapid linkage of innate immunological signals to adaptive immunity by the brain-fat axis
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“Increase in activation of Gnrhr may result in excitation of pyramidal neurons (61, 62) although data on the expression of its ligand GnRH are controversial (63, 64).”
BackgroundUnraveling the Role of Ataxin-2 in Metabolism
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Gut hormone GIP induces inflammation and insulin resistance in the hypothalamus
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Control of obesity and glucose intolerance via building neural stem cells in the hypothalamus
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“Hypothalamic IκB kinase-β and nuclear factor κB regulate mammalian lifespan extension by inhibiting gonadotropin-releasing hormone, representing immune-neuroendocrine integration [12].”
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Aging-associated lncRNAs are evolutionarily conserved and participate in NFκB signaling
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“accumulating evidence indicates that changes in the hypothalamus initiate reproductive senescence (Downs andWise, 2009; Lu et al., 1994; Rubin, 2000; Wise, 1993; Wise et al., 2002; Yin and Gore, 2006; Zhang et al., 2013).”
BackgroundAnti‐inflammaging effects of human alpha‐1 antitrypsin
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“All of these pathways converge on NF-KB, the master transcription regulator that controls the expression of immune-responsive genes (Zhang et al., 2013; Guo et al., 2014).”
BackgroundWhole-Exome Sequencing in 22 Young Ischemic Stroke Patients With Familial Clustering of Stroke
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SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice
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“onstrating the importance of this phenomenon to the health of the whole organism [54].”
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“Recent evidence identifies the medial basal hypothalamus as coordinating systemic aging, including muscle weakness, reduced bone mass, and poor cognition, through neuroinflammation [19].”
BackgroundSenescence in Bacteria and Its Underlying Mechanisms
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“…hypothalamus-enriched gene, mimics age-associated changes in sleep quality and adiposity Akiko Satoh,1 Cynthia S. Brace,1 Nick Rensing2 and Shin-ichiro Imai1 1Department of Developmental Biology, 2Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA”
Background
Metadata
- Authors
- Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., Li, B., Liu, G., & Cai, D.
- Affiliations
- Albert Einstein College of Medicine (US)
- Corresponding author
- Cai, Dongsheng
- Venue
- Nature
- Published
- 2013-05
- Volume
- 497
- Issue
- 7448
- Pages
- 211-216
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3756938
- OpenAlex
- W2098009444
- Cited by
- 834
- References
- 45
- Citations by year
- 2026: 36 · 2025: 45 · 2024: 57 · 2023: 54 · 2022: 58 · 2021: 76 · 2020: 76 · 2019: 62 · 2018: 64 · 2017: 78 · 2016: 72 · 2015: 62 · 2014: 59 · 2013: 34
- FWCI
- 26.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R01AG031774)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078750)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- lifespan extension, IKKβ, NF-κB, gonadotropin-releasing hormone, neurogenesis, metabolic inflammation, reproductive aging, GnRH treatment
- MeSH terms
- Aging, Animals, Brain, Cognition, Female, Hypothalamus, Gonadotropin-Releasing Hormone, Longevity, Male, Mice, Inbred C57BL, Reproduction, NF-kappa B, Microglia, Mice, Knockout, Mice, I-kappa B Kinase, Neurogenesis
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