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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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Plakkot, B., Agostino, A. D., & Subramanian, M. (2023) · Cells · doi:10.3390/cells12050769 · Cited by 17
“Systemic aging is directed by the hypothalamic IKKβ/NF-κB pathway via inflammatory crosstalk between neurons and microglia by inhibiting gonadotropin-releasing hormone (GnRH) production, and so counteracting inflammation or GnRH therapy could partly regress degenerative signs of aging [77].”
BackgroundXu, P., Estrada, S., Etteldorf, R., Liu, D., Shahid, M., Zeng, W., Früh, D., Reuter, M., Breteler, M. M. B., & Aziz, N. A. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105513 · Cited by 18
How does healthy aging impact on the circadian clock?
Popa‐Wagner, A., Buga, A.-M., Dumitraşcu, D. I., Uzoni, A., Thome, J., & Coogan, A. N. (2015) · Journal of Neural Transmission · doi:10.1007/s00702-015-1424-2 · Cited by 17
“Normal healthy aging is associated with low-grade chronic neuroinflammation (‘‘inflammaging’’; Baylis et al. 2013) and alterations of inflammatory processes in the hypothalamus have recently been shown to induce remarkable senescence-resistant phenotypes (Zhang et al. 2013a).”
BackgroundGenetic control of circadian rhythms and aging
Solovev, I. A., Dobrovolskaya, E., & Moskalev, A. (2016) · Russian Journal of Genetics · doi:10.1134/s1022795416040104 · Cited by 17
O'Keeffe, S., Beynon, A. L., Davies, J. S., Moynagh, P. N., & Coogan, A. N. (2017) · European Journal of Neuroscience · doi:10.1111/ejn.13553 · Cited by 16
“…recent studies have raised questions as to whether NF-jB activity is constitutive in young adult neurons in the basal state (Herkenham et al., 2011; Listwak et al., 2013; Zhang et al., 2013), indicating that activity in glia or endothelia may be linked to CNS processes linked to NK-jB activity.”
BackgroundInfluentialPayán‐Gómez, C., Rodríguez-Gomez, D. A., Amador-Munoz, D. P., & Ramírez-Clavijo, S. R. (2018) · Brain Sciences · doi:10.3390/brainsci8120227 · Cited by 16
“Inflammation is one of the hallmarks of aging, and the hypothalamus integrates inflammatory responses with systemic control of aging through nuclear factor κB (NF-κB) and microglia-neuron neuroimmune crosstalk [66,67].”
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Sadagurski, M., Debarba, L. K., Werneck‐de‐Castro, J. P., AWADA, A. A., Baker, T. A., & Bernal‐Mizrachi, E. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00183.2019 · Cited by 16
Marbouti, L., Zahmatkesh, M., Riahi, E., & Sabet, M. S. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.110985 · Cited by 16
Single-cell transcriptomic profiling of the hypothalamic median eminence during aging
Chen, Z., Li, S., Xu, M., Liu, C. C., Ye, H., Wang, B., & Wu, Q. (2022) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2022.01.001 · Cited by 16
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Sarkopenie und Frailty in der Neurologie
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Physiology of Gonadotropin-Releasing Hormone (Gnrh): Beyond the Control of Reproductive Functions
Maggi, R. (2016) · MOJ Anatomy & Physiology · doi:10.15406/mojap.2016.02.00063 · Cited by 16
“[34], whereas sex steroids did not, support the notion that GnRH may be involved in AD independently of its hormonal activity.”
BackgroundInfluentialKuwahara‐Otani, S., Maeda, S., Kobayashi, K., Minato, Y., Tanaka, K., Yamanishi, K., Hata, M., Li, W., Hayakawa, T., Noguchi, K., et al. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.03.051 · Cited by 16
A Reassessment of Genes Modulating Aging in Mice Using Demographic Measurements of the Rate of Aging
de Magalhães, J. P., Thompson, L. M., de Lima, I., Gaskill, D., Li, X., Thornton, D., Yang, C., & Palmer, D. H. (2018) · Genetics · doi:10.1534/genetics.118.300821 · Cited by 17
“NF-kB activity in the hypothalamus of mice increases with age and mice expressing constitutively active IKK-b in the mediobasal hypothalamus (MBH) exhibited shortened life spans (Zhang et al. 2013).”
BackgroundInfluentialvan Gastel, J., Hendrickx, J. O., Leysen, H., Martin, B., Veenker, L., Beuning, S., Coppens, V., Morrens, M., & Maudsley, S. R. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9554-7_39 · Cited by 16
Debate on human aging and lifespan
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Peng, B., Klausen, C., Campbell, L., Leung, P. C. K., Horne, A. W., & Bedaiwy, M. A. (2016) · Fertility and Sterility · doi:10.1016/j.fertnstert.2016.02.003 · Cited by 15
Deciphering the role of skin aging in pigmentary disorders
Yang, Y., Wu, Y., Xiang, L. F., Picardo, M., & Zhang, C. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.12.032 · Cited by 17
Pi, X., Zhao, Q., Wang, J., Zhang, X.-L., Yuan, D., Hu, S., He, Y., Zhang, C., Zhou, Z.-Y., & Wang, T. (2021) · Pharmaceutical Biology · doi:10.1080/13880209.2021.1961824 · Cited by 14
“In the brain, the theory of ‘hypothalamic microinflammation’ mainly emphasises the fundamental role of inflammation in ageing-related NDDs development (Zhang et al. 2013, 2017).”
BackgroundXu, Y., Li, W., Shi, M., Xu, X., Guo, D., Liu, Z., Chen, L., Zhong, X., & Cao, W. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109560 · Cited by 15
Park, H., Kwon, H., Lee, K.-Y., Kim, Y. E., Son, J., Choi, N.-Y., Lee, E. J., Han, M.-H., Park, D. W., Kim, S., et al. (2023) · Brain, behavior, and immunity · doi:10.1016/j.bbi.2023.10.021 · Cited by 13
Arellano, M. G., VanHeest, M., Emmadi, S., Abdul‐Hafez, A., Ibrahim, S. A. E.-F., Thiruvenkataramani, R. P., Teleb, R. S., Omar, H., Kesaraju, T., Mohamed, T., et al. (2024) · Bioengineering · doi:10.3390/bioengineering11060524 · Cited by 15
Barbour, C. C., Coxworth, J. E., & Hawkes, K. (2015) · AGE · doi:10.1007/s11357-015-9746-4 · Cited by 15
“Gene expression in the hypothalamus is also of paramount importance for aging in general because GnRH from the hypothalamus promotes neurogenesis, and aging is characterized by diminished neurogenesis (Zhang et al. 2013).”
BackgroundAging and the Krüppel-like factors.
Hsieh, P. N., Sweet, D. R., Fan, L., & Jain, M. K. (2017) · PubMed · Cited by 15
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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