NF-κB
The transcriptional master switch of chronic inflammation and inflammaging
Definition
NF-κB (nuclear factor kappa B) is a transcription factor controlling expression of hundreds of genes related to inflammation, immune response, cellular proliferation, and survival. Its chronic activation is the central mechanism of inflammaging — the low-grade systemic inflammation that defines ageing — and is implicated in virtually all chronic diseases: atherosclerosis, type 2 diabetes, cancer, neurodegeneration, autoimmunity, and sarcopenia.
Detailed explanation
NF-κB regulation: at rest, it is retained in the cytoplasm bound to its inhibitor IκB. Upon stimulus (bacterial LPS, cytokines, ROS, tissue damage), IKK phosphorylates IκB, which is degraded, and NF-κB translocates to the nucleus, binds DNA, and activates transcription of pro-inflammatory genes: IL-6, IL-1β, TNF-α, COX-2, iNOS, adhesion molecules, and metalloproteinases.
Chronic activation with age: cellular senescence, intestinal dysbiosis with endotoxemia, mitochondrial free radicals, AGEs, and accumulated DNA damage continuously activate NF-κB. The resulting signalling maintains a state of chronic low-grade inflammation — the common pathological substrate of ageing.
Evidence-based natural NF-κB inhibitors: SIRT1 activation (NAD+, resveratrol): deacetylates the p65 subunit, inhibiting its transcriptional activity. Polyphenols: curcumin (potent direct inhibitor), EGCG from green tea, quercetin, sulforaphane. Omega-3 fatty acids: reduce IKK activation. Spermidine and autophagy: autophagy degrades inflammasome components. Regular exercise: chronic anti-inflammatory effect (basal IL-6 reduction).
Controlled NF-κB inhibition is one of the central goals of healthspan — not total blockade (which would compromise immunity), but normalisation of its chronically elevated tone due to ageing.
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