As we age, oxidative stress increases throughout the body as cells lose the ability to detoxify reactive oxygen species. While scientists have been aware of this process for some time, its underlying mechanisms have remained largely unknown. Recently, researchers at Northwestern University School of Medicine and the University of Michigan School of Medicine conducted a study to elucidate the underlying processes of oxidative stress in the brain and how they may lead to cognitive decline. Their research is published in eLife.
Over time, cells become less able to detoxify reactive oxygen species- byproducts of cellular respiration- and thus accumulate oxidative stress. This results in damage to the body’s cells, proteins, and DNA. There are various risk factors for oxidative stress including pollution, alcohol consumption, and obesity.
Previous research has suggests that one possible source of oxidative stress in the brain is an excess accumulation of iron. To understand more about this potential source, the researchers behind the present study examined iron levels in different organs of both young and aged mice.
In doing so, they found that the brain was the only organ to exhibit an increase in both cytoplasmic and mitochondrial iron, and that these increased iron levels were more prominant in older rather than younger mice. Further inspection found that age-related iron accumulation is linked to an upregulation of the gene that codes for hepcidin, a peptide hormone produced in the liver that controls systemic iron homeostasis.
As increased levels of hepcidin are linked to reduced levels of ferroportin-1 (FPN1), a protein that exports iron from neuronal cells, the researchers say that this genetic pathway may explain excess iron accumulation in the aged brain.
While the detailed mechanism behind iron accumulation requires more research, they say that being able to restore intracellular iron levels by suppressing brain-derived hepcidin may lead to improvements in age-related cognitive decline.
The researchers note that ‘iron chelators’- substances that bind to iron and make it biologically unavailable- already exist to treat coronary artery disease. For use in the brain, however, any such substance would need to pass through the blood-brain barrier. Towards this end, the researchers have already identified one possible substance that could be used in the brain and are thus further exploring its potential.