Hypothesis

VEN density in the anterior cingulate and insular cortex directly supports interoceptive fidelity, which in turn modulates autonomic outflow to preserve organ function and delay mortality. Loss of VENs disrupts this mechanistic chain, accelerating systemic aging.

Mechanistic rationale

• VENs are large, sparsely branched pyramidal cells with high basal metabolic rates and enriched expression of mitochondrial biogenesis regulators (e.g., PGC‑1α) and neurotrophic receptors (TrkB). In SuperAgers, upregulated BDNF‑TrkB signaling and reduced microglial activation protect these cells from tau and TDP‑43 pathology {2,3}.
• Their strategic location within the allostatic‑interoceptive network enables VENs to translate visceral afferent signals into sympathetic‑parasympathetic balance via projections to the hypothalamus and brainstem vagal nuclei. Disruption of this output reduces heart‑rate variability and elevates pro‑inflammatory cytokines, promoting organ‑level wear and tear {4,5}.
• We propose that VEN‑driven vagal tone acts as a peripheral "gatekeeper" that limits inflammasome activation in distant tissues; when VENs decline, this gate weakens, leading to cumulative organ damage measurable as declining renal clearance, hepatic stiffness, or cartilage thickness.

Testable predictions

1. In a longitudinal cohort of adults aged 60‑90, baseline VEN density estimated by high‑resolution myelin‑sensitive MRI will predict interoceptive accuracy (heartbeat detection task) two years later, even after controlling for global gray matter volume.
2. Interoceptive accuracy will mediate the relationship between VEN density and annual change in a composite organ‑health index (eGFR, liver elastography, arterial stiffness) and all‑cause mortality over a five‑year follow‑up.
3. Pharmacological enhancement of BDNF signaling (e.g., with a TrkB agonist) in aged mice will increase VEN survival, improve heartbeat‑evoked potentials, and raise vagal‑mediated HRV, thereby slowing the progression of diet‑induced hepatic fibrosis.
4. Conversely, chemogenetic silencing of VENs in young adult mice will produce interoceptive deficits, reduced HRV, and accelerated accumulation of serum IL‑6 and creatinine, mimicking premature organ aging.

Falsifiability

If VEN density shows no predictive power for interoceptive performance, or if interoceptive measures fail to mediate organ‑health outcomes despite robust VEN‑organ correlations, the proposed mechanistic link is refuted. Similarly, if BDNF‑targeted interventions rescue VENs without improving vagal tone or organ health, the causal chain would be incomplete.

This hypothesis integrates selective VEN vulnerability, interoceptive decline, and autonomic regulation to explain why these neurons are both a marker of resilience and a leverage point for interventions targeting systemic aging.