Maintaining glutathione levels with the use of N-acetyl cysteine (NAC) may be a worthwhile preventative strategy in combating the effect of xenobiotics in an older population, according to a recent experimental study.
Ageing causes a disruption in the cellular redox homeostatic mechanisms that protect against free radical damage from oxidative, environmental, pathological and toxicological stressors. The resulting increase in reactive oxygen species (ROS) and reactive nitrogen species (RNS) is causally linked with many disease states.
Another effect of ageing is a decrease in the function of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription protein that plays a key role in stimulating the production of endogenous antioxidants and enzymes. As the gene expression of the phase 2 detoxification enzymes is reliant on hepatic Nrf2 activation, the ability to detoxify effectively may be limited in an ageing population.
Therefore, researchers tested if the age-related decline in Nrf2 correlated with a reduction in glutathione (GSH) dependent detoxification pathways, and whether providing a pre-treatment of NAC moderated this decline.
A synthetic vitamin K derivative (menadione) with a high redox capacity was used to increase free radical activity. This was also chosen as the ROS produced are primarily detoxified by GSH-dependent mechanisms.
The results indicated a higher susceptibility to menadione and a greater loss of GSH hepatocytes and glutathione peroxidase 4 concentrations (GPX4) in the older subjects. It showed an >80% decline in GSH hepatocytes, compared to the younger subjects with a 60% decline. Additionally the hepatic GSH reserves were more rapidly and extensively lost.
As GPX4 works at the expense of GSH and GSH is diminished with age, researchers provided the subjects with NAC to replenish the cysteine needed for GSH production. Pre-treatment of NAC demonstrated significant increases in the resistance to menadione free radical activity, with a reversal of the age-related susceptibility.
The researchers concluded that ‘Providing NAC to increase substrate supply of cysteine may circumvent the age-related decline in GSH synthetic enzymes that attenuation of Nrf2 engenders. Thus, using NAC as a prophylactic instead of an intervention may allow GSH levels to be maintained for detoxification in older adults.’
- Thomas NO, Shay KP, Kelley AR, et al. Glutathione maintenance mitigates age-related susceptibility to redox cycling agents. Redox Biol. 2016;10:45-52. [Full Text]