Neurotransmitter Systems and Systemic Resilience in the Healthy Aging Brain

Abstract

Physiological brain aging is driven by progressive neuro-glial-vascular remodeling, in which neurotransmitter systems serve as the core functional network integrating central resilience and peripheral systemic signaling. This narrative review provides a comprehensive synthesis of the molecular, cellular, and circuit-level mechanisms underlying healthy brain aging. Centered on classical and modulatory neurotransmitter systems, we examine how neurochemical trajectories interact with key regulators of cellular resilience, including the SIRT1/Klotho/mTORC1 signaling network, epigenetic modifications such as the N(6)-methyldeoxyadenosine (N6medA) clock, extracellular matrix dynamics, and multi-organ (muscle–gut–liver–brain) axes. We also discuss how socioeconomic and environmental exposures, such as childhood poverty and air pollution, contribute to individual aging trajectories throughout life. Recent advances in multimodal neuroimaging, spatial transcriptomics (IRISeq), and AI-based brain-age estimation (e.g., ResNet-CrossViT) are highlighted as promising approaches for identifying biomarkers capable of distinguishing physiological aging from the earliest stages of neurodegeneration. Collectively, healthy brain aging represents a dynamic process of biological adaptation in which neurotransmitter remodeling, cellular resilience, metabolic homeostasis, and systemic interactions jointly determine cognitive outcomes. Understanding these interconnected mechanisms provides a framework for developing preventive strategies aimed at preserving cognitive function and extending brain health span.