Julian West
posted 7 months ago

NLRP3 - Aging and Chronic Inflammation (beyond Senescent Cells)

LongevityCell BiologyPharmacologyInflammasomes IL-1β IL-18 Life123 CANTOS BioAge Labs Inflammation Inflammaging NLRP3 Pyroptosis Healthspan

Every poignant dramatic story has an arch-villain. The aging process has many! A well-known one is chronic inflammation - sometimes referred to as "Inflammaging" (the vicious cycle between inflammation and aging.)

An often-discussed source of chronic inflammation are senescent cells - but they aren't the only one. The NLRP3 inflammasome (shown in the image) is believed to play an important role, too. I think it looks like a classical Corinthian-style Greek column, which I inserted into the screen shot from an awesome brief animation by the University of Queensland Institute for Molecular Bioscience , which shows how its components come together: https://www.youtube.com/watch?v=2812ion3aUk

Not only is the inflammasome elegant, but it normally plays a positive role in fighting infection and injury: like a "volunteer fire brigade" of olden times, the components that make up the structure of the inflammasome come together as needed. BUT if its regulation goes haywire, then it's like a rogue fire brigade that douses everything with water, well after the fire is gone!

The net result includes the production of pro-inflammatory cytokines interleukin IL-1β and IL-18, as well as pyroptosis (cell suicide): all those actions stir up into action the innate (non-specific) immune system. Well, that's excellent when there's an infection or injury - but toxic when there's no reason for it!

One of the components of this inflammasome is an activated form of the NLRP3 protein.

The thinking is, intervene against the NLRP3 protein, and take out the chronic inflammation (i.e. turn off the over-active NLRP3 inflammasome.)

Various inhibitors are known against NLRP3, and more are being developed. One company working on that is the Longevity-Science company BioAge Labs : they provide excellent infographics at https://bioagelabs.com/nlrp3 . Very recently, on Oct. 13, they announced that they will present updates on their NLRP3 inhibitor program at three upcoming conferences; in particular, they promised a "family of potent, structurally differentiated NLRP3 inhibitors".(https://www.businesswire.com/news/home/20221013005356/en/BioAge-Labs-to-Present-Data-on-Novel-Brain-Penetrant-NLRP3-Inhibitors-for-Treatment-of-Neurodegeneration-and-Brain-Aging-at-Upcoming-Conferences)

At the first of those conferences, the VP of BioAge Labs, Rusty Montgomery, said:

Our analyses showed that NLRP3 levels rise with age and correlate positively with mortality and cognitive decline. We have synthesized new compounds that inhibit NLRP3 inflammasome in vitro and in vivo, are as or more potent than known NLRP3 inhibitors, have novel structures and chemical properties, and penetrate the blood-brain barrier. (https://www.discoveryontarget.com/neurodegeneration-targets)

MORE INFO

  • A 2022 paper that I think is one of the more readable ones on the subject, and with excellent diagrams: "NLRP3 Inflammasome in Vascular Disease: A Recurrent Villain to Combat Pharmacologically" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8868353). In particular, it describes the clinical trial CANTOS, which demonstrated that "the inhibition of one of the main products of NLRP3 inflammasome activation, IL-1β, can diminish the risk of major cardiovascular events".
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