A 36-week open-label trial conducted at Baylor College of Medicine was recently published in Clinical and Translational Medicine. This small trial documented multiple physiological deficits among older adults compared to young adults with dramatic change across many biomarkers in older adults after 24 weeks of supplementation with the glutathione (GSH) precursors glycine (Gly) and N-acetylcysteine (NAC) together (GlyNAC).
In this study, 8 older adults (OA, age 71-80) were supplemented with Gly (1.33 mmol/kg/day) and cysteine (0.81 mmol/kg/day, as NAC). Various biomarkers were collected at the beginning of the study, as well as every 12 weeks for 36 weeks (the last 12 weeks were without supplementation). Young adults (YA) did not receive supplementation, but provided baseline values for comparison. The following differences were noted:
- Glutathione levels: RBC reduced‐GSH in OA were 76% lower than YA, but increased 200% with GlyNAC.
- Oxidative stress: TBARS and F2‐isoprostane concentrations were 845% and 318% higher in OA, but both declined ~75% following GlyNAC. 8‐hydroxy‐deoxyguanosine (8‐OHdG) levels, a marker of DNA damage, were significantly higher by 348%, but dropped 66% with GlyNAC.
- Mitochondrial function: Mitochondrial fuel oxidation was measured by calorimetry and reported as respiratory quotient, mitochondrial fatty‐acid, and glucose oxidation. OA had 54% lower mitochondrial fatty‐acid oxidation and 51% higher mitochondrial glucose oxidation, both improved by GlyNAC to YA levels.
- Inflammatory Markers: Initial levels (in OA): IL‐6 934% higher, TNFα 116% higher, hsCRP 88% higher, and IL‐10 29% lower. GlyNAC supplementation for 24 weeks modulated multiple pathways, with reduction in IL‐6, TNFα, hsCRP by 77, 57% and 49%, and an increase in IL‐10 (an anti-inflammatory cytokine) by 38%.
- Blood Sugar: Fasting plasma concentrations of glucose and insulin were 15% and 469% higher, respectively, and insulin resistance (HOMA-IR) was 571% higher. Following GlyNAC, reductions were noted for fasting plasma glucose (9% lower), insulin (55% lower) and insulin resistance (59% lower).
- Endothelial function: Measured by the following plasma biomarkers; sVCAM1 (soluble vascular cell adhesion molecule‐1), sICAM1 (soluble intercellular adhesion molecule‐1), and E‐selectin. GlyNAC supplementation decreased sICAM1, sVCAM1 and E‐selectin by 60%, 46% and 35%.
- Other: Similar differences and improvements were noted for body fat, muscle strength, gait speed, muscle breakdown, and cognitive function.
While this was a small study and not placebo-controlled, it is not the first to draw connections between glutathione expression and declining function as well as aging itself. It is also not the first to show that a drop in the synthesis of glutathione among older adults is the problem, but one that can be nearly restored with GlyNAC.
There seem to be two general explanations for insufficient glutathione and its link to many functional deficits; a decline in production observed in an aging population, and an increased demand due to either oxidative stress or environmental pollutants (and sometimes both a drop in synthesis and a higher burden of exposure may occur). For example, age-related conditions such as neurodegenerative disease, osteoarthritis, as well as overall mortality and frailty have been associated with declines in glutathione levels, while non-alcoholic fatty liver disease (NAFLD) and other hepatic diseases, as well as diabetes, are also tied to increased exposure to both environmental and oxidative stress that deplete glutathione.
Despite the cause, boosting glutathione levels supports the metabolic and mitochondrial function that underlies diverse physiological processes; participants with NAFLD given oral glutathione (300mg per day) had a median decline in ALT of nearly 13%, along with reductions in triglycerides, non-esterified fatty acids, and ferritin. Participants with type 2 diabetes, who were found to have reductions in glutathione synthesis, had levels restored when given GlyNAC at the same dose used among older adults.
Glutathione has long been recognized as perhaps the most important intracellular antioxidant and detoxifier of many endogenous and exogenous toxins, but only recently have there been new insights into its role as a key mediator of cellular and protein function. Specifically, its post-translational modification of the thiol group on many proteins may be directly responsible for cellular viability – in other words, a decrease in reduced GSH may shift the balance within a cell toward S-glutathionylation of proteins that impairs cellular function, providing signals related to apoptosis and inflammation, for example.
While NAC is often used alone to boost glutathione levels (it is the rate-limiting precursor for glutathione synthesis), its use with glycine may provide greater support than either nutrient alone. Glycine has been shown to be conditionally essential for a variety of metabolic conditions, for example, and may also provide support for methylation, particularly important as more oxidized glutathione likely contributes to global hypomethylation.
The diverse benefits seen in this study among older adults provide additional support to the idea that the age-related decline in glutathione may be responsible for many age-related deficits. It is also encouraging to see that when glutathione levels are restored, so many of the physiological changes that support metabolic function return closer to normal. It is worth noting that these gains may require ongoing supplementation to maintain, as they receded 12 weeks after stopping GlyNAC.