This review maps how histone post-translational modifications, including metabolite-derived acylations, convert transient inflammatory and metabolic signals into persistent chromatin states across microglia, astrocytes, and neurons in Alzheimer's disease. The authors apply three causality criteria — perturbation, persistence, and reversibility — to separate chromatin marks that merely accompany pathology from those that sustain disease-associated cell states after the initiating stimulus resolves. Therapeutic strategies targeting histone-modifying enzymes, chromatin readers, and upstream metabolic inputs are evaluated as routes to restoring chromatin plasticity.
Key Points
- Histone modifications convert transient brain inflammation into self-sustaining cellular states
- Metabolite availability directly shapes chromatin marks through acylation feedback loops
- Perturbation, persistence, reversibility distinguish causal chromatin states from passive associatio
Longevity Analysis
Chromatin functions as a record of prior metabolic and immune exposure, which explains why brain inflammation can persist long after the triggering insult has cleared — a mechanism that parallels the entrenchment of senescent and trained-immune states elsewhere in the body. Because the substrates for histone acylation are drawn from central metabolism, fuel availability, mitochondrial output, and inflammatory load become upstream levers on how neural cells read their own genome. Reducing the chronic signals that drive these marks matters as much as any enzyme-targeted intervention, since reversibility depends on removing what maintains the state rather than overriding it.
Original published by Wiley Aging Cell, by Junyi Liang, Huawen Cao, Xiumin Ren, Nan Sha, Xueqing Han, Ling Jiang, Bin Liu, Weiming Zhao .