# Age- Related Mild Cognitive Impairment and novel protective role of Glutathione: implications for Alzheimer's Disease

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $477,413

## Abstract

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.

## Key facts

- **NIH application ID:** 9938375
- **Project number:** 5R01AG054131-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Rajagopal Viswanath Sekhar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $477,413
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938375

## Citation

> US National Institutes of Health, RePORTER application 9938375, Age- Related Mild Cognitive Impairment and novel protective role of Glutathione: implications for Alzheimer's Disease (5R01AG054131-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9938375. Licensed CC0.

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