Aging cellOct 26, 2026

Changes in Gene Packaging Linked to Aging, Brain Inflammation, and Metabolism in Alzheimer's Disease

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 28, 2026

Abstract

Histone modifications may influence the persistence of cellular states associated with Alzheimer's disease.

Aging, neuroinflammation, and metabolic dysfunction are interconnected in Alzheimer's disease.
Histone modifications are proposed to regulate inflammatory and stress responses in brain cells.
Amyloid-beta, tau pathology, and metabolic dysfunction may impact histone-modifying processes.
Interactions between metabolism and chromatin could stabilize disease-related cellular states.
Cellular senescence and neuroimmune memory are highlighted as significant factors in disease progression.
A framework for evaluating causality in chromatin states distinguishes those associated with ongoing pathology from those that can persist.

Simplified

Aging, neuroinflammation and metabolic dysfunction are tightly intertwined in Alzheimer's disease (AD), but how transient pathological signals become persistent cellular states remains poorly understood. Histone post-translational modifications (PTMs) provide a dynamic interface between extracellular stimuli, cellular metabolism and chromatin state. This Review examines how canonical histone modifications and emerging metabolite-derived acylations regulate inflammatory and stress-responsive programmes across microglia, astrocytes and neurons during aging and AD. We discuss how amyloid-β, tau pathology, metabolic dysfunction and innate immune signaling converge on histone-modifying machinery, and how reciprocal interactions between metabolism and chromatin may stabilize disease-associated cell states. Particular attention is given to cellular senescence and neuroimmune memory, while emphasizing the context dependence of individual histone marks across cell types, genomic regions and disease stages. We further evaluate evidence for causality using three criteria: perturbation, persistence and reversibility. This framework distinguishes chromatin states that accompany ongoing pathology from those capable of sustaining pathological cell states beyond their initiating signals. Finally, we consider therapeutic strategies targeting histone-modifying enzymes, chromatin readers and metabolic inputs to restore chromatin plasticity and promote resolution of chronic neuroinflammation.

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Changes in Gene Packaging Linked to Aging, Brain Inflammation, and Metabolism in Alzheimer's Disease

Abstract

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