Original Contribution
Do glutathione levels decline in aging human brain?

https://doi.org/10.1016/j.freeradbiomed.2016.01.029Get rights and content

Highlights

  • There is much controversy on whether GSH is deficient in aged brain.

  • GSH and GSSG were quantified in 74 autopsied human brains from 1D–99y of age.

  • GSH levels are similar in aged and infant human brain.

  • GSH levels do not decline during human adult brain aging.

Abstract

For the past 60 years a major theory of “aging” is that age-related damage is largely caused by excessive uncompensated oxidative stress. The ubiquitous tripeptide glutathione is a major antioxidant defense mechanism against reactive free radicals and has also served as a marker of changes in oxidative stress. Some (albeit conflicting) animal data suggest a loss of glutathione in brain senescence, which might compromise the ability of the aging brain to meet the demands of oxidative stress. Our objective was to establish whether advancing age is associated with glutathione deficiency in human brain. We measured reduced glutathione (GSH) levels in multiple regions of autopsied brain of normal subjects (n=74) aged one day to 99 years. Brain GSH levels during the infancy/teenage years were generally similar to those in the oldest examined adult group (76–99 years). During adulthood (23–99 years) GSH levels remained either stable (occipital cortex) or increased (caudate nucleus, frontal and cerebellar cortices). To the extent that GSH levels represent glutathione antioxidant capacity, our postmortem data suggest that human brain aging is not associated with declining glutathione status. We suggest that aged healthy human brains can maintain antioxidant capacity related to glutathione and that an age-related increase in GSH levels in some brain regions might possibly be a compensatory response to increased oxidative stress. Since our findings, although suggestive, suffer from the generic limitations of all postmortem brain studies, we also suggest the need for “replication” investigations employing the new 1H MRS imaging procedures in living human brain.

Section snippets

1. Introduction

Oxidative stress is considered a hallmark of human aging [1], [2], [3], [4]; accordingly a variety of antioxidants have been avidly sought as possible dietary supplements or therapeutic reagents for the purpose of anti-aging and protection from degenerative aging changes [5], [6]. The antioxidant glutathione (γ-l-glutamyl-l-cysteinylglycine, GSH, the reduced form), which is synthesized de novo by γ-glutamyl cysteine ligase and glutathione synthetase, plays a pivotal role in supporting oxidative

2. Materials and methods

This study was approved by the Centre for Addiction and Mental Health Research Ethics Board. Brain tissues were obtained at necropsy from a total of 74 subjects (male, n=44; female, n=30) who died without evidence of neurological or psychiatric disease (see Table 1 for subject information and known or suspected cause of death) or brain pathology when the fixed half brain was used for neuropathological examination [postmortem interval (PMI, from 3 to 27 h), 12.9±0.8 h, mean±SEM]. The agonal status

3.1. Overall changes of GSH from birth to senescence

Levels of GSH were not significantly correlated with age from infancy (21 h) to 99 years of age in brain regions examined with the exception of a slight negative correlation in the cerebellar cortex (r=−0.30, n=67, p=0.013; see Table 2). One way ANOVA disclosed differences amongst the six subdivided age groups in caudate (F5,64=3.68, p=0.005), frontal cortex (F5,64=6.63, p<0.0001), and cerebellar cortex (F5,61=4.42, p=0.002) but not in occipital cortex (F5,63 =1.00, p=0.43), suggesting

4. Discussion

The main finding of our study is that, in contradistinction to some preclinical animal data, brain levels of GSH did not decline with advancing age from early adulthood to senescence in the human. This suggests that aging might not compromise the glutathione antioxidant system in the adult human brain.

5. Conclusions

We found in autopsied human brain that levels of the major antioxidant GSH were not decreased during adult aging, a finding that might not be predicted based on a somewhat conflicting preclinical literature. Although our observations do suggest that the brain glutathione system is not compromised in the aging adult human, we consider our data to be preliminary and to suffer from the generic limitations inherent in all postmortem brain studies. Although measurement of GSH in living brain is not

Disclosure statement

The authors have no conflicts of interest to disclose.

Acknowledgments

This study was supported in part by the US NIDA/NIH DA07182 (SK), the New Zealand Institute of Environmental Science and Research, Ltd. (PF, SK), and the Centre for Addiction and Mental Health Foundation.

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