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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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Cites
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., Nadon, N. L., Wilkinson, J. E., Frenkel, K., Carter, C. S., et al. (2009) · Nature · doi:10.1038/nature08221 · Cited by 3,766
Mechanisms underlying inflammation in neurodegeneration
Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C., & Gage, F. H. (2010) · Cell · doi:10.1016/j.cell.2010.02.016 · Cited by 3,580
Pathways towards and Away from Alzheimer’s Disease
Mattson, M. P. (2004) · Nature · doi:10.1038/nature02621 · Cited by 3,052
Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208
The ageing systemic milieu negatively regulates neurogenesis and cognitive function
Villeda, S. A., Luo, J., Mosher, K. I., Zou, B., Britschgi, M., Bieri, G., Stan, T. M., Fainberg, N., Ding, Z., Eggel, A., et al. (2011) · Nature · doi:10.1038/nature10357 · Cited by 1,763
Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity
Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H., & Cai, D. (2008) · Cell · doi:10.1016/j.cell.2008.07.043 · Cited by 1,350
Self-citationSIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin
Michishita, E., McCord, R. A., Berber, E., Kioi, M., Padilla-Nash, H., Damian, M., Cheung, P., Kusumoto, R., Kawahara, T. L. A., Barrett, J. C., et al. (2008) · Nature · doi:10.1038/nature06736 · Cited by 1,111
Microglial cell origin and phenotypes in health and disease
Saijo, K., & Glass, C. K. (2011) · Nature Reviews Immunology · doi:10.1038/nri3086 · Cited by 1,100
Kawahara, T. L. A., Michishita, E., Adler, A. S., Damian, M., Berber, E., Lin, M., McCord, R. A., Ongaigui, K. C. L., Boxer, L. D., Chang, H. Y., et al. (2009) · Cell · doi:10.1016/j.cell.2008.10.052 · Cited by 1,090
Saijo, K., Winner, B., Carson, C. T., Collier, J. G., Boyer, L., Rosenfeld, M. G., Gage, F. H., & Glass, C. K. (2009) · Cell · doi:10.1016/j.cell.2009.01.038 · Cited by 957
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Items 301–400 of 835
NLRP3 inflammasome activation in the thymus of MPTP-induced Parkinsonian mouse model
Wen, L., Zhang, Q.-S., Heng, Y., Chen, Y., Wang, S., Yuan, Y., & Chen, N. (2018) · Toxicology Letters · doi:10.1016/j.toxlet.2018.02.003 · Cited by 35
Cai, B., Seong, K.-J., Bae, S., Kook, M. S., Chun, C., Lee, J. H., Choi, W., Jung, J., & Kim, W.-J. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1496-3 · Cited by 37
Mukherjee-Clavin, B., Mi, R., Kern, B., Choi, I. Y., Lim, H., Oh, Y., Lannon, B. M., Kim, K. J., Bell, S., Hur, J. K., et al. (2019) · Nature Biomedical Engineering · doi:10.1038/s41551-019-0381-8 · Cited by 36
Tinnitus, hearing loss and inflammatory processes in an older Portuguese population
Haider, H. F., Ribeiro, S., Martins, C. G., Ribeiro, D., Trigueiros, N., Szczepek, A. J., Caria, H., Hoare, D. J., Paço, J. C., & Borrego, L. M. (2019) · International Journal of Audiology · doi:10.1080/14992027.2019.1698775 · Cited by 36
“Besides being associated with inflammatory or infectious diseases, changes 68 in circulating levels of IL1 β, IL6 and TNF-α have been associated with aging, exposure 69 to stress, and some neurological disorders (Zhang et al. 2013).”
BackgroundXiang, L., Wu, Q., Osada, H., Yoshida, M., Pan, W., & Qi, J. (2020) · Aging · doi:10.18632/aging.103521 · Cited by 35
“Hypothalamus combatant aging-related health problem is restored via immune-neuroendocrine integration and immune inhibition or gonadotropin-releasing hormones (GnRH) [26].”
BackgroundAdult hypothalamic neurogenesis and sleep–wake dysfunction in aging
Kostin, A., Alam, A., McGinty, D., & Alam, M. N. (2020) · SLEEP · doi:10.1093/sleep/zsaa173 · Cited by 33
Obstructive Sleep Apnea-hypopnea Syndrome as a Novel Potential Risk for Aging
Li, Y., & Wang, Y. (2021) · Aging and Disease · doi:10.14336/ad.2020.0723 · Cited by 37
“contribute to numerous aging-related changes, such as muscle weakness, skin atrophy, bone fragility, and reduced neurogenesis, which indicated a novel association between inflammation and aging [99].”
BackgroundMostafizar, M., Cortes-Pérez, C. M., Snow, W. M., Djordjevic, J., Adlimoghaddam, A., & Albensi, B. C. (2021) · Cells · doi:10.3390/cells10061335 · Cited by 36
“NF-κB-mediated brain inflammation has been linked with both aging and neurodegenerative disorders [40,41], including Alzheimer’s disease (AD) [42], which is a progressive brain disorder that is most prevalent in individuals between 65 and 85 years old [43].”
BackgroundInflammatory cytokines and appetite in older hospitalized patients
Pourhassan, M., Babel, N., Sieske, L., Westhoff, T. H., & Wirth, R. (2021) · Appetite · doi:10.1016/j.appet.2021.105470 · Cited by 35
Understanding the aging hypothalamus, one cell at a time
Hajdarovic, K. H., Yu, D., & Webb, A. E. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.10.004 · Cited by 34
“With age, hypothalamic inflammation increases, and abrogation of inflammation by overexpressing a dominant-negative form of IκB-α which inhibits NF-κB significantly extended lifespan in male mice, although precise effect size was not reported [71].”
BackgroundMetabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus
Mobbs, C. V., Moreno, C. L., & Poplawski, M. M. (2013) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.05.007 · Cited by 34
Disruption of neurogenesis by hypothalamic inflammation in obesity or aging
Purkayastha, S., & Cai, D. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9279-z · Cited by 36
Self-citationMeng, G., Zhong, X., & Mei, H. (2016) · PLoS ONE · doi:10.1371/journal.pone.0150624 · Cited by 34
Reece, A. S., Wang, W., & Hulse, G. K. (2018) · Medical Hypotheses · doi:10.1016/j.mehy.2018.04.011 · Cited by 34
Age-Related Hormones Changes and Its Impact on Health Status and Lifespan
Biagetti, B., & Puig‐Domingo, M. (2023) · Aging and Disease · doi:10.14336/ad.2022.1109 · Cited by 41
“Mouse models’ experiments show that gonadotropic axis has an important role in longevity [22].”
BackgroundEffect of aging on microRNAs and regulation of pathogen recognition receptors
Olivieri, F., Procopio, A. D., & Montgomery, R. R. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.03.006 · Cited by 35
Hughes, B. G., & Hekimi, S. (2016) · Genetics · doi:10.1534/genetics.116.192369 · Cited by 34
Liu, L., An, D., Xu, J., Shao, B., Li, X., & Shi, J. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00076 · Cited by 34
“Blocking endogenous TNF-α, which is mainly generated by microglia (Zhang et al., 2013), significantly reduces focal ischemic brain injury and infarct size (Barone et al., 1997).”
BackgroundAcarbose protects from central and peripheral metabolic imbalance induced by benzene exposure
Debarba, L. K., Mulka, A., de Lima, J. B. M., Didyuk, O., FAKHOURY, P. I., Koshko, L., AWADA, A. A., Zhang, K., Klueh, U., & Sadagurski, M. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.05.073 · Cited by 32
Oh, S.-Y., Jang, M. J., Choi, Y., Hwang, H., Rhim, H., Lee, B., Choi, C. W., & Kim, M. S. (2021) · Scientific Reports · doi:10.1038/s41598-021-88463-6 · Cited by 35
The roles of GnRH in the human central nervous system
Wickramasuriya, N., Hawkins, R. D., Atwood, C., & Butler, T. (2022) · Hormones and Behavior · doi:10.1016/j.yhbeh.2022.105230 · Cited by 43
Programmed ageing: decline of stem cell renewal, immunosenescence, and Alzheimer's disease
Lathe, R., & Clair, D. S. (2023) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12959 · Cited by 37
Adult Neurogenesis in Sheep: Characterization and Contribution to Reproduction and Behavior
Lévy, F., Batailler, M., Meurisse, M., & Migaud, M. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00570 · Cited by 34
“Additionally, a recent study also reported an enhancement of the hypothalamic proliferating activity in aged mice by gonadotropin releasing hormone (Zhang et al., 2013).”
BackgroundLopez de Maturana, R., Aguila, J. C., Sousa, A., Vazquez, N., del Rio, P., Aiastui, A., Gorostidi, A., Lopez de Munain, A., & Sanchez-Pernaute, R. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.11.018 · Cited by 38
Open Genes—a new comprehensive database of human genes associated with aging and longevity
Rafikova, E., Nemirovich-Danchenko, N. M., Ogmen, A., Parfenenkova, A., Velikanova, A., Tikhonov, S., Peshkin, L., Rafikov, K., Spiridonova, O., Belova, Y., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad712 · Cited by 34
Decoster, L., Trova, S., Zucca, S., Bulk, J., Gouveia, A., Ternier, G., Lhomme, T., Legrand, A., Gallet, S., Boehm, U., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01724-1 · Cited by 38
GIT2 Acts as a Systems-Level Coordinator of Neurometabolic Activity and Pathophysiological Aging
Martin, B., Chadwick, W., Janssens, J., Premont, R. T., Schmalzigaug, R., Becker, K. G., Lehrmann, E., Wood, W. H., Zhang, Y., Siddiqui, S., et al. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00191 · Cited by 34
“, the hypothalamus (24), we identified the GPCR-interacting protein GIT2 as a “keystone” of the aging process.”
BackgroundThe connections of Locus Coeruleus with hypothalamus: potential involvement in Alzheimer’s disease
Giorgi, F. S., Galgani, A., Puglisi‐Allegra, S., Busceti, C. L., & Fornai, F. (2021) · Journal of Neural Transmission · doi:10.1007/s00702-021-02338-8 · Cited by 38
“In brief, the retinal-hypothalamic tract, which conveys information on environmental light conditions, reaches the SCN. Neurons belonging to the latter nucleus target GABAergic neurons in the MPO, thus modulating their activity according to circadian rhythm.”
BackgroundResultInfluentialGenetic enhancement: an avenue to combat aging-related diseases
Cai, Y., Ji, Z., Wang, S., Zhang, W., Qu, J. T., Belmonte, J. C. I., & Liu, G. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac054 · Cited by 33
Self-citationNew Horizons: Gonadotropin-Releasing Hormone and Cognition
Prévot, V., Tena‐Sempere, M., & Pitteloud, N. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad319 · Cited by 35
Derous, D., Mitchell, S. E., Green, C. L., Chen, L., Han, J. J., Wang, Y., Promislow, D., Lusseau, D., Speakman, J. R., & Douglas, A. (2016) · Aging · doi:10.18632/aging.100895 · Cited by 34
Nelson, B. S., Black, K. L., & Daniel, J. M. (2016) · eNeuro · doi:10.1523/eneuro.0321-16.2016 · Cited by 32
“The current data support previous work on the effects of GnRH on learning and memory whereby both peripheral and central administration of GnRH to aged male and female mice increased neurogenesis throughout the brain as well as enhanced hippocampus-dependent memory (Zhang et al., 2013).”
ResultTherapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease
Horowitz, A. M., & Villeda, S. (2017) · F1000Research · doi:10.12688/f1000research.11437.1 · Cited by 32
GIT2—A keystone in ageing and age-related disease
van Gastel, J., Boddaert, J., Jushaj, A., Premont, R. T., Luttrell, L. M., Janssens, J., Martin, B., & Maudsley, S. R. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.02.002 · Cited by 32
“It is thus a vital region of the brain in the AC CE PT ED M AN US CR IP T ageing process, since it trophically coordinates both central and peripheral functions (Cong et al., 2012; Stranahan et al., 2012a; Wang et al., 2010; Zhang et al., 2013).”
BackgroundSalehi, A., Loganathan, N., & Belsham, D. D. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2018.08.009 · Cited by 31
“582 Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and 583 GnRH, Nature.”
BackgroundInfluentialGuo, J., Wang, Y., Jiang, P., Yao, H., Zhao, C., Hu, X., Cao, Y., Zhang, N., Fu, Y., & Shen, H. (2019) · Microbial Pathogenesis · doi:10.1016/j.micpath.2019.103792 · Cited by 32
Anti-aging activity and their mechanisms of natural food-derived peptides: current advancements
Li, J., Wang, J., Zhang, N., Li, Y., Cai, Z., Li, G., Liu, Z., Liu, Z., Wang, Y., Shao, X., et al. (2023) · Food Innovation and Advances · doi:10.48130/fia-2023-0028 · Cited by 34
Self-citationProteomic profiling of mitochondria: what does it tell us about the ageing brain?
Ingram, T. L., & Chakrabarti, L. (2016) · Aging · doi:10.18632/aging.101131 · Cited by 33
“In the hypothalamus of mice, inhibition of NF-kB signalling in microglia was capable of extending lifespan [120].”
BackgroundDysregulation of BDNF in Prefrontal Cortex in Alzheimer’s Disease
Aarons, T., Bradburn, S., Robinson, A., Payton, A., Pendleton, N., & Murgatroyd, C. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190049 · Cited by 31
Aging-related modifications to G protein-coupled receptor signaling diversity
van Gastel, J., Leysen, H., Boddaert, J., Vangenechten, L., Luttrell, L. M., Martin, B., & Maudsley, S. R. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107793 · Cited by 32
Friends and foes: Extracellular vesicles in aging and rejuvenation
Lananna, B. V., & Imai, S. (2021) · FASEB BioAdvances · doi:10.1096/fba.2021-00077 · Cited by 30
Hypothalamic microinflammation
Cai, D., & Khor, S. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-820683-6.00023-3 · Cited by 33
Self-citationKhoshnan, A., Sabbaugh, A., Calamini, B., Marinero, S., Dunn, D., Yoo, J. H., Ko, J., Lo, D. C., & Patterson, P. H. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx315 · Cited by 30
SGK1/FOXO3 Signaling in Hypothalamic POMC Neurons Mediates Glucocorticoid-Increased Adiposity
Deng, Y., Xiao, Y., Yuan, F., Liu, Y., Jiang, X., Deng, J., Fejes‐Tóth, G., Náray‐Fejes‐Tóth, A., Chen, S., Chen, Y., et al. (2018) · Diabetes · doi:10.2337/db17-1069 · Cited by 32
Role of Glial Immunity in Lifespan Determination: A Drosophila Perspective
Kounatidis, I., & Chtarbanova, S. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01362 · Cited by 35
Saha, P., Ajgaonkar, S., Maniar, D., Sahare, S., Mehta, D. S., & Nair, S. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1370951 · Cited by 29
Immune aging and infectious diseases
Chen, R., Zou, J., Chen, J., Wang, L., Kang, R., & Tang, D. (2024) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003410 · Cited by 35
Androgen receptors and experimental bone loss — an in vivo and in vitro study
Steffens, J. P., Coimbra, L. S., Rossa, C., Kantarcı, A., Dyke, T. E. V., & Spolidório, L. C. (2015) · Bone · doi:10.1016/j.bone.2015.10.001 · Cited by 30
The Association of Inflammation with Food Intake in Older Hospitalized Patients
Pourhassan, M., Böttger, S., Janssen, G., Sieske, L., & Wirth, R. (2017) · The journal of nutrition health & aging · doi:10.1007/s12603-017-0976-2 · Cited by 30
Sarahian, N., Sarvazad, H., Sajadi, E., Rahnejat, N., & Eskandari Roozbahani, N. (2021) · Reproductive Health · doi:10.1186/s12978-021-01203-x · Cited by 30
Age-Dependent Neurochemical Remodeling of Hypothalamic Astrocytes
Santos, C. L., Roppa, P. H. A., Chiarello, P. T., Fontella, F. U., Souza, D. O., Bobermin, L. D., & Quincozes‐Santos, A. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0786-x · Cited by 34
FitzPatrick, L. M., Hawkins, K., Delhove, J. M. K. M., Fernández, E., Soldati, C., Bullen, L. F., Nohturfft, A., Waddington, S. N., Medina, D. L., Bolaños, J. P., et al. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.03.015 · Cited by 30
“…models have impli- 1766 Stem Cell Reports j Vol. 10 j 1766–1781 j June 5, 2018 j ª 2018 The A This is an open access article under the CC BY-NC-ND license (http://creativ cated NF-kB activation in NSC commitment (Denis-Donini et al., 2008; Li et al., 2012; Rolls et al., 2007; Zhang et al., 2013b).”
BackgroundThinking outside the brain for cognitive improvement: Is peripheral immunomodulation on the way?
Zheng, X., Zhang, X., An, K., Ran, C., Wang, G., & Hao, H. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.06.020 · Cited by 29
“Amore recent studyalso showed that nuclear factor-kappaB (NF-kB) activation in the hypothalamus mediated the development of systemic aging in mice (Zhang et al., 2013), which may form a vicious cycle with the central pathology to drive cognitive decline.”
Ursolic acid regulates aging process through enhancing of metabolic sensor proteins level
Bahrami, S. A., & Bakhtiari, N. (2016) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2016.04.047 · Cited by 31
Sexual dimorphism of frailty and cognitive impairment: Potential underlying mechanisms
Ruan, Q., D’Onofrio, G., Wu, T., Greco, A., Sancarlo, D., & Yu, Z. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.6988 · Cited by 30
“Inflammatory and stress responses may activate nuclear factor (NF)- κ B in the hypothalamus and induce a signaling pathway that results in a reduction in the neuronal production of gonadotropin-releasing hormone (GnRH) (73).”
Ball, H. C., levari-Shariati, S., Cooper, L. N., & Aliani, M. (2018) · PLoS ONE · doi:10.1371/journal.pone.0196154 · Cited by 32
Bai, X. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1117-8_14 · Cited by 32
Prévot, V., & Sharif, A. (2022) · Journal of Neuroendocrinology · doi:10.1111/jne.13104 · Cited by 33
Xue, W., Yang, Q., Chen, Y., Zou, R.-X., Xing, D. M., Xu, Y., Liu, Y., & Wang, H. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/5645324 · Cited by 30
Probiotics- its functions and influence on the ageing process: A comprehensive review
Choudhary, P., Kathuria, D., Suri, S., Bahndral, A., & Naveen, A. K. (2023) · Food Bioscience · doi:10.1016/j.fbio.2023.102389 · Cited by 36
Pangrazzi, L., & Meryk, A. (2024) · Biology · doi:10.3390/biology14010017 · Cited by 32
“This persistent NF-κ B activation leads to increased production of pro-inflammatory cytokines and chemokines, further exacerbating the inflammatory state [48,49].”
Gulej, R., Patai, R., Ungvari, A., Kállai, A., Tarantini, S., Yabluchanskiy, A., Huffman, D. M., Conboy, M. J., Conboy, I. M., Mika Kivimaki, B., et al. (2025) · GeroScience · doi:10.1007/s11357-025-01657-y · Cited by 29
Miyazaki, Y., Kaneko, K., Iguchi, S., Mizushige, T., Kanamoto, R., Yoshikawa, M., Shimizu, T., & Ohinata, K. (2014) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201400100 · Cited by 28
Sleep and ageing: from human studies to rodent models
McKillop, L. E., & Vyazovskiy, V. V. (2020) · Current Opinion in Physiology · doi:10.1016/j.cophys.2020.03.004 · Cited by 31
Changes of nNOS expression in the tuberal hypothalamic nuclei during ageing
Moiseev, K. Y., Vishnyakova, P. A., Порсева, В. В., Masliukov, A. P., Spirichev, A. A., Emanuilov, A. I., & Masliukov, P. M. (2020) · Nitric Oxide · doi:10.1016/j.niox.2020.04.002 · Cited by 28
Identifying Isl1 Genetic Lineage in the Developing Olfactory System and in GnRH-1 Neurons
Taroc, E. Z. M., Katreddi, R. R., & Forni, P. E. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.601923 · Cited by 23
FoxO6 inhibits cell proliferation in lung carcinoma through up-regulation of USP7
HU, H.-J., Zhang, L., Wang, Z., & GUO, X.-X. (2012) · Molecular Medicine Reports · doi:10.3892/mmr.2015.3362 · Cited by 28
“To further analyze whether downregulation of FOXO6 was NF-κ B/p65-dependent, the A549 cells were transfected with dominant negative IkB α , which inhibits the translocation of p65 from the cytoplasm to the nucleus (15).”
Jat, P., Perkins, N. D., & Mowla, S. N. (2013) · OncoTargets and Therapy · doi:10.2147/ott.s36160 · Cited by 33
“preventing aging-related hypothalamic IKKβ and NF-κB activation, which normally inhibit gonadotropin-releasing hormone (GnRH).(71) It is currently thought that genotoxic stress activates the NF-κB pathway, in mice, by stimulating Poly [ADP-ribose] polymerase 1 (PARP-1) and ATM, which induces the synthesis of poly aden…”
BackgroundInvolvement of NF-κBIZ and related cytokines in age-associated renal fibrosis
Chung, K. W., Jeong, H. O., Lee, B., Park, D., Kim, D. H., Choi, Y. J., Lee, E. K., Kim, K. M., Park, J. W., Yu, B. P., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.14614 · Cited by 28
“Previous studies have revealed the importance of NF-κB in the aging process, especially in aged kidneys [20] and brain [28].”
BackgroundGlucose-Induced Transcriptional Hysteresis: Role in Obesity, Metabolic Memory, Diabetes, and Aging
Mobbs, C. V. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00232 · Cited by 30
Choi, J., Choi, S.-Y., Hong, Y., Han, Y., Oh, S., Lee, B., Choi, C. W., & Kim, M. S. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114812 · Cited by 29
Metcalfe, S. M., Bickerton, S., & Fahmy, T. M. (2017) · Current Pharmaceutical Design · doi:10.2174/1381612822666161206141744 · Cited by 27
“A second highlight publication plus accompanying N&V article provides evidence of how inflammation in the periphery is sensed by the brain during aging [13, 14].”
BackgroundZhang, W., Jia, L., Cai, G., Shao, F., Lin, H., Liu, Z., Liu, F., Zhao, D., Li, Z., Bai, X., et al. (2017) · The journal of nutrition health & aging · doi:10.1007/s12603-017-0874-7 · Cited by 27
Recent insights into the cellular and molecular determinants of aging
Ruan, L., Zhang, X., & Li, R. (2018) · Journal of Cell Science · doi:10.1242/jcs.210831 · Cited by 28
“…function in aged mice Castellano et al., 2017 GnRH Injection of GnRH to old mice Promote adult neurogenesis at hypothalamus and hippocampus Zhang et al., 2013 GDF11 Daily injection of GDF11 to old mic Enhance neurogenesis Katsimpardi et al., 2014 REST Conditional knockout in the mouse…”
BackgroundSantos, C. L., Bobermin, L. D., Souza, D. O., & Quincozes‐Santos, A. (2018) · Metabolic Brain Disease · doi:10.1007/s11011-018-0311-6 · Cited by 27
Organelle aging: Lessons from model organisms
Bouska, M. J., Huang, K., Kang, P., & Bai, H. (2019) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2019.03.011 · Cited by 27
“…are involved in nutrition and metabolic pathways (Kenyon et al., 1993; Tatar et al., 2001; Kaeberlein et al., 2005), stress response (Hsu et al., 2003; Morley and Morimoto, 2004; Tullet et al., 2008), inflammatory signaling (Zhang et al., 2013), and epigenetic regulation (Rogina et al., 2002).”
BackgroundHypothalamic NAD+-Sirtuin Axis: Function and Regulation
Roh, E., & Kim, M. (2020) · Biomolecules · doi:10.3390/biom10030396 · Cited by 30
“Recently, it has also been suggested as an important area for dictating systemic aging processes [3].”
BackgroundRole of mitochondrial DNA in diabetes Mellitus Type I and Type II
Al-Ghamdi, B. A., Al-Shamrani, J. M., El‐Shehawi, A. M., Al-Johani, I., & Al-Otaibi, B. G. (2022) · Saudi Journal of Biological Sciences · doi:10.1016/j.sjbs.2022.103434 · Cited by 31
Novel Lys63-linked ubiquitination of IKKβ induces STAT3 signaling
Gallo, L. H., Meyer, A. N., Motamedchaboki, K., Nelson, K. N., Haas, M., & Donoghue, D. J. (2014) · Cell Cycle · doi:10.4161/15384101.2014.988026 · Cited by 28
Leite, M. R., Cechella, J. L., Pinton, S., Nogueira, C. W., & Zeni, G. R. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.05.006 · Cited by 27
Modulating adult neurogenesis through dietary interventions
Heberden, C. (2016) · Nutrition Research Reviews · doi:10.1017/s0954422416000081 · Cited by 27
“Recently, a study by Zhang et al.(47) showed that inflammation in the hypothalamus increases with age, as measured by NF-κB activation in the microglia; this ageing process negatively regulated gonadotropin-releasing hormone (GnRH) synthesis, and GnRH delivery into the third ventricle could reverse age-induced neuroge…”
Harnessing cellular aging in human stem cell models of amyotrophic lateral sclerosis
Ziff, O. J., & Patani, R. (2018) · Aging Cell · doi:10.1111/acel.12862 · Cited by 27
“Recognition that mouse aging involves the loss of hypothalamic stem cells inspired ablation studies which consistently led to accelerated aging and lifespan shortening (Zhang et al., 2013, 2017).”
BackgroundRejuvenating Strategies of Tissue-specific Stem Cells for Healthy Aging
Wang, M., Chen, J., Chen, F., Liu, Q., Sun, Y., Chen, Y., Yang, T., Bao, Y., & Hu, Y. (2018) · Aging and Disease · doi:10.14336/ad.2018.1119 · Cited by 27
Sex hormone replacement therapy in periodontology—A systematic review
Chaves, J. D. P., Figueredo, T. F. M., Warnavin, S. V. S. C., Pannuti, C. M., & Steffens, J. P. (2019) · Oral Diseases · doi:10.1111/odi.13059 · Cited by 27
17-α-Estradiol Has Sex-Specific Effects on Neuroinflammation That Are Partly Reversed by Gonadectomy
Debarba, L. K., Jayarathne, H. S. M., Miller, R. A., Garratt, M., & Sadagurski, M. (2021) · The Journals of Gerontology Series A · doi:10.1093/gerona/glab216 · Cited by 27
GnRH pulse frequency and irregularity play a role in male aging
Wang, Z., Wu, W., Kim, M. S., & Cai, D. (2021) · Nature Aging · doi:10.1038/s43587-021-00116-5 · Cited by 30
Self-citationWang, C., Zhang, H., Fan, J., Li, Q., Guo, R., Pan, J., Liu, Y., Peng, J., Zhu, Q., Feng, Y., et al. (2022) · Neuro-Oncology · doi:10.1093/neuonc/noac261 · Cited by 26
Self-citationHypothalamic Menin regulates systemic aging and cognitive decline
Leng, L., Yuan, Z., Su, X., Chen, Z., Yang, S., Chen, M., Zhuang, K., Lin, H. Z., Sun, H., Li, H., et al. (2023) · PLoS Biology · doi:10.1371/journal.pbio.3002033 · Cited by 26
Sustained NF κB inhibition improves insulin sensitivity but is detrimental to muscle health
Zhang, N., Valentine, J. M., Zhou, Y., Li, M. E., Zhang, Y., Bhattacharya, A., Walsh, M. E., Fischer, K. E., Austad, S. N., Osmulski, P. A., et al. (2017) · Aging Cell · doi:10.1111/acel.12613 · Cited by 26
“…mutant in mice had global anti-aging effects, including prolonging lifespan, improving cognition, and increasing dermal thickness, bone density, muscle size, exercise endurance, and tendon resistance, whereas overexpression of constitutively active IKKb had opposite effects (Zhang et al., 2013).”
BackgroundNuruddin, S., Skaaraas, G. H. E. S., Lillehaug, S., Leergaard, T. B., Nilsson, L. N. G., Ropstad, E., Krogenæs, A., Haraldsen, I., & Torp, R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103607 · Cited by 27
“Furthermore, Gnrh agonist therapy has been shown to decelerate aging in animals [8] and reduce the risk of developing AD in prostate cancer patients [9].”
BackgroundMolecular footprint of Medawar’s mutation accumulation process in mammalian aging
Turan, Z. G., Parvizi, P., Dönertaş, H. M., Tung, J., Khaitovich, P., & Somel, M. (2019) · Aging Cell · doi:10.1111/acel.12965 · Cited by 28
“(Salminen et al., 2012; Zhang et al., 2013)).”
Loss of Chondroitin Sulfate Modification Causes Inflammation and Neurodegeneration in skt Mice
Macke, E. L., Henningsen, E., Jessen, E., Zumwalde, N. A., Landowski, M., Western, D., Russell, W. L., Liu, C., Gruenke, N. P., Doebley, A.-L., et al. (2019) · Genetics · doi:10.1534/genetics.119.302834 · Cited by 25
“…which is also observed in multiple age-related diseases such as cardiovascular disease, diabetes, cancer, and neurodegenerative diseases (Danesh et al. 2000; Duncan et al. 2003; van Greevenbroek et al. 2013; Pereira and Alvarez-Leite 2014; Chen and Xu 2015; Zhao et al. 2015; Kempuraj et al. 2016).”
BackgroundCytosolic Self-DNA—A Potential Source of Chronic Inflammation in Aging
Akbari, M., Shanley, D. P., Bohr, V. A., & Rasmussen, L. J. (2021) · Cells · doi:10.3390/cells10123544 · Cited by 25
Bonetto, V., & Grilli, M. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1187263 · Cited by 26
“, miR-335-3p, miR-192 ↓NF-κB activation, restored GnRH secretion in hypothalamus and control of ageing speed (Zhang et al., 2013)”
BackgroundSadagurski, M., Landeryou, T., Cady, G., Bartke, A., Bernal‐Mizrachi, E., & Miller, R. A. (2015) · Physiological Reports · doi:10.14814/phy2.12379 · Cited by 25
“Aging-related activation of NF-kB signaling in brain or hypothalamus can extend lifespan (Zhang et al. 2013) and our results support the idea that reduction in inflammatory pathways in the hypothalamus may contribute to the slow aging process of CL mice.”
BackgroundMethodInfluentialInfluence of age, irradiation and humanization on NSG mouse phenotypes
Knibbe, J., Fields, N., Chaudoin, T. R., Epstein, A. A., Makarov, E., Akhter, S. P., Gorantla, S., Bonasera, S. J., Gendelman, H. E., & Poluektova, L. Y. (2015) · Biology Open · doi:10.1242/bio.013201 · Cited by 25
Application of biological age assessment of Chinese population in potential anti-ageing technology
Li, X., Zhang, J., Sun, C., Zhang, Y., Cai, R., Fu, S., Zheng, J., & Huang, D. (2018) · Immunity & Ageing · doi:10.1186/s12979-018-0140-9 · Cited by 24
The role of non-neuronal cells in hypogonadotropic hypogonadism
Smedlund, K., & Hill, J. W. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.110996 · Cited by 26
“GnRH release is decreased after NF-κB activation in immortalized GnRH neurons (Zhang et al., 2013).”
BackgroundNeural Progenitor Cells and the Hypothalamus
Makrygianni, E. A., & Chrousos, G. P. (2023) · Cells · doi:10.3390/cells12141822 · Cited by 30
“By contrast, high molecular weight molecules, such as several protein hormones and cytokines, are not able to freely enter the CVOs but instead utilize transcytosis systems at the BBB [336,338].”
BackgroundInfluentialTargeting immunosenescence for improved tumor immunotherapy
Liu, Z., Zuo, L., Zhou, Z., Liu, S., Ba, Y., Zuo, A., Ren, Y., Zhang, C., Chen, Y., Ma, H., et al. (2024) · MedComm · doi:10.1002/mco2.777 · Cited by 24
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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