Hypothesis

Higher von Economo neuron (VEN) density in the anterior cingulate and frontoinsular cortices enhances vagal afferent signaling, which in turn reduces peripheral inflammatory biomarkers; conversely, VEN loss diminishes this anti‑inflammatory tone and accelerates age‑related inflammation.

Mechanistic Rationale

VENs are large, metabolically active neurons that express high levels of mitochondrial uncoupling protein 2 (UCP2) and receive dense input from visceral afferents via the nucleus tractus solitarius Von Economo neurons and insular cortex - the bridge between soma and psyche. Their rapid conduction enables real‑time broadcasting of interoceptive states to autonomic nuclei. When VEN integrity is preserved, as observed in superagers Special von Economo neurons may hold key to super-sharp memory in superagers, they sustain vagal efferent activity that inhibits NF‑κB signaling in splenic macrophages, lowering circulating IL‑6 and TNF‑α. In behavioral variant frontotemporal disease, selective VEN loss Selective Frontoinsular von Economo Neuron and Fork Cell Loss disrupts this brake, permitting microglial activation and systemic inflammation.

We propose that the energetic vulnerability of VENs makes their activity sensitive to NAD⁺ availability. Boosting NAD⁺ with nicotinamide riboside (NR) should enhance UCP2‑mediated mitochondrial resilience, preserve VEN firing, and strengthen vagal anti‑inflammatory output.

Predictions and Experimental Design

1. Baseline correlation – In a cohort of 200 adults aged 60‑90, higher VEN density (measured with a novel PET ligand targeting ENPP6, a VEN‑enriched protein) will predict lower plasma IL‑6, CRP, and mitochondrial DNA copy number in peripheral blood mononuclear cells (p<0.01).
2. Intervention arm – 100 participants receive NR (500 mg BID) for 6 months; 100 receive placebo. We will assess changes in VEN PET signal, heartbeat detection accuracy (interoceptive metric), and inflammatory panels monthly.
3. Falsifiable outcome – If NR does not increase VEN PET signal or improve interoceptive accuracy, and inflammatory markers remain unchanged versus placebo, the hypothesis is refuted.
4. Mediation analysis – We will test whether changes in interoceptive accuracy mediate the effect of NR on cytokine reduction, using bootstrapped indirect effects.

Potential Implications

Confirming this link would position VENs as a peripheral‑central interface for inflammaging, offering a biomarker (VEN PET or interoceptive task) for early detection of inflammaging risk. It would also justify metabolic interventions (NR, NAD⁺ boosters) or vagal neuromodulation as strategies to preserve VEN function and extend healthspan, directly translating superager resilience into actionable therapies.