Hypothesis

Interoceptive awareness training (IAT) preserves Von Economo neuron (VEN) density in aging humans by boosting mitochondrial biogenesis and suppressing neuroinflammation through the PGC‑1α/BDNF axis and reduced glucocorticoid exposure.

Mechanistic Reasoning

VENs are densely packed in the anterior insula and express high levels of glucocorticoid receptors (GR) and mitochondrial biogenesis regulators such as PGC‑1α [1]. Frequent interoceptive signals from the body activate the insular‑VEN circuit, which in turn dampens hypothalamic‑pituitary‑adrenal (HPA) axis output via inhibitory projections to the paraventricular nucleus [3]. Lower circulating cortisol reduces GR‑mediated transcriptional repression of PGC‑1α, allowing VENs to upregulate oxidative phosphorylation and antioxidant enzymes [2]. Concurrently, interoceptive training elevates BDNF release from insular pyramidal neurons, further activating TrkB‑PI3K‑Akt signaling that promotes mitochondrial fusion and inhibits NF‑κB‑driven cytokine production.

Predictions

1. Structural – After 12 months of IAT, 7T MRI will show significantly less thinning of layer Vb in the anterior insula (VEN‑rich zone) compared with an active control group (e.g., health education).
2. Molecular – Plasma neurofilament light (NfL) will rise slower in the IAT group, and circulating BDNF will be higher at 6 and 12 months.
3. Functional – Improvements in interoceptive accuracy (measured by heartbeat‑tracking task) will mediate the relationship between training attendance and VEN preservation.
4. Cognitive – Participants with preserved VEN thickness will exhibit slower decline in episodic memory and executive function over 24 months.

Experimental Design

• Participants: 200 cognitively normal adults aged 65‑80, stratified by baseline interoceptive accuracy.
• Intervention: 8‑week mindfulness‑based interoceptive exposure program (daily 20‑min body‑scan + weekly group session) followed by monthly booster sessions for 12 months.
• Control: Matched health‑education program covering nutrition, sleep, and social engagement without interoceptive focus.
• Outcomes:
  • Primary: Change in anterior insula layer Vb thickness measured with 0.5 mm 7T MRI at baseline, 12, and 24 months.
  • Secondary: Plasma NfL, BDNF, cortisol; interoceptive accuracy; composite cognitive score (Prevent Alzheimer’s Cognitive Composite).
• Analysis: Mixed‑effects models testing group × time interaction; mediation analysis to assess whether change in interoceptive accuracy accounts for VEN preservation.

Falsifiability

If IAT fails to produce a statistically significant difference in anterior insula layer Vb thickness (or shows equal thinning to control) and does not alter plasma NfL or BDNF trajectories, the hypothesis that interoceptive training preserves VENs via mitochondrial/anti‑inflammatory mechanisms would be refuted. Conversely, a positive result would support the mechanistic link and justify larger trials targeting VEN resilience.

Translational Impact

Demonstrating a non‑invasive, behavioral means to safeguard VENs would fill a major gap in the neuro‑biotech horizon, offering a low‑cost strategy to delay frontotemporal dementia and Alzheimer’s‑related social‑cognitive decline while awaiting disease‑modifying drugs.