Hypothesis

We propose that von Economo neurons (VENs) in the anterior insular cortex act as epigenetic sentinels that translate interoceptive stress into a propagating epigenetic drift, thereby driving multiple hallmarks of aging.

Mechanistic Model

VENs are large, spindle‑shaped neurons with high basal firing rates and enriched expression of activity‑dependent transcription factors (Fos, Egr1). Interoceptive afferents from the vagus and spinal cord deliver calcium‑rich signals that activate CaMKIV/CREB pathways in VENs. Persistent calcium influx impairs TET‑mediated DNA demethylation and recruits DNMT3a, leading to focal hypermethylation at promoters of longevity genes such as Foxo3 and Sirt1. The altered epigenetic state is packaged into extracellular vesicles (exosomes) containing miRNA‑124, miRNA‑132 and histone fragments, which are released into the cerebrospinal fluid and taken up by nearby astrocytes, microglia and peripheral immune cells. This vesicle‑mediated transfer spreads the epigenetic noise, amplifying genomic instability, proteostatic decline and mitochondrial dysfunction across tissues. This view aligns with the idea that epigenetic information loss is an upstream driver Information Theory of Aging PMID:38102202 and is supported by partial reprogramming experiments that reset multiple hallmarks simultaneously OSK rejuvenation. Hierarchical transcription factor networks (FOXO/DAF-16, HSF-1, AMPK, mTOR) integrate nutrient and stress signals to reshape the epigenome Transcription factor networks in aging PubMed:27456767.

Testable Predictions

1. Chemogenetic silencing of VENs in 20‑month‑old mice will reduce cortical and serum epigenetic age (DNAmHorvath) by at least 15 % after four weeks, without altering gross locomotion.
2. Optogenetic stimulation of VENs in 2‑month‑old mice will increase hippocampal DNMT3a activity (measured by immunofluorescence) and decrease doublecortin‑positive neuroblasts within seven days.
3. Subdiaphragmatic vagotomy or broad‑spectrum antibiotic depletion of the gut microbiome will attenuate VEN‑associated hypermethylation at Foxo3 promoters in aged mice.
4. Comparative bisulfite sequencing of VEN‑enriched insular layers from human centenarians (≥100 y) will show methylation levels comparable to those of 30‑year‑old controls, whereas age‑matched septuagenarians will display significant drift.

Falsifiability

If any of the above interventions fails to produce the predicted directional change in epigenetic clocks or downstream hallmarks (e.g., VEN silencing does not alter DNAmAge, VEN activation does not increase DNMT3a, or microbiome depletion does not modify VEN methylation), the hypothesis that VENs serve as upstream epigenetic regulators of aging is refuted.