Synaptic aging and neurodegeneration: the role of synaptic vesicle dynamics and neurotransmitter imbalance.

Abstract

Synaptic aging is a core manifestation of brain aging arising from the convergence of fundamental biological aging processes, including genomic instability, loss of proteostasis, mitochondrial dysfunction, oxidative stress, and chronic low-grade inflammation. As highly energy-dependent and protein-rich sites of neuronal communication, synapses are particularly vulnerable to age-associated molecular stress. Accumulating evidence indicates that age-related impairments in synaptic vesicle trafficking, recycling, and neurotransmitter homeostasis precede neuronal loss and represent early drivers of cognitive decline and neurodegeneration. Disruption of vesicle dynamics compromises neurotransmitter release, synaptic plasticity, and circuit stability, thereby accelerating synaptic failure. Dysregulation of key neurotransmitter systems, including acetylcholine, dopamine, glutamate, and γ-aminobutyric acid, further exacerbates synaptic dysfunction and cognitive impairment. These changes are driven by interconnected aging mechanisms, wherein impaired proteostasis promotes the accumulation of dysfunctional synaptic proteins, mitochondrial dysfunction limits ATP availability for vesicle mobilisation, and persistent neuroinflammation heightens synaptic vulnerability. Emerging evidence also implicates age-related blood-brain barrier disruption and gut-brain axis dysregulation as additional modulators of synaptic integrity via immune, metabolic, and neurochemical pathways. This review synthesises recent advances in understanding the molecular mechanisms of synaptic aging, with a focus on vesicle dynamics and neurotransmitter imbalance, and discusses therapeutic strategies aimed at enhancing synaptic resilience to promote healthy brain aging.