The Thioredoxin Antioxidant System in Aging and Longevity
Sabotaging antioxidant systems can shorten life span in model organisms, but that doesn't necessarily imply that one can lengthen life by improving on biological antioxidant capacity. Yes, oxidative stress rises with age, and the presence of too many oxidizing molecules is harmful to a cell, but the presence of those oxidizing molecules and the damage they cause to cellular machinery is also a signal that produces greater cell maintenance and other beneficial outcomes. Cellular biochemistry is complicated, and it is rarely the case that relationships are simple and linear. General delivery of antioxidants as supplements has been shown to have no effect, or even mildly negative effects, on long-term health. Targeting antioxidants to the mitochondria on the other hand appears modestly beneficial.
Thioredoxin and thioredoxin reductase are evolutionarily conserved antioxidant enzymes that protect organisms from oxidative stress. These proteins also play roles in redox signaling and can act as a redox-independent cellular chaperone. In most organisms, there is a cytoplasmic and mitochondrial thioredoxin system. The role of the cytoplasmic and mitochondrial thioredoxin systems in determining lifespan has been examined in multiple genetic model organisms through increasing or decreasing the expression of thioredoxin or thioredoxin reductase.
While there is evidence for a contribution of the thioredoxin systems to longevity in yeast, worms, flies, mice, and humans, the relative importance of each component of these systems varies between species. In yeast and C. elegans, disruption of the cytoplasmic thioredoxin system results in the largest detrimental effect on longevity, while disruption of the mitochondrial thioredoxin system has minimal impact on lifespan. In Drosophila, both the cytoplasmic and mitochondrial thioredoxin systems affect lifespan, with the largest effect observed with the cytoplasmic thioredoxin reductase.
In mice, both the cytoplasmic and mitochondrial thioredoxin systems are essential for life as disruption of any of the components results in embryonic lethality. Thus, it appears that in more complex organisms, there is a greater reliance on thioredoxin systems for survival and an increased importance of the mitochondrial thioredoxin system compared to less complex organisms.
While it is not possible to genetically manipulate the expression levels of thioredoxin system genes in humans, multiple studies have identified genetic variants that are associated with extended longevity. In a study comparing oldest-old individuals (age 92-93) with middle-aged individuals, an allele of the cytoplasmic thioredoxin reductase gene TXNRD1 was found to be associated with longevity. These results suggest that the thioredoxin system may also contribute to longevity in humans.