A great many videos relating to the SENS rejuvenation biotechnology program and the SENS Research Foundation can be found online these days. There is often a long lag between an event and videos of that event being posted, however. So it's hard to tell whether I'm a little late or very late to notice these two videos from a SENS Research Foundation event at the end of last year; they were posted earlier this month.

SENS Research Foundation celebrated its progress in 2012 with a party at Evidence Studios in Los Angeles on December 20. CEO Mike Kope delivered the evening's first presentation, describing the organization's growth and maturation over the past year. Rice University's Dr. Jacques Mathieu followed with an in-depth description of current LysoSENS research. Finally, CSO Dr. Aubrey de Grey gave an overview of each extramural project that SRF is funding, including research at Cambridge, Harvard, and Yale.

The LysoSENS program that aims to clear damaging intracellular aggregates from our cells by searching for bacterial enzymes that can be used as a basis for designing precisely targeted drugs. So far several candidates have emerged for some of the compounds that show up in our cells with advancing age. You can find out more about this research program at the SENS Research Foundation website.

Source:
http://www.fightaging.org/archives/2013/05/videos-from-the-sens-research-foundation-evidence-studios-event-in-december-2012.php

In past centuries exposure to infectious disease and malnutrition caused high mortality rates in children. Those who survived did so with a greater burden of various forms of low-level biological damage. Degenerative aging is caused by an accumulation of damage and thus remaining life expectancy is reduced. Researchers here dig up historical demographic data that supports this view, showing that people who survived high childhood mortality went on to live shorter lives on average:

Early environmental influences on later life health and mortality are well recognized in the doubling of life expectancy since 1800. To further define these relationships, we analyzed the associations between early life mortality with both the estimated mortality level at age 40 and the exponential acceleration in mortality rates with age characterized by the Gompertz model.

Using mortality data from 630 cohorts born throughout the 19th and early 20th century in nine European countries, we developed a multilevel model that accounts for cohort and period effects in later life mortality. We show that early life mortality, which is linked to exposure to infection and poor nutrition, predicts both the estimated cohort mortality level at age 40 and the subsequent Gompertz rate of mortality acceleration during aging.

After controlling for effects of country and period, the model accounts for the majority of variance in the Gompertz parameters (about 90% of variation in estimated level of mortality at age 40 and about 78% of variation in Gompertz slope). The gains in cohort survival to older ages are entirely due to large declines in adult mortality level, because the rates of mortality acceleration at older ages became faster.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23626899

Source:
http://www.fightaging.org/archives/2013/05/early-mortality-rates-predict-late-mortality-rates.php

Decellularization is the process of taking an existing organ and stripping its cells, leaving the intricate skeleton of the extracellular matrix intact. That can then be repopulated by a patient's own cells to recreate a donor organ for transplant, though only a few organs have been successfully rebuilt in this way so far. As a technique this has many advantages over simple transplants: it removes the possibility of immune rejection, makes the use of animal organs practical, and rehabilitates donor organs that would otherwise be unsuitable:

[Perhaps a fifth of the] kidneys from deceased donors are thrown away each year due to damage. A paper [published] earlier this month suggests that they could be put to use as raw material for engineering new kidneys. The study's authors treated discarded human kidneys with a detergent, which cleared the organ of cells and left only the cells' extracellular matrices. The eventual plan is to grow the patients' own cells on the scaffold, producing a kidney that the patients would be less likely to reject than an ordinary transplant. "These kidneys maintain their innate three-dimensional architecture, their basic biochemistry, as well as their vessel network system."

The scientists tested the scaffold for antigens that might cause a patient to reject the organ and found that they had been eliminated along with the cells. When the researchers transplanted the modified kidneys into pigs and connected their vasculature to the pigs' circulatory systems, blood pumped through the kidneys at normal pressure. "With about 100,000 people in the U.S. awaiting kidney transplants, it is devastating when an organ is donated but cannot be used. These discarded organs may represent an ideal platform for investigations aimed at manufacturing kidneys for transplant."

Link: http://www.the-scientist.com/?articles.view/articleNo/35694/title/Recycling-Kidneys/

Source:
http://www.fightaging.org/archives/2013/05/decellularization-may-enable-use-of-more-donor-organs.php

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.

Source:
http://www.fightaging.org/archives/2013/05/mitochondrially-targeted-antioxidant-ss-31-reverses-some-measures-of-aging-in-muscle.php

There is some debate over whether the accumulation of damage to nuclear DNA contributes meaningfully to degenerative aging. It certainly raises the odds of cancer, but are its effects beyond that significant? Here is an open access paper in search of evidence, in which the authors suggest that epigenetic changes in individual cells result from repair of significant forms of damage such double strand breaks. The theory is that a growing disarray in cellular behavior is caused by scattered mutations and epigenetic changes, and this disarray contributes to aging, for example via degrading the ability of stem cells to maintain tissues - but again there are the questions of degree, and whether this sort of thing is significant in comparison to the other causes of aging:

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

Source:
http://www.fightaging.org/archives/2013/05/arguing-for-the-role-of-nuclear-dna-damage-in-aging.php