Oxidative theories of aging place the blame for the damage of aging on reactive oxidizing molecules, generated most notably in the mitochondria of your cells, and which tend to break the protein machinery they react with. Oxidative stress is the term given to ongoing damage (and efforts to repair it) caused by the presence of oxidative molecules in and around cells. Levels of oxidative stress can alter as a result of heat, exposure to ionizing radiation, the details of diet, and all sorts of other environmental influences.

The relationship between oxidative stress and the pace of aging is far from straightforward, however. There is more oxidative stress with age, but this is an expected result of carrying a high level of cellular and molecular damage. Some very long-lived species, such as naked mole rats, show very high levels of oxidative stress but don't appear to be particularly harmed by it. Mild oxidative stress can be beneficial, triggering increased cellular maintenance for a time to produce a net benefit. Oxidative compounds are also widely used in our biochemistry for necessary signaling purposes.

You can see the nature of this complex relationship between oxidative stress and aging by looking at what happens in interventions that reliably slow aging and extend life, such as calorie restriction in rodents:

Oxidative stress is observed during aging and in numerous age-related diseases. Dietary restriction (DR) is a regimen that protects against disease and extends lifespan in multiple species. However, it is unknown how DR mediates its protective effects. One prominent and consistent effect of DR in a number of systems is the ability to reduce oxidative stress and damage. The purpose of this review is to comprehensively examine the hypothesis that dietary restriction reduces oxidative stress in rodents by decreasing reactive oxygen species (ROS) production and increasing antioxidant enzyme activity, leading to an overall reduction of oxidative damage to macromolecules.

The literature reveals that the effects of DR on oxidative stress are complex and likely influenced by a variety of factors, including sex, species, tissue examined, types of ROS and antioxidant enzymes examined, and duration of DR. [In] a majority of studies, dietary restriction had little effect on mitochondrial ROS production or antioxidant activity. On the other hand, DR decreased oxidative damage in the majority of cases. Although the effects of DR on endogenous antioxidants are mixed, we find that glutathione levels are the most likely antioxidant to be increased by dietary restriction, which supports the emerging redox-stress hypothesis of aging.

While thinking about antioxidants and their effect on aging, it's important to remember that location matters immensely. Ingested antioxidants of the sort you can buy in the store are convincingly demonstrated to do nothing for your health, and there is evidence to suggest that they are actually mildly harmful - for example by blocking some of the oxidant-based signaling mechanisms the body uses to dial up cellular housekeeping and muscle growth responses after exercise. Meanwhile researchers are demonstrating benefits in mice by targeting designed antioxidant compounds to the mitochondria in cells, the place that most oxidants are generated. Those antioxidants are not yet available for the rest of us, however. The antioxidant pills from the store don't deliver their contents to your mitochondria, and are thus not terribly helpful.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23743291

Source:
http://www.fightaging.org/archives/2013/06/reviewing-the-literature-on-calorie-restriction-and-oxidative-stress.php

New approaches to electromechanical artificial hearts involve the replacement of some portions of the machine with tissue, such as the cow heart tissue used in this case. The end result is a more durable apparatus that better interfaces with the body, though it's still the case that artificial heart technology cannot replace a biological heart for the long term:

A new kind of artificial heart that combines synthetic and biological materials as well as sensors and software to detect a patient's level of exertion and adjust output accordingly is to be tested in patients at four cardiac surgery centers in Europe and the Middle East. If the "bioprosthetic" device, made by the Paris-based Carmat, proves to be safe and effective, it could be given to patients waiting for a heart transplant.

In Carmat's design, two chambers are each divided by a membrane that holds hydraulic fluid on one side. A motorized pump moves hydraulic fluid in and out of the chambers, and that fluid causes the membrane to move; blood flows through the other side of each membrane. The blood-facing side of the membrane is made of tissue obtained from a sac that surrounds a cow's heart, to make the device more biocompatible. "The idea was to develop an artificial heart in which the moving parts that are in contact with blood are made of tissue that is [better suited] for the biological environment."

That could make patients less reliant on anti-coagulation medications. The Carmat device also uses valves made from cow heart tissue and has sensors to detect increased pressure within the device. That information is sent to an internal control system that can adjust the flow rate in response to increased demand, such as when a patient is exercising.

Link: http://www.technologyreview.com/news/515021/the-latest-artificial-heart-part-cow-part-machine/

Source:
http://www.fightaging.org/archives/2013/05/a-bioprosthetic-heart.php

Enhanced regeneration can result from introducing new stem cells into a patient, and this effect is the basis for a very broad range of first generation transplant therapies. In most cases the benefit doesn't result from the transplanted stem cells setting forth to create replacement cells for damaged tissue. Instead it is caused by chemical signals produced by the transplanted cells: these signals spur native cell populations to take action. So naturally the next step here is for researchers to gain a good enough understanding of stem cell signals to remove the need for cell transplants, replacing them with a therapy based on introducing the signal molecules directly.

It's very hard to say how rapidly this line of research will progress in comparison to the ongoing development of therapies that involve cells, a field in full swing. But in the long term it seems likely that directly adjusting the state and behavior of a patient's native cells will win out over indirect methods. Using the signals may just be another indirect method to be replaced by something better down the line, such as targeted epigenetic engineering that reprograms specific cell populations without going through any of the evolved signal paths.

But that is a way from here, as the use of stem cells in therapy is still two decades away from its peak usage and effectiveness - if we want to take the standard view of fifty year cycles in broad technologies, waxing to full effectiveness and then waning as they are replaced by something better. The cycle may run faster this century: we'll see whether that is the case or not, something that is determined by the degree to which the timing depends on human organization versus technological capacity. The former isn't speeding up, while the latter is.

Meanwhile, here is an open access paper that illustrates the way in which scientists are presently looking at stem cell signals. The research community is clearly on the way towards a range of these signal compounds repackaged and repurposed as drug candidates to induce exceptional regeneration. I expect that line of development will be well underway by the early 2020s.

hESC-secreted proteins can be enriched for multiple regenerative therapies by heparin-binding

Tissue regeneration and maintenance dramatically and invariably decline with age, eventually causing failure of multiple organ systems in all mammals. In muscle, the loss of tissue regeneration with age is thought to be imposed by signaling changes in the satellite stem cell niche, and interestingly, the aging of stem cell niches is to some extent similar between muscle, brain, blood, and other tissues. Our previous work found that human embryonic stem cells (hESCs) produce soluble secreted molecules that can counteract the age-imposed inhibition of muscle regeneration, an "anti-aging" activity that is lost when the hESCs differentiate.

Numerous mitogenic proteins are expressed by hESCs and are known to act through [key regulatory signaling pathways] implicated in the control of adult tissue regeneration. The precise identity of the pro-myogenic factors that are secreted by hESCs and the molecular mechanism of their action in muscle stem and progenitor cells is still work in progress; however, the effects of one of these molecules, FGF-2, was studied here in detail. FGF-2 is known to be secreted by hESCs and is also contained in the growth/expansion medium of embryonic stem cells.

This work builds upon our findings that proteins secreted by hESCs exhibit pro-regenerative activity, and determines that hESC-conditioned medium robustly enhances the proliferation of both muscle and neural progenitor cells. Importantly, this work establishes that it is the proteins that bind heparin which are responsible for the pro-myogenic effects of hESC-conditioned medium, and indicates that this strategy is suitable for enriching the potentially therapeutic factors. Additionally, this work shows that hESC-secreted proteins act independently of the mitogen FGF-2, and suggests that FGF-2 is unlikely to be a pro-aging molecule in the physiological decline of old muscle repair. Moreover, hESC-secreted factors improve the viability of human cortical neurons in an Alzheimer's disease (AD) model, suggesting that these factors can enhance the maintenance and regeneration of multiple tissues in the aging body.

You'll find more on the role of FGF-2 regarding stem cells and aging back in last year's archives. The authors quoted above suggest that past work on FGF-2 can't be the whole picture, based on their observations, and something more complex is taking place - which is the usual story in life science research. Nothing is ever simple.

• Commentary on FGF Signaling and Stem Cell Aging
• Inhibiting FGF2 in Mice Slows Muscle Stem Cell Decline With Age

Source:
http://www.fightaging.org/archives/2013/05/considering-the-regenerative-signals-emitted-by-transplanted-stem-cells.php

Researchers recently published a set of encouraging data resulting from the use of stem cell transplants in the treatment of forms of leukemia. Once a particular new technique is adopted in medical practice, further progress is often a matter of steady incremental improvement. Here that improvement is quite considerable over the past decade, a reflection of the pace of medical science in general:

Survival rates have increased significantly among patients who received blood stem cell transplants from both related and unrelated donors. [The] study authors attribute the increase to several factors, including advances in HLA tissue typing, better supportive care and earlier referral for transplantation. The study analyzed outcomes for more than 38,000 transplant patients with life-threatening blood cancers and other diseases over a 12-year period - capturing approximately 70 to 90 percent of all related and unrelated blood stem cell transplants performed in the U.S.

At 100 days post-transplant, the study shows survival significantly improved for patients with myeloid leukemias (AML) receiving related transplants (85 percent to 94 percent) and unrelated transplants (63 percent to 86 percent). At one-year post-transplant, patients who received an unrelated transplant showed an increased survival rate from 48 to 63 percent, while the survival rate for related transplant recipients did not improve. Similar results were seen for patients with acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). In addition to improved survival, the authors note a significant increase in the overall number of patients receiving transplants. Related and unrelated transplant as treatment for ALL, AML, MDS and Hodgkin and non-Hodgkin lymphomas increased by 45 percent - from 2,520 to 3,668 patients annually. This is likely due to the use of reduced-intensity conditioning therapy and a greater availability of unrelated volunteer donors.

Link: http://www.sciencedaily.com/releases/2013/05/130528180857.htm

Source:
http://www.fightaging.org/archives/2013/05/stem-cell-transplants-for-leukemia-showing-improved-outcomes.php

Billionaires are just like you and I, but with deeper pockets. They will age and die on the same schedule as the rest of us, as future life span is almost entirely determined by the pace of progress in medical science and the availability of modern medicine is very flat. Within a few years of any new medical technology arriving in the clinic it settles to a price that can be widely afforded. If you're sixty and sitting on your retirement fund then there's very little in the way of medicine that a billionaire could afford but you can't. The billionaire can afford a dedicated hospital with new wall murals, but the therapies are exactly the same as those you'd buy for yourself: a stem cell transplant or infusion of enzymes doesn't care about the size of your bank balance.

Here is another way in which billionaires are just like the rest of us: very few of them care enough about aging to death to do anything about it. Or they don't believe that anything can be done, or they are not up to speed with the present state of longevity science and the potential of SENS-style rejuvenation biotechnology, or any one of the other reasons offered up whenever people's attitudes towards aging are discussed.

Just as a small fraction of the public care enough about aging to do something about it - ranging from donating a little money or time to organizations like the Methuselah Foundation or SENS Research Foundation all the way up to quitting work, going back to school, and becoming a researcher - a small number of billionaires also take steps. Again, these range from modest donations through to the hard right turn in life to take a different path and focus fully on the problem of aging. Unfortunately of these folk only one is a patron for SENS, while the others are focus on different areas that are, ultimately, not particularly relevant to our future longevity for one reason or another. Such is life.

So you might say that SENS, the research program we'd like to see gain a vocal zealot willing to spend hundreds of millions of dollars, is bracketed by billionaires. Interested billionaires in fields just off to the left, interested billionaires in fields just off to the right. The optimistic view is that yes, it's just a matter of time until someone is convinced and takes the plunge - because, clearly, some people are thinking along parallel lines and thus we should expect there to be more in the future.

Larry Ellison

Of all the mentioned billionaires, Ellison comes closest to the right direction, but in many ways he's the least interested. He established the Ellison Medical Foundation in the 1990s to explore aging - not because longevity is a passion, but rather because aging research is a good source of intellectual and organizational challenges in the field of molecular biology. Molecular biology was the object, and aging research the happenstance outlet. So the end result is effectively an extension of the National Institute on Aging, and therefore focused on work that has little relevance to extending life. The majority of NIA-funded research is a matter of investigation, not intervention.

Peter Thiel

Thiel has funneled some millions of dollars into SENS research and is to be commended for doing so in a very public way at a time when you could still be ridiculed for it. He is also engaged in producing a broader environment of philanthropy within the networks he can reach with the aim of promoting greater investment and interest. SENS is just one of many radical projects he backs, however, a single part of the large jigsaw puzzle that is Thiel's attempt to influence the building of a better future.

David Murdock

Murdock's interest with longevity extends only so far as its intersection with diet and clean living. He has founded a research institute, the North Carolina Research Campus - and I think that if you manage to create a legacy of scientific research then it's hard to say you went far wrong in life. The focus here is on diet, however, which is very beneficial for health (such as via calorie restriction) but most likely of limited utility when it comes to extending human life. You can't eat your way to reaching 100 years of age with any certainty, and most people with superbly healthy lifestyles nonetheless age to death by 90. The future of longevity is modern medicine.

John Sperling

Sperling has funded a number of ventures of relevance to medicine and health, with a slant on longevity that is similar to the old school "anti-aging" businesses, such as Kronos Optimal Health. These are of no great utility when it comes to extending life: they are simply high end optional health services. At one point Sperling looked set to do much more and talked a good game about longevity, but per Wikipedia he is now more focused on environmental causes than human aging.

Dmitry Itskov

Itskov is taking the hard right turn in life in order to set up and promote his 2045 Initiative: tackle aging by moving out of biology and into machine bodies as soon as possible. He has a vision and is prepared to step up to the plate and put his reputation on the line in order to promote it with the financial muscle available to him. It's only a couple of years into this process, so we shall see how it goes once the initial run has settled down into the slow grind of advocacy, networking, and research funding. But from what we've seen so far, this is the sort of passion for a cause I'd like to see settle onto SENS rather than what looks like a much harder path to eliminate aging.

I'll say this for Itskov: a world in which a billionaire is prepared to openly and loudly back work on machine bodies and artificial minds is a world in which people don't laugh at high net worth individuals who back research into rejuvenation biotechnology. Once someone has planted a flag all the way out there on the field, other people become much more comfortable with what are now less radical gestures. We're somewhere in the middle of a sea change for the public perception of transhumanist technologies: robotics, AI, rejuvenation, and so forth. The cultural space within which people treated these fields as jokes and science fiction is vanishing rapidly, squeezed out by current events.

Source:
http://www.fightaging.org/archives/2013/05/bracketed-by-billionaires.php

Some age-related conditions are greatly impacted by exercise, and a sedentary lifestyle is one of the factors raising the risk of suffering these conditions. Type 2 diabetes is the best known of these, a lifestyle disease that you can actually exercise and diet your way out of if you work at it hard enough. Peripheral artery disease isn't so escapable, being a later stage in the process of deterioration, but exercise is still beneficial to a point comparable to other options for treatment:

Peripheral arterial disease (PAD) is a common vascular disease that reduces blood flow capacity to the legs of patients. PAD leads to exercise intolerance that can progress in severity to greatly limit mobility, and in advanced cases leads to frank ischemia with pain at rest. It is estimated that 12 to 15 million people in the United States are diagnosed with PAD, with a much larger population that is undiagnosed.

The presence of PAD predicts a 50% to 1500% increase in morbidity and mortality, depending on severity. Treatment of patients with PAD is limited to modification of cardiovascular disease risk factors, pharmacological intervention, surgery, and exercise therapy. Extended exercise programs that involve walking approximately five times per week, at a significant intensity that requires frequent rest periods, are most significant.

Preclinical studies and virtually all clinical trials demonstrate the benefits of exercise therapy, including improved walking tolerance, modified inflammatory/hemostatic markers, enhanced vasoresponsiveness, adaptations within the limb (angiogenesis, arteriogenesis, and mitochondrial synthesis) that enhance oxygen delivery and metabolic responses, potentially delayed progression of the disease, enhanced quality of life indices, and extended longevity. [The] benefits are so compelling that exercise prescription should be an essential option presented to patients with PAD in the absence of contraindications. Obviously, selecting for a lifestyle pattern that includes enhanced physical activity prior to the advance of PAD limitations is the most desirable and beneficial.

Is there a lesson here? Yes: exercise regularly. Don't be sedentary.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23720270

Source:
http://www.fightaging.org/archives/2013/05/exercise-versus-peripheral-artery-disease.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

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

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

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

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

Progress towards a therapy for the rare accelerated aging condition progeria continues. It remains unclear as to whether the mechanisms responsible for progeria exist in normal aging to a level that is in any way significant. Progeria is caused by malformed prelamin A, and tiny amounts of broken prelamin A can be found in old tissues - but it would really require a therapy for progeria that addressed the issues with prelamin A to easily find out whether this has any meaningful contribution to normal aging.

The classical form of progeria, called Hutchinson-Gilford Progeria Syndrome (HGPS), is caused by a spontaneous mutation, which means that it is not inherited from the parents. Children with HGPS usually die in their teenage years from myocardial infarction and stroke.

The progeria mutation occurs in the protein prelamin A and causes it to accumulate in an inappropriate form in the membrane surrounding the nucleus. The target enzyme, called ICMT, attaches a small chemical group to one end of prelamin A. Blocking ICMT, therefore, prevents the attachment of the chemical group to prelamin A and significantly reduced the ability of the mutant protein to induce progeria. "We are collaborating with a group in Singapore that has developed candidate ICMT inhibitor drugs and we will now test them on mice with progeria. Because the drugs have not yet been tested in humans, it will be a few years before we know whether these drugs will be appropriate for the treatment of progeria."

"The resemblance between progeria patients and normally-aged individuals is striking and it is tempting to speculate that progeria is a window into our normal aging process. The children develop osteoporosis, myocardial infarction, stroke, and muscle weakness. They display poor growth and lose their hair, but interestingly, they do not develop dementia or cancer." [The researchers are] also studying the impact of inhibiting ICMT on the normal aging process in mice.

Link: http://www.eurekalert.org/pub_releases/2013-05/uog-ptf051413.php

Source:
http://www.fightaging.org/archives/2013/05/inhibiting-icmt-as-a-progeria-therapy.php

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.

Source:
http://www.fightaging.org/archives/2013/05/reviewing-the-results-of-calorie-restriction-primate-studies.php

There are all sorts of good reasons to avoid becoming fat. Excess fat tissue is linked to an increased risk of all the common diseases of aging, and correlates well with a shorter life expectancy and higher lifetime medical expenditures. Fat tissue creates higher levels of chronic inflammation and alters the signaling environment in the body, causing a wide range of changes. Here is another of them:

Having too much body fat makes arteries become stiff after middle age, a new study has revealed. In young people, blood vessels appear to be able to compensate for the effects of obesity. But after middle age, this adaptability is lost, and arteries become progressively stiffer as body fat rises - potentially increasing the risk of dying from cardiovascular disease. The researchers suggest that the harmful effects of body fat may be related to the total number of years that a person is overweight in adulthood. Further research is needed to find out when the effects of obesity lead to irreversible damage to the heart and arteries, they said.

Researchers [scanned] 200 volunteers to measure the speed of blood flow in the aorta, the biggest artery in the body. Blood travels more quickly in stiff vessels than in healthy elastic vessels, so this allowed them to work out how stiff the walls of the aorta were using an MRI scanner. In young adults, those with more body fat had less stiff arteries. However, after the age of 50 increasing body fat was associated with stiffer arteries in both men and women. Body fat percentage, which can be estimated by passing a small electric current through the body, was more closely linked with artery stiffness than body mass index, which is based just on weight and height.

"We don't know for sure how body fat makes arteries stiffer, but we do know that certain metabolic products in the blood may progressively damage the elastic fibres in our blood vessels. Understanding these processes might help us to prevent the harmful effects of obesity."

Link: http://www.sciencedaily.com/releases/2013/05/130515085333.htm

Source:
http://www.fightaging.org/archives/2013/05/excess-body-fat-hardens-arteries.php

We'll take a short excursion into ranking futurists for today, prompted by a recent article that offers a (transhumanism-slanted) opinion on the identity of the most important futurists of the past few decades.

The Most Significant Futurists of the Past 50 Years

Our visions of the future tend to be forged in the pages of science fiction. But for the past half-century, a number of prominent thinkers, activists, and scientists have made significant contributions to our understanding of what the future could look like. Here are 10 recent futurists you absolutely need to know about. Needless to say, there were dozens upon dozens of amazing futurists who could have been included in this article, so it wasn't easy to pare down this list. But given the width and breadth of futurist discourse, we decided to select thinkers whose contributions should be considered seminal and highly influential to their field of study.

Those selected include Robert Ettinger, one of the founders of modern cryonics, and Aubrey de Grey, who presently works to make his SENS roadmap to human rejuvenation a reality. Ray Kurzweil is notably absent from the list.

It isn't mentioned as a selection criteria in the article, but I think that ranking the importance of futurists by how effectively they help to create the future that they envisage isn't all that bad of an idea. Advocates and popularists play a needed role in moving from vision to reality, but progress also needs people to perform and orchestrate the actual work of research and development. Kurzweil, for example, is a popularist and an advocate with respect to his futurism: beyond the books and films and persuasion his day job as an inventor and entrepreneur is so far largely irrelevant to the future he envisages. I don't think anyone can argue that he isn't important in the arena of ideas regarding machine intelligence, accelerating change, and how this will all play out in the decades ahead. But how much more important would Kurzweil be if, for example, he had decided a decade or two back to create a company like Zyvex as a long term play to advance molecular manufacturing, or something equivalent in AI work?

In contrast Ettinger and de Grey both founded successful organizations devoted to realizing their particular visions: the Cryonics Institute and the SENS Research Foundation. Both were instrumental in creating the groundwork and the early community of supporters to enable a new industry and branch of research in applied medicine. That seems like the best approach to futurism to me: not just persuasion, but also working to create the change you want to see in the world.

Source:
http://www.fightaging.org/archives/2013/05/are-the-most-influential-futurists-those-who-put-in-the-work-to-make-their-visions-real.php

There are any number of techniques under development that allow individual cells to be destroyed provided that you can distinguish them from their neighbors: the challenge is in finding characteristic differences in the cells you want destroyed, such as cancer cells or senescent cells. Most of the efforts aimed at producing targeted cell destruction therapies are taking place in the cancer research community, but senescent cells accumulate with age and contribute to degenerative aging - they must also be destroyed. Unfortunately good ways to target senescent cells are somewhat lacking. Candidate mechanisms are emerging, however, and here is another of them:

Due to its role in aging and antitumor defense, cellular senescence has recently attracted increasing interest. However, [the] detection of senescent cells remains difficult due to the lack of specific biomarkers. ndeed, most determinants of cellular senescence, such as the upregulation of p53, p16Ink4a, p21WAF/CIP1 or SASP-associated cytokines, are not exclusively observed in senescence, but can also occur in other types of stress responses. In addition, alterations like SAHF or DNA-SCARS formation are frequently observed, but not necessarily a mandatory feature or exclusive to senescent cells.

The current gold standard for the detection of senescence is the so-called senescence-associated ?-galactosidase (SA-?-Gal) activity. Although SA-?-Gal has been first suggested as a distinct enzyme, its activity is derived from lysosomal ?-Gal encoded by the GLB1 gene. ?-Gal is an accepted marker of senescence, but its reliability and specificity have been questioned, as a positive ?-Gal reaction has also been detected in human cancer cells that were chemically induced to differentiate, or upon contact inhibition. Moreover, several cell types, such as epithelial cells and murine fibroblasts generally show a weak ?-Gal staining.

In the present study, we investigated several lysosomal hydrolases for their suitability as senescence markers and identified ?-fucosidase, a lysosomal glycosidase involved in the breakdown of glycoproteins, oligosaccharides and glycolipids, as a novel biomarker for senescence. We demonstrate that ?-fucosidase is upregulated [in] all canonical types of cellular senescence, including replicative, DNA damage- and oncogene-induced senescence. Our results suggest that detection of ?-fucosidase might be a highly valuable biomarker for senescence in general and in particular in those cases where SA-?-Gal activity fails to properly discriminate between senescent- and non-senescent cells.

Link: http://www.landesbioscience.com/journals/cc/article/24944/?show_full_text=true

Source:
http://www.fightaging.org/archives/2013/05/a-possible-biomarker-for-senescent-cells.php

Three of the better known efforts to create a drug that modestly slows the rate of aging are centered on the following items:

• Resveratrol analogs that target sirtuins
• Rapamycin analogs that target mTOR
• Metformin

Of these, ways to manipulate the activity of sirtuins have received the greatest attention over the past decade, but there is little to show for all that money and time beyond a modest gain in the understanding of metabolism. There are no replicated, solid results of life extension in mice via sirtuin-influencing drugs, and I'd go so far as to say that the field is under something of a cloud at present. Metformin is in a similar position: while a large body of work relates to its use as a treatment for type 2 diabetes, the evidence for its ability to extend life in laboratory animals is mixed at best. Rapamycin is the only one of the three that can boast solid, replicated evidence of life extension in mice. It is a drug that has been in use as an immunosuppressant for more than a decade, but its ability to extend life is a more recent finding.

For today I thought I'd point out a couple of open access items containing recent findings on the use of rapamycin and metformin in the context of aging. While I don't believe that this branch of research is particularly relevant to extending human life by any meaningful amount in the near term, it is interesting to watch and may help to shed more light on the relative importance of various aspects of our biology in aging. The metformin paper in particular is an educational attempt to tie in the senescent cell aspect of aging to study results:

Metformin, aging and cancer

Metformin, a widely used antidiabetic drug, has been linked to a reduced cancer incidence in some retrospective, hypothesis-generating studies. What is the mechanism by which aging may increase cancer incidence? Although many molecular changes correlate with aging, the presence of senescent cells capable of secreting inflammatory cytokines may be involved. This senescence associated secretory phenotype (SASP) consists of multiple cytokines, chemokines, growth factors and extracellular matrix degrading enzymes that can potentially affect normal tissue structure.

The SASP probably evolved as a gene expression program to assist the senescent tumor suppression response and tissue repair after damage and should be viewed as an initial adaptive response. However, [chronic] SASP [like chronic inflammation] may cause a microenvironment in old tissues that facilitates tumor initiation and then stimulates cancer cell growth.

This unfortunate interaction between senescent cells and cancer cells has been reproduced in experimental mouse models where senescent fibroblasts stimulated tumor progression. [During] experiments to study the potential cancer prevention activity of metformin, we found serendipitously that the drug prevented the expression of many proteases, cytokines and chemokines in senescent cells. We thus propose that metformin prevents cancer by modulating the SASP in tissues where senescent cells were not naturally cleared.

Prolonged Rapamycin treatment led to beneficial metabolic switch

In the first robust demonstration of pharmacologically-induced life extension in a mammal, rapamycin increased longevity of mice via either feeding or injection. However, rapamycin treatment also showed the detrimental metabolic effects, including hyperinsulinemia, hyperlipidemia, glucose intolerance and insulin resistance. Those observations present a paradox of improved survival despite metabolic impairments. How rapamycin extended lifespan with such paradoxical metabolic effects remains to be elucidated.

In the various studies of rapamycin treatment, length of rapamycin treatment varied from two weeks to two years. With short-term rapamycin treatment, mice showed the detrimental metabolic effects, while a much longer length (up to 1.5 to 2 years) of rapamycin treatment led to increased longevity. Duration of rapamycin treatment may be one of the key factors that determine outcomes of the treatment. Longer-term rapamycin treatment may cause beneficial metabolic "switch" that is associated with enhanced insulin signaling and extended longevity.

We [recently] reported that duration of rapamycin treatment indeed has differential effects on metabolism. In our study, rapamycin was given to mice for two, six or 20 weeks. Consistently with the previous reports, mice with two weeks of rapamycin treatment had characteristics of metabolic syndrome. Mice with six weeks of rapamycin treatment were in the metabolic transition status. When rapamycin treatment continued for 20 weeks, the detrimental metabolic effects were reversed or diminished.

It's worth taking some time to look over the state of research for these front-runners in the old-school drug discovery approach to extending life. I find it serves well as a way to inoculate yourself against unfounded optimism and unreasonable expectations, both now and the next time that both the "anti-aging" marketplace and biotech startups tout something that you can buy to supposedly influence metabolism and aging. If you have an enthusiasm for living longer, better to channel it into exercise, calorie restriction, and fundraising for the SENS Research Foundation.

Source:
http://www.fightaging.org/archives/2013/05/comments-on-rapamycin-and-metformin.php

Retinal implants that can provide a crude substitute for vision in some forms of blindness are a work in progress at this time, but the path ahead seems fairly clear:

Some people with artificial retinas can read large letters, see slow-moving cars, or identify tableware. Other patients experience no benefit. The variation can be ascribed in some cases to the exact placement of the neuron-stimulating array in the tissue-paper-thin retina as well as the state of the remaining neurons and pathways in each individual's eye. How well people can learn to use the device and retrain their brain is also important. At its best, the current level of vision is very pixelated. What's seen are bursts of light called phosphenes. "It's not restoring vision like you and I think of, it's restoring mobility. They provide contrast so that someone can see a difference in light and dark to the point where they can tell how to walk through a doorway. This is very much the beginning. Retina prostheses are at the stage cochlear implants were 30 years ago. That technology went from being an aid for lip reading to the point now where children with a cochlear implant can go through normal school and even use mobile phones. With retinal implants, we now know it has clinical benefit to patients, and I think we are going to see this technology develop very rapidly over the next decade."

Thousands of pixels [in comparison to the present 60 or so] will likely be required for facial recognition and other detailed visual tasks, and many artificial retina technologies will have trouble getting to such large numbers of pixels because they depend on wires. Wires are used to connect a power supply to electrodes, which requires a surgical procedure to lay the connection through the eyeball. To avoid this limitation, [researchers] are developing a wireless system that transmits image data captured by a video camera to a photovoltaic chip in the eye. Instead of transmitting visible light to the chip, his system uses near-infrared light that is beamed to flexible arrays of small pixels in the retina. The team has tested the system in blind rats and is now working with a company to test the device in patients. But even thousands of pixels are a long way from one million, "which is roughly what we have in the natural eye. And even at that, there is a lot of processing that the retina does that we are going to be skipping with an artificial retina."

Link: http://www.technologyreview.com/news/514081/can-artificial-retinas-restore-natural-sight/

Source:
http://www.fightaging.org/archives/2013/05/the-present-state-of-artificial-retinas.php

In later years the immune system falls into a malfunctioning state of overactivation and ineffectiveness, generating damaging chronic inflammation while at the same time failing to defend against pathogens and destroy damaged cells.

It is recognized that the immune system, comprising both innate (nonspecific) and acquired (specific) components, is an intricate defence system that is highly conserved across vertebrate species, and has, from an evolutionary perspective, undergone strong pressures to maximize survival to allow procreation. The significant improvements in human survival and lifespan to well beyond childbearing ages have been totally "unpredicted" by evolution. As a consequence, human immune systems are exposed to considerable additional antigenic exposure outside the forces of natural selection. It is in this situation that immunity begins to exert negative effects on human ageing (antagonistic pleiotropy), leading to gradual systemic failures.

Research into age-related changes of the immune system is gathering pace as its importance within the context of multiple pathologies in ageing populations is realized. As part of this advance, [researchers] described the phenomenon of "inflammaging" at the turn of the millennium as part of the spectrum of immunosenescence. Inflammaging denotes an upregulation of the inflammatory response that occurs with age, resulting in a low-grade chronic systemic proinflammatory state.

Inflammaging is believed to be a consequence of a cumulative lifetime exposure to antigenic load caused by both clinical and subclinical infections as well as exposure to noninfective antigens. The consequent inflammatory response, tissue damage and production of reactive oxygen species that cause oxidative damage also elicits the release of additional cytokines, principally from cells of the innate immune system but also from the acquired immune response. This results in a vicious cycle, driving immune system remodelling and favouring a chronic proinflammatory state where pathophysiological changes, tissue injury and healing proceed simultaneously. Irreversible cellular and molecular damage that is not clinically evident slowly accumulates over decades.

Link: http://hplusmagazine.com/2013/05/07/understanding-how-we-age-insights-into-inflammaging/

Source:
http://www.fightaging.org/archives/2013/05/insights-into-inflammaging.php

Parabiosis involves joining the circulatory systems of two animals. This is of interest for a number of studies in which old mice and young mice are linked together, known as heterochronic parabiosis. The young mice acquire a little of the metabolic, cellular, and gene expression changes characteristic of old mice, while in the the old mice some of these measures reverse towards more youthful levels. In stem cell activity in particular, the environment of signals present in the blood seems to dictate age-related decline as much as does any inherent damage to stem cells or their niches. This reinforces the view of stem cell aging as an evolved reaction to the cellular damage of aging that acts to extend life by reducing cancer risk, but at the cost of a slow decline into death due to ever more poorly maintained tissues and organs.

Heterochronic parabiosis studies in mice have been taking place for some years now, and researchers are beginning to link differences in gene expression and protein levels in old tissues versus young tissues to specific age-related conditions. The next logical step is to see if age-related dysfunction can be reversed by changing these protein levels in old animals:

Young blood reverses heart decline in old mice

Pumping young blood around old bodies - at least in mice - can reverse cardiac hypertrophy - the thickening and swelling of the heart muscle that comes with age and is a major cause of heart failure. After just four weeks, the older mouse's heart had reverted to almost the same size as that of its younger counterpart. The hearts of the young mice were unaffected, even though they were pumping some blood from the older mice.

After ruling out the effect of reduced blood pressure on the older mice, the team identified a potential candidate: a protein called GDF11, which was present in much higher quantities in the blood of the young mice. To test the effect of GDF11, the researchers gave old mice with cardiac hypertrophy daily injections of it for 30 days. At the end of the treatment, their hearts were significantly smaller than those in a second group of mice of the same age and with the same condition, but that had been injected with saline.

Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy

The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation.

Using modified aptamer-based proteomics, we identified the TGF-? superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.

Overriding declines in stem cell activity and forms of tissue degeneration by changing the levels of protein signals present in aged tissues is clearly going to be an important field of medicine in the near future. It may ultimately even take over from stem cell transplants as the principle mode of treatment for many age-related conditions. Some of those transplant therapies are most likely working through the same mechanisms, after all. Regeneration happens because the introduced stem cells are altering the signaling environment and waking up native stem cells, not because they are building new cells and patching up tissue structures.

However, one caveat is that this sort of work doesn't address any of the cellular and molecular damage that initiated the evolved response to reduce stem cell activity. That damage is still there: mitochondrial DNA mutations, high levels of oxidative damage, harmful build up of various forms of metabolic byproducts in and around cells, and so on. At the very least one would expect a growing risk of cancer to accompany a resurgence in stem call activity in an old person - which may be an entirely acceptable risk as cancer therapies improve past chemotherapy and towards targeted cell killers with no side effects.

Even if short term benefits can be obtained via altered signaling protein levels in old tissue, it is still the case that the underlying damage of aging must be repaired. Boosting stem cell activity so far appears to be a better class of potential treatment for many conditions than the best of what can be found in the clinic today, but it is still a form of patching over the underlying causes rather than fixing them.

Source:
http://www.fightaging.org/archives/2013/05/parabiosis-points-to-gdf-11-as-a-means-to-reverse-age-related-cardiac-hypertrophy.php