NF-κB

What it is

NF-κB (nuclear factor kappa B) is a transcription-factor family (p65/RelA, p50, p52, c-Rel, RelB) that responds to pathogens, cytokines, DNA damage, and reactive oxygen species. It drives expression of pro-inflammatory cytokines, adhesion molecules, and survival factors.

Why it matters in aging

NF-κB activity rises with age across tissues. Persistent activation is the central driver of:

• Inflammaging (Chronic inflammation).
• SASP secreted by senescent cells.
• Atherosclerosis progression.
• Cancer survival pathways.
• Neurodegeneration via microglial activation.

Cross-talk

• SIRT1 deacetylates p65 to silence NF-κB.
• AMPK opposes NF-κB; mTOR amplifies it.
• NLRP3 inflammasome activation feeds NF-κB output.

What modulates it

Most "anti-inflammatory" interventions act partly through NF-κB suppression: exercise, omega-3 fatty acids, polyphenols, statins, GLP-1 agonists, colchicine.

Clinical translation

NF-κB pathway inhibition has been extensively pursued in oncology and inflammatory disease, though systemic inhibitors have been plagued by immunosuppression and toxicity. For longevity, the approach is generally not to inhibit NF-κB outright but to reduce upstream drivers (senescent-cell burden, TNF-α, IL-1β).

Key upstream drivers relevant to aging

• Senescence-associated secretory phenotype (SASP) amplifies NF-κB activation both autocrine and paracrine.
• Damage signals (DAMPs, PAMPs) from failing cells drive TLR- and NLRP3-mediated NF-κB activation.
• Mitochondrial DNA leak into the cytosol activates cGAS-STING → NF-κB.

Interventions that dampen NF-κB indirectly

• Rapamycin via mTOR inhibition.
• Senolytics by removing SASP sources.
• Anti-IL-1β agents (canakinumab in CANTOS trial).
• Anti-inflammatory diet patterns.

Related entries

Chronic inflammation, Cellular senescence, cGAS-STING.

Related entries

Chronic inflammation, Cellular senescence, hsCRP.