Free Radicals, Oxidative Stress, and You

One "anti-aging" buzzword term you'll frequently find in mainstream media and supplement catalogs is Free Radical. Free radicals are definitely real, and there's at least some indication that they play a role in some of the major health concerns associated with aging (and that antioxidant activity is worth examining). But it's important to avoid thinking in terms of "magic bullet" approaches to longevity medicine, and free radicals are quite commonly cited in literature intended to help sell antioxidant supplements or present a simplified mainstream-media-friendly description of changes that occur with aging (and what might be done to help people maintain good health well into what we now think of as "old age").

Diet And Lifestyle Optimization Aren't Enough

Most people know the term "free radical" due to the fact that dietary and supplementary antioxidants enjoyed a few years in the spotlight as potential harbingers of prolonged youth and vibrance for all. However, more recent and broader study results have been mixed at best. There are many different kinds of antioxidants, with different bioavailabilities, side effects, and chemical behaviors in the body. Some studies indicate that certain kinds of antioxidants can even be deleterious in certain populations -- the most prominent example of this is the study which indicated increased cancer rates in smokers taking beta-carotene supplements. Vitamin E was being hailed as a sort of panacea for elderly ills a few years back, but its status has drifted back into "questionable" in response to data indicating possible increased mortality in supplement-takers.

While there are certainly weaknesses in all these studies, it is clear that nobody really interested in prolonging their healthspan can simply pop a few drugstore vitamins and expect definitive positive results. Eating a healthy diet rich in fresh vegetables and low in processed starches and "empty calories" (e.g., chips, sugary sodas) can help many people lower their risk factors for particular health problems (such as diabetes), but just being alive and having metabolic processes going on in the body all the time means that oxidative stress will be present and will contribute toward the accumulation of damage no matter what you're eating.

Many health-oriented sites on the Web and popular magazine articles and books will emphasize the role of nutrients, diet, and moderate exercise in promoting longevity. If you follow the advice from the better sources in that particular pool of information, you might indeed end up gaining yourself a few extra years of health in old age. But when I think of "longevity", I don't think in terms of "living to age 80 and still being able to play golf", as most of the aforementioned sources probably do. I think in terms of "living to age 80 and not having to worry about increased risk of cancer, immune collapse, organ failure, heart disease, atherosclerosis, Alzheimer's, or any number of other things that have long resulted in pain and death for people in your age group". Why should any group of people be expected to just accept pain and death, particularly on account of a factor as ludicrously arbitrary as how old they are?

Free radical activity and resultant oxidative stress is only one subject of interest in the quest for effective longevity medicine, but it's an important one, and it certainly falls into the category of an area of science worth pursuing. Though I can certainly appreciate that many sites and books these days are promoting the value of healthy living, I think they're aiming too low, that we as a society and we as individuals who care deeply about other individuals need to realize that dietary changes and (possibly) certain supplements might only gain us a few additional years at best. In order to deal effectively with the damage caused by oxidative stress -- and by "effectively" I mean "effective at a level that no amount of dietary tweaking or lifestyle optimization can presently touch" -- we need to find ways of cleaning up the damage, and helping the body protect itself from damage.

I'll focus on two aspects of physiology that relate to oxidative stress: mitochondrial mutation and advanced glycation end-product (AGE) formation.

Dealing With The Vulnerable Mitochondrial Genome

The role of mitochondria in age-related health decline is thought to be twofold: mitochondria produce free radicals in the course of performing their necessary metabolic activity, and additionally, they contain their own DNA separate from the nuclear DNA that characterizes us as individuals at the genetic/molecular level. During ATP production, the free radicals emitted by a mitochondrion can in turn damage that mitochondrion to the point where its DNA mutates. Mutant mitochondria are problematic both because they perform their duties less effectively and because they frequently continue to replicate, effectively overwhelming the cell with poorly functioning components and stepped-up production of free radicals.

One theorized method by which mutant mitochondria and associated damage might be mitigated is being explored in MitoSENS research. From the MitoSENS page:

The goal of MitoSENS is to obviate mtDNA mutations by expressing the mtDNA genes from the nucleus. Fortunately, we would be completing a process that evolution has already started. The mitochondrial genome originally had thousands of genes, but evolution has reduced it to a mere 13 (protein encoding) genes in humans. By studying how nature transfered expression of other genes from the mitochondria to the nucleus, we can identify the necessary steps to transfer the remaining 13 genes (in humans).

The concept of MitoSENS hinges upon the idea that the 13 remaining protein-encoding genes in the mitochondrial genome would be better protected from mutation-causing damage if they were moved to the nucleus of the cell. An important component of this idea is the fact that we've got something of an evolutionary head start when it comes to this endeavor -- if thousands of the original mitochondrial genes moved into the nucleus over the course of evolution, it would be quite prudent to reverse-engineer the process by which that occurred, and see if aspects of that process could be applied to the 13 laggards of concern here.

Practically speaking, copies of these 13 genes might be placed in the nucleus (after being modified so that the mechanisms by which the mitochondrion draws in the proteins it needs will operate on them), where they would function as necessary to produce the required proteins for the mitochondrion. This would reduce the impact of oxidative stress, since it is the vulnerability of mitochondrial DNA to injury that predisposes mitochondria to injury and mutation in the first place.

The success of MitoSENS depends, among other things, on the fine-tuning of effective gene therapy. But if lab results do end up indicating its potential effectiveness in humans, we'll be that much closer to helping obviate the problems caused by mitochondrial DNA mutations, provided that it isn't discovered that the 13 genes in the mitochondrion actually need to be there for some reason.

John Allen and Carol Allen of the School of Biological Sciences, Queen Mary, University of London theorize that the presence of mtDNA relates to the division of labor between the male and female sexes in the reproductive sense -- that is, since babies are born with undamaged mitochondria, they must have therefore inherited a "protected" copy of mitochondria from their mother. Mitochondrial DNA cannot be inherited from the father, since sperm are energy-intensive themselves, meaning that the mitochondria they use would be predamaged even if it weren't destroyed in the process of fertilization.

In short, mitochondria themselves might actually be sorted into two groups with two distinct purposes: genetic template (from the mother) and somatic (for energy conversion). The Allens posit that since the mitochondrion is one of the "worst possible environments" for genes, there must therefore be a corresponding good evolutionary reason for the presence of these genes -- possibly the necessity of having proteins in the closest possible proximity to the genes that code for them in order to assure efficient energy transfer.

If this theory turns out to be true, moving the 13 remaining mitochondrial genes into the nucleus might not work -- or at least, doing so might make it impossible for mitochondria to function as effective energy converters, which would of course mean they wouldn't be of much use to us. However, regardless of whether the mitochondria really are sorted into "genetic template" and "somatic" sets, it seems that a truly effective implementation of MitoSENS would make any possible gene-protein proximity requirement moot. Whether this turns out to be possible or not remains to be seen, but at any rate, the sooner experimental data is obtained, the better.

EDIT: Commenter daedalus2u expresses his skepticism about moving mitochondrial genes into the nucleus as follows -

I am quite sure that moving mtDNA into the nucleus won't work, particularly for large cells like nerves. Mitochondria necessarilly spend a lot of time away from the nucleus, out at the tippy end of the axon. The proteins that are coded in mtDNA are the active sites of the respiratory chain. The ones coded by the nucleus are regulatory proteins. It is the active sites that will get damaged and need to be replaced. That can't happen away from the nucleus if only nuclear coded proteins are available.

AGEs and Oxidative Stress

Advanced Glycation End-products (AGEs) are, quite predictably, the chemicals produced following the conclusion of a glycation event. Glycation occurs when a sugar molecule bonds to a protein or lipid molecule in the absence of an enzyme (a protein that accelerates a particular reaction)(1). AGEs can enter the body through a person's diet (they are particularly present in "browned" and caramelized foods), and they are also produced in the body during sugar metabolism. No matter their origin, though, AGEs are thought to disrupt the functioning of cells and molecules in the body and increase the production of oxidative stress, causing further damage -- and promoting the development of conditions such as diabetes, stroke, neuropathy, and cancer.

A person could, presumably, make some dietary changes that might reduce the prevalence of AGEs in their system -- by, for instance, being more careful about what sugars they consume (since certain sugars produce more glycations than others, and fewer glycations means fewer AGEs). Additionally, food producers might do well to avoid using AGEs as they have more commonly been doing recently (as flavor and color enhancers). But regardless of what a person eats, there is no way to completely avoid AGE production -- glycation is going to happen no matter what, and it would be extremely unrealistic to expect that metabolism itself could be reverse-engineered and modified not to result in AGEs any time in the foreseeable future. Metabolism has quite a bit of evolutionary clout behind it, and rather than trying to deconstruct it (which could be time-consuming at best and disastrous at worst), it's probably best to just find out what the more detrimental aspects of metabolism are and see what can be done about them while leaving the basic metabolic mechanisms intact. This is where the concept of repairing, rather than trying to prevent, damage comes in.

It could be that AGE-breakers and related compounds might comprise some of the most easily-achievable rungs on the ladder toward actuarial escape velocity, especially when you consider that AGEs and the stress they induce on the body contribute to so many of the common conditions leading to mortality in old age (and, in fact, contribute considerably toward many of the obvious manifestations most people associate with aging). Compounds like Alagebrium have demonstrated at least some efficacy in human clinical trials in the treatment of hypertension, aortic stiffness, and kidney dysfunction.

One thing I can't help but wonder in reading about AGE-breakers is how long it will take to get such compounds into the standard pharmacopoeia, so that they are regularly prescribed for such conditions as hypertension (or even as general health-maintenance drugs, used by the same demographic that might seek out cholesterol-lowering medications, perhaps). So far, clinical trials of Alagebrium (ALT-711) seem to be indicating a low incidence of side effects, and the compound has even been approved for inclusion in an Avon skin care product.

However, there are different types of AGEs in the body, and further research and clinical trials must continue in order to identify compounds effective at addressing the most prevalent types of AGEs found in elderly humans.

In Conclusion...

Knowing how oxidative stress affects the body, and how this stress might be reduced or mitigated, takes some of the mystery out of what goes on in aging bodies -- and as the mystery dissolves further and further, it will become more and more difficult to perceive age-related death as a kind of cosmically significant force or personified figure as many today still do. I look forward to following further developments in this and other areas of science.

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1 - The enzyme-catalyzed version of sugar-molecule bonding has a different name, glycosylation.