Although elderly humans have an increased risk of cognitive decline which begins as mild cognitive impairment (MCI) and progresses to Alzheimer's disease, underlying mechanisms are poorly understood, and interventions limited. Published evidence links MCI to elevated oxidative stress caused by increased levels of reactive oxygen species (ROS). To defend against the damaging potential of ROS (which causes oxidative stress, OxS), cells normally depend on antioxidants, and Glutathione (GSH) is the main component of human endogenous intracellular antioxidant defenses. GSH is a tripeptide composed of three amino-acids, cysteine, glycine and glutamic acid. Since elderly humans are known to have an increased risk of developing elevated OxS and GSH deficiency, we investigated and reported that intracellular GSH deficiency in elderly humans occurs primarily due to intracellular deficiency of two of its precursor amino-acids cysteine and glycine, but not glutamic acid, and that these GSH-deficient elderly humans had elevated ROS levels indicating elevated OxS. Supplementing cysteine (as n-acetylcysteine) plus glycine orally as capsules for 2-weeks replenished their own intracellular concentrations, improved intracellular GSH synthesis, restored intracellular GSH levels and lowered ROS/OxS to levels seen in younger humans. GSH is also a key component of mitochondrial antioxidant defenses, and GSH depletion induces mitochondrial dysfunction with elevated ROS levels, neuronal injury and apoptosis. We studied and reported that mitochondrial dysfunction and OxS in aging (elderly humans and aged mice) can be improved by correcting GSH deficiency. These findings have implications for MCI in elderly humans. In a small ongoing open-label pilot study investigating the long-term safety and impact of supplementing cysteine and glycine on mitochondrial function, OxS and cognitive function (NCT02348762), we found significant improvements in memory, language and executive function at 4w, 12w and 24w after starting cysteine plus glycine supplementation, and these benefits appear to recede 12w after stopping these supplements. These preliminary data support the exciting possibility that cysteine plus glycine supplementation in elderly humans could improve MCI by improving GSH concentrations, mitochondrial function, and/or improving vascular/endothelial function, and by lowering OxS. The goals of this pilot trial are to (a) establish the relationship in older humans between MCI, GSH deficiency, impaired mitochondrial fuel oxidation and elevated OxS, and (b) determine proof-of- concept of whether supplementing cysteine plus glycine to correct these defects improves MCI in aging.

Public Health Relevance

Elderly humans have an increased risk of dementia which begins as mild defects in memory called mild cognitive impairment ? we do not know why this happens and there is no effective treatment. Our group found that supplementing the diets of such elderly humans with protein building blocks called cysteine and glycine improves their cognitive function, and when these supplements are stopped the benefits begin to decline. This exploratory study will find out if this effect is real and identify factors responsible for cognitive impairment (and improvement) by studying a bigger group of elderly humans with mild cognitive impairment who will be evaluated 12 weeks after receiving either cysteine plus glycine or a placebo protein, and a further 12-weeks after stopping these supplement proteins.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Ryan, Laurie M
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Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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