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.

The DNA damage theory of aging postulates that the main cause of the functional decline associated with aging is the accumulation of DNA damage, ensuing cellular alterations and disruption of tissue homeostasis. Stem cells are at high risk of accumulating deleterious DNA lesions because they are so long-lived. Such damage may limit the survival or functionality of the stem cell population and may even initiate or promote carcinogenesis.

The ultra-high resolution of transmission electron microscopy (TEM) offers the intriguing possibility of detecting core components of the DNA repair machinery at the single-molecule level and visualizing their molecular interactions with specific histone modifications. We showed that damage-response proteins [such as] 53BP1 can be found exclusively at heterochromatin-associated DNA double-strand breaks (DSBs).

Using 53BP1-foci as a marker for DSBs, hair follicle stem cells (HFSCs) in mouse epidermis were analyzed for age-related DNA damage response (DDR). We observed increasing amounts of 53BP1-foci during the natural aging process independent of telomere shortening [suggesting] substantial accumulation of DSBs in HFSCs. Electron microscopy [showed] multiple small 53BP1 clusters diffusely distributed throughout the highly compacted heterochromatin of aged HFSCs.

Based on these results we hypothesize that these lesions were not persistently unrepaired DSBs, but may reflect chromatin rearrangements caused by the repair or misrepair of DSBs. Collectively, our findings support the hypothesis that aging might be largely the remit of structural changes to chromatin potentially leading to epigenetically induced transcriptional deregulation.

Link: http://dx.doi.org/10.1371/journal.pone.0063932

[Researchers] analyzed mice genomes as a function of longevity and found a group of three genes situated on chromosome number two that, up to this point, had not been suspected of playing any role in aging. But the numbers didn't lie: a 50 percent reduction in the expression of these genes - and therefore a reduction in the proteins they code for - increased mouse life span by about 250 days [in a lineage that normally lives between 400 to 900 days]. Next, the team reproduced the protein variations in a species of nematode, Caenorhabditis elegans. "By reducing the production of these proteins during the worms' growth phase, we significantly increased their longevity." The average life span of a worm manipulated in this way went from 19 to more than 30 days, an increase of 60 percent. The scientists then conducted tests to isolate the common property and determined that the presence of mitochondrial ribosomal proteins (MRPs) is inversely proportional to longevity.

The researchers concluded that a lack of MRP at certain key moments in development created a specific stress reaction known as an "unfolded protein response" within the mitochondria. "The strength of this response was found to be directly proportional to the life span. However, we noted that it was more pronounced if the protein imbalance - the reduction in MRP - occurred at a young age. A similar stimulation in an adult did not affect the worms' longevity." What's more, the effect can be induced without genetically manipulating the worms. "Exposure to certain readily available drugs inhibits ribosomal function and thus causes the desired reaction." In other words, mitochondria are sensitive to certain antibiotics, and the drugs can be used to prolong life.

The process examined in worms exists in mice (and humans for that matter), so it looks like the next step is to explore these specific antibiotics in mice to see whether they also exhibit longevity effects and dependence on age at treatment.

Link: http://www.sciencedaily.com/releases/2013/05/130522131120.htm

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.

Senescence is assumed to be a cell-autonomous tumor-suppressor mechanism, because it is accompanied by irreversible cell-cycle arrest occurring mainly in response to irreparable telomeric and non-telomeric DNA damage. This has been especially well demonstrated for fibroblasts, the major cell component of the stroma. Yet fibroblast senescence may contribute to promoting cancer development and evolution, in a non-cell-autonomous, paracrine way, as suggested by the observation that senescent fibroblasts can stimulate growth, the epithelial-mesenchymal transition (EMT), and invasiveness of premalignant and malignant cells. This results from the fact that senescing fibroblasts develop a senescence-associated secretory phenotype (SASP) similar to that of carcinoma-associated fibroblasts, characterized by increased expression and secretion of growth factors, inflammatory cytokines, and matrix metalloproteinases.

We investigated here whether the senescent fibroblast secretome might have an impact on the very first stages of carcinogenesis. We chose the cultured normal primary human epidermal keratinocyte model, because after these cells reach the senescence plateau, cells with transformed and tumorigenic properties systematically and spontaneously emerge from the plateau. In the presence of medium conditioned by autologous senescent dermal fibroblasts, a higher frequency of post-senescence emergence was observed and the post-senescence emergent cells showed enhanced migratory properties and a more marked epithelial-mesenchymal transition. Using pharmacological inhibitors, siRNAs, and blocking antibodies, we demonstrated that the MMP-1 and MMP-2 matrix metalloproteinases, known to participate in late stages of cancer invasion and metastasis, are responsible for this enhancement of early migratory capacity. We present evidence that MMPs act by activating the protease-activated receptor 1 (PAR-1), whose expression is specifically increased in post-senescence emergent keratinocytes.

Developing the means to periodically clear out and destroy senescent cells is a necessary part of any future package of rejuvenation therapies, such as those of the SENS research program. Good progress is being made in targeted cell killing technologies by the cancer research community, and there are a number of possible mechanisms that might be used to distinguish senescent cells from healthy cells, so this type of therapy looks very feasible from a technical perspective.

Link: http://dx.doi.org/10.1371/journal.pone.0063607