Hypothesis

Peripheral immune senescence drives selective loss of von Economo neurons (VENs) through circulating mitochondrial DNA that activates neuronal TLR9, providing a direct mechanistic link between inflammaging and interoceptive decline.

Mechanistic rationale

Aged immune cells accumulate dysfunctional mitochondria and release oxidized mtDNA into the bloodstream [2]. This mtDNA acts as a damage‑associated molecular pattern (DAMP) that engages TLR9 on microglia and neurons [5]. VENs, located in the frontoinsular cortex, express unusually high levels of TLR9 and depend on oxidative phosphorylation to support their large, rapidly conducting axons [6]. Chronic exposure to circulating mtDNA therefore triggers TLR9‑dependent NF‑κB signaling in VENs, amplifying local SASP‑like responses, impairing mitochondrial bioenergetics, and culminating in excitotoxic calcium overload. This model extends the framework by specifying a molecular bridge—mtDNA/TLR9—that explains why VENs, despite being rare, are disproportionately affected in aging and early neurodegeneration, while other neuronal populations remain relatively spared.

Testable predictions

• Aged mice will show elevated plasma oxidized mtDNA and increased TLR9 immunoreactivity in VENs compared with young controls.
• Genetic deletion of Tlr9 specifically in VENs (using a Fezf2‑Cre line) will prevent age‑related loss of VEN density and preserve frontoinsular synaptic markers.
• Pharmacological neutralization of circulating mtDNA (e.g., with anti‑CpG oligonucleotides) administered to aged mice will reduce VEN loss and improve performance on interoceptive tasks such as visceral pain discrimination and social preference assays.
• Adoptive transfer of senescent T cells from old donors into young recipients will recapitulate VEN TLR9 activation and interoceptive deficits, an effect blocked by a TLR9 antagonist.

Falsifiability

If aged animals exhibit no rise in plasma mtDNA, or if VEN‑specific Tlr9 knockout fails to protect VENs despite confirmed knockout efficiency, the hypothesis is refuted. Likewise, if neutralizing mtDNA does not ameliorate interoceptive behavior, the proposed DAMP‑TLR9 axis is unlikely to be the primary link.

References (inline)

[2] https://doi.org/10.1126/science.aax0860 [5] https://doi.org/10.1038/nn.3586 [6] https://doi.org/10.1016/j.neuron.2020.02.014