Hypothesis: High metabolic demand of von Economo neurons (VENs) makes their survival dependent on systemic NAD+ levels, and declining NAD+ drives both VEN loss and interoceptive decline, which in turn mirrors peripheral inflammaging.

Mechanism

VENs in the anterior cingulate and fronto‑insular cortex exhibit elevated glucose uptake and mitochondrial activity to support rapid signaling for social and interoceptive processing [2]. This energetically intense phenotype generates reactive oxygen species that sensitize VENs to declines in cellular NAD+, a key cofactor for sirtuin‑mediated DNA repair and mitochondrial homeostasis. When peripheral NAD+ falls with age, sirtuin activity wanes in VENs, increasing vulnerability to tau accumulation and neuroinflammation. Consequently, VEN density drops, impairing the cortical hub that integrates visceral signals, leading to measurable interoceptive deficits.

Predictions

1. In humans, lower plasma NAD+ will correlate with reduced VEN‑proxy signal (e.g., PET ligand binding or MRI‑based cortical thickness in ACC/fronto‑insular cortex) and poorer performance on heartbeat‑tracking interoceptive tasks.
2. Individuals showing this NAD+/VEN/interoceptive triad will exhibit higher peripheral inflammaging markers (serum IL‑6, TNF‑α, shorter leukocyte telomere length) independent of chronological age.
3. Pharmacological or lifestyle interventions that raise NAD+ (e.g., nicotinamide riboside, intermittent fasting, exercise) will attenuate VEN loss and interoceptive decline in aged animal models, accompanied by reduced neurofibrillary tangle burden in VEN‑rich layers.

Experimental Design

• Human cohort: Recruit 150 participants aged 60‑90, stratified by cognitive status (superagers, typical agers, mild cognitive impairment). Collect fasting plasma NAD+, perform ACC/fronto‑insular structural MRI, administer a validated interoceptive accuracy task (heartbeat detection), and measure serum IL‑6, TNF‑α, telomere length. Use hierarchical modeling to test whether NAD+ predicts VEN‑proxy MRI metrics, which in turn predict interoceptive scores and inflammaging markers.
• Animal study: Aged C57BL/6 mice receive nicotinamide riboside (400 mg/kg/day) or vehicle for 6 months. Post‑treatment, quantify VEN density via immunostaining for FEZF2 in layer Vb of ACC/fronto‑insular cortex, assess interoceptive sensitivity using a visceral discomfort avoidance assay, and quantify tau pathology (AT8 immunoreactivity) and neuroinflammation (Iba1).

Falsifiability

If NAD+ levels show no relationship with VEN‑proxy imaging, interoceptive performance, or peripheral inflammaging across the cohort, or if NAD+ boosting fails to rescue VEN density and interoceptive function in aged mice, the hypothesis would be refuted. Conversely, supportive data would position VENs as a mechanistic bridge linking cellular metabolism, interoceptive awareness, and systemic aging, offering a biomarker‑target pair for rejuvenation strategies.