Elevated oxidative stress and subsequent mitochondrial dysfunction are associated with biological aging. Glutathione (GSH, γ-glutamylcysteinylglycine) the most abundant, endogenous, intracellular antioxidant, could protect mitochondria from oxidative stress, whereas GSH deficiency accelerates the rate of aging and aging-related diseases. In prior rodent studies, the supplementation of glycine and n-acetylcysteine (GlyNAC), which includes the glutathione precursor amino acids glycine and cysteine provided as NAC, can 1) correct GSH synthesis and concentrations, 2) lower ABBREVIATION OxS, and 3) improve mitochondrial dysfunction and insulin resistance. However, no randomized clinical trial has yet evaluated the feasibility of whether GlyNAC supplementation in older adults could improve GSH deficiency, OxS, IR, mitochondrial dysfunction, physical function, and aging.
This double-blinded RCT included 12 young adults (21-40 years-old) and 12 older adults (61-80 years-old) with a body mass index (BMI) >27, but excluding those with known diabetes, untreated hypo/hyperthyroidism, heart disease, difficulty walking, or pregnancy, etc. Both groups received GlyNAC at doses of 100 mg/kg/d each of glycine and NAC, as well as other 12 older adults receiving 200 mg/kg/d of isonitrogenous alanine placebo for 16 weeks.
GSH concentrations in muscle or red blood cells at baseline was lower in the older adult group compared to the young adult group. After GlyNAC treatment, GSH concentrations in muscle and red blood cells increased but decreased markers for oxidative stress, while no improvements were seen in the young adult group or the placebo-treated older adult group. Compared to the younger adult group, older adult groups at baseline showed a lower level of gait speed and 6-minute walking distance, but 16 weeks of GlyNAC treatment significantly increased gait speed. Additionally, supplementing GlyNAC was also closely associated with the hallmarks of aging, including mitochondrial dysfunction, mitochondrial biogenesis, intercellular communication, nutrient sensing, loss of proteostasis, stem-cell exhaustion, genomic damage, cellular senescence, and telomere attrition. Specifically, regarding mitochondrial dysfunction, only the older adult cohort treated with GlyNAC significantly lowered 65% mitochondrial glucose oxidation (MGO), and upregulated 78% mitochondrial fatty-acid oxidation (MFO) towards levels not different from the young adult group. In older adults, GlyNAC supplementation upregulated markers of mitochondrial biogenesis and energy metabolism, improved intercellular communication, as well as down-regulated of HOMA-IR, fasting insulin, and (pAMPK)/AMPK and thus indicating alterations of nutrient sensing. Additionally, GlyNAC supplementation resulted in the upregulation of mitophagy and Pax7 expression, as well as downregulation of 8-OHdG, p16INK4α, and Muscle POT1 expression, respectively indicating the impacts on loss of proteostasis, stem-cell exhaustion, genomic damage, cellular senescence, and telomere attrition. GlyNAC supplementation for 16-weeks in older adults decreased triglyceride concentrations, waist circumference, with a trend toward decreasing both body weight and BMI. The trial reported no adverse events.
Next, let’s discuss the results and the limitations of this study, including: 1) why does protein supplementation not improve intracellular GSH or OxS, but GlyNAC does? And 2) what would be the ideal GlyNAC supplementation treatment period; i.e. why was this study conducted for 16-weeks?
To answer the questions, we need to understand how GSH is generated. GSH synthesis occurs in two steps, catalyzed by the enzymes glutamate cysteine ligase and GSS, to form the tripeptide glutathione. GSH is an intracellular antioxidant, synthesized inside cells and not via plasma delivery, consumption, or administration. Each tissue maintains a different amount of GSH (based on its metabolic demands) by providing the required synthesis building blocks rather than providing the protein itself. Intracellular GSH can detoxify H2O2 to water, thereby protecting membranes, protein, lipid, and the genome from oxidative damage. As for the best treatment duration, in an open-label trial GlyNAC supplementation for 16-weeks or 24-weeks resulted in similar outcomes, while withdrawing GlyNAC for 12-weeks led to loss/decrease of benefits.
Limitations of this study include a small sample population of healthy older adults with high BMI in order to ensure safety. What remains unanswered is whether it is safe for older adults with normal triglyceride concentrations (i.e. impacts on immune system) and/or with age-related diseases including cancer. This study does also not control for variables, incl. dietary patterns of the study volunteers.
In summary, this RCT found that GlyNAC supplementation in older adults significantly improved/corrected GSH deficiency, OxS, mitochondrial dysfunction, physical function, waist circumference, and 7 hallmarks of aging affecting mitochondria, inflammation, IR, mitophagy, genomic damage, cellular senescence, and stem cells. This article provides a safe treatment, a beneficial supplement and possibility for elderly people to live a healthy life and prolong their lifespan. Hopefully, there will be more clinical research about safe and efficient treatment in elderly people related to age-related diseases in the future.
– Jingyi Yang, Research Assistant at USC Longevity Institute