Iron, Antioxidants, Chelation, and the Damage of Aging

Oxidative damage to cells and important molecules is generally considered an important root cause of aging, though there's certainly a great deal of ongoing debate in the scientific community over exactly how and why this is the case. I noticed an open access review paper today that makes an effort to tie inconsistencies in the observed behavior of antioxidants - sometimes demonstrated to prolong healthy life and otherwise improve matters, and more often shown to do very little - with the presence of iron. The main foundation for this theory is that:

in some circumstances (especially the presence of poorly liganded iron) molecules that are nominally antioxidants can actually act as pro-oxidants. The reduction of redox stress thus requires suitable levels of both antioxidants and effective iron chelators.

An iron chelator is a substance that can bind iron and remove it from ongoing reactions with other molecules - such as the way iron turns mild oxidants into very damaging oxidants.

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation.

Also of interest: iron has been implicated in a different area of aging biochemistry, the buildup of chemical junk called lipofuscin in lysosomes within our cells that prevents the normal processes of cellular recycling and generally makes a mess of things. For example, when cells can't deal with iron correctly, lipofuscin becomes an even bigger problem:

Further experiments confirmed that when TRPML1 is defective, iron becomes trapped in the lysosome. One result of the buildup is formation of a brownish waste material, lipofuscin, known as the "aging pigment." In skin cells, lipofuscin is the culprit responsible for the dreaded liver spots that appear with increasing age, but in nerve, muscle and other cells, its accumulation has more serious consequences.

Precisely targeted chelation - aimed at the lysosomes though gene engineering or other sophisticated strategies, which won't happen using anything you can buy in the store - has been proposed as a way to deal with lipofuscin accumulation. This is analogous to the way in which antioxidants precisely targeted to the mitochondria, oxidative damage central in your cells, have a good track record of extending healthy life in experiments with mice and lesser animals.

So back to the original paper I mentioned, which concludes:

Overall we argue, by synthesising a widely dispersed literature, that the role of poorly liganded iron has been rather underappreciated in the past, and that in combination with peroxide and superoxide its activity underpins the behaviour of a great many physiological processes that degrade over time.

Which may be the case. I'm still sold on the idea that where you target antioxidants in the cell is the dominant explanation for experimental observations to date, however. Targeted to the mitochondria, we see a balance of experiments showing extended healthy life. Targeted elsewhere, the balance of experiments show no significant effect. When we consider that the cell is a highly specialized grouping of components, each serving a very different purpose, this sort of result makes a lot of sense.

Comments

Thanks to Reason for drawing attention to my Open Access review at
http://www.biomedcentral.com/1755-8794/2/2. Actually I did comment that intracellular targeting of anti-oxidants/ chelators would be a good idea, so I fully agree with this thinking. I also blog about this kind of thing (including hormesis) at http://blogs.bbsrc.ac.uk/
Kind regards,
Douglas.

Posted by: Douglas Kell at June 1st, 2009 12:56 AM

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