Epigenetic Regulation of Modulatory Neurotransmitter System Integrity in the Aging Brain: A Scoping Review Across the Lifespan

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Abstract
Age-related changes in neurotransmitter systems contribute to declines in cognitive, emotional, and motor function, yet the biological mechanisms linking these changes to aging are not completely understood. Epigenetic regulation offers a promising framework to bridge this gap. DNA methylation-based biomarkers of biological aging (i.e., epigenetic clocks) capture cumulative and dynamic aspects of biological aging that may reflect vulnerability in neural systems beyond chronological age. However, whether these indices track with the integrity of neurotransmitter systems has not been systematically examined. This scoping review synthesizes evidence across human studies to evaluate how epigenetic aging processes influence neurotransmitter gene regulation and system function across the lifespan. We included 109 studies spanning 2005–2026. GABAergic genes (GAD1, GABRA2) showed the most consistent and reproducible age-related promoter hypermethylation across the cortex, inversely correlated with mRNA expression and corroborated by MRS evidence of cortical GABA decline. Dopaminergic and serotonergic evidence during normative aging was sparse; most epigenetic data in these systems came from disease cohorts. Histone modifications converged on neurotransmission and synaptic-plasticity loci, predominantly in Alzheimer’s disease tissue. Subcortical and brainstem nuclei central to monoaminergic and cholinergic systems remain under-investigated for normative aging epigenetic processes. Environmental and social determinants, socioeconomic status, childhood adversity, and chronic stress, were consistently associated with accelerated peripheral epigenetic aging, but brain-specific data are scarce.

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