Hypothesis

Preserved von Economo neuron (VEN) density in superagers sustains high interoceptive precision, which in turn reflects lower systemic inflammation and cellular senescence, making interoceptive accuracy a measurable peripheral biomarker of VEN integrity and biological aging.

Mechanistic Rationale

VENs are large, metabolically active projection neurons that relay visceral autonomic signals from the anterior insula to anterior cingulate networks, enabling rapid error detection and autonomic adjustment (The von Economo neurons in fronto-insular and anterior cingulate cortex). In superagers, VENs resist age‑related loss despite heightened metabolic demand, coinciding with reduced plasma p‑tau181, lower neuroinflammation, and preserved cholinergic tone (Special von Economo neurons may hold key to super-sharp memory in 80+ superagers). We propose that intact VEN‑mediated interoceptive signaling maintains homeostatic control over peripheral immune axes via the vagal anti‑inflammatory pathway; thus, high interoceptive precision predicts reduced circulating inflammatory cytokines (e.g., IL‑6, TNF‑α) and lower markers of cellular senescence (e.g., p16^INK4a^‑positive cells in blood). Conversely, VEN degeneration disrupts this gut‑brain‑immune loop, leading to heightened interoceptive noise, maladaptive autonomic output, and accelerated peripheral aging.

Testable Predictions

1. Across a cohort of adults aged 65‑90, individuals scoring in the top quartile on a validated interoceptive accuracy task (e.g., heartbeat detection or gastric distension discrimination) will show significantly higher VEN‑region cortical thickness on MRI and lower plasma IL‑6/TNF‑α than those in the bottom quartile.
2. Longitudinally, baseline interoceptive precision will predict slower rates of anterior cingulate/fronto‑insula atrophy over 2 years, independent of baseline cognition.
3. Pharmacological enhancement of cholinergic signaling (e.g., donepezil) will improve interoceptive accuracy and concomitantly reduce peripheral inflammatory markers in participants with mild VEN‑related cortical thinning.
4. Genetic up‑regulation of KLOTHO in animal models will increase VEN‑like neuronal markers in the fronto‑insula and improve interoceptive performance, accompanied by decreased colonic IL‑1β expression.

Potential Experimental Approach

• Recruit 200 community‑dwelling older adults; assess interoceptive accuracy using a multimodal heartbeat‑tracking and water‑load gastric distension paradigm.
• Acquire high‑resolution 3T MRI to quantify cortical thickness and surface area in anterior cingulate and fronto‑insula (VEN‑rich zones).
• Collect fasting plasma for cytokine panel (IL‑6, TNF‑α, IL‑1β) and senescence‑associated secretory phenotype (SASP) factors; isolate peripheral blood mononuclear cells for p16^INK4a^ flow cytometry.
• Follow participants annually for 24 months to track cortical change and interoceptive scores.
• In a parallel double‑blind pilot, assign 40 participants with borderline VEN thinning to 6 months of donepezil vs placebo; repeat interoceptive and biomarker assessments.
• Validate findings in transgenic mice overexpressing KLOTHO: immunohistochemistry for VEN‑markers (e.g., BDNF, ATF3) in fronto‑insula, intra‑gastric balloon distension to measure visceral sensitivity, and colonic cytokine ELISA.

If interoceptive precision reliably mirrors VEN health and peripheral aging hallmarks, it could serve as a low‑cost, scalable biomarker to identify protective factors and gauge efficacy of neuroprotective interventions in broader aging populations.