Impact of Aging on Brain Redox Balance: Mechanistic Links to Synaptic Dysfunction and Neurodegenerative Disease

Abstract

Aging remains the most significant risk factor driving the development and progression of neurodegenerative diseases, as it reflects the gradual accumulation of molecular and cellular changes over time. Disturbance of redox balance has been recognized among these changes as a primary mechanism that links aging to synaptic decline. The imbalance favoring the production of reactive oxygen species over the capability of the antioxidant systems to neutralize them results in oxidative stress, which selectively disrupts synaptic morphology and function. In this scenario mitochondrial dysfunction is a significant factor since it not only raises oxidative stress but also reduces the energy supply necessary for standard cellular activity. At the same time, the decline of the endogenous antioxidant system due to aging further weakens neuronal defense. Oxidative modification of synaptic proteins changes their composition and roles, thereby reducing neurotransmission and plasticity. These interconnected processes underlie the pathological basis of major neurodegenerative diseases, such as Parkinson's and Alzheimer's. The complexity of the involved systems restricts the success of redox-balance-restoring therapeutic strategies, although they have a high potential. Hence, further work is necessary to enhance redox-based therapies and facilitate their translation for neurodegeneration in aging.