VEN Density in Anterior Insula Sustains Vagal‑Mediated Anti‑Inflammatory Signaling to Decelerate Systemic Aging

Hypothesis

Higher baseline density of Von Economo neurons (VENs) in the anterior insular cortex preserves interoceptive precision, which in turn sustains vagal‑mediated anti‑inflammatory signaling and slows systemic inflammaging.

Mechanistic Rationale

VENs are large, spindle‑shaped projection neurons with fast conduction velocities that link fronto‑insula networks to brainstem autonomic centers, especially the dorsal vagal complex [1]. In superagers, VEN density remains stable or increases, correlating with preserved cortical thickness in layer‑specific zones that support sustained functional demand [2]. It's plausible that this structural reserve enables robust top‑down regulation of vagal outflow, maintaining a cholinergic anti‑inflammatory pathway that dampens peripheral cytokine production (e.g., IL‑6, TNF‑α) [3]. When interoceptive precision declines—reflected in reduced heartbeat detection accuracy and lower body‑trust scores—vagal tone weakens, allowing low‑grade inflammation to rise, which accelerates frailty and cognitive decline [4]. Thus, VEN density acts as a structural biomarker for the capacity of the insula‑vagus axis to counteract inflammaging.

Testable Predictions

1. In a cohort of adults aged 40‑80, baseline VEN density measured by 7T MRI layer‑specific segmentation will positively correlate with interoceptive precision (heartbeat tracking accuracy and body‑trust questionnaire scores) [3].
2. Baseline VEN density will negatively predict the 5‑year change in plasma inflammaging markers (IL‑6, CRP, fibrinogen), with interoceptive precision mediating this relationship (significant indirect effect).
3. Participants who undergo a 12‑week interoceptive training protocol (mindful body‑scan + biofeedback) will show increased functional connectivity between anterior insula and dorsal vagal complex (measured by resting‑state fMRI) and a concomitant reduction in inflammaging markers, but only if they have baseline VEN density above the cohort median.
4. In Prader‑Williams syndrome, where VEN distribution is atypical [5], we expect lowered interoceptive precision and elevated inflammaging relative to age‑matched controls, supporting the disease‑specific vulnerability arm of the hypothesis.

Methods Outline

• Recruit 200 participants stratified by age (40‑59, 60‑79) and superager status (memory performance >2 SD above age‑norm).
• Acquire 7T structural MRI; use cortical layer‑specific segmentation to quantify VEN‑rich layer III density in anterior cingulate and anterior insula (region‑of‑interest defined by histology‑validated atlases).
• Assess interoceptive precision via heartbeat detection task (Schandry method) and the Multidimensional Assessment of Interoceptive Awareness (MAIA) body‑trust subscale.
• Collect fasting blood samples for IL‑6, CRP, fibrinogen at baseline and annually for 5 years.
• Measure functional aging annually via gait speed, Short Physical Performance Battery, and frailty index.
• For the intervention arm (n=80), randomize to interoceptive training or active control (health education); repeat MRI/fMRI and biomarkers post‑intervention and at 1‑year follow‑up.
• Conduct mediation analysis (bootstrapped 5,000 samples) to test whether interoceptive precision mediates the VEN density → inflammaging link.

Expected Impact

Confirming this hypothesis would establish a neuro‑biological bridge linking a rare neuron class to whole‑body healthspan, offering a concrete target for biomarkers and interventions aimed at preserving resilience in aging.