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Downregulation of the NF-κB protein p65 is a shared phenotype among most anti-aging interventions
Ahmed M Elmansi1,2, Abraham Kassem1, Rafael M Castilla1
1Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Abstract:
Many aspects of inflammation increase with aging in mice and humans. Transcriptomic analysis revealed that many murine anti-aging interventions produce lower levels of pro-inflammatory proteins. Here, we explore the hypothesis that different longevity interventions diminish NF-κB levels, potentially mediating some of the anti-inflammatory benefits of lifespan-extending interventions. We found that the NF-κB protein p65 is significantly downregulated in the liver of several kinds of slow-aging mice. These included both sexes of GHRKO and Snell Dwarf mutant mice, and in females only of PAPPA KO mice. P65 is also lower in both sexes of mice treated with rapamycin, canagliflozin, meclizine, or acarbose, and in mice undergoing caloric restriction. Two drugs that extend lifespan of male mice, i.e. 17α-estradiol and astaxanthin, however, did not produce lower levels of p65. We also measured other canonical NF-κB signaling regulators, including the activators IKKα and IKKβ and the inhibitor IκB-α. We found that those regulators do not consistently change in a direction that would lead to of NF-κB inhibition. In contrast, we found that NCoR1, an HDAC3 cofactor and a transcription co-repressor that regulates p65 activity, was also downregulated in many of these mouse models. Finally, we report downregulation of three p65 target proteins that regulate the metabolic and inflammatory states of the liver (HNF4α, IL-1β, and CRP) in multiple slow-aging mouse models. Together, these data suggest that NF-κB signaling, might be inhibited in liver of multiple varieties of slow aging mice. This establishes p65 as a potential target for novel longevity interventions.
Insights
Aging increases inflammation. Longevity interventions may reduce inflammation by lowering nuclear factor-kappa B (NF-κB) levels, particularly the p65 protein, in the liver, suggesting a new target for anti-aging therapies.
Area of Science:
- Gerontology
- Molecular Biology
- Immunology
Background:
- Inflammation is a hallmark of aging in both mice and humans.
- Transcriptomic studies indicate that anti-aging interventions reduce pro-inflammatory proteins.
- The role of NF-κB signaling in the anti-inflammatory effects of longevity interventions requires further investigation.
Purpose of the Study:
- To test the hypothesis that longevity interventions reduce NF-κB levels, mediating anti-inflammatory benefits.
- To investigate the expression of NF-κB subunit p65 and other signaling regulators in various mouse models of slow aging.
- To identify potential molecular targets for novel longevity interventions.
Main Methods:
- Analysis of NF-κB p65 protein levels in the liver of different slow-aging mouse models (GHRKO, Snell Dwarf, PAPPA KO).
- Assessment of p65 levels in mice treated with lifespan-extending drugs (rapamycin, canagliflozin, meclizine, acarbose, 17α-estradiol, astaxanthin) and caloric restriction.
- Measurement of other NF-κB pathway components (IKKα, IKKβ, IκB-α), NCoR1, and p65 target proteins (HNF4α, IL-1β, CRP).
Main Results:
- NF-κB p65 was significantly downregulated in the liver of GHRKO and Snell Dwarf mice (both sexes) and PAPPA KO mice (females).
- p65 levels were reduced in mice treated with rapamycin, canagliflozin, meclizine, acarbose, and those on caloric restriction.
- NCoR1 and p65 target genes (HNF4α, IL-1β, CRP) were also downregulated in several slow-aging models, while other NF-κB regulators showed inconsistent changes.
Conclusions:
- NF-κB signaling, specifically the p65 subunit, appears to be inhibited in the liver of multiple slow-aging mouse models.
- Downregulation of NCoR1 and key p65 target proteins further supports NF-κB inhibition.
- NF-κB p65 represents a potential therapeutic target for interventions aimed at promoting longevity and reducing age-related inflammation.
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