#1

A new paper by Richard Miller’s group. Unfortunately paywalled. Please post if you can get the full paper.

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.

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#2

Here you go @RapAdmin

s11357-024-01466-9.pdf (3.3 MB)

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#3

Awesome - thanks!

Rapamycin, which extends lifespan in male and female mice, acts as an immunosuppressant and diminishes inflammation by inhibiting production of inflammatory cytokines including IL-6 and TNF-α in macrophages and T helper cells tested in vitro and suppressing T-cell proliferation [10–12]. In vivo, rapamycin downregulated inflammatory markers TNF-α and COX-2 in the liver [13]. Previous data from our lab have shown a consistent decline in hepatic MAPK-p38 phosphorylation, an upstream activator of various pro-inflammatory pathways, including NF-κB, in long-lived mice treated with rapamycin, acarbose, and 17α-estradiol [14].

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#4

Quite a few molecules suppress p65, including statins like pitavastatin in the liver - here is a study in rats, so caveat:

Quote:

“The hepatoprotective efficacy of Pit was associated with the upregulation of Nrf2/HO‐1 and downregulation of NF‐κB and PI3K/Akt signalling pathways.”

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#5

It’s a nice paper, and I’m not surprised that NF-KB is inhibited by so many anti-aging interventions (it’s considered the ‘master’ transcriptional regulator of inflammation).

For people into psychedelics, it’s interesting that some potently suppress TNF-a/TNFR signalling (TNFR is probably the most important transmembrane receptor in NF-KB activation). DOI in particular, can inhibit TNF-a signalling with low picomolar potency, which is pretty crazy (the psychedelic effects are already very potent with low nanomolar potency and doses in the single milligram range, so the anti-inflammatory effects are ~1,000 times more potent).

When I dealt with a severe case of gastritis from 2019 to 2022, one of the few things that alleviated my symptoms during that time was psychedelics, which I attributed to an anti-inflammatory effect. Not all psychedelics helped (LSD and 5-MeO-MiPT did for example, while DMT had no such effect), and my symptoms would generally improve about 24 hrs after tripping, with the improvement lasting somewhere between 3-7 days.

Charles Nichols (son of David Nichols, the godfather of psychedelic pharmacology) has done and continues to do much of research in this space. His lab published a paper this year suggesting that the mechanism involves suppression of arginase-1 (which some might recognize as a key enzyme in the Urea cycle/nitrogen metabolism).

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#6

Yes, quite a few supplements we talk about in the forum downregulate NF‐κB. Examples include astragalus, berberine, baicalin, boswellia, punicic acid, sulforaphane, L. reuteri. Additionally, chronic stress upregulates NF‐κB.

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#7

Targeting inflammaging at its roots

This study, published in the Nature journal Experimental & Molecular Medicine, begins with a discussion of age-related chronic inflammation (inflammaging) and its contributions to aging. Specifically, the researchers focus on neuroinflammation, which occurs when age-affected brain microglia begin sending out pro-inflammatory signals, particularly the cytokine NF-κB [1]. While considerable research has elucidated many of the fundamental reasons why this signaling occurs [2], treatments have remained elusive.

NF-κB, in particular, has been well documented; many papers on age-related diseases have pinpointed it as a problem and potential target [3]. However, while these researchers have noted that despite the existence of more than 700 NF-κB inhibitors in the laboratory, there is not a single one that has gone through the clinical trial process.

These researchers’ candidate is a variant of a known natural inhibitor, IκB. Replacing two of its amino acids prevents this protein from being degraded by cells as the natural version would be; this engineered super-repressor is termed srIκB, and it is intended to linger in the cellular cytoplasm and inhibit NF-κB in a long-lasting way.

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