Fight Aging!

The path from laboratory to clinic is a lengthy one. It helps to keep an eye on specific projects across the years to better calibrate one's expectations for new lines of research. Today's example of the mitochondrially targeted antioxidant molecule SkQ1, a form of plastiquinone, has been under development for quite the long time, starting with Russian lab work that first attracted my notice ten years ago - and of course had been going on for quite some time prior to that, stuck on the wrong side of the language barrier to catch the best opportunities for investment and interest. Following years of animal studies of various sorts, SkQ1 is presently being brought to the clinic by the European company Mitotech. They are in the midst of a human trial for dry eye syndrome and have recently obtained a patent in the US:

Mitotech S.A., a Luxembourg based clinical stage biotechnology company focused on age-related disorders, announced that it received a U.S. patent covering deceleration of aging in living organisms by its lead compound SkQ1. "The main aspect of the mechanism of action of our lead compound is protecting mitochondria from oxidative stress, which is a confirmed key factor in cell aging. That's one of the reasons SkQ1 proved to be effective in a wide spectrum of models of age-related disorders. This particular patent, however, may pave the way for Mitotech to pursue aging as a standalone indication. Of course, that would be a major undertaking in terms of the volume of clinical development and regulatory work, but we think it's an attractive opportunity and the field is wide open for a break-through technology."

One of the more intriguing outcomes of targeted mitochondrial antioxidant research is that it has shown promise as a treatment for a number of quite different eye conditions, such as cataracts, glaucoma, and dry eye syndrome. That is the path that was eventually chosen for initial commercial development. Dry eye syndrome is not to be dismissed lightly; ask anyone unfortunate enough to have suffered it. It is quite prevalent in old age and produces an negative impact on quality of life far larger than one might imagine would result from the tiny systems failures that cause the condition. That said, the reason that this community is interested in mitochondrially targeted antioxidants is because of the possibility that they can slow one of the forms of damage that contributes to degenerative aging, within which dry eye syndrome is but the tiniest mote.

As for any discussion of mitochondrially targeted antioxidants such as plastiquinones, SS-31, and MitoQ, it is worth taking a moment to point out that they are very different from the common or garden antioxidants that you can buy in the store. It is generally accepted in the research community that taking general antioxidant supplements is modestly harmful over the long term. In animal studies it tends to reduce life span by a modest amount. One of the mechanisms by which this might occur is that antioxidants will intercept and suppress the excess reactive oxygen species generated during exercise. That excess is a signal, and spurs a range of activities that result in everything from additional cellular maintenance to muscle repair and growth. This is something to bear in mind. Mitochondrially targeted antioxidants, on the other hand, localize to the mitochondria in cells. They primarily soak up reactive molecules there, not generally throughout tissues. This produces a range of effects because mitochondria are of great importance to cellular metabolism, and also of great importance in the aging process.

There are a couple of things going on for mitochondria in aging. The one that is the subject of more research is a downstream result of the many forms of molecular damage in aging, in which mitochondrial operation in cells declines in general, and tissues suffer as a result. This is a very complex and still poorly understood situation governed by epigenetics and scores of related, interdependent reactions to the low-level damage of aging, and which varies widely between tissue types and individuals. The less well researched issue is that mitochondria suffer damage to their DNA, separate from that of the cell nucleus. If genes essential to normal mitochondrial operation are deleted or damaged as a result, then the mutant mitochondria can either replicate more rapidly or become more resistant to quality control than their undamaged peers - it isn't clear which is the case at this point. Regardless, such mutants quickly take over cells and run rampant, turning these host cells into damaging exporters of reactive molecules that can cause all sort of harm in tissues both near and far. How does this DNA damage come about? It might be breakage during replication, but the consensus candidate has long been the generation of reactive oxygen species that happens inside mitochondria, right next door to their vulnerable DNA. Experiments with increased levels of natural mitochondrial antioxidants such as catalase provide supporting evidence for this proposition. Delivering artificial mitochondrially targeted antioxidants is thought to reduce the pace of mutational damage, and thus modestly improve healthy life span in this way.

Given the complexity of mitochondrial biochemistry, and its influential role on metabolism as a whole, I should say that almost everything I've said above has been disputed by one or more research groups at some point in time. The consensus is of varied resilience and always under attack. When it comes to the effects of mitochondrially targeted antioxidants on various medical conditions, their relevance may be as much damping down some of the oxidative signaling produced by mitochondria in inflamed tissues, or protecting mitochondria from an influx of oxidative molecules arriving from elsewhere, as anything else. This seems to help slow progression of a number of diseases with inflammatory components, as inflammation and oxidative stress go hand in hand. For all the focus on aging in the materials on SkQ1, the more rigorous life span studies of SkQ1 show only modest extension of life in short-lived animals, such as the recent demonstration of 10% life extension in flies. This is really not large enough to make it something that I'd consider worth chasing as an intervention in aging; short-lived species have very plastic life spans, and a 10% gain in flies is small in comparison to, say, the outcomes for calorie restriction. Get out there and exercise more and eat less, and you'll probably be doing more for your long-term health. If, however, as seems to be the case, these targeted antioxidants can have a significant positive impact on the later stages of a fair number of different age-related diseases that involve raised levels of oxidative stress and inflammation, well, then that was still research and development time well spent, even if it wasn't the outcome hoped for.