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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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Selenium, aging and aging-related diseases
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Branched-chain amino acid catabolism is a conserved regulator of physiological ageing
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Neuroinflammatory basis of metabolic syndrome
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Self-citationDissecting Aging and Senescence—Current Concepts and Open Lessons
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“Importantly, the hypothalamus, suggested to be a superordinate pacemaker in the aging process, mediates its functional role through NF-κB signaling, an aforementioned effector in cellular senescence and putatively programmed aging [23,24,89].”
BackgroundHepatic lipid metabolism and non-alcoholic fatty liver disease in aging
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“Since aging is modulated by insulin-like signals in the brain (Taguchi et al., 2007; Kappeler et al., 2008; Zhang et al., 2013), this pathway could function as a molecular bridge between physiological aging and AD pathogenesis (Carro et al., 2002).”
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“Numerous recent publications further illuminate the role of the mTOR pathway (and related pathways) in aging.(35,131-168) If used properly, rapamycin improves immunity and decreases infections and their complications.”
BackgroundYan, J., Zhang, H., Yin, Y. I., Li, J., Tang, Y., Purkayastha, S., Li, L., & Cai, D. (2014) · Nature Medicine · doi:10.1038/nm.3616 · Cited by 143
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“These disturbances of central inflammation have been shown to be a hallmark of AD [26].”
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“Proc Natl Acad Sci USA 105(17):6368–6373.”
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“Aging is characterized by a gradual and progressive functional decline of physiological functions and organ systems with advancing time leading to the increased risk of debility, disease, and the end of lifespan [1, 2].”
Background“Hypothalamic Microinflammation” Paradigm in Aging and Metabolic Diseases
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“Remarkably and from a much larger perspective, hypothalamicmicroinflammation was found to programmatically control whole-body aging (Zhang et al., 2013, 2017a).”
BackgroundInfluentialSelf-citationThe potential role of necroptosis in inflammaging and aging
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The special relationship: glia–neuron interactions in the neuroendocrine hypothalamus
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MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage
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The DNA Damage Response in Neurons: Die by Apoptosis or Survive in a Senescence-Like State?
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Mouse models of ageing and their relevance to disease
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“Mouse models of HGPS are models of laminopathies based on modification of the Lamna gene or its processing enzyme (Zhang et al., 2013a).”
InfluentialAge- and tissue-specific expression of senescence biomarkers in mice.
Hudgins, A. D., Tazearslan, C., Tare, A., Zhu, Y., Huffman, D., & Suh, Y. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00059 · Cited by 124
“We also chose the hypothalamus because it has been implicated in the regulation of the aging process (Zhang et al., 2017), as mediated through NF-κB signaling (Zhang et al., 2013), a major pathway involved in SASP factor induction (Malaquin et al., 2016).”
Mouse Models to Disentangle the Hallmarks of Human Aging
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“Conversely, inhibition of NF-κB signaling through genetic manipulation in the hypothalamus extended longevity in mice.(236) Moreover, this work demonstrated that NF-κB activation reduced gonadotropin-releasing hormone production, and the decline in this hormone contributed to the development of age-related phenotypes,…”
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“For example, gonadotropin-releasing hormone (GnRH) that acts on the hypothalamus was shown to promote brain rejuvenation but the mechanism remained unknown (27).”
BackgroundMetformin: Do we finally have an anti-aging drug?
Anisimov, V. N. (2013) · Cell Cycle · doi:10.4161/cc.26928 · Cited by 125
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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