Hypothesis

We propose that declining nuclear acetyl-CoA in aging hippocampi suppresses surprise‑driven synaptic tagging by reducing histone acetylation at plasticity genes, thereby biasing the system toward over‑consolidation of existing memories. Restoring nuclear acetyl-CoA specifically during novel experience will reinstate tagging and improve flexible learning without globally increasing acetylation.

Mechanistic Basis

Nuclear acetyl-CoA generated by ACSS2 fuels histone acetyltransferases that acetylate H3K9 at promoters of immediate‑early genes such as Arc, Egr2, Nr4a2, and Grin1 (ACSS2 knockdown reduces nuclear acetyl-CoA, lowering H3K9ac at memory genes and impairing hippocampal spatial memory). In aged tissue, reduced acetyl-CoA shifts the balance toward HDAC activity (e.g., SIRT1) causing chromatin compaction at these loci (aged T cells show increased SIRT1 occupancy at core histone gene promoters with reduced H3K9/14 acetylation). This epigenetic state lowers the probability that a novel, surprising event triggers the synaptic tagging cascade needed for capture of newly synthesized plasticity proteins (aged mice fail behavioral tagging tasks unless p75NTR is absent).

We further hypothesize that the tagging mechanism depends on a transient surge of nuclear acetyl-CoA that coincides with neuromodulatory signals (e.g., locus coeruleus norepinephrine) signaling prediction error. When acetyl-CoA is scarce, this surge fails to achieve sufficient H3K9ac, preventing tag formation and favoring the stabilization of existing synapses—increased synaptic tenacity and reduced turnover (synapse turnover slows with age, increasing synaptic stability and limiting adaptability).

Testable Predictions

1. Pharmacological elevation of nuclear acetyl-CoA (via ACSS2 overexpression or acetate supplementation) administered only during a novel experience will rescue synaptic tagging in aged mice, measured by increased Arc‑dependent protein capture at tagged synapses.
2. The rescue will be blocked by inhibiting HAT activity (e.g., with C646) or by genetically preventing H3K9 acetylation at Arc promoter (K9R knock‑in), demonstrating that the effect is histone‑acetylation dependent.
3. In the absence of a novel experience, elevating nuclear acetyl-CoA will not alter baseline synaptic strength or memory consolidation, indicating that the effect is gated by surprise signaling.
4. Aged mice showing restored tagging will exhibit reduced inter‑individual epigenetic similarity in hippocampal tissue, reversing the epigenetic assimilation observed in very old brains (advanced chronological age >75 years is associated with increased inter-individual similarity of DNA modification profiles).

Experimental Approach

• Use aged (18‑month) C57BL/6 mice with a Cre‑dependent ACSS2 overexpression vector targeted to hippocampal excitatory neurons (CaMKIIα‑Cre).
• Deliver acetate in drinking water to boost systemic acetyl‑CoA precursors.
• Subject mice to a behavioral tagging paradigm: weak training (sub‑threshold) followed by a strong, novel stimulus (e.g., novel object exploration) known to trigger locus coeruleus norepinephrine release.
• Quantify tagging via immunofluorescence for newly synthesized Arc protein at synapses labeled with a photoswitchable tag during the weak training phase.
• Measure hippocampal H3K9ac levels at Arc, Egr2, Nr4a2, and Grin1 promoters by ChIP‑qPCR.
• Assess synaptic turnover using in vivo two‑photon imaging of dendritic spines over weeks.
• Perform whole‑brain bisulfite sequencing to evaluate epigenetic similarity across individuals.

Potential Outcomes and Falsifiability

If nuclear acetyl-CoA elevation during novelty restores tagging, improves flexible learning, and reduces epigenetic assimilation, the hypothesis is supported. Failure to rescue tagging despite restored acetyl-CoA, or rescue that occurs without novelty, would falsify the claim that acetyl-CoA acts specifically as a surprise‑gated cofactor for synaptic tagging. Additionally, if HAT inhibition blocks the rescue while HDAC inhibition mimics it, the mechanistic link to histone acetylation is confirmed. This framework directly tests whether aging‑related rigidity stems from a metabolic gate on experience‑dependent chromatin remodeling rather than indiscriminate decay.