Changes in levels of the antioxidant glutathione in brain and blood across the age span of healthy adults: A systematic review

Aging is characterized by a gradual decline of the body's biological functions, which can lead to increased production of reactive oxygen species (ROS). Antioxidants neutralize ROS and maintain balance between oxidation and reduction. If ROS production exceeds the ability of antioxidant systems to neutralize, a damaging state of oxidative stress (OS) may exist. The reduced form of glutathione (GSH) is the most abundant antioxidant, and decline of GSH is considered a marker of OS. Our review summarizes the literature on GSH variations with age in healthy adults in brain (in vivo, ex vivo) and blood (plasma, serum), and reliability of in vivo magnetic resonance spectroscopy (MRS) measurement of GSH. A systematic PubMed search identified 35 studies. All in vivo MRS studies (N = 13) reported good to excellent reproducibility of GSH measures. In brain, 3 out of 4 MRS studies reported decreased GSH with age, measured in precuneus, cingulate, and occipital regions, while 1 study reported increased GSH with age in frontal and sensorimotor regions. In post-mortem brain, out of 3 studies, 2 reported decreased GSH with age in hippocampal and frontal regions, while 1 study reported increased GSH with age in a frontal region. Oxidized glutathione disulfide (GSSG) was reported to be increased in caudate with age in 1 study, suggesting OS. Although findings in the brain lacked a clear consensus, the majority of studies suggested a decline of GSH with age. The low number of studies (particularly ex vivo) and potential regional differences may have contributed to variability in the findings in brain. In blood, in contrast, GSH levels predominately were reported to decrease with advancing age (except in the oldest-old, who may represent a select group of particularly successful agers), while GSSG findings lacked consensus. The larger number of studies assessing agespecific GSH level changes in blood (N = 16) allowed for more robust consensus across studies than in brain. Overall, the literature suggests that aging is associated with increased OS in brain and body, but the timing and regional distribution of changes in the brain require further study. The contribution of brain OS to brain aging, and the effect of interventions to raise brain GSH levels on decline of brain function, remain understudied. Given that reliable tools to measure brain GSH exist, we hope this paper will serve as a catalyst to stimulate more work in this field.