Antioxidants of the sort you can buy at the store and consume are pretty much useless: the evidence shows us that they do nothing for health, and may even work to block some beneficial mechanisms. Targeting antioxidant compounds to the mitochondria in our cells is a whole different story, however. Mitochondria are swarming bacteria-like entities that produce the chemical energy stores used to power cellular processes. This involves chemical reactions that necessarily generate reactive oxygen species (ROS) as a byproduct, and these tend to react with and damage protein machinery in the cell. The machinery that gets damaged the most is that inside the mitochondria, of course, right at ground zero for ROS production. There are some natural antioxidants present in mitochondria, but adding more appears to make a substantial difference to the proportion of ROS that are soaked up versus let loose to cause harm.

If mitochondria were only trivially relevant to health and longevity, this wouldn't be a terribly interesting topic, and I wouldn't be talking about it. The evidence strongly favors mitochondrial damage as an important contribution to degenerative aging, however. Most damage in cells is repaired pretty quickly, and mitochondria are regularly destroyed and replaced by a process of division - again, like bacteria. Some rare forms of mitochondrial damage persist, however, eluding quality control mechanisms and spreading through the mitochondrial population in a cell. This causes cells to fall into a malfunctioning state in which they export massive quantities of ROS out into surrounding tissue and the body at large. As you age ever more of your cells suffer this fate.

In recent years a number of research groups have been working on ways to deliver antioxidants to the mitochondria, some of which are more relevant to future therapies than others. For example gene therapy to boost levels of natural mitochondrial antioxidants like catalase are unlikely to arrive in the clinic any time soon, but they serve to demonstrate significance by extending healthy life in mice. A Russian research group has been working with plastinquinone compounds that can be ingested and then localize to the mitochondria, and have shown numerous benefits to result in animal studies of theSkQ series of drug candidates.

US-based researchers have been working on a different set of mitochondrially targeted antioxidant compounds, with a focus on burn treatment. However, they recently published a paper claiming reversal of some age-related changes in muscle tissue in mice using their drug candidate SS-31. Note that this is injected, unlike SkQ compounds:

Mitochondrial targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice

Mitochondrial dysfunction plays a key pathogenic role in aging skeletal muscle resulting in significant healthcare costs in the developed world. However, there is no pharmacologic treatment to rapidly reverse mitochondrial deficits in the elderly. Here we demonstrate that a single treatment with the mitochondrial targeted peptide SS-31 restores in vivo mitochondrial energetics to young levels in aged mice after only one hour.

Young (5 month old) and old (27 month old) mice were injected intraperitoneally with either saline or 3 mg/kg of SS-31. Skeletal muscle mitochondrial energetics were measured in vivo one hour after injection using a unique combination of optical and 31 P magnetic resonance spectroscopy. Age related declines in resting and maximal mitochondrial ATP production, coupling of oxidative phosphorylation (P/O), and cell energy state (PCr/ATP) were rapidly reversed after SS-31 treatment, while SS-31 had no observable effect on young muscle.

These effects of SS-31 on mitochondrial energetics in aged muscle were also associated with a more reduced glutathione redox status and lower mitochondrial [ROS] emission. Skeletal muscle of aged mice was more fatigue resistant in situ one hour after SS-31 treatment and eight days of SS-31 treatment led to increased whole animal endurance capacity. These data demonstrate that SS-31 represents a new strategy for reversing age-related deficits in skeletal muscle with potential for translation into human use.

So what is SS-31? If look at the publication history for these authors you'll find a burn-treatment focused open access paper that goes into a little more detail and a 2008 review paper that covers the pharmacology of the SS compounds:

The SS peptides, so called because they were designed by Hazel H. Sezto and Peter W. Schiler, are small cell-permeable peptides of less than ten amino acid residues that specifically target to inner mitochondrial membrane and possess mitoprotective properties. There have been a series of SS peptides synthesized and characterized, but for our study, we decided to use SS-31 peptide (H-D-Arg-Dimethyl Tyr-Lys-Phe-NH2) for its well-documented efficacy.

Studies with isolated mitochondrial preparations and cell cultures show that these SS peptides can scavenge ROS, reduce mitochondrial ROS production, and inhibit mitochondrial permeability transition. They are very potent in preventing apoptosis and necrosis induced by oxidative stress or inhibition of the mitochondrial electron transport chain. These peptides have demonstrated excellent efficacy in animal models of ischemia-reperfusion, neurodegeneration, and renal fibrosis, and they are remarkably free of toxicity.

Given the existence of a range of different types of mitochondrial antioxidant and research groups working on them, it seems that we should expect to see therapies emerge into the clinic over the next decade. As ever the regulatory regime will ensure that they are only approved for use in treatment of specific named diseases and injuries such as burns, however. It's still impossible to obtain approval for a therapy to treat aging in otherwise healthy individuals in the US, as the FDA doesn't recognize degenerative aging as a disease. The greatest use of these compounds will therefore occur via medical tourism and in a growing black market for easily synthesized compounds of this sort.

In fact, any dedicated and sufficiently knowledgeable individual could already set up a home chemistry lab, download the relevant papers and synthesize SkQ or SS compounds. That we don't see this happening is, I think, more of a measure of the present immaturity of the global medical tourism market than anything else. It lacks an ecosystem of marketplaces and review organizations that would allow chemists to safely participate in and profit from regulatory arbitrage of the sort that is ubiquitous in recreational chemistry.

Broad public understanding and support is a necessary part of scaling rejuvenation research programs like SENS into a scientific community the size of the cancer or Alzheimer's establishments. At a small scale, even up to millions of dollars, research funds can be obtained whether or not the man in the street knows or cares about what is happening in the laboratory. Philanthropists can be convinced, foundations approached, and so forth: all that is needed there are scientific credentials and a talent for opening doors and making connections.

Once you start talking about sourcing hundreds of millions of dollars, however, the goal must be something that most people know of and approve. That level of resources requires scores of funding organizations and laboratories, an ecosystem of hundreds of researchers willing to join in, an eager next generation being taught in graduate programs, and the persuasion of thousands of people who make funding and research allocation decisions. None of that can credibly happen for a research program that lacks support in the public eye. Unpopular or unknown research takes place, certainly, but awareness must accompany growth.

Numerous different approaches can be taken in raising awareness for a particular branch of scientific research. One method of bootstrapping focuses first on raising research funds from philanthropists in the absence of public support - which is challenging, but you have to start somewhere - and then publicizing ongoing research programs through the normal channels. A subset of the overlapping journal and media industries deals with research publicity, for example, and that is one way to talk to the public. Another approach is the years-long drudgery of advocacy: knocking on doors, giving talks, going to conferences, making connections, and writing on the topic. These two are largely the approach taken by the SENS Research Foundation and Methuselah Foundation, and are effectively a trade of time for money.

There are more expensive methods of publicity, such as making infomercial-length programs and putting them in front of television audiences, for example. Production costs will set you back $50,000 for a few-minute piece and $250,000 for a 30 minute slot, if done by professionals who know the business. Per-showing cost for a single channel can be thousands of dollars. If someone gives you this sort of coverage for free - such as by deciding to make a film about your efforts - then obviously you don't look the gift horse in the mouth, but for most initiatives the filmmakers don't come knocking until there is already so much attention that their efforts are largely moot.

There is a good reason as to why research charities don't tend to go in for this sort of thing, even aside from considering whether or not a cost-benefit argument could be made for creating video publicity materials - something that is hard to do for intangibles like public attention. The good reason is that most research is cheap. Consider that Jason Hope's $500,000 donation to the SENS Research Foundation made back at the end of 2010 continues to keep two labs working on the foundation of AGE-breaker therapies. For the $250,000 cost of a profession publicity video for public consumption you could set up a modest lab and hire two smart industry biotechnologists for a year - or get twice those resources working in an established academic lab, where remuneration is nowhere near as grand and economies of scale are somewhat better.

Thus it isn't hard to make the choice between expensive publicity and getting research done, given that progress in research is (a) the point of the exercise, and (b) generates its own opportunities for low-cost publicity as results roll in. If we were still in a 1970s-like situation regarding the cost of biotechnology then perhaps one could field an argument for greater expenditures on publicity, because without large-scale funding there would be no meaningful progress, and public support is necessary for that end goal. Things are different today, however - and just as well. Capable, low cost biotechnology makes meaningful progress in medicine much more likely to occur, as it enables smaller, less wealthy, and more numerous groups to contribute to advancing the state of the art.

A range of methods to target specific types of cell in the body are presently under development: immune cells, nanoparticles, viruses, and bacteria can all be used to deliver payloads to specific cells, provided that a suitable sensor mechanism can be established for the target in question. One of the benefits of this approach is that almost all existing methods used to destroy cells can be adapted for this new world of precision therapies. Tiny amounts of proven chemotherapy compounds can be loaded into nanoparticles and remain effective in destroying the cancer cells they are delivered to, but the severe side effects of standard chemotherapy are almost entirely eliminated. Chemotherapy in its present incarnation is a very unpleasant exercise, and targeting is a great leap forward in the application of chemical attacks on cancer.

Radiation is also used as a cancer treatment. As for chemotherapy, the present state of the art in available treatments involves a range of techniques that aim to to hurt the cancer more than the rest of the patient. It's still a pretty unpleasant exercise - not something that anyone would choose to undergo unless it were the least worst available option. Like chemotherapy compounds, radioactive compounds can also be cut down to amounts as small as individual atoms and loaded up onto nanoparticles or other delivery systems. For example, last month researchers reported on the use of a type of bacteria that only infects cancer cells as a carrier for radioactive materials that destroy those infected cells.

Tiny amounts of highly radioactive compounds are like tiny amounts of poison - they don't cause much harm at all outside the target cells, and this is the key to building therapies that have minimal side-effects. Here is another recent example of targeted therapy development using radioactive materials, but with nanoparticles as the delivery agent this time:

Researchers Develop Radioactive Nanoparticles that Target Cancer Cells

Cancers of all types become most deadly when they metastasize and spread tumors throughout the body. Once cancer has reached this stage, it becomes very difficult for doctors to locate and treat the numerous tumors that can develop. Now, researchers at the University of Missouri have found a way to create radioactive nanoparticles that target lymphoma tumor cells wherever they may be in the body.

In an effort to find a way to locate and kill secondary tumors [researchers] have successfully created nanoparticles made of a radioactive form of the element lutetium. The MU scientists then covered the lutetium nanoparticles with gold shells and attached targeting agents. [Previous research] has already proven the effectiveness of similar targeting agents in mice and dogs suffering from tumors. In that research, the targeting agents were attached to single radioactive atoms that were introduced into the bodies of animals with cancer. The targeting agents were able to seek out the tumors existing within the animals, which were then revealed through radio-imaging of those animals.

In their current research, the MU scientists have shown the targeting agents can deliver the new radioactive lutetium nanoparticles to lymphoma tumor cells without attaching to and damaging healthy cells in the process. "This is an important step toward developing therapies for lymphoma and other advanced-stage cancers. The ability to deliver multiple radioactive atoms to individual cancer cells should greatly increase our ability to selectively kill these cells."

Twenty years from now cancer will be comparatively well controlled: the trend is towards highly effective therapies, thousands of researchers are involved in building them, and a lot of money is flowing into this work. Cancer doesn't worry me anywhere near as much as common causes of sudden death in the elderly such as heart failure and stroke. If, against the odds, you find yourself nailed by cancer in the 2030s - and I think that this is an unlikely outcome for anyone in a wealthier region of the world - then even the worst case scenarios still allow you plenty of time to wrap up matters and arrange your own cryopreservation. Heart failure and stroke arrive with no such warning, and the only way to reliably deal with all of the causes of functional degeneration in the heart and brain is to implement SENS rejuvenation biotechnologies. Despite tremendous progress in recent years the SENS program remains in a comparatively early stage of funding and support within the research community - it is tiny in comparison to the cancer research community, and funding is the greatest obstacle to faster progress.

It wouldn't be too far wrong to regard ourselves as ambulatory chemical processing plants: biology is very complicated and highly organized chemistry, a collection of reactions and products. The operation of our metabolism is as much based on processing oxygen as it is on processing food. Thus you don't don't have to wander all that far into the scientific literature on the biology of aging to find mention of reactive oxygen species (ROS), the mechanisms of oxidative stress, and the various oxidative theories of aging, such as the mitochondrial free radical theory of aging. All sorts of reactive molecules containing oxygen can be found in our biology at any given time, an inevitable byproduct of being an oxygen-processing species.

Cells and their components are intricate assemblies of protein machinery, but all it takes to disrupt a component is for it to react with a passing ROS molecule. It'll quickly be replaced by a cell's repair mechanisms, but in the meanwhile it is broken. Oxidative stress refers to the level of ongoing damage caused by ROS; ambient levels of ROS can rise due to environmental circumstances such as heat or radiation exposure, but we're more interested in what happens during aging. Older theories of aging based on oxidative damage suggest that aging is caused by an accumulation of this damage, and indeed levels of oxidative stress rise with aging, but the relationship isn't that simple.

Evolutionary selection is very ready to use any tool to hand. An individual's biology is a set of interconnected systems that share component molecules, and which are tied together into feedback loops and signal exchanges. Just like every other molecule in our biology reactive oxygen species were long ago co-opted into all sorts of vital mechanisms. This means that it is far from straightforward to talk about ROS and aging, as there are many different roles in metabolism for what at first sight seems to be nothing but a damaging, toxic class of molecule, and these roles are affected by rising levels of ROS in different ways. The specific location in cells and the body and the present circumstances all matter when it comes to what happens when ROS levels increase.

For example, it has been shown that some of the benefits of exercise are based on slightly increased levels of ROS as a signal. Increased use of muscle results in a higher output of ROS from the mitochondrial power plants working away in muscle cells, and cells react to this change with greater housekeeping efforts - an outcome known as hormesis. If tissues and bloodstream are bathed in antioxidants that soak up those ROS, then these benefits of exercise can be blocked. Thus general use of antioxidants in a normal metabolism may potentially do more harm than good.

Similarly, it seems fairly clear at this point, based on work in mice, that targeting antioxidants specifically to mitochondria is a beneficial strategy, and this presumably works by soaking up ROS at source before they can cause harm. How does this impact exercise and its effects on health? As yet unknown. Further, a range of life-extending genetic alterations in nematode worms work by globally increasing or globally reducing ROS output from mitochondria, with either outcome resulting in longer-lived worms. Increased ROS works through hormesis, by increasing repair activities, while reduced ROS output directly reduces damage, or at least that is the present consensus.

Mitochondria are important in aging - that much is worth taking away as a lesson here. I view much of the research into ROS and mitochondria as little more than a confirmation that it is vital to develop the range of envisaged biotechnologies that enable mitochondrial repair and replacement. The mitochondrial free radical theory of aging suggests that aging is in large part caused by the way in which mitochondria damage themselves with their own ROS output. It is that damage that is the important thing, not the ROS, but mitochondrial damage has such a great impact on aging and longevity that even modest changes in either (a) the pace at which they damage themselves or (b) the likelihood of damaged mitochondria being replaced by cellular maintenance mechanisms, both of which are influenced by rates of ROS production, have a measurable effect on longevity in shorter-lived species.

But back to complexity resulting from the uses that ROS are put to in our biology. Here are a couple of papers that illustrate a few more of the ways in which nothing is simple:

Rejuvenation of Adult Stem Cells: Is Age-Associated Dysfunction Epigenetic?

The dysfunctional changes of aging are generally believed to be irreversible due to the accumulation of molecular and cellular damage within an organism's somatic cells and tissues. However, the importance of potentially reversible cell signaling and epigenetic changes in causing dysfunction has not been thoroughly investigated. Striking evidence that increased oxidative stress associated with hematopoietic stem cells (HSCs) from aging mice causes dysfunction has been reported. Forced expression of SIRT3, which activates the reactive oxygen species (ROS) scavenger superoxide dismutase 2 (SOD2) [to] reduce oxidative stress, functionally rejuvenates mouse HSCs.

These data, combined with numerous other reports, suggest that ROS act as a signal transducer to play a critical regulatory role in HSCs and at least in some other stem cells. It is likely that ectopic expression of SIRT3 restores homeostasis in gene expression networks sensitive to oxidative stress. This result was surprising because age-associated damage from impaired DNA repair had been thought to be irreversible in old HSCs. These data are consistent with a hypothesis that potentially reversible processes, such as aberrant signaling and epigenetic drift, are relevant to cellular aging. If true, rejuvenation of at least some aged cells may be simpler than generally appreciated.

Endothelium, heal thyself

[The endothelium] cooperates with leukocytes to create openings to provide the infection-fighting cells ready access to their targets. By and large, these ensuing "micro-wounds" are short-lived; as soon as the cells have crossed the endothelium, these pores and gaps quickly heal, restoring the system's efficient barrier function. In cases when these gaps fail to close - and leakage occurs - the results can be devastating, leading to dramatic pathologies including sepsis and acute lung injury.

[Researchers] set up experimental models that mimicked acute, intense inflammation. Using dynamic time-lapse and high-resolution confocal microscopy, the investigators could see the process by which leukocytes were breaching the endothelial cell. In the course of a 10-minute span, they observed that a single endothelial cell tolerated the passage of at least seven leukocytes directly through its body, and that within this brief period, the gaps closed, leaving no sign of the pores.

This response [is] fundamentally dependent on proteins (i.e. NADPH oxidases) that can generate reactive oxygen species (ROS), specifically hydrogen peroxide. ROS are widely implicated in causing cellular, tissue and organ damage when present at excessive levels in the body. But, these findings show that low levels of these molecules - when produced in discrete locations within the cell - are highly protective. "It's tempting to speculate that excess ROS causes vascular breakdown by short-circuiting the recuperative response process and creating 'white noise' that dis-coordinates and disrupts micro-wound healing. It appears that we've got an essential homeostatic self-repair mechanism that is completely dependent on the generation of intracellular ROS, which is opposite to our typical thinking about ROS in cardiovascular health and disease."

In the past few years two ongoing studies of long term calorie restriction (CR) in primates have started to publish their results on longevity. Both research programs have been underway for more than 20 years, one run by the National Institute on Aging and the other by the University of Wisconsin-Madison. Researchers have followed small groups of rhesus monkeys to see how the benefits to health and life expectancy resulting from a restricted calorie intake compare with those obtained in mice and other short-lived species. At this point the results are ambiguous, unfortunately: one study shows a modest gain in life expectancy that has been debated, while the other shows no gain in life expectancy, and that result has also been debated.

Calorie restriction does produce considerable benefits in short term measures of health in rhesus monkeys and humans, that much is definitive, but the present consensus in the research community is that it doesn't greatly extend life in longer-lived primates - perhaps a few years at most in humans. Differences and issues in the two primate studies mean that effects of this size on longevity may never be clear from the data generated. Other factors will wash it out, such as differences in the diet fed to the control groups, or the different age at which calorie restriction started. Certainly the results so far support the conjecture that calorie restriction is exceedingly good for health but doesn't have the same impressive effects on longevity as it does in short-lived animals. Why that is the case is a puzzle to be solved - but not one that has a great deal of relevance to the future of human longevity. One would hope that we'll be a long way down the road to rejuvenation therapies by the time another set of better constructed primate studies are nearing completion.

You'll find a long article over at the SENS Research Foundation that examines the NIA and Wisconsin primate studies, their differences, and their results in great detail - but I'm just going to skip ahead and quote some of the conclusions:

CR in Nonhuman Primates: A Muddle for Monkeys, Men, and Mimetics

In this post, I have sketched out in detail two major possible interpretations of the disparate mortality outcomes in the NIA and WNPRC nonhuman primate CR studies. The "Diminishing Returns" hypothesis posits that the health and longevity benefits of "CR" reported in the WNPRC study were merely the unsurprising results of one group of animals being fed a high-sucrose, low-nutrient chow on a literally ad libitum basis, and another group being kept to portions of that diet low enough to avoid the deranged metabolisms flowing from obesity and (possibly) fructose toxicity. In this interpretation, the more severe restrictions of energy intake imposed at the NIA - particularly when the chow to which access was restricted may have been healthier to begin with - led to no further health benefit, because there are none to be gained: the dramatic age-retarding effects of CR observed in laboratory rodents and other species do not translate into longevous species such as primates, and the sole benefit of controlling energy intake is avoidance of overweight and obesity.

The "Dose-Response" hypothesis begins from the same interpretation of the WNPRC study, but posits that far from being excessive (or, at best, superfluous) to that required for good health, the additional energy restriction imposed at NIA were too little, and imposed during too narrow a window, to elicit a clear signal in health and lifespan benefits; this is supported by the evidence that the NIA primates were not especially hungry, and only weakly and inconsistently exhibited improvements in risk factors and endocrine signatures of CR that are seen both in life-extending CR in rodents, and in humans under rigorous CR.

Unfortunately, it seems very unlikely that this question will be resolved. Even the narrow question of whether the age-retarding effects of CR in laboratory rodents translate into nonhuman primates could only be established with confidence after yet another trial in nonhuman primates. [Such] a study is extremely unlikely in light of the enormous expense of the first two trials, disappointment (and possibly embarrassment) with the results, [and] the ill winds for nonhuman primate research. [Even] if such a well-designed and well-executed study were initiated: what then? Supposing that support were maintained for the duration of the experiment [it] would be a further three decades before the earliest point at which survival data could be reported.

The timescales involved in resolving these questions cannot be reconciled with the immediate imperatives that drive us to pose them. With the scale of the humanitarian, economic, and social crisis that looms in the coming decades due to global demographic aging and associated ill-health, the near-term need for effective interventions against the aging process could not be greater. Whether CR can retard aging in nonhuman primates or not; whether it can retard aging in humans or not; whether even effective CR mimetics can somehow be shepherded through clinical trials - even the most optimistic projection for retarding aging through such approaches is inadequate to the needs and suffering of aging world.

The point made in the article is the same one that should be made for all means of slowing the pace of aging by altering metabolism, whether by the use of drugs to replicate some of the changes caused by calorie restriction or via other mechanisms. These are very difficult and challenging projects, certainly very expensive in time and funds, and which will produce poor and uncertain end results even if successful. Ways to modestly slow aging do nothing for people who are already old, and we will grow old waiting for success in the development of drugs that can safely tinker our metabolisms into a state of slower aging.

The better approach is that outlined by the SENS Research Foundation: targeted therapies to repair the known forms of cellular and molecular damage that cause aging. This path is cheaper, more certain, and the resulting therapies will be capable of rejuvenation - of reversing degenerative aging, not just slowing it down a little. They will be greatly beneficial for the old, and extend the length of life lived in health and vigor. This is why I say that calorie restriction studies are irrelevant to the future of our health and longevity: the only thing that really matters is whether or not the SENS vision or similar repair therapies are prioritized, funded, and developed.