Nrf2 regulates a range of proteins associated with cellular repair and stress resistance, and is considered a longevity-assurance gene. There is more of it and its activities in some long-lived species, and also as a result of some of the interventions known to modestly slow aging in laboratory species. Levels of Nrf2 decline significantly with aging, however, and the balance of evidence suggests that we'd be modestly better off if that didn't happen. Researchers are slowly tracing back down the chain of cause and consequence to better understand the proximate causes of this loss:
Nrf2 is both a monitor and a messenger. It's constantly on the lookout for problems with cells that may be caused by the many metabolic insults of life - oxidative stress, toxins, pollutants, and other metabolic dysfunction. When it finds a problem, Nrf2 essentially goes back to the cellular nucleus and rings the alarm bell, where it can "turn on" up to 200 genes that are responsible for cell repair, detoxification of carcinogens, protein and lipid metabolism, antioxidant protection and other actions. "At least one important part of what we call aging appears to be a breakdown in genetic communication, in which a regulator of stress resistance declines with age. As people age and their metabolic problems increase, the levels of this regulator, Nrf2, should be increasing, but in fact they are declining."
Nrf2 is so important that it's found in many life forms, not just humans, and it's constantly manufactured by cells throughout the body. About half of it is used up every 20 minutes as it performs its life-protective functions. Metabolic insults routinely increase with age, and if things were working properly, the amount of Nrf2 that goes back into the nucleus should also increase to help deal with those insults. Instead, the level of nuclear Nrf2 declines. "The levels of Nrf2, and the functions associated with it, are routinely about 30-40 percent lower in older laboratory animals. We've been able to show for the first time what we believe is the cause."
The reason for this decline is increasing levels of a microRNA called miRNA-146a. MicroRNAs were once thought to be "junk DNA" because researchers could see them but they had no apparent biological role. They are now understood to be anything but junk - they help play a major role in genetic signaling, controlling what genes are expressed, or turned on and off to perform their function. In humans, miRNA-146a can turn on the inflammation processes that, in something like a wound, help prevent infection and begin the healing process. But with aging, this study now shows that miRNA-146a expression doesn't shut down properly, and it can significantly reduce the levels of Nrf2. This can cause part of the chronic, low-grade inflammation that is associated with the degenerative diseases that now kill most people in the developed world, including heart disease, cancer, diabetes and neurological disease. "The action of miRNA-146a in older people appears to turn from a good to a bad influence. It may be causing our detoxification processes to decline just when we need them the most."