Hypothalamic Programming of Systemic Aging Involving IKKβ/NF-κB and GnRH

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Summary

Aging is a result of gradual and overall functional deteriorations across the body; however, it is unknown if an individual tissue works to primarily mediate aging progress and lifespan control. Here we found that the hypothalamus is important for the development of whole-body aging in mice, and the underlying basis involves hypothalamic immunity mediated by IKKβ/NF-κB and related microglia-neuron immune crosstalk. Several interventional models were developed showing that aging retardation and lifespan extension are achieved in mice through preventing against aging-related hypothalamic or brain IKKβ/NF-κB activation. Mechanistic studies further revealed that IKKβ/NF-κB inhibits GnRH to mediate aging-related hypothalamic GnRH decline, and GnRH treatment amends aging-impaired neurogenesis and decelerates aging. In conclusion, the hypothalamus has a programmatic role in aging development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating aging-related health problems.

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Most cited references 46

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Inflammation is associated with many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In this Review, we discuss inducers, sensors, transducers, and effectors of neuroinflammation that contribute to neuronal dysfunction and death. Although inducers of inflammation may be generated in a disease-specific manner, there is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators. A major unanswered question is whether pharmacological inhibition of inflammation pathways will be able to safely reverse or slow the course of disease. 2010 Elsevier Inc. All rights reserved.

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Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

David Harrison, Randy Strong, Zelton Sharp … (2009)

Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruit flies1–5. However, whether inhibition of mTOR signalling can extend life in a mammalian species was unknown. We report here that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. Based on age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. These are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.

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Yasumasa Yoshiyama, Makoto Higuchi, Bin Zhang … (2007)

Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, but earlier pathologies may herald disease onset. To investigate this, we studied wild-type and P301S mutant human tau transgenic (Tg) mice. Filamentous tau lesions developed in P301S Tg mice at 6 months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age. Remarkably, hippocampal synapse loss and impaired synaptic function were detected in 3 month old P301S Tg mice before fibrillary tau tangles emerged. Prominent microglial activation also preceded tangle formation. Importantly, immunosuppression of young P301S Tg mice with FK506 attenuated tau pathology and increased lifespan, thereby linking neuroinflammation to early progression of tauopathies. Thus, hippocampal synaptic pathology and microgliosis may be the earliest manifestations of neurodegenerative tauopathies, and abrogation of tau-induced microglial activation could retard progression of these disorders.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 24 June 2013

Publication date (Electronic): 01 May 2013

Publication date (Print): 9 May 2013

Publication date PMC-release: 09 November 2013

Volume: 497

Issue: 7448

Pages: 211-216

Affiliations

[1 ]Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461

[2 ]Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461

[3 ]Institute of Aging, Albert Einstein College of Medicine, Bronx, NY 10461

Author notes

[* ]Address correspondence to: Dongsheng Cai, M.D., Ph.D., Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, Phone: 718-430-2426, Fax: 718-430-2433, dongsheng.cai@ 123456einstein.yu.edu

[4]

These authors equally contributed to this work.

Article

Manuscript ID: NIHMS463346

DOI: 10.1038/nature12143

PMC ID: 3756938

PubMed ID: 23636330

SO-VID: 1f2e8375-1e64-475d-8e25-1d83c852598d

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Funding

Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK

Award ID: R01 DK078750 || DK

Funded by: National Institute on Aging : NIA

Award ID: R01 AG031774 || AG

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Hypothalamic Programming of Systemic Aging Involving IKKβ/NF-κB and GnRH

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Aging Pathobiology and Therapeutics

Most cited references 46

Mechanisms underlying inflammation in neurodegeneration.

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model.

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Cited by 334

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