Hypothesis

Circadian fluctuations in brain-derived neurotrophic factor (BDNF) drive rhythmic expression of the base excision repair (BER) enzymes OGG1 and APE1 in neurons through CREB‑dependent transcription. When the circadian‑BDNF axis is intact, OGG1 and APE1 levels peak during the subjective day, enhancing removal of 8‑oxoguanine lesions and limiting mitochondrial DNA release. Disruption of this axis flattens BDNF oscillations, leading to constitutively low BER capacity, accumulation of oxidative DNA damage, and activation of the cGAS‑STING inflammatory pathway.

Mechanistic Rationale

• The suprachiasmatic nucleus coordinates daily BDNF release via rhythmic neuronal firing and calcium‑dependent transcription (see BDNF positively correlates with OGG1 and APE1 expression via CREB-binding sites in promoters).
• CREB phosphorylation follows BDNF‑TrkB signaling and directly binds promoter regions of OGG1 and APE1, as shown in multiple neuronal models.
• Mitochondrial OGG1 isoform activity is therefore gated by the nuclear‑encoded OGG1 transcription rhythm, coupling DNA repair to the metabolic state.
• In aging, dampened circadian BDNF peaks reduce CREB activation, lowering OGG1/APE1 transcription and exacerbating the age‑related decline documented in hippocampus and cortex (OGG1 activity decreases with aging, particularly mitochondrial isoforms, resulting in increased 8-oxoG in hippocampus and cortex).
• Persistent 8‑oxoG leads to mitochondrial dysfunction, mtDNA release, and cGAS‑STING mediated inflammation, linking repair failure to neurodegeneration.

Testable Predictions

1. Rhythmic BER expression – In young wild‑type mice, hippocampal OGG1 and APE1 mRNA and protein will show ~24 h oscillations that align with BDNF peaks (subjective day).
2. Clock dependence – Neuron‑specific Bmal1 knockout will abolish BDNF rhythmicity, flatten OGG1/APE1 expression, and elevate steady‑state 8‑oxoG levels compared with controls.
3. BDNF rescue – Exogenous BDNF administered at the circadian peak in Bmal1‑deficient mice will restore OGG1/APE1 transcription and reduce 8‑oxoG and mtDNA‑induced cGAS‑STING signaling.
4. TrkB blockade – Pharmacological inhibition of TrkB in intact animals will dampen OGG1/APE1 rhythms without affecting core clock gene expression, uncoupling the clock from repair.
5. Human relevance – Post‑mortem hippocampal tissue from individuals with robust circadian rest‑activity rhythms will display higher OGG1/APE1 and lower 8‑oxoG than age‑matched arrhythmic subjects.

Falsifiability

If any of the following are observed, the hypothesis is refuted:

• No detectable circadian variation in neuronal OGG1 or APE1 levels despite robust BDNF rhythms.
• Genetic or environmental disruption of the circadian‑BDNF axis fails to alter OGG1/APE1 expression or 8‑oxoG accumulation.
• Restoring BDNF rhythmicity does not rescue BER capacity or mitigate mitochondrial inflammation in arrhythmic models.

These outcomes can be assessed with qPCR, western blotting, immunohistochemistry for 8‑oxoG, mtDNA ELISA, and cGAS‑STING readouts (e.g., IFN‑β phosphorylation) in mouse models and human tissue.

Conclusion (optional)

By positioning BDNF as the circadian gatekeeper of neuronal BER, this hypothesis redirects focus from direct clock control of repair genes to neurotrophic signaling as the proximate mechanism linking temporal order to genome stability. It offers a clear, experimentally tractable framework for testing whether strengthening circadian BDNF signaling can serve as a geroprotective strategy against neurodegenerative DNA damage.