Chronic
Inflammation
“Inflammaging” — the slow-burning systemic inflammation that accumulates with age — predicts cardiovascular events, cancer risk, and cognitive decline more reliably than almost any other single biomarker.
The Mechanism
NF-κB — the master inflammatory switch of aging
Inflammaging has five converging sources. SASP from senescent cells is the largest — secreting IL-6, IL-1β, and TNF-α continuously into surrounding tissue. Gut permeability allows bacterial LPS to enter circulation, triggering TLR4/NF-κB. Mitochondrial ROS activate the NLRP3 inflammasome, producing IL-1β. Immune senescence(exhausted T-cells, skewed macrophages) impairs resolution. Visceral adiposeacts as a SASP-like endocrine organ.
The convergence point is NF-κB. It integrates all these signals and transcribes the inflammatory gene program: COX-2 (prostaglandins), iNOS (nitric oxide), IL-6, IL-1β, TNF-α, and MMP-3/9 (ECM-degrading). Targeting NF-κB upstream — via NRF2, SIRT1, or SPM precursors — is more durable than targeting individual cytokines downstream.
hs-CRP is the clinical readout. C-reactive protein is produced by the liver in response to IL-6 — making it a downstream integrator of systemic NF-κB activity. Values above 3.0 mg/L independently predict cardiovascular events (JUPITER trial), all-cause mortality (Ridker et al.), and accelerated cognitive decline.
The good news: inflammaging is highly modifiable. Omega-3 index moving from 4% to 8% reduces hs-CRP ~30%. Sulforaphane reduces CRP in human airway models within 4 weeks. Exercise training reduces hs-CRP ~20% in sedentary adults at 3 months. The TNiC stack targets NF-κB from three independent angles — NRF2 (upstream ROS), SIRT1 (direct NF-κB deacetylation), and SPM precursors (active resolution).
Monitoring
Inflammaging biomarker panel
Log hs-CRP, IL-6, and homocysteine in the Lab Tracker to monitor trend over time.
Evidence-Graded Interventions
Anti-inflammaging interventions with human evidence
Tier A = multiple human RCTs. Tier B = at least one human trial + mechanistic data.
Sulforaphane (NRF2 / NF-κB)
Tier AThe most mechanistically complete anti-inflammatory compound with human evidence. NRF2 activation upregulates HO-1, NQO1, and GCLC — which neutralize the ROS that drive NF-κB activation. Simultaneously, NRF2 directly suppresses NF-κB transcriptional activity via IκBα. A human airway study (PMID: 27356680) demonstrated significant CRP and IL-6 reduction.
GlyNAC (Glutathione / Oxidative Stress)
Tier AOxidative stress is the upstream activator of NF-κB. When ROS oxidize IκB kinase (IKK), it phosphorylates IκB, releasing NF-κB to the nucleus. GlyNAC rebuilds glutathione — the primary intracellular ROS scavenger — breaking this chain at its root. Three human RCTs confirm reduced inflammatory markers alongside oxidative stress restoration.
Omega-3 (EPA + DHA)
Tier AEPA and DHA are precursors to specialized pro-resolving mediators (SPMs): resolvins, protectins, and maresins. SPMs actively terminate inflammation by clearing cellular debris, reducing neutrophil infiltration, and reprogramming macrophages from M1 (pro-inflammatory) to M2 (resolving) phenotype. The REDUCE-IT trial (PMID: 30145941) showed 25% reduction in MACE with 4g icosapentaenoic acid.
Zone 2 + Resistance Exercise
Tier AExercise has a biphasic inflammatory effect: acute transient IL-6 spike triggers sustained anti-inflammatory IL-10 and IL-1Ra. Chronic training reprograms macrophage phenotype, reduces visceral adipose (major SASP source), and upregulates NRF2 in skeletal muscle. Sedentary individuals have 30–50% higher hs-CRP than aerobically fit age-matched controls.
Resveratrol (SIRT1 / NF-κB)
Tier BSIRT1 deacetylates the p65 subunit of NF-κB at K310, suppressing its transcriptional activity without blocking upstream signaling. This is a particularly targeted anti-inflammatory mechanism — it reduces chronic NF-κB output while preserving acute inflammatory responses needed for infection defense.
Extinguish inflammaging.
Build a multi-angle NF-κB suppression protocol: NRF2 + SIRT1 + omega-3. Track hs-CRP quarterly in the Lab Tracker.