Fight Aging!

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

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/

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

Billionaires are just like you and me, 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.

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

Dmitry Itskov is the wealthy businessman who drives the 2045 Initiative, an advocacy and development program aimed at producing artificial replacements for the human body and eventually brain: a life extension plan that involves discarding as much of our biology as rapidly as possible. This is a stark contrast with other initiatives that aim to remove aging as a cause of death and disability by better maintaining our biology. The Global Futures 2045 conference is taking place in New York a few weeks, hence more media notice has been given to the project of late.

In this interview with Itskov you can see there is a lot of religious aspiration mixed in with the technological goals, which is both interesting from a cultural perspective and somewhat disquieting. Though perhaps the latter reaction is just parochial unfamiliarity at work - religion in public isn't something you typically see all that much of in the futurist and longevity science communities of the English-language world:

Basically, if you're asking me about what brought me to the project - to the idea - I would say it was kind of an evolution of my personal world view. You know, I had been successful in business, but I understood that I wasn't happy with just getting and spending money. It was just an epiphany when I realized that I wanted just to be of service to humanity - to create a project which will be really useful that could probably change the world. And I can further explain why I want it to be changed. I have always been in the technology business. I've always been connected to technology and I've been interested in life extension technology, but finally it was my personal spiritual quest and the desire to understand the real meaning of life and my place in this universe and that led me to the spiritual side of the project and I started meeting spiritual masters and talking to them - trying to ask them questions about the soul, about the nature of a human being. And from those meetings came the idea to mix science and technology and to establish a kind of public project which could raise all those questions which are so important to humanity now-a-days; the period when we are facing these numerous crises. In parallel with talking to spiritual masters, I started my consultations with scientists and that was how we created the broad map, which you can find on our website - the broad map of the Avatar Project.

So, the global goal is to create and realize a new strategy for the development of humanity which could meet global civilization changes and finally lead us to the kind of new world which will be based on five main principles, as I say. Those principles are high spiritually, high culture, high ethics, high science and high technologies. And the core of the idea is basically the assumption that now we need two revolutions. Two revolutions which actually plays in two parts: the first one is a spiritual one that could change the world view of people and the values which could set new goals and second is a technological revolution which could significantly accelerate the progress of the technology which would unite people and probably establish a new mega-project which could make the scientists in the future new super stars in our society.

Link: http://www.opednews.com/articles/Immortality-Technologist-E-by-Rob-Kall-130528-65.html

There isn't a great deal of funding for research into aging in comparison to the rest of medicine. It is greatly underfunded given its importance in biology, and this continues to be the case even after a decade or two of growing interest. Research into the manipulation of aging is a tiny field within aging research - most aging research is still a matter of gathering data. Lastly, research aimed at treating and reversing aging is a tiny fraction of work on manipulation of aging. The US National Institute on Aging has a $1 billion yearly budget, and might be a third of spending in the US on aging research; the SENS Research Foundation, which is arguably the only group managing research programs to realize plausible means of rejuvenation, has a yearly budget of $3 million.

This is what entrepreneurs, ever optimistic, call "a growth opportunity." Astronomical budgets are dedicated to medicine, merely vast budgets for amassing information about aging, and infinitesimal budgets are all that is presently available to stop the suffering, pain, death, and expense caused by aging. Rejuvenation research must grow if we are to see significant progress before we age to death.

Why is the budget for rejuvenation research tiny? My intuitive response to that is that is a combination of (a) that it has only recently become plausible to work on building therapies capable of rejuvenation, somewhere within the last 20 years, (b) few people know anything about the science that supports the plausibility of treating and reversing aging, and (c) few people care enough about living longer to do anything about it. Plus I might argue that the "anti-aging" marketplace sidetracks people into useless activities, while aggressively spreading misinformation about how we might go about extending life.

I noticed a post at Immortal Life that argues slightly differently: the root of not having enough funding is that we are failing to raise it. That we are bad at advocacy, or at least insufficient in numbers, and need to become better. It's an interesting position: are we terrible advocates by virtue of not having achieved the sweeping gains that, say, the AIDS advocacy community managed in a few short years in the 1980s? Or are we acceptably good at what we do but still early in the game - where the trajectory is more like that of the decades preceding the establishment of today's massive cancer research establishment?

Radical Life Extension's Problem isn't Lack of Funding - it's Weak Advocacy

When asked what the biggest bottleneck for Radical or Indefinite Longevity is, most thinkers say funding. Some say the biggest bottleneck is breakthroughs and others say it's our way of approaching the problem (i.e. seeking healthy life extension as opposed to more comprehensive methods of indefinite life-extension), but the majority seem to feel that what is really needed is adequate funding to plug away at developing and experimentally-verifying the various, sometimes mutually-exclusive technologies and methodologies that have already been proposed. I claim that Radical Longevity's biggest bottleneck is not funding, but advocacy.

This is because the final objective of increased funding for Radical Longevity and Life Extension research can be more effectively and efficiently achieved through public advocacy for Radical Life Extension than it can by direct funding or direct research, per unit of time or effort. Research and development obviously still need to be done, but an increase in researchers needs an increase in funding, and an increase in funding needs an increase in the public perception of RLE's feasibility and desirability.

There is no definitive timespan that it will take to achieve indefinitely-extended life. How long it takes to achieve Radical Longevity is determined by how hard we work at it and how much effort we put into it. More effort means that it will be achieved sooner. And by and large, an increase in effort can be best achieved by an increase in funding, and an increase in funding can be best achieved by an increase in public advocacy. You will likely accelerate the development of Indefinitely-Extended Life, per unit of time or effort, by advocating the desirability, ethicacy and technical feasibility of longer life than you will by doing direct research, or by working towards the objective of directly contributing funds to RLE projects and research initiatives.

I'd qualify that last point by suggesting that an hour of advocacy is only better than giving an hour of your wages to the SENS Research Foundation if that hour of advocacy actually results in more money showing up for SENS projects. I believe I'm still ahead of the game by that measure, but I'm nowhere near as certain of that as I'd like to be. It really does all come down to money at this precise point in time, now that there exists an established rejuvenation research program that can soak up many more millions of dollars with ease. With enough money the next five to ten years will produce such amazing results in the laboratory that using research to generate publicity looks like a better option than using publicity to generate funds for research.

But of course no-one is going to turn down publicity-generated funds should someone figure out how to make that work well in the intervening time. Over the long haul, it is the case that publicity and science have to move together, it's just here and now that resources for research look to have a better value than resources for publicity.

As an aside, and while we're on the subject of money, Immortal Life appears to be run by the same folk who managed Transhumanity.net before it was transferred to the Zero State initiative. The site as a whole illustrates why it's hard to build a for-profit single topic site for radical life extension: there is no technology available today that can achieve that goal, so the only legitimate flow of money is towards research. Everyone in the interested marketplaces that might pay the site owner to run ads or ads-disguised-as-content are in the business of selling dreams, lies, and other things that don't really matter. So if you focus on money, you end up slipping away from the ongoing research that matters and towards supplement pills and other dead ends. This, at least, has been the historical and ongoing outcome of these efforts - but that doesn't mean that it always must be. There are, after all, reputable general interest futurist sites, so you'd think there are some methodologies that might work without having to become a shill for the "anti-aging" market and supplement sellers. I'm just appropriately skeptical, given the past.

Longevity is inherited to some degree, with the evidence suggesting that the contribution of your genes grows in importance in old age. Prior to that point, your lifestyle choices are far more significant to long-term health. Nonetheless, some genetic lineages are superior to others when it comes to tilting the odds in favor of a longer life. One of the objectives for longevity science is to make these differences irrelevant, swamping them in the benefits to health and longevity created by therapies capable of rejuvenation. For example, why would anyone care about inherited cancer risk if clinics could reliably cure or prevent all cancer? No-one cares about the genetic risks associated with influenza or smallpox, and that is exactly because these are controlled, cured conditions.

[Researchers] analysed data from a series of interviews conducted with 9,764 people taking part in the Health and Retirement Study. The participants were based in America, and were followed up over 18 years, from 1992 to 2010. [The scientists] discovered that people who had a long-lived mother or father were 24% less likely to get cancer.

The scientists compared the children of long-lived parents to children whose parents survived to average ages for their generation. The scientists classified long-lived mothers as those who survived past 91 years old, and compared them to those who reached average age spans of 77 to 91. Long-lived fathers lived past 87 years old, compared with the average of 65 to 87 years. The scientists studied 938 new cases of cancer that developed during the 18 year follow-up period.

They found that overall mortality rates dropped by up to 19 per cent for each decade that at least one of the parents lived past the age of 65. For those whose mothers lived beyond 85, mortality rates were 40 per cent lower. The figure was a little lower (14 per cent) for fathers, possibly because of adverse lifestyle factors such as smoking, which may have been more common in the fathers.

"Previous studies have shown that the children of centenarians tend to live longer with less heart disease, but this is the first robust evidence that the children of longer-lived parents are also less likely to get cancer. We also found that they are less prone to diabetes or suffering a stroke. These protective effects are passed on from parents who live beyond 65 - far younger than shown in previous studies, which have looked at those over the age of 80. Obviously children of older parents are not immune to contracting cancer or any other diseases of ageing, but our evidence shows that rates are lower. We also found that this inherited resistance to age-related diseases gets stronger the older their parents lived."

"Interestingly from a nature versus nurture perspective, we found no evidence that these health advantages are passed on from parents-in-law. Despite being likely to share the same environment and lifestyle in their married lives, spouses had no health benefit from their parents-in-law reaching a ripe old age. If the findings resulted from cultural or lifestyle factors, you might expect these effects to extend to husbands and wives in at least some cases, but there was no impact whatsoever."

Link: http://www.sciencedaily.com/releases/2013/05/130528122508.htm

Chronic inflammation appears to be a primary mechanism that links excess adipose tissue, fat in other words, with an increased risk of age-related medical conditions and early death. Become fat and you suffer far more inflammation than your thin peers, and that has a significant impact on your health over the years, even for comparatively modest gains in weight.

Here researchers demonstrate an association between increased mortality and a specific characteristic of fat tissue that doesn't appear to involve inflammation, however - so there must be other ways in which fat tissue sabotages your health and life expectancy:

Knowledge of adipose composition in relation to mortality may help delineate inconsistent relationships between obesity and mortality in old age. We evaluated relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density, mortality, biomarkers, and characteristics. VAT and SAT density were determined from computed tomography scans in persons aged 65 and older, Health ABC (n = 2,735) and AGES-Reykjavik (n = 5,131), and 24 nonhuman primates (NHPs). Associations between adipose density and mortality (4-13 years follow-up) were assessed with Cox proportional hazards models. In NHPs, adipose density was related to serum markers and tissue characteristics.

Higher density adipose tissue was associated with mortality in both studies with adjustment for risk factors including adipose area, total fat, and body mass index. In women, hazard ratio [for] the densest quintile (Q5) versus least dense (Q1) for VAT density [was] 1.95 (Health ABC) and 1.88 (AGES-Reykjavik) and for SAT density, 1.76 (Health ABC) and 1.56 (AGES-Reykjavik). In men, VAT density was associated with mortality in Health ABC, 1.52, whereas SAT density was associated with mortality in both Health ABC, 1.58, and AGES-Reykjavik, 1.43. Higher density adipose tissue was associated with smaller adipocytes in NHPs. There were no consistent associations with inflammation in any group. Higher density adipose tissue was associated with lower serum leptin in Health ABC and NHPs, lower leptin mRNA expression in NHPs, and higher serum adiponectin in Health ABC and NHPs.

[We conclude that] VAT and SAT density provide a unique marker of mortality risk that does not appear to be inflammation related.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23707956

The future of medical drugs will largely involve the manufacture of proteins that precisely interact with our biochemistry to achieve specific effects. They will either be existing proteins with a role in regulating metabolism, stem cell activity, immune cell response, and so on, or they will be entirely new nanomachinery intended to produce results that our biology cannot achieve on its own, such as the effective destruction of harmful waste products, for example. These designed proteins will be delivered the old-fashioned way, via injection, for a good many years yet. Ultimately, however, managing the manufacture and the timing and location of protein delivery will move into the body under the control of sophisticated tiny factory machines - mass-produced entities that will in fact bear a great deal of resemblance to cells.

What is a cell, after all, but a flexible protein factory that manages its output in response to the surrounding environment? Why reinvent the wheel when a perfectly functional version is right there to be reverse engineered? Or used as-is, for that matter: present day stem cell therapies are just like future treatments that will deliver tiny mobile drug factories into a patient's tissues. Today's crude cell therapies appear to work because the newly introduced cells are, for a short time at least, manufacturing proteins that change the behavior of local cells. This is a little bit of the future made possible by harnessing existing biological machinery. Researchers can even reach beyond the use of plain cells today, such as by altering stem cells to generate specific desired compounds:

Engineered stem cell advance points toward treatment for ALS

[Researchers] used adult stem cells from human bone marrow and genetically engineered the cells to produce compounds called growth factors that can support damaged nerve cells. The researchers then implanted the cells directly into the muscles of rats that were genetically modified to have symptoms and nerve damage resembling ALS.

In people, the motor neurons that trigger contraction of leg muscles are up to three feet long. These nerve cells are often the first to suffer damage in ALS, but it's unclear where the deterioration begins. Many scientists have focused on the closer end of the neuron, at the spinal cord, but [others] observes that the distant end, where the nerve touches and activates the muscle, is often damaged early in the disease. "We know that the neuro-muscular junction is a site of early deterioration, and we suspected that it might be the villain in causing the nerve cell to die. It might not be an innocent victim of damage that starts elsewhere."

The injected stem cells survived for at least nine weeks, but did not become neurons. Instead, their contribution was to secrete one or both growth factors. "These motor nerve cells have extremely long connections, and replacing these cells is still challenging. But we aim to keep the neurons alive and healthy using the same growth factors that the body creates, and that's what we have shown here."

Cells and cell-like entities are steadily on their way to becoming the dominant tools of medicine. The more that researchers know about cells, the more useful they become in this role. Programmable protein factories in the form of cells or pseudo-cells will ultimately take over from the direct delivery of designed protein machinery in the same way that the creation of designed protein machinery will soon replace the old-fashioned and haphazard process of discovering and testing naturally occurring drugs. This is progress.

The cancer drug bexarotene has been shown to have potential as a treatment for Alzheimer's disease, at least in mice, but the latest research results show that it isn't working the way that researchers think it should. Incidentally, this sort of repurposing of an existing drug is a direct consequence of regulatory costs: it is so enormously expensive to go through the already excessive and expanding safety trials required by the US Food and Drug Administration for any new drug that companies prefer to eke out marginal benefits from existing drugs rather than work on building something new and better. This is one of the many ways in which the present state of medical regulation makes medicine worse.

[Researchers] reviewed previously published findings on the drug bexarotene, approved by the U.S. Food and Drug Administration for use in cutaneous T cell lymphoma. [They] were able to verify that the drug does significantly improve cognitive deficits in mice expressing gene mutations linked to human Alzheimer's disease, but could not confirm the effect on amyloid plaques.

[A] study was published last year stating that bexarotene improved memory and rapidly cleared amyloid plaques from the brains of Alzheimer's model mice expressing mouse Apolipoprotein E (APOE). Amyloid plaques consist of toxic protein fragments called amyloid beta that seem to damage neurons in the brain and are believed to cause the associated memory deficits of Alzheimer's disease and, eventually, death. Bexarotene is a compound chemically related to vitamin A that activates Retinoic X Receptors (RXR) found everywhere in the body, including neurons and other brain cells. Once activated, the receptors bind to DNA and regulate the expression of genes that control a variety of biological processes. Increased levels of APOE are one consequence of RXR activation by bexarotene.

"We were already set up to repeat the [study] to see if we could independently arrive at the same findings. While we were able to verify that the mice quickly regained their lost cognitive skills and confirmed the decrease in amyloid beta peptides in the interstitial fluid that surrounds brain cells, we did not find any evidence that the drug cleared the plaques from their brains." [Researchers] postulate that the drug works through a different biological process, perhaps by reducing soluble oligomers which, like the plaques, are composed of the toxic amyloid beta protein fragments. However, the oligomers are composed of smaller amounts of amyloid beta and, unlike the plaques, are still able to "move."

"We did find a significant decrease in soluble oligomers. It is possible that the oligomers are more dangerous than the plaques in people with Alzheimer's disease. It also is possible that the improvement of cognitive skills in mice treated with bexarotene is unrelated to amyloid beta and the drug works through a completely different, unknown mechanism."

Link: http://www.eurekalert.org/pub_releases/2013-05/uops-dra052113.php

The standard script is being followed for drug development based on rapamycin, by the look of things. Rapamycin reliably extends life in mice, which is more than can be said for the last set of overhyped alleged longevity-enhancing drugs, but it's still not worth getting excited about this sort of thing. The most likely end result is a rapamycin-like drug that lacks the worst side-effects, is of marginal benefit to humans, and which is only legally available as a palliative treatment for people suffering late-stage age-related disease - the regulatory environment in the US blocks all other options. Pharmacology to slow aging is simply not a viable path to greatly extended healthy life, and is of very limited use for old people.

A new study by Dr. Yiqiang Zhang and colleagues of the Barshop Institute for Longevity and Aging Studies at the University of Texas Health Science Center at San Antonio, has found that mice fed the drug rapamycin as part of their diet starting when they were 19 months old (roughly equivalent to 60 human years of age) had lifespan increases more modest than in some previous studies. Compared to untreated mice, the lifespan of the treated rodents increased by an average of about 3 percent, or 7 percent for mice who had lived to older age already.

The ability of rapamycin-related drugs to potentially slow the aging process as suggested in the animal experiments at The University of Texas Health Science Center San Antonio like the ones cited above, and others, led to establishment of a new biotech company, Rapamycin Holdings Inc., which is licensing exclusive rights to intellectual property central to several aspects of the rapamycin-related drugs, and which hopes to exploit new commercial possibilities for rapamycin. The company has announced that since 2010 it has been working to advance commercialization of products stemming from the patent pending technology developed by the Health Science Center researchers, and that more clinical trials will yield the next preclinical results by mid-year 2013, and advance Phase 1 trials shortly thereafter.

Rapamycin Holdings will be looking to raise an additional $6 million as it approaches the point of taking its first drug product to Phase 1 clinical trials. On December 7, 2012, Rapamycin Holdings Chief Executive Officer George Fillis announced that the company has acquired those exclusive rights from the UT Health Science Center and its collaborator, Southwest Research Institute. Rapamycin Holdings signed the license agreement with STTM, a multi-institution University of Texas technology-management office operated by the Health Science Center.

Link: http://bionews-tx.com/news/2013/05/27/rapamycin-holdings-hopes-to-exploit-commercial-potential-of-ut-health-science-center-anti-aging-drug-research/

From a point of view of materials and time it is not costly to set up a home laboratory for the purposes of synthesizing chemical compounds or even perform simple procedures in biotechnology - raising bacteria, assaying genes in lower animals, and so on. It is, however, illegal to just forge ahead and do this in most US states or in much of Europe due to the many prosaic, stupid laws that encrust the body politic. Such laws hang around for long after they stop serving whichever special interest wrote them and bribed politicians to pass them. Then there are the cases of mass hysteria that become written into law and continue onward for decades no matter how much harm they cause, such as the drug war.

It is in fact the drug war, and not the normal background level protectionism of licenses and zoning, that turns DIYbio, amateur chemistry and other similar citizen science activities into an expensive and risky endeavor. It should be cheap, but the cost is now all in the risk. The state has shown great willingness to smash first and ask questions later, if at all, and this leads to things like reagent providers only selling to registered labs, requirements to register all glassware, and raids conducted on people who followed all the rules - because the left hand doesn't care what the right hand said, and local police departments make out like bandits from confiscation and auction of assets belonging to those merely accused of breaking laws. Where there are incentives, there will be those who follow the incentives, and the incentives today are very much aligned with less citizen science and more police accusation.

The present state of medical regulation is every bit as bad as the drug war, and indeed very much influenced by it when it comes to thing like painkillers. The massive body of law concerning medicine and life science research accomplishes numerous iniquities beyond ensuring that people suffer more pain at times when drugs could prevent that suffering: it slows development; it makes therapies much more expensive; it eliminates whole regions of development by making them too costly to attempt; it prohibits some classes of therapy by fiat, such as those that aim to treat degenerative aging; it makes it illegal for a dying person to make an educated decision about trying an experimental therapy. And so forth.

At some point the massive wall of laws, all of the forbiddances telling people that they cannot try to make their lives better, will run headlong into the fact that it is becoming ever cheaper to synthesize drugs and the basis for therapies in a home laboratory. All it takes is knowledge and the willingness to undertake civil disobedience: to disregard a law because it is evil and unjust. It has to be said that near every law that touches on medicine in this day and age is evil and unjust, and the costs they impose in their aggregate cause great pain, suffering, and death. What might have been accomplished without the ball and chain of regulation is invisible, however, and therefore easily waved away by those who claim that regulation is necessary. Everyone takes the present state of affairs as the way things are and looks little past it.

Unlike recreational drugs, it is clear that the costs and the benefits for manufacturing your own medicine are not yet at the point of spurring people to action at the level of small chemistry or biotech laboratories. The knowledge is still too specialized, the complexity of the work too great, and the benefits too narrow. This will change, however, and think it will largely change on the benefit side of the equation. For example, consider mitochondrially targeted antioxidants like SS-31 and SkQ compounds: synthesizing them is an exercise in organic chemistry that is many steps in sophistication above the bucket chemistry of a recreational drug laboratory, but I have to imagine that there will be a market for these things once the public starts to appreciate that they seem to have significant effects on aging tissue. SS-31 produces endurance benefits in older mice when tested, and that's probably a draw if it does the same for people. The athletics community certainly includes an underground of experimental biochemistry, one of the consequences of all the money floating around there.

Targeted antioxidants shown to reverse some aspects of aging and extend life in mice are a trivial exercise in comparison to what is coming down the line, however. It won't be too many years from now before researchers can describe exactly how to repair and replace damaged mitochondria, construct infused enzyme solutions that destroy specific metabolic waste products that contribute to aging, and so forth. The future of medicine to treat aging and extend life will consist of a whole range of precisely designed proteins like the waste-product-chewing enzymes that can be manufactured in an appropriately equipped biotech lab. The cost of materials will continue to fall, the knowledge needed to perform the work will continue to disseminate, and when the upside of civil disobedience is rejuvenation and more years of healthy life then there will be a whole lot more civil disobedience.

In actual fact, I think that the scenario of distributed scofflaw medical manufacture will happen along the way, long before SENS-like rejuvenation biotechnology is at a point where portions of it could - in theory - be performed in a sufficiently well equipped home laboratory. Something better than SS-31 will emerge, or at least something better equipped to catch the public imagination, and grey and black markets will bloom. I'm looking forward to it: the present system of medical regulation is ugly, repressive, and costs lives: the sooner it collapses in the face of ubiquitous disregard the better.

Here is another of the signs that the more conservative advocates for aging research are slowly moving towards a better position on human longevity. This is a new campaign that's somewhat like the Longevity Dividend, but a touch more ambitious in its tone. If you look at the proposed research agenda, you'll see that it's clearly not the rejuvenation biotechnology of SENS, as the declared aim is still only to slow aging, but it's a step in the right direction. A rising tide floats all boats, and the more that the mainstream of the research community agrees that something can and should be done about aging, the easier it becomes to gain support and funding for rejuvenation research:

Scientists who study aging now generally agree that it is malleable and capable of being slowed. Rapid progress in recent years toward understanding and making use of this malleability has paved the way for breakthroughs and interventions that will increase human health in later life by opposing the primary risk factor for virtually every disease we face as we grow older - aging itself. Better understanding of this "common denominator" of disease could usher in a new era of preventive medicine, enabling interventions that stave off everything from dementia to cancer to osteoporosis. Poised as we are for an unprecedented aging of our population and staggering increases in chronic age-related diseases and disabilities, even modest extensions of healthy lifespan could produce outsized returns of extended productivity, reduced caregiver burdens, lessened Medicare spending, and more effective healthcare in future years. The field of aging research is poised to make transformational gains in the near future. Few, if any, areas for investing research dollars offer greater potential returns for public health.

The payoffs from such focused attention and investment would be large and lasting. Therapies that delay aging would lessen our healthcare system's dependence on the relatively inefficient strategy of trying to redress diseases of aging one at a time, often after it is too late for meaningful benefit. They would also address the fact that while advances in lowering mortality from heart attack and stroke have dramatically increased life expectancy, they have left us vulnerable to other age-related diseases and disorders that develop in parallel, such as Alzheimer's disease, diabetes, and frailty. Properly focused and funded research could benefit millions of people by adding active, healthy, and productive years to life. Furthermore, the research will provide insights into the causes of and strategies for reducing the periods of disability that generally occur at the end of life. As University of Michigan gerontologist Richard Miller aptly puts it, "The goal isn't to prolong the survival of someone who is old and sick, but to postpone the period of being old and sick. Not to produce a lot more standard-issue 100-year-olds, but to produce a brand new kind of 100-year-old person."

Link: http://www.healthspancampaign.org/

Stephen Cave is the author of an interesting book on the relationship between the desire for immortality and the rise of civilization. In this short op-ed, however, his argument against the plausibility of radical life extension through progress in medical technology is a bad one, amounting essentially to "it hasn't happened yet, so it won't happen."

This is the hallmark of someone who doesn't have a good appreciation of the present state of scientific knowledge. Firstly, these are the opening years in a revolutionary leap in the capabilities of biotechnology and medicine: the speed of progress is far more rapid now than it has ever been. Secondly the SENS research program is a plausible, detailed path to halt and reverse degenerative aging, and could be completed in a couple of decades given sufficient funding. The logical outcome of working SENS therapies is that in the future people will live for thousands of years - and the timeline for development means that some of those people are alive today.

But there are plenty of folk who for various reasons don't want to hear any of that, and would rather just reject it all out of hand instead of taking a serious look at the evidence:

There is a dangerous idea gaining ground in our culture. It spreads with every headline that promises a cure for cancer or celebrates the discovery of a "gene for longevity". The idea is that science and technology can make us live forever. [You] will be familiar with the prophets of this movement: men such [as] Ray Kurzweil, who promises immortality by mid-century, or Aubrey de Grey, who says we will soon be living for 1,000 years. They claim that the progress we have seen in life expectancy in past centuries can be extended, even accelerated, until ageing, disease and death are defeated for good. One problem: it's not going to happen.

The ancient Egyptians thought they had cracked it 4,000 years ago. Two millennia later, China's First Emperor was convinced an elixir was within his grasp. Since then, sages and scientists have believed they could develop a potion that would turn back the clock. You may have heard about Harvard medical professor Charles-Édouard Brown-Séquard's theory that injecting extract of dog testicles would grant eternal youth; or the double Nobel Prize-winning Linus Pauling's campaign for vitamin C as the panacea for all our ills. All these believers have had one thing in common: they are now pushing up daisies.

Believers argue that the precedent of the past is not a good guide to the future - progress, after all, has never been more rapid. But the reality is that as our population ages, we are beginning to see the full extent of the toll time takes on us. One demographer has estimated that curing all cancers, heart disease and stroke - currently the three biggest killers in developed countries - would only push up life expectancy by 15 years as our body is crumbling anyway. There are many other Malthusian monsters waiting to finish us, from our own tendency to over-indulge in sugar and salt to our microbial enemies, who evolve as rapidly as we do. Surviving is not something that can be done by drinking a magic elixir: it must be done every minute of every day. And in the end probability will always be against us.

Present day medicine does nothing to change the root causes of age-related conditions. Patching over the damage of stroke does nothing to stop the next stroke, and successfully pushing a cancer into remission does nothing to address the DNA damage that progressively raises the odds of the next cancer occurring. The only way to live much longer than we do now is to repair the cellular and molecular damage that causes these conditions to exist, and also causes people to be old. This is a new approach to medical therapies for a new age of biotechnology. People like Cave have seen radical advances in medicine in their lifetimes - why are they so resistant to the idea that radical advances continue to take place?

Link: http://www.wired.co.uk/magazine/archive/2013/05/ideas-bank/sorry

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.

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

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/

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.

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

The unfolded protein response is a housekeeping mechanism that repairs disarrayed protein machinery in cells or guides those cells to self-destruction if there is too much damage. Like many cellular repair and quality control mechanisms, it appears to be associated with longevity via its effects on mitochondria - but in this case only in early life, which raises a number of as yet unanswered questions:

[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

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

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

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

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

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

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

Cells that have divided too many times or are damaged become senescent, removing themselves from the cell cycle as a protective measure that reduces the risk of cancer by preventing damaged cells from being active. Senescent cells should be destroyed, either by the immune system or by the mechanisms of programmed cell death, but some evade this fate and their numbers grow with age. These cells exhibit a range of damaging behaviors: promoting senescence in surrounding cells, releasing compounds that harm nearby tissue structure, and so forth. Sadly, and despite their role in cancer suppression, they also serve to increase the risk of cancer:

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

The biochemistry of Alzheimer's disease is complex, and the tools available to researchers only recently up to the task of deciphering it all. Understanding the way in which the condition develops is still an ongoing work in progress:

Amyloid fibrils can form the foundations of huge protein deposits - or plaques - long-seen in the brains of Alzheimer's sufferers, and once believed to be the cause of the disease, before the discovery of "toxic oligomers" [a] decade or so ago. A plaque's size and density renders it insoluble, and consequently unable to move. Whereas the oligomers, which give rise to Alzheimer's disease, are small enough to spread easily around the brain - killing neurons and interacting harmfully with other molecules - but how they were formed was until now a mystery.

The new work [shows] that once a small but critical level of malfunctioning protein "clumps" have formed, a runaway chain reaction is triggered that multiplies exponentially the number of these protein composites, activating new focal points through "nucleation". It is this secondary nucleation process that forges juvenile tendrils, initially consisting of clusters that contain just a few protein molecules. Small and highly diffusible, these are the "toxic oligomers" that careen dangerously around the brain cells, killing neurons and ultimately causing loss of memory and other symptoms of dementia.

"We are essentially using a physical and chemical methods to address a biomolecular problem, mapping out the networks of processes and dominant mechanisms to 'recreate the crime scene' at the molecular root of Alzheimer's disease. With a disease like Alzheimer's, you have to intervene in a highly specific manner to prevent the formation of the toxic agents. Now we've found how the oligomers are created, we know what process we need to turn off."

Link: http://www.sciencedaily.com/releases/2013/05/130520154217.htm

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

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

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

Researchers Develop Radioactive Nanoparticles that Target Cancer Cells

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

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

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

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

Researchers investigate the ability of lower animals like the salamander to regenerate limbs and organs with the hopes that some of these mechanisms also exist in humans, just turned off at some point in our evolutionary history. Even if this is not the case, it may be that a greater understanding of the mechanisms of salamander regeneration will lead to ways to improve human regenerative capacity.

Salamanders' immune systems are key to their remarkable ability to regrow limbs, and could also underpin their ability to regenerate spinal cords, brain tissue and even parts of their hearts. [Researchers] found that when immune cells known as macrophages were systemically removed, salamanders lost their ability to regenerate a limb and instead formed scar tissue. "Now, we need to find out exactly how these macrophages are contributing to regeneration. Down the road, this could lead to therapies that tweak the human immune system down a more regenerative pathway."

Salamanders deal with injury in a remarkable way. The end result is the complete functional restoration of any tissue, on any part of the body including organs. The regenerated tissue is scar free and almost perfectly replicates the injury site before damage occurred. There are indications that there is the capacity for regeneration in a range of animal species, but it has, in most cases been turned off by evolution. "Some of these regenerative pathways may still be open to us. We may be able to turn up the volume on some of these processes. We need to know exactly what salamanders do and how they do it well, so we can reverse-engineer that into human therapies."

Link: http://www.eurekalert.org/pub_releases/2013-05/mu-dsh051613.php

Ten years from now targeted therapies that selectively deliver cell-killing mechanisms to cancer cells will be the dominant method of treating cancer. This sort of technology offers the prospect of removing cancer cells even after metastasis, and with few side effects:

Nanomedicine started creating its own footprint in the sands of cancer research back in the mid-1970s when a group of European researchers discovered what would eventually become known as the liposome. These nano-sized, spherical structures form spontaneously when naturally occurring or synthetic lipids are exposed to water. Although they were identified by accident, these same researchers soon realized the potential of liposomes to carry drugs to diseased cells and tissues.

Around the same time, Massachusetts Institute of Technology research engineer Robert Langer also developed nanoparticles as chains of hydrocarbons known as polymers. Decades later, researchers have shown that such targeted nanoparticle therapies can effectively deliver drug cargo to tumors, while sparing the rest of the body's cells from the drug's toxic effects. Indeed, both types of nanoparticles are in clinical development as cancer-drug delivery vehicles, and some liposome-based have even made it to the market. There are now a total of three nanoparticles on the market as cancer therapies, and at least a dozen more are currently making their way through clinical trials.

The liposome platform is limited, however, in that it cannot release the drug into the tumor in a regulated way. The mechanism of drug release from liposomes is not well-understood, and may involve complex processes such as disruption of the liposome membrane or fusion with cellular membranes. In contrast, the polymer-based nanoparticles [allow] researchers to design treatments that release the chosen drug at a predictable rate controlled by diffusion. "While the first generation of drugs using [lipid] nanotechnology were considered pioneering at the time and became successful blockbuster cancer drugs, they were essentially reformulations of older drugs. Now, the next generation [using polymers] is taking nanotechnology to a whole new level with the ability to fundamentally change the efficacy and safety of drugs. The properties of these advanced compounds are well suited to target rapidly proliferating cells such as cancer cells, and several are already in the clinic."

Link: http://www.the-scientist.com/?articles.view/articleNo/35629/title/Nano-vehicles-for-Cancer-Drugs/

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

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

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

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

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

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

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

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

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

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

Endothelium, heal thyself

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

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

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

A recent publication by the Institute of Economic Affairs (PDF format) looks at studies that suggest retirement leads to worse long-term health and shorter remaining life expectancy. You'll find the meaningful discussion on how researchers went about trying to identify cause and effect in the PDF rather than the press article quoted below: does the data actually show that retirement causes worsening health versus a tendency for people with worsening health to retire, for example?

A study out of the U.K. suggests that while it may provide an initial sense of relief and well-being, over the long-term, retirement is bad for your health, increasing the likelihood of developing depression and at least one physical illness. The study's author [analyzed] data from a survey of 11 European countries that sampled 7,000 to 9,000 people between the ages of 50 and 70 using two separate methodologies. He found that retirement had a "consistent negative impact" on physical health that worsens as the number of years spent in retirement increase.

[The author] also analyzed past studies on the subject of retirement and health and found that their results were mixed, with some finding a positive impact and others a negative or neutral one. The researcher attributes these varied results largely to a failure to distinguish short-term effects from long-term ones and to take the length of retirement into account. In the short term, retirees may experience a boost to health, he says, but this is outweighed by the negative impacts that manifest over the medium and long term.

[The author] acknowledges that there are many variables in any one individual's retirement that can often have contradictory effects on physical and mental health. Retirement can decrease work-related pressures and stress, for example, but it can also cut retirees off from the social networks they formed at work and lead to greater isolation, which can negatively affect health. By contrast, it can lead to more leisure time, which can result in new non-work-related social contacts or more participation in physical activities that positively affect health and well-being. "Untangling cause and effect in the relationship between retirement and health is very difficult. Whereas the short-term impacts of retirement on health is somewhat uncertain, the longer-term effects are consistently negative and large."

Link: http://www.cbc.ca/news/business/story/2013/05/16/business-retirement-health.html

Osteoarthritis is one of the more common age-related conditions, and at the present time little can be done to treat the causes other than to alter lifestyle in ways that usually slow down the progression of the condition. Signs of progress towards effective therapies are on the horizon, however:

[Scientists] have turned their view of osteoarthritis (OA) inside out. Literally. Instead of seeing the painful degenerative disease as a problem primarily of the cartilage that cushions joints, they now have evidence that the bone underneath the cartilage is also a key player and exacerbates the damage. In a proof-of-concept experiment, they found that blocking the action of a critical bone regulation protein in mice halts progression of the disease.

Using mice with ACL (anterior cruciate ligament) tears, which are known to lead to OA of the knee, the researchers found that, as soon as one week after the injury, pockets of subchondral bone had been "chewed" away by cells called osteoclasts. This process activated high levels in the bone of a protein called TGF-beta1, which, in turn, recruited stem cells to the site so that they could create new bone to fill the holes. But the bone building and the bone destruction processes were not coordinated in the mice, and the bone building prevailed, placing further strain on the cartilage cap. It is this extraneous bone formation that [researchers] believe to be at the heart of OA, as confirmed in a computer simulation of the human knee.

With this new hypothesis in hand, complete with a protein suspect, the team tried several methods to block the activity of TGF-beta1. When a TGF-beta1 inhibitor drug was given intravenously, the subchondral bone improved significantly, but the cartilage cap deteriorated further. However, when a different inhibitor of TGF-beta1, an antibody against it, was injected directly into the subchondral bone, the positive effects were seen in the bone without the negative effects on the cartilage. The same result was also seen when TGF-beta1 was genetically disrupted in the bone precursor cells alone.

Link: http://www.eurekalert.org/pub_releases/2013-05/jhm-nto051713.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.

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 β-galactosidase (SA-β-Gal) activity. Although SA-β-Gal has been first suggested as a distinct enzyme, its activity is derived from lysosomal β-Gal encoded by the GLB1 gene. β-Gal is an accepted marker of senescence, but its reliability and specificity have been questioned, as a positive β-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 β-Gal staining.

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

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

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.

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

Therapeutic cloning or somatic cell nuclear transfer are names given to a method of producing embryonic stem cells from a patient's own cells. These embryonic stem cells could then be used to generate cells of any type as a basis for regenerative therapies. Making the process work has proven to be challenging, however, both from a technical point of view and thanks to misguided attempts to make it illegal. In recent years the focus shifted towards work on induced pluripotent stem cells instead, but a research group now claims success in the original goal:

Scientists [have] successfully reprogrammed human skin cells to become embryonic stem cells capable of transforming into any other cell type in the body. It is believed that stem cell therapies hold the promise of replacing cells damaged through injury or illness. The technique used [is] a variation of a commonly used method called somatic cell nuclear transfer, or SCNT. It involves transplanting the nucleus of one cell, containing an individual's DNA, into an egg cell that has had its genetic material removed. The unfertilized egg cell then develops and eventually produces stem cells.

Previous unsuccessful attempts by several labs showed that human egg cells appear to be more fragile than eggs from other species. Therefore, known reprogramming methods stalled before stem cells were produced. To solve this problem, the [researchers] studied various alternative approaches first developed in monkey cells and then applied to human cells. Through moving findings between monkey cells and human cells, the researchers were able to develop a successful method. The key to this success was finding a way to prompt egg cells to stay in a state called "metaphase" during the nuclear transfer process. Metaphase is a stage in the cell's natural division process (meiosis) when genetic material aligns in the middle of the cell before the cell divides. The research team found that chemically maintaining metaphase throughout the transfer process prevented the process from stalling and allowed the cells to develop and produce stem cells.

Link: http://www.eurekalert.org/pub_releases/2013-05/ohs-ort051313.php

If you visit Fight Aging! on a regular basis you'll know that I strongly favor the SENS Research Foundation and the approach taken by its founders, advisors, and staff to speed the development of human rejuvenation. I think we could do with another ten or twenty similar organizations, and certainly a hundredfold increase in the funding for rejuvenation research, but right now we have just the one. So send the Foundation a donation if you're feeling flush today, because there's no-one else out there at the moment who can do as much for your future longevity with that money.

Or rather I should say that there are dozens and possibly hundreds of people out there who can do as much for your future longevity with those funds - it's just that you don't know who they are. Would you know enough to chase down William Bains in the UK and ask him to work on AGE-breaker drugs for glucosepane, for example? Or pick the group at the Buck Institute best placed work on ways to selectively destroy senescent cells by interfering in their characteristic biology? Or have Janko Nikolich-Žugich in Arizona work on restoring the aged immune system by removing unwanted T cells? Of course not. But there is a whole world of researchers out there with useful specialist knowledge and who are these days quite willing to work on the foundation technologies needed for human rejuvenation - provided that the funding can be found.

Organizations like the SENS Research Foundation are the interface between you and the research community: the Foundation staff provide domain knowledge and relationships needed in order to direct funds effectively. Without their work it would be impossible for folk like you or I to help make this field of science move faster - we wouldn't know where to start or who to talk to, never mind where to send funds, and finding out would be so costly in comparison to what we could donate as to make the whole exercise pointless.

The SENS Research Foundation is the watering hole, not the herd. It is the gateway, not the city. It is the door to a network of researchers who are interested in human rejuvenation, but that network is a greater and broader thing than the Foundation. I bring up this point because many people look no further than the gateway: they see the SENS Research Foundation and think of an enclosed group, off to one side of the scientific community, doing its own thing in isolation, and therefore easy to dismiss. For all that this point of view is absolutely incorrect, it is not uncommon. You'll see it liberally applied to biotechnology companies, noted laboratories, and other organizations that are also gateways to broader scientific networks. People look at an organization, see its staff performing some research work in its own domain, but fail to see beyond that to take in the great tree of relationships and connections behind the name plate.

The greatest achievement of the folk behind the SENS Research Foundation (and the Methuselah Foundation before it) is their construction of a lasting and growing network of supporters of rejuvenation research within the life sciences. This was quite the task over the past decade and involved a lot of persuasion, changing the culture of the research community to become more receptive towards longevity science, building relationships, holding conferences, and tireless advocacy. It is that web of relationships, and not the existence of the Foundation per se, that enables growth in funding and progress towards the goal of ending aging. As for all areas of human endeavor, it is relationships and networking that make the world turn: the Foundation is a mailbox, a guidebook, and a banner for a larger community, an outgrowth of that community even, and it is the community that gets things done.

This is worth bearing in mind, because it's all to easy to focus on organizations rather than people and thus miss the whole point of the exercise.

Women tend to live longer than men, and there are any number of competing explanations as to why this is the case. They range from risk of mortality relating to lifestyle choices to evolutionary selection operating on the male role in reproduction to various differences in biochemistry that exist between the genders. That the female immune system ages more slowly shouldn't be terribly surprising - but it might be cause or consequence.

Women's immune systems age more slowly than men's, [and] the slower decline in a woman's immune system may contribute to women living longer than men. Researchers looked at the blood of healthy volunteers in Japan, ranging in age between 20 and 90 years old; in both sexes the total number of white blood cells per person decreased with age. The number of neutrophils decreased for both sexes and lymphocytes decreased in men and increased in women. Younger men generally have higher levels of lymphocytes than similarly aged women, so as aging happens, the number of lymphocytes becomes comparable.

Looking in more detail it became apparent that the rate in decline in T cells and B cells was slower for women than men. Both CD4+ T cells and NK cells increased with age, and the rate of increase was higher in women than men. Similarly an age-related decline in IL-6 and IL-10 was worse in men. There was also a age-dependent decrease in red blood cells for men but not women.

"The process of aging is different for men and women for many reasons. Women have more oestrogen than men which seems to protect them from cardiovascular disease until menopause. Sex hormones also affect the immune system, especially certain types of lymphocytes. Because people age at different rates a person's immunological parameters could be used to provide an indication of their true biological age."

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=131061&CultureCode=en

Amyloids are solid masses that form in tissues as a result of misfolded proteins. The amount of amyloid increases with age, perhaps due to a failure of mechanisms that keep the levels of damaged or misfolded proteins under control, and this is thought to cause harm and contribute to degenerative aging. In most cases researchers are still lacking a full understanding of the mechanisms involved, however. At the very least having solid clumps and fibrils present where they shouldn't exist can disrupt tissue integrity or even cause larger scale issues such as clogging blood vessels.

One approach to removing amyloid involves the use of the immune system. Immune therapies direct immune cells to attack and break down a specific target, and much of the innovation in their use as a therapy to remove amyloid is happening in the Alzheimer's research community. That condition is associated with amyloid beta, but we can hope that any successful therapies will prove adaptable to other forms of amyloid and thus applicable to human rejuvenation.

Alzheimer's disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. AD is strongly associated with Amyloid-beta (Abeta) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising target for the development of AD therapeutics.

Within the past decade convincing data has arisen positioning the soluble prefibrillar Abeta-aggregates as the prime toxic agents in AD. However, different Abeta aggregate species are described but their remarkable metastability hampers the identification of a target species for immunization. Passive immunotherapy with monoclonal antibodies (mAbs) against Abeta is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function.

Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate a cognitive stabilization. Thus, it might be the more promising strategy reducing the whole spectrum of Abeta-aggregates than to focus on a single aggregate species for immunization.

Link: http://www.immunityageing.com/content/10/1/18/abstract

Telomeres are repeating sequences of nucleic acids that cap the ends of chromosomes in the cell nucleus and stop actual gene-coding DNA from being chopped off when a cell divides. The mechanisms of DNA replication require extra leg room at the ends of the strand, a trailing sequence that is not copied over to the new strand under assembly - and the primary role of telomeres is to be the part that is dropped on the floor. A little of their length is thus lost with every cell division. This shortening acts as a clock to count cell divisions, and cells with very short telomeres stop replicating - they either enter cellular senescence (which ideally then causes the immune system to destroy them) or destroy themselves directly via programmed cell death mechanisms.

Telomere length is more dynamic than this simple picture, however. In some cell populations, such as the various types of stem cell that maintain tissues and produce new cells to replace those lost or damaged, an enzyme called telomerase continually lengthens telomeres so as to allow a cell lineage to continue dividing indefinitely.

Ordinary, non-stem cell populations exhibit a range of telomere lengths, some short, some long. You might imagine that a population of cells replenished more frequently or recently by stem cells will have longer telomeres on average. A population that is receiving less support might have shorter telomeres. Researchers have shown that a higher proportion of short telomeres in white blood cells correlates well with ill health or stress, and somewhat correlates with age. Some more complex measures of telomere length, a step above just taking the average, have been shown to correlate well with age, however, and other techniques do a fair job of predicting future life expectancy in laboratory animals.

A few years back a brace of startup biotech companies were aiming to address aspects of aging by lengthening telomeres through the use of telomerase. None of that went anywhere, unfortunately, but it's possible that they were just too early - it is frequently the case that all of the first batch of companies in a new area of biotechnology fail. It's a tough business to be in. I was a skeptic at the time regarding their potential for success based on my expectation that telomere length will prove not to be a root cause of aging.

Nonetheless, researchers are demonstrating extension of life in mice through telomerase these days, but it is as yet unknown as to exactly why this works. Perhaps it makes stem cells work harder to maintain tissues, perhaps there is just one critically limiting type of stem cell or tissue that benefits from more telomerase, or perhaps it involves other effects causes by increased levels of telomerase that have nothing to do with telomere length. It is worth bearing in mind that there are considerable differences in natural levels of telomerase and the resulting telomere dynamics between mice and people, however. Telomerase therapy is probably not something you'd want to just up and try without the research community first obtaining a much greater understanding of why it works to extend life in mice.

Why? Well, the risk of telomere lengthening in humans is cancer. Any mechanism that globally, or possibly even narrowly, extends telomere length in people will raise the risk of suffering cancer. The whole system of telomere dynamics and cellular senescence is intimately tied to the processes of cancer suppression, while all cancers evolve ways of lengthening their telomeres to allow unlimited cell division. Boosting your telomerase levels looks a lot more risky to me than, say, undergoing first generation stem cell transplants.

There continues to be a lot of activity in telomere research and development. The present brace of telomere-related biotech startups are commercializing ways to measure telomere length rather than extend it. The products are tests that will at first add another measure to inform patients on the state of their health, then possibly act as an effective biomarker of biological age, and perhaps later prove useful in further research if it turns out that telomerase-based therapies can be beneficial in humans.

How Long Will You Live?

A growing number of researchers say telomere length is a critically important indicator of how old we really are, and of how many healthy years we may have in front of us. A new industry is sprouting up around the science of longevity, offering telomere testing to the public - and Nobel laureate Elizabeth Blackburn is a notable part of it. Her company, Telome Health, is set to launch a telomere test later this year, joining a handful of others that already do. Like a cholesterol or blood-pressure test, telomere testing could one day become standard in doctors' offices.

And maybe in the future, we'll be able to slow or reverse the effects of aging -the vision of researchers searching for ways to boost telomerase, a goal already achieved in lab mice. Some are already marketing so-called "telomerase activators" to a public hungry for ways to stop the clock, although no such drugs have been approved. With so many companies rushing to come on board, "there's a lot of weird stuff going on out there," cautions Jerry W. Shay of the University of Texas Southwestern Medical Center, an expert on cell biology and telomere length.

Certainly you should be looking askance at any group that's selling herbal "telomerase activators" - it's the standard garbage from the supplement marketplace, and sadly that's the place that formerly funded companies doing original research often end up. It's hard to make money doing something useful in medical research, but depressingly easy to make money doing something useless in the supplement business. The traditional model here is to grab a little research that's somewhat relevant, scare up a bunch of Chinese herb extracts, and then hope that if you market the thing hard enough it'll overcome the obvious ineffectiveness and pointlessness. If you can buy out the shell of a company formerly doing research to try to profit from its one-time reputation, then all the better. Caveat emptor is the watchword, as ever.

So where do telomeres fit in the taxonomy of cause versus secondary effect in aging? Because of the dynamic nature of telomere length I'm given to think that it's a secondary effect: get sick and average telomere length in white blood cells shortens; get well and it lengthens again. This sounds very much like a system responding to circumstances, and those circumstances most likely include the general level of cellular damage, inflammation, and metabolic waste products - all of which grow with age. As for so many other similar questions about aging, the fastest and cheapest way to answer this question about telomere length is to implement the Strategies for Engineered Negligible Senescence (SENS): build the biotechnologies to repair these forms of damage and then see what happens to telomere length once its done. That is a good deal easier at this point than obtaining a full understanding of the aging of human biology.

None of the above precludes short telomeres from causing further damage or changes of their own, of course. Aging proceeds as a cascade of harmful effects as damage causes further damage and flailing biological systems cope badly with the new circumstances they find themselves in. Here is a recent article on how telomere length can impact gene expression and thus the operation of metabolism in a previously unsuspected way, for example:

Telomeres Affect Gene Expression

DUX4, a gene responsible for the genetic disease facioscapulohumeral muscular dystrophy (FSHD), is normally silenced because it sits next to a telomere - a protective DNA sequence that caps the ends of chromosomes, according to [a recent study]. But as telomeres shorten, as they do with age, DUX4 expression climbs, which may explain the late onset of FSHD. Another gene, called FRG2, which sits 100 kilobases away from the telomere, is also affected by telomere length.

"This was completely unexpected. We think that DUX4 and FRG2 are the tip of an iceberg." Due to shrinking telomeres, many genes might gradually become more active as we get older, which may be important for several diseases of old age. "This represents a very significant general advance in our understanding of how telomere shortening may affect human biology."

Ames dwarf mice lack growth hormone and as a consequence live much longer than their peers. Here the biochemistry of this lineage is considered in light of the membrane pacemaker hypothesis of aging, which suggests that the degree of resistance to oxidative damage in cell membranes is a driving factor in determining longevity. Thus similar species with different proportions of more resistant and less resistant molecules making up their cell membranes have different life spans. Is it possible that this can happen within a species thanks to genetic engineering of the sort that produced the Ames dwarf mouse lineage?

Membrane fatty acid (FA) composition is correlated with longevity in mammals. The "membrane pacemaker hypothesis of ageing" proposes that animals which cellular membranes contain high amounts of polyunsaturated FAs (PUFAs) have shorter life spans because their membranes are more susceptible to peroxidation and further oxidative damage. It remains to be shown, however, that long-lived phenotypes such as the Ames dwarf mouse have membranes containing fewer PUFAs and thus being less prone to peroxidation, as would be predicted from the membrane pacemaker hypothesis of ageing.

Here, we show that across four different tissues, i.e., muscle, heart, liver and brain as well as in liver mitochondria, Ames dwarf mice possess membrane phospholipids containing between 30 and 60 % PUFAs (depending on the tissue), which is similar to PUFA contents of their normal-sized, short-lived siblings. However, we found that that Ames dwarf mice membrane phospholipids were significantly poorer in n-3 PUFAs. While lack of a difference in PUFA contents is contradicting the membrane pacemaker hypothesis, the lower n-3 PUFAs content in the long-lived mice provides some support for the membrane pacemaker hypothesis of ageing, as n-3 PUFAs comprise those FAs being blamed most for causing oxidative damage. By comparing tissue composition between 1-, 2- and 6-month-old mice in both phenotypes, we found that membranes differed both in quantity of PUFAs and in the prevalence of certain PUFAs. In sum, membrane composition in the Ames dwarf mouse supports the concept that tissue FA composition is related to longevity.

At some point a research group will find a way to alter only membrane constituent molecules and no other factors in laboratory mice, which should go some way towards quantifying the effect on aging and longevity. The challenge with using any of the well known long-lived lineages of mice is that many aspects of their metabolism are different - it is difficult to point to any one of those and talk about how important it may or may not be to extended longevity given the presence of the others.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23640425

Levels of the essential amino acid methionine in the diet appear to be involved in generating the beneficial effects of calorie restriction on health and longevity. Some portion of the resulting changes in the operation of metabolism is based on sensing low levels of methionine. It is thus possible that humans might obtain benefits comparable to those generated by calorie restriction from a sensibly constructed low-methionine diet with a normal calorie intake. The research in support of this supposition is still sparse in comparison to that for calorie restriction, however.

It was first reported in 1993 that rats subjected to a diet restricted in methionine (MR) enjoyed comparable life spans to rats that were on caloric restriction (CR). In the first experiments, methionine was reduced to ⅕ its normal level in the diet, and growth of the rats was severely stunted. We can't live entirely without methionine - the body would not be able to make any proteins at all. Restricting methionine is likely to have impacts on growth, health, and wellbeing that are as yet unstudied in humans. Rats fed a diet without methionine developed steatohepatitis (fatty liver), anemia and lost two thirds of their body weight over 5 weeks. In one experiment where methionine was severely restricted but not eliminated entirely, ⅕ of the mice died, and the other ⅘ went on to live longer than control mice.

Here's a clue about why methionine is special. The instructions for making proteins is coded into DNA, via the genetic code, which specifies words of 3 DNA letters, each corresponding to one of the 20 amino acids. The genetic code also contains "punctuation", instructions to start and stop. The "start codon" is also the word for methionine. Every chain of amino acids that the body constructs begins with methionine. No methionine - no protein synthesis. A shortage of methionine means that the body is inhibited in making every kind of protein. More genes are expressed (more proteins synthesized) as the body grows older. Perhaps methionine restriction is putting a brake on this production of extra proteins that are not produced when we're young, and that contribute to aging.

Methionine restriction in practice involves eating foods that are low in methionine. Though all protein has methionine, some protein sources are much lower in methionine than others. All animal sources (including milk and especially eggs) are high in methionine. So a methionine-restricted diet is a vegan diet, not just any vegan diet, but a subset of vegan protein sources. There appear to be no general rules. For example, almonds are a good source of low-methionine protein, but Brazil nuts are terrible. Even a strict vegan diet would only reduce methionine intake by about 1/2. Extrapolating from the rodent experiments, we may need to reduce by ~ 3/4 before crossing a threshold where benefits kick in.

Link: http://joshmitteldorf.scienceblog.com/2013/05/13/could-cutting-this-one-nutrient-make-you-live-longer/

"Cui bono?", "to whose benefit?", is a question that should never be far from mind. It is rarely the case that the loudest threads in our grand, connected cultural conversation represent the best, the most useful, or the most virtuous of what is possible. That is just as true in any subculture as it is in the mainstream: follow the money and much becomes clear.

Longevity hotspots might not be a term familiar to you, but Blue Zones might be thanks to a fair degree of publicity for that latter term. They mean the same thing, but the latter is a brand rather than a description. A small industry associated with this brand is devoted to promoting the idea that some parts of the world exhibit pockets of exceptional human longevity. It is convenient for various businesspeople to act as though this is proven beyond a doubt and that the root causes involve aspects of local culture, diet, and lifestyle that can be packaged up and sold. So the world goes on: this sort of thing is a textbook example of how small science projects on minor aspects of human longevity can spawn commercial monstrosities set on muddying the waters, promoting myths, and profiting from the credulous.

It is by no means certain that longevity hotspots exist in actuality, or at least not in the sense that Blue Zone business ventures would like you to think, but those most interested in carrying on a dialog on this topic - i.e. marketing folk involved in tourism, diet, lifestyle coaching, and so forth - don't really care to hear that message. Nonetheless:

Designating longevity hotspots: cautions concerning the instability of per capita centenarian estimates

Estimates of per capita centenarians in a Utah population varied between one per 12,864 and one per 4,675, depending on the data that were used, the population assumptions that were made, and the boundary limits that were employed. In general, caution is warranted in claims about the existence of longevity hotspots.

Performing any sort of statistical study on human populations in a given geographical area, even on something as apparently simple as age, is enormously complex. People move and data is ever incomplete or outright false. Some locations attract the wealthy in large numbers, a demographic already well correlated with greater life expectancy. When a region in the US with good demographic data can produce a threefold range of results for a simple population question, one has to wonder about the accuracy of other studies - and the smaller the group the less helpful that statistical procedures become.

This is not to say that there is nothing to be learned by comparing different populations with different lifestyles, but I would be extremely surprised to see the end results be anything other than additional support for the value of exercise and calorie restriction (and derived measures such as body mass index). These line items strongly correlate with health in large statistical studies.

Neither exercise nor calorie restriction will let you reliably live to see 100, however. The only thing that can achieve that goal is significant progress in new medical science. Longevity hotspots are, like so much of what is discussed in relation to aging these days, nothing but a sideshow - something that occupies time and energy and attention, and all to no good end. That the data is most likely flawed and what little science there was is now largely buried beneath an industry that strives to make money by promoting magical thinking and ignorance just makes the joke a little more black.

When it comes to evolutionary influences on longevity, the evidence supports the idea that species with a high mortality rate due to external causes (e.g. being eaten) will tend to be short-lived. There is no evolutionary pressure to develop the biological mechanisms that will lead to longer reproductive lives if near all individuals are killed comparatively early in life. This study is a novel way to add further supporting evidence to this point of view:

Evolutionary hypotheses for ageing generally predict that delayed senescence should evolve in organisms that experience lower extrinsic mortality. Thus, one might expect species that are highly toxic or venomous (i.e. chemically protected) will have longer lifespans than related species that are not likewise protected. This remarkable relationship has been suggested to occur in amphibians and snakes.

First, we show that chemical protection is highly conserved in several lineages of amphibians and snakes. Therefore, accounting for phylogenetic autocorrelation is critical when conservatively testing evolutionary hypotheses because species may possess similar longevities and defensive attributes simply through shared ancestry. Herein, we compare maximum longevity of chemically protected and nonprotected species, controlling for potential nonindependence of traits among species using recently available phylogenies.

Our analyses confirm that longevity is positively correlated with body size in both groups which is consistent with life-history theory. We also show that maximum lifespan was positively associated with chemical protection in amphibian species but not in snakes. Chemical protection is defensive in amphibians, but primarily offensive (involved in prey capture) in snakes. Thus, we find that although chemical defence in amphibians favours long life, there is no evidence that chemical offence in snakes does the same.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23638626

Some degree of human longevity is genetic rather than the result of environment and lifestyle choice; researchers have guessed that perhaps 25% of variations are genetic, but this is hardly a firm number. It appears to be the case that survival at extreme old age is more influenced by genetic variations than it is in early old age, for example. Given that some predisposition to longevity is thus inherited, it isn't surprising to find that risk levels for specific conditions of aging also correlate with familial longevity:

Based on comparisons of people in their 90s, their spouses, siblings, children and their children's spouses, researchers found that the offspring of people with exceptional longevity were about 40 percent less likely than peers to be cognitively impaired between ages 65 and 79. "It's not necessarily that these individuals never become cognitively impaired, but what it seems like is that there is a delayed onset of cognitive impairment."

For the new study, the researchers used data on cognitive impairment from 1,870 people who are part of the Long Life Family Study, which includes volunteer participants in New York, Massachusetts, Pennsylvania and Denmark. The study included 1,510 people with a family history of longevity and 360 of their spouses, but for this study, researchers used information on just the volunteers who were 89 years old or older when they were recruited.

Overall, the researchers found that about 6 percent of the volunteers' children were cognitively impaired between ages 65 and 79 years old, compared to 13 percent of their spouses and about 11 percent of their cousins. Among the study's long-lived older generation, participants were just as likely to be cognitively impaired by about age 90 as their siblings or spouses. "These families seem relatively protected, but once they reach extreme old age - say after 90 (years old) - their rates of cognitive impairment become comparable."

Link: http://www.reuters.com/article/2013/05/06/us-family-dementia-idUSBRE9450VL20130506

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.

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/

An article on the development of prosthetic organs, a field that continues to provide competition for regenerative medicine:

Proponents of biological organ replacements have recently been encouraged by the development of 3D tissue printing, which offers the tantalising possibility that we might build organs mechanically, layer by layer - a much faster process than growing them in the lab. But printing complex internal organs like the liver or heart is still some way off, and the technology will face similar issues to traditional tissue engineering when it comes to implanting. In the meantime, some scientists are pursuing a different approach, combining biological tissue with synthetic materials and/or mechanical and electronic components to create what could be called hybrid or even cyborg organs (cyborgans, if you will), which are more easily manufactured, longer lasting and more successful once implanted into the body.

On one level this means incorporating some biological material into a largely man-made device. French firm Carmat [has] begun animal trials on one of the world's most advanced designs for an artificial heart, which includes some biological elements.The two chambers inside the Carmat heart are each divided by a biomembrane that separates blood on side from hydraulic fluid on the other. Tiny motors controlled by an electronic sensor system pump the hydraulic fluid in and out of the chambers, in turn causing the membrane to pump the blood. To increase haemocompatiblity, the membrane is made from animal tissue that helps move the blood without damaging cells. Microporous biological and synthetic biomaterials also cover every other surface that comes in contact with the blood, in order to prevent material from sticking to them.

But scientists are also combining biological and synthetic materials in a more fundamental way, creating permanent artificial structures or scaffolds and then growing living cells around them. [Researchers are] already preparing to clinically trial blood vessels and tracheae (windpipes) made in this way, and [are] also developing urethrae, bladders and cardiac patches for healing hearts.

Link: http://www.theengineer.co.uk/medical-and-healthcare/in-depth/body-builders-developing-cyborg-organs/1016241.article

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-β 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.

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/

Autoimmune diseases like rheumatoid arthritis are one of the few remaining classes of condition where little can be done for many sufferers at this time, and where researchers still know comparatively little about specific causative mechanisms. The most effective treatments are based on suppressing the immune system rather than addressing root causes, and even those are hit and miss.

Meanwhile here is one of the signs that this may all be changing in the years ahead, as modern tools allow a greater understanding and ability to manipulate facets of the immune system:

"We found that fat in the knee joints secretes a protein called pro-factor D which gives rise to another protein known as factor D that is linked to arthritis. Without factor D, mice cannot get rheumatoid arthritis." [With] the discovery of pro-factor D in mice with rheumatoid arthritis, [researchers are] working on gene therapies to eliminate the protein in localized areas. However, these findings still need to be extended to humans. "We are looking at vaccines, drugs or inhibitors to stop the local secretion of pro-factor D in the mouse. Our goal would be to stop the disease before it progresses and leads to joint destruction."

Factor D is part of the complement system, a complex array of over 40 proteins that help the body fight off bacteria and other pathogens. In studies with arthritic mice, [researchers] previously found that the complement pathway involving factor D made the mice susceptible to inflammatory arthritis. [Removing] factor D, rather than the entire complement system, achieves the same result without compromising other parts of the system that can fight infection.

While it's theoretically possible to destroy the entire complement system in humans to prevent arthritis, it eventually returns along with a renewed risk of contracting the disease. In the meantime, patients can get infections and other complications because they lack this critical part of the immune system. "The complement system is both friend and foe. We believe we can shut down one part of the complement system that triggers disease without shutting down the rest. If so, we will be making a major stride toward treating and perhaps even curing rheumatoid arthritis."

Link: http://www.eurekalert.org/pub_releases/2013-05/uocd-dsf050713.php

New ways to extend mouse life span arrive at a steady pace these days. It's all largely genetic engineering to alter the operation of metabolism in various ways, and the results help to shed light on the roles of specific genes and on the way in which metabolism and environment together determine the pace of aging. These examples of life extension are not rejuvenation, however, and nor do they lie on any road that leads to rejuvenation. Thus they have little to no bearing on whether or not you and I will lead extended healthy lives: the only way that will happen is for research programs like SENS to make significant progress. SENS-like research aims to repair the underlying causes of aging in a deliberate, targeted fashion and thus reverse aging. It is a completely different approach to research and the development of therapies than that of trying genetic alternations in search of those that can modestly slow down aging.

But still, I post on the topic of genetically engineered mouse longevity for the same reasons I post on topics like the evolution of aging - because it is interesting, not because it will necessarily have any meaningful application in the near term. Below is a recent example in which the human gene for MTH1 / NUDT1 causes enhanced longevity when expressed in mice. The enzyme produced from this genetic blueprint cuts down on oxidative damage to both nuclear and mitochondrial DNA, and the gain in mouse life span is thus an expected outcome under any of the free radical theories of aging.

Prolonged Lifespan with Enhanced Exploratory Behavior in Mice Overexpressing the Oxidized Nucleoside Triphosphatase hMTH1

In this study we used the hMTH1-Tg mouse model to investigate how oxidative damage to nucleic acids affects aging. hMTH1-Tg mice express high levels of the hMTH1 hydrolase that degrades 8-oxodGTP and 8-oxoGTP and excludes 8-oxoguanine from both DNA and RNA. Compared to wild-type animals, hMTH1-overexpressing mice have significantly lower steady-state levels of 8-oxoguanine in both nuclear and mitochondrial DNA of several organs, including the brain. hMTH1 overexpression prevents the age-dependent accumulation of DNA 8-oxoguanine that occurs in wild-type mice.

These lower levels of oxidized guanines are associated with increased longevity and hMTH1-Tg animals live significantly longer than their wild-type littermates. Neither lipid oxidation nor overall antioxidant status are significantly affected by hMTH1 overexpression. The significantly lower levels of oxidized DNA/RNA in transgenic animals are associated with behavioral changes. These mice show reduced anxiety and enhanced investigation of environmental and social cues.

There some muddying of the water here, of course. Nothing is ever simple in biology. The first item to consider is that it's possible that differences in activity levels in the mice could account for some of the longevity differences shown in the research. This is hard to control for, harder than calorie restriction, which is the other thing you have to keep track of in any mouse study. If your mice happen to eat less because your treatment makes them nauseous, or they eat less because they're spending more time running around, then they'll live somewhat longer.

The more interesting line item, however, is the difference between reducing oxidative damage to nuclear DNA versus reducing oxidative damage to mitochondrial DNA. There is some debate over whether nuclear DNA damage contributes meaningfully to aging (as opposed to its contribution to cancer risk), whereas there is a far greater consensus on the importance of mitochondrial DNA damage in degenerative aging. More of it is bad, less of it is good.

I would be very interested to see the results of a similar study in which researchers figure out how to keep the protective enzymes localized to either the nucleus or the mitochondria. My expectation would be that you'd only see increased life span for the mitochondrial localization, which would make sense when considering the extended life that result from studies in which levels of natural antioxidants like catalase are enhanced in mouse mitochondria.

To go along with yesterday's post on the economic disaster of entitlements, here's another piece from someone who sees this as a defining issue in which longevity is important. Yet even if life spans were not increasing and even without the prospect of radical life extension in the near future, states would still be on a path to eventual collapse through growth in entitlements, forced transfers of wealth, and the accompanying corruption that arises with the centralization of power. This is the historical outcome resulting from the growth of a state in its late stages, even in periods of history without ongoing increases in life expectancy.

Truly historic discoveries and therapies are coming online right now that will radically decrease the threat and cost of autoimmune disorders, cancers, cardiovascular disease, Alzheimer's, arthritis, obesity and diabetes, as well as dangerous influenzas, HIV and other virus-borne diseases. [Clearly], this is good news both for humanity in general and investors specifically. However, these changes will be, by definition, enormously disruptive. As is always the case when big changes create new winners and dethrone the old ones. How big will these changes be?

Consider the fact that already, life extension is our No. 1 public-policy challenge. It is, in fact, the root cause of our current mortgage and debt fiascos - both only symptoms of successful life-extending technologies. The technologies that have precipitated these crises, however, will soon be overshadowed by the wave of revolutionary biotech innovation. Even those who have no personal interest in life-extension strategies, beyond those supplied by conventional medical networks, will have to deal with the social and economic problems they cause. Our lives will be profoundly affected by emerging biotechnologies that will push maximum healthy life spans up much faster and further than ever before.

Typically, when I say that life extension brings problems, the default assumption is that I'm referring to traditional fears of resource depletion and overpopulation. I'm not. [To] be clear, there is nothing about longer lives that is inherently adverse. Personally, I'm completely in favor of much longer health spans. Rather, the problem has been the failure to recognize and adjust to accelerating increases in life expectancies. This failure has led to ballooning expenditures and unsustainable debt. I should clarify and restate this thesis: Obsolete actuarial tables and expectations about the length and cost of retirement, especially on the medical cost front, are the proximate causes of the international fiscal meltdown.

Though many people portray the crisis as ideological, especially if their proposed solution is raising taxes, it's actually about math. And it's pretty simple math at that. The working young, who have always paid a disproportionate portion of the retirement and medical costs of the older and generally wealthier population, cannot bear that load in a demographically transforming world.

I would be one of those who see this as ideological. Present economic crises are caused by the ideologies that say its fine to force people to create a communal pool of funds under the control of elites, to suppress free markets in insurance and medicine, to force people to use fiat currencies that allow enormous levels of debt spending by elites, and so on and so forth. All these things trace back to the existence of a coercive state, its inexorable growth, and its inevitable corruption.

Link: http://dailyreckoning.com/catastrophically-successful-life-extension/

Nitric oxide levels show up in a range of mechanisms linked to aging and general health, in particular those to do with blood vessel function. Here is an interesting study that may or may not be examining an example of hormesis, a beneficial response to very minor levels of damage caused by UV light, such as that in sunlight:

Researchers have shown that when our skin is exposed to the sun's rays, a compound is released in our blood vessels that helps lower blood pressure. The findings suggest that exposure to sunlight improves health overall, because the benefits of reducing blood pressure far outweigh the risk of developing skin cancer.

Production of this pressure-reducing compound - called nitric oxide - is separate from the body's manufacture of vitamin D, which rises after exposure to sunshine. Until now it had been thought to solely explain the sun's benefit to human health. [Researchers] studied the blood pressure of 24 volunteers who sat beneath tanning lamps for two sessions of 20 minutes each. In one session, the volunteers were exposed to both the UV rays and the heat of the lamps. In the other, the UV rays were blocked so that only the heat of the lamps affected the skin. The results showed that blood pressure dropped significantly for one hour following exposure to UV rays, but not after the heat-only sessions. Scientists say that this shows that it is the sun's UV rays that lead to health benefits. The volunteers' vitamin D levels remained unaffected in both sessions.

"We suspect that the benefits to heart health of sunlight will outweigh the risk of skin cancer. The work we have done provides a mechanism that might account for this, and also explains why dietary vitamin D supplements alone will not be able to compensate for lack of sunlight. We now plan to look at the relative risks of heart disease and skin cancer in people who have received different amounts of sun exposure. If this confirms that sunlight reduces the death rate from all causes, we will need to reconsider our advice on sun exposure."

Link: http://www.eurekalert.org/pub_releases/2013-05/uoe-scb050713.php

Alex Zhavoronkov of the Biogerontology Research Foundation and the International Aging Research Portfolio (IARP) has written a popular science book that will be coming out next month. The topic is the defeat of aging, but the focus is on potential economic transformations, particularly those relating to unsustainable entitlements such as pensions, medicare, social security, and the like. These entitlements threaten the destruction of entire economies and societies by virtue of the fact that they cannot be continued indefinitely, and yet no group in society seems willing to do what needs to be done in order to avoid that result.

The Ageless Generation: How Advances in Biomedicine Will Transform the Global Economy

Historically, a continued failure to address national overspending has led to dire results: hyperinflation, extreme unemployment, civil unrest, and ironically, as economies collapse, a loss of funding for the same senior entitlement programs that created the crisis in the first place. Poor financial management was one of the main contributing factors behind the advent of Nazi Germany as well as the collapse of the USSR that put millions of its senior citizens into poverty. As Aldous Huxley warned, "That men do not learn very much from the lessons of history is the most important of all the lessons that history has to teach."

Will we learn from history? Fortunately, we may be bailed out by technology, which has advanced so rapidly in the past decade that a medical solution to these economic problems is now tantalizingly close. Through scientific means, we can dramatically enhance the health and youthfulness of the aging population over the next couple of decades.

This would redefine our current conception of 65 as the standard age of retirement. If tomorrow's 65-year-olds were as healthy as 55-year-olds today, seniors could work an extra ten years if they chose to do so. If millions of seniors continued to pay into the system while postponing their entrance into these senior entitlement programs by a decade or more, the problems of Social Security and Medicare could be pushed decades into the future. And the cycle would continue, as medical researchers would have more time to extend even further the health and vitality of seniors virtually eliminating the retirement age. As you will soon learn, the longevity breakthroughs we could see in the next 20 years could change the entire landscape of aging, including its social and economic implications.

Will we learn from history? The evidence to hand suggests that the answer is "no." The short term incentives for (a) those receiving entitlements and (b) the political elite who do well for themselves on the graft and corruption enabled by centralization of power combine to lead us all off the cliff in the end. The two sides even collaborate after a fashion in the system of voting for more entitlements. This, combined with an enormous military expenditure, is how all empires end - and the American empire-in-all-but-name will be no different.

I am skeptical that technological advances in medicine will do more than patch a small part of the overall problem. The problem is centralized, unaccountable power in the hands of those who make up the state. If it isn't social security that brings down the system in the end, at the point at which the elite run out of other people's money to steal, waste, and transfer to their allies, then it will be some other form of entitlement or abuse of the financial system.

The defeat of aging will of course be very welcome, and is a goal that should be pursued for what it can do to save lives and ameliorate suffering, not for its ability to let the corrupt upper crust continue being corrupt and in charge for a little longer. I am given to think that the technological advances that will do the most to help with the issues of power, entitlements, and economic destruction, are those involving space flight and cheap, reliable orbital access, however. Historically the only thing that has kept the depredations and corruptions of established states at least somewhat in check is the existence of an accessible frontier, a place to which large sections of the population can emigrate in order to escape a controlled, taxed, doomed economy. So very much of the malaise of the modern world is due, I think, to the lack of an effective frontier.

An essay on the causes of aging and what we might do to prevent them can be found at the SENS Research Foundation outreach blog:

The diseases of old age. Age-related disease. The diseases of aging. We've all heard this language used by medical experts. But what do we mean by them? What is the mysterious connection between aging and the diseases of aging? And how is SENS Research Foundation targeting that connection to keep people healthy and prevent and cure the suffering of old age's diseases and disabilities?

While we sometimes prefer not to think about it, we all know that people lose their health as they age. Angina, Alzheimer's, breast and prostate cancers, chronic kidney disease ... With rare exceptions caused by birth defects, severe congenital mutations, or traumatic injury, these diseases are never present in young adults. Their first subtle hints crop up in the years between our forties and our seventies, accompanied by the weakening of our muscles (even in athletes), loss of cushioning in our joints, failing of the eyesight, and a generalized decay of the body's resilience and health. Over time, the minor aches and vague malaise of middle age devolve more or less rapidly into clinical diagnoses, leaving us with a rising burden of disease, disability, and dependence.

But why does this happen? What is it about these diseases that causes them to slowly creep into our bodies after decades of relatively healthy life, each joining and building on the others, as if they were so many poorly-coordinated orchestra musicians, playing at different speeds, starting at different times, and raising a cacophony that gets louder and louder until it reveals itself as a terrible, secret symphony? And what can the answers to those questions tell us about what to do about them?

Link: http://www.sens.org/outreach/outreach-blog/aging-and-cure-diseases-aging

Progress is noted in the techniques needed to build functional heart tissue:

Biomedical engineers have grown three-dimensional human heart muscle that acts just like natural tissue. This advancement could be important in treating heart attack patients or in serving as a platform for testing new heart disease medicines. The "heart patch" grown in the laboratory from human cells overcomes two major obstacles facing cell-based therapies - the patch conducts electricity at about the same speed as natural heart cells and it "squeezes" appropriately. Earlier attempts to create functional heart patches have largely been unable to overcome those obstacles. The source cells used by [the] researchers were human embryonic stem cells. These cells are pluripotent, which means that when given the right chemical and physical signals, they can be coaxed by scientists to become any kind of cell - in this case heart muscle cells, known as cardiomyocytes.

"The structural and functional properties of these 3-D tissue patches surpass all previous reports for engineered human heart muscle. This is the closest man-made approximation of native human heart tissue to date. In past studies, human stem cell-derived cardiomyocytes were not able to both rapidly conduct electrical activity and strongly contract as well as normal cardiomyocytes. Through optimization of a three-dimensional environment for cell growth, we were able to 'push' cardiomyocytes to reach unprecedented levels of electrical and mechanical maturation."

"Currently, it would take us about five to six weeks starting from pluripotent stem cells to grow a highly functional heart patch. When someone has a heart attack, a portion of the heart muscle dies. Our goal would be to implant a patch of new and functional heart tissue at the site of the injury as rapidly after heart attack as possible. Using a patient's own cells to generate pluripotent stem cells would add further advantage in that there would likely be no immune system reaction, since the cells in the patch would be recognized by the body as self."

Link: http://www.eurekalert.org/pub_releases/2013-05/du-dsb050613.php

One of the side-effects of research into Parkinson's disease is that scientists are making more rapid progress in understanding the mechanisms of mitophagy than would otherwise be the case. Mitophagy is a set of quality control mechanisms that recycle mitochondria, the bacteria-like powerplants in our cells, and like the more general quality control mechanisms of autophagy it is important in aging and longevity. Boosted autophagy or mitophagy shows up in many of the genetic and metabolic alterations shown to extend life in laboratory animals, and has been shown to be required for some of them - no autophagy means no additional longevity.

This is all thought to be a matter of housekeeping: if cells and cellular components are more damaged or cluttered with waste products, then the life span of the organism is shorter as a result. If damage is reduced and more rapidly repaired when it does occur, life span lengthens. Mitochondrial damage in particular is thought to be connected to the pace of aging, by virtue of the fact that cells with damaged mitochondria can fall into malfunctioning states that export damaging reactive compounds to the surrounding tissues.

The focus on mitophagy in Parkinson's research has come about because some forms of Parkinson's are genetic in origin: the patients have a mutation in one of the proteins that form the machinery of mitophagy, making the process function less effectively. This translates to more damaged mitochondria, more cellular and mitochondrial dysfunction, and at the end of the day more dead dopamine-generating neurons. That last item, the loss of a specialized population of neurons, is the proximate cause of the symptoms of Parkinson's disease - but a range of low level biological process contribute to how exactly it happens.

I mention all of this because the research I wanted to point out today involves the protein called parkin: its association with Parkinson's disease was discovered prior to present theorizing on its involvement in mitophagy, hence the name. Researchers have now shown that more parkin means more mitophagy and longer-lived flies:

Single Gene May Extend Lifespan by 25 Percent

Scientists at UCLA have found a single gene that, when stimulated to be overexpressed, extends the healthy life span of fruit flies by more than 25 percent. The gene, called parkin, plays an important role in disposing of damaged proteins within a cell. Previous studies have suggested that protein build up within cells may play an important role in aging. In fruit flies, and potentially in humans, parkin "marks" damaged proteins and instructs the cell to dispose of them.

By stimulating parkin expression, thereby boosting the power of the "cellular garbage disposal," David Walker, lead author of the study, was able to keep a group of fruit flies alive much longer than normal. "In the control group, the flies are all dead by day 50. In the group with parkin overexpressed, almost half of the population is still alive after 50 days. We have manipulated only one of their roughly 15,000 genes, and yet the consequences for the organism are profound."

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan

Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin, an E3 ubiquitin ligase that functions to promote the ubiquitin-proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed.

Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster, increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Long-lived Parkin-overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored.

We show that the mitochondrial fusion-promoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced Drosophila Mitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration.

The theory at least is that the resulting life extension in flies is due to boosted mitophagy, and thus a greater pace of recycling of damaged mitochondria. The current understanding of the machinery involved is that parkin interacts with mitofusin to label mitochondria for destruction. Equally at this stage in the research, it might also turn out to be the case that a related but different process is adjusted by overexpressing parkin - there's still room for uncertainty, but time will tell one way or another.

A range of studies suggest that variations in mitochondrial DNA influence human longevity, which is what we'd expect given the mass of evidence for the importance of mitochondria DNA damage in aging, and the role of mitochondrial function in many age-related diseases. Here, however, is a study showing no statistically identifiable effects resulting from different mitochondrial DNA haplotypes in the old:

Inherited genetic variation of mitochondrial DNA (mtDNA) could account for the missing heritability of human longevity and healthy aging. Here, we show no robust association between common genetic variants of mtDNA and frailty (an "unhealthy aging" phenotype) or mortality in 700, more than 85-year-old, participants of the Newcastle 85+ study. Conflicting data from different populations underscore our conclusion that there is currently no compelling link between inherited mtDNA variants and aging.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23639206

The graying of hair with increasing age is an early sign of increased oxidative stress in skin tissues around hair follicles. Researchers here demonstrate that it can be locally reversed by an antioxidant-based strategy. This shouldn't be taken to indicate that antioxidants are of general utility: the researchers are carefully augmenting the role of a specific natural antioxidant enzyme in an intricate chemical process, not just picking any random antioxidant and throwing it into the mix.

People who are going gray develop massive oxidative stress via accumulation of hydrogen peroxide in the hair follicle, which causes our hair to bleach itself from the inside out. The build up of hydrogen peroxide was caused by a reduction of an enzyme that breaks up hydrogen peroxide into water and oxygen (catalase). Hair follicles could not repair the damage caused by the hydrogen peroxide because of low levels of enzymes that normally serve this function (MSR A and B). Further complicating matters, the high levels of hydrogen peroxide and low levels of MSR A and B, disrupt the formation of an enzyme (tyrosinase) that leads to the production of melanin in hair follicles. Melanin is the pigment responsible for hair color, skin color, and eye color.

The report shows that this massive accumulation of hydrogen peroxide can be remedied with a proprietary treatment developed by the researchers described as a topical, UVB-activated compound called PC-KUS (a modified pseudocatalase). What's more, the study also shows that the same treatment works for the skin condition, vitiligo.

Link: http://www.eurekalert.org/pub_releases/2013-05/foas-gha050313.php

As reported a couple of days ago, researchers have again demonstrated a link between aging and NF-κB, altering its levels in the hypothalamus it to both modestly lengthen and shorten life in mice. This may be completely a matter of dialing down chronic inflammation in later life, or it may also touch on other common ground in the overlap between metabolism and aging such as insulin signaling.

In the course of their work, the researchers followed some of the connections in this biological jigsaw puzzle to study other proteins and genes involved in generating extended life in mice via inhibition of NF-κB in the hypothalamus. One of these is gonadotropin-releasing hormone (GnRH), and the researchers found that enhancing its levels in the hypothalamus has much the same effect as inhibition of NF-κB. This side of the research gained the attention of the fellow who runs Extreme Longevity:

Can GnRH Administration Reduce Aging?

[The scientists] showed that regular GnRH administration to middle aged mice increased the number of brain cells and reduced signs of aging in the animals. To wit they specially said "GnRH treatment (peripheral) reduced the magnitude of ageing histology in control mice," and "GnRH led to an amelioration of ageing-related cognitive decline."

But of course the holy grail question here is simply can regular peripheral administration of GnRH increase lifespan? I contacted lead author Dongshen Cai MD-PhD and asked if the group had any lifespan data on regular GnRH treatment.

"We don't have lifespan data regarding GnRH treatment," he replied.

Too bad. Imagine if simply a weekly or so injection of GnRH from early middle age onwards could lead to decades more good health and reduction of disease? [Clearly] this is an experiment that should be tried in animals right away. Fortunately Dr. Cai agrees, "it is in our plan," he says.

It has to be said that I generally don't think of this sort of study in these terms. I'm not looking to see whether there's a treatment that can be pulled out, because in most cases a 20% life extension in mice by some form of metabolic manipulation (gene therapy, altering levels of proteins, and so forth) isn't going to be all that relevant to the future of human longevity. For one, it's not rejuvenation, it's only slowing aging. Secondly, mice have very plastic life spans, as is the case for most shorter-lived species. All sorts of things that are either known to do very little to nothing for human life span or are expected to do very little to nothing for human life span can nonetheless extend life by 10%-30% in mice.

So what I see here in the NF-κB / GnRH work is the potential for a therapy that might be applied to modestly reduce inflammation or improve the metabolic profile of older people. Something comparable to rapamycin, in other words, a marginal gain. Perhaps it's a little better than today's best therapies that produce similar effects, and perhaps it's not. I'll wager that it's not going to be as good as regular exercise and calorie restriction. So overall it's not something that I'd give a lot of time and interest to. As a general rule if a research result isn't producing actual rejuvenation then it's not going to have the potential to be a part of greatly extending lives in humans. We have a medical industry presently near-entirely focused on picking mechanisms like this and then using them to produce palliative, marginally effective patches to slap over some of the end stage consequences of aging. The dominant paradigm is to try to alter metabolism late in the game for a small benefit, and without attempting repairing the underlying damage that caused all the harm in the first place. This is a paradigm doomed to poor results, high costs, and ultimate failure.

We have to move on past this methodology of medicine and clinical application of research. The future is SENS and similar projects that aim to repair the causes of aging rather than putting patches on the consequences. It seems fairly clear to me from the performance of the medical establishment to date that only repair can be reliably expected to grant us additional decades of healthy life.

The immune system malfunctions with age, producing harmful chronic inflammation while failing to adequately respond to pathogens and failing to destroy potentially cancerous and senescent cells. Characteristic changes in immune cell populations accompany these changes, and in past years researchers have shown that adjusting these populations by destroying some of the unwanted immune cells can reverse at least some immune system declines.

Here is an open access paper that focuses on changes in the population of regulatory T cells with aging. These are cells involved in suppressing the immune response, for example so as to prevent the immune system from attacking healthy tissues:

Over the course of the human life, age-related diseases develop because of the failure of genetic traits to remain beneficial, as they were in younger years when they aided in successful reproduction. Longevity is correlated with optimal natural immunity. Immunosenescence (aging of the immune system) is continuously influenced by chronic antigenic stimulation, such as infections. This explains why the probability of a long lifespan is improved in an environment of reduced pathogen burden. In the presence of low pathogen burden one can expect a balanced state of immune responses and alter the chances of having advanced inflammatory responses

Older persons have higher autoimmunity but a lower prevalence of autoimmune diseases. A possible explanation for this is the expansion of many protective regulatory mechanisms highly characteristic in the elderly. Of note is the higher production of peripheral T-regulatory cells.

The frequent development of autoimmunity in the elderly was suggested to take place in part due to the selection of T cells with increased affinity to self-antigens or to latent viruses. These cells were shown to have a greater ability to be pro-inflammatory, thereby amplifying autoimmunity. During aging, thymic T-regulatory cell output decreases in association with the loss of thymic capacity to generate new T cells. However, to balance the above mentioned autoimmunity and prevent the development of autoimmune diseases, there is an age-related increase in [peripheral T-regulatory cells]. It remains unclear whether this is an age-related immune dysfunction or a defense response. Whatever the reason, the expansion of T-regulatory cells requires payment in terms of an increased incidence of cancer and higher susceptibility to infections.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616810/

Any mechanism that appears common to all cancers, or even just a wide range of cancers, is worth examination to see if it might serve as the basis for a therapy. Here is an example of speculative research of this nature:

[Researchers] have identified a gene that, when repressed in tumor cells, puts a halt to cell growth and a range of processes needed for tumors to enlarge and spread to distant sites. The researchers hope that this so-called "master regulator" gene may be the key to developing a new treatment for tumors resistant to current drugs. "This master regulator is normally turned off in adult cells, but it is very active during embryonic development and in all highly aggressive tumors studied to date. Our work shows for the first time that switching this gene off in aggressive cancer cells dramatically changes their appearance and behavior."

Genes in the master regulator's family, known as high mobility group or HMG genes, [are] essential for giving stem cells their special powers, and that's no coincidence. [Many] investigators consider cancer cells to be the evil twin of stem cells, because like stem cells, cancer cells must acquire special properties to enable the tumor to grow and metastasize or spread to different sites.

[Researchers applied techniques to block the HMGA1 gene] to several strains of human breast cancer cells in the laboratory, including the so-called triple negative cells - those that lack hormone receptors or HER2 gene amplification. Triple-negative breast cancer cells tend to behave aggressively and do not respond to many of our most effective breast cancer therapies. The team [found] that the cells with suppressed HMGA1 grow very slowly and fail to migrate or invade new territory like their HMGA1-expressing cousins. The team next implanted tumor cells into mice to see how the cells would behave. The tumors with HMGA1 grew and spread to other areas, such as the lungs, while those with blocked HMGA1 did not grow well in the breast tissue or spread to distant sites.

Link: http://www.hopkinsmedicine.org/news/media/releases/making_cancer_less_cancerous

Naked mole rats are well studied by the aging research community: there are large colonies of naked mole rats in US laboratories, and a steady output of new papers on naked mole rat biology from numerous research groups. Their genome was sequenced in 2011, in advance of many other species that you might consider more pressing candidates. Naked mole rats are interesting to scientists for a number of reasons, the most important of which are that (a) they live nine times longer than similarly sized rodent species and (b) are immune to cancer. Researchers hope that there is something to be learned here about the relative importance of different metabolic processes in degenerative aging, and further that the biological mechanisms by which naked mole rats suppress cancer so effectively might lead to a form of cancer therapy for humans.

I noticed a couple of recent papers on the topic of naked mole rat biology, starting with the usual consideration of oxidative damage in aging, which is one of the areas where this species is strikingly unusual. An old naked mole rat has all the measures of a very high load of oxidative damage, but none of the degeneration that another rodent species would be exhibiting with those same measures. Their biochemistry in some way shrugs off the consequences of such damage - you might look at the membrane pacemaker theory of longevity for some further context on this research.

Elevated protein carbonylation and oxidative stress do not affect protein structure and function in the long-living naked-mole rat: A proteomic approach

The 'oxidative stress theory of aging' predicts that aging is primarily regulated by progressive accumulation of oxidized macromolecules that cause deleterious effects to cellular homeostasis and induces a decline in physiological function. However, our reports on the detection of higher level of oxidized protein carbonyls in the soluble cellular fractions of long-living rodent naked-mole rats (NMRs, lifespan ∼30yrs) compared to short-lived mice (lifespan ∼3.5yrs) apparently contradicts a key tenet of the oxidative theory.

As oxidation often inactivates enzyme function and induces higher-order soluble oligomers, we performed a comprehensive study to measure global protein carbonyl level in different tissues of age-matched NMRs and mice to determine if the traditional concept of oxidation mediated impairment of function and induction of higher-order structures of proteins are upheld in the NMRs. We made three intriguing observations with NMRs proteins: (1) protein carbonyl is significantly elevated across different tissues despite of its exceptional longevity, (2) enzyme function is restored despite of experiencing higher level of protein carbonylation, and (3) enzymes show lesser sensitivity to form higher-order non-reducible oligomers compared to short-living mouse proteins in response to oxidative stress.

These unexpected intriguing observations thus strongly suggest that oxidative modification may not be the only criteria for impairment of protein and enzyme function; cellular environment is likely be the critical determining factor in this process and may be the underlying mechanism for exceptional longevity of NMR.

In another paper we find that naked mole rats also appear to laugh in the face of their version of amyloid beta, the aggregate that shows up in damaging clumps in late stage Alzheimer's disease. Old naked mole rats naturally have as much amyloid beta as mice deliberately engineered to have high levels of amyloid beta, and apparently suffer few or no ill effects as a result.

Amyloid beta and the longest-lived rodent: the naked mole-rat as a model for natural protection from Alzheimer's disease

Amyloid beta (Aβ) is implicated in Alzheimer's disease (AD) as an integral component of both neural toxicity and plaque formation. Brains of the longest-lived rodents, naked mole-rats (NMRs) approximately 32 years of age, had levels of Aβ similar to those of the 3xTg-AD mouse model of AD. Interestingly, there was no evidence of extracellular plaques, nor was there an age-related increase in Aβ levels in the individuals examined (2-20+ years).

The NMR Aβ peptide showed greater homology to the human sequence than to the mouse sequence, differing by only 1 amino acid from the former. This subtle difference led to interspecies differences in aggregation propensity but not neurotoxicity; NMR Aβ was less prone to aggregation than human Aβ. Nevertheless, both NMR and human Aβ were equally toxic to mouse hippocampal neurons, suggesting that Aβ neurotoxicity and aggregation properties were not coupled. Understanding how NMRs acquire and tolerate high levels of Aβ with no plaque formation could provide useful insights into AD, and may elucidate protective mechanisms that delay AD progression.

Not all researchers are presently convinced that enough evidence exists to place mitochondrial DNA damage front and center as an important cause of aging. I would agree that the tools and measurements discussed below leave some room for argument over what they mean, but at this time the research community is very close to being able to repair mitochondrial DNA, not just talk about it. Thus I think that the best approach for the next few years is to actually go ahead and repair the damage in laboratory animals, and see what happens - that should settle the debate one way or another.

Protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage is well known to be necessary to longevity. The relevance of mitochondrial DNA (mtDNA) to aging is suggested by the fact that the two most commonly measured forms of mtDNA damage, deletions and the oxidatively induced lesion 8-oxo-dG, increase with age. The rate of increase is species-specific and correlates with maximum lifespan.

It is less clear that failure or inadequacies in the protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage are sufficient to explain senescence. DNA containing 8-oxo-dG is repaired by mitochondria, and the high ratio of mitochondrial to nuclear levels of 8-oxo-dG previously reported are now suspected to be due to methodological difficulties. Furthermore, [mice lacking the MnSOD natural antioxidant] incur higher than wild type levels of oxidative damage, but do not display an aging phenotype. Together, these findings suggest that oxidative damage to mitochondria is lower than previously thought, and that higher levels can be tolerated without physiological consequence.

A great deal of work remains before it will be known whether mitochondrial oxidative damage is a "clock" which controls the rate of aging. The increased level of 8-oxo-dG seen with age in isolated mitochondria needs explanation. It could be that a subset of cells lose the ability to protect or repair mitochondria, resulting in their incurring disproportionate levels of damage. Such an uneven distribution could exceed the reserve capacity of these cells and have serious physiological consequences. Measurements of damage need to focus more on distribution, both within tissues and within cells. In addition, study must be given to the incidence and repair of other DNA lesions, and to the possibility that repair varies from species to species, tissue to tissue, and young to old.

In this context, you might also look at the membrane pacemaker theory regarding oxidative damage to mitochondria and longevity differences between species. It places an emphasis on resistance to damage and the consequences of damage over the actual levels of damage.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3455271/

A short article on the need to remember that cryopreserved people are not gone in the same way that the dead are gone, and their interests are served by the maintenance of some form of continued connection to society:

Anyone who has ever reflected on the fragility of human life and the seemingly inevitable rise and fall of complex societies cannot fail to be concerned about the fate of patients in cryopreservation. Cryonics organizations have learned from the early days and abandoned the practice of accepting patients without complete prepayment - a practice that almost invariably guarantees a tragic loss of life when family members or the cryonics organization can no longer afford to care for them. Alcor has given a lot of thought to the financial and legal requirements of keeping patients in cryopreservation but it is understandable that people question the prospect of cryonics patients making it to the time where a suitable treatment of their disease will be available.

This challenge is further exacerbated by the fact that cryonics patients do not have the legal standing that ordinary human beings (or patients) enjoy. [The] first step to protect cryonics patients is to strengthen your cryonics organization and the legal and logistical structures that have been erected to keep them in cryopreservation. But almost just as important is to give people who have not made cryonics arrangements themselves reasons to protect them. In the case of surviving family members that is usually not a challenge but time may eventually pass the direct descendants of those people by as well.

One important practice that can be strengthened is to give these people a face. Cryopreserved persons are not just a homogenous group of anonymous people (unless they chose to be so!) but are our friends, family members, and patients who would like their story to be told. Fortunately, in the age of the internet this has become a lot easier. Social networking websites like Facebook retain the profiles of deceased and cryopreserved persons unless the family requests removal. Cryonics organizations themselves can offer opportunities for members, friends, and family members to maintain their presence online.

Link: http://www.evidencebasedcryonics.org/2013/04/25/protecting-cryonics-patients/

NF-κB shows up in a number of places in longevity research, and it's associated with mechanisms known to mediate the relationship between metabolism and the pace of aging. In particular it is associated with the processes of inflammation, which regular readers will know are significant in the aging process. The immune system falls into a malfunctioning state of worsening chronic inflammation in later life, and this contributes to further degenerative aging to some degree.

Selective inhibition of NF-κB has been shown to extend life span in flies, as well as revert some aspects of skin and blood vessel aging in mice. This might have something to do with diminished inflammation, or it may work through other mechanisms, such as alterations to insulin signaling - which is a whole other collection of genes and biochemistry that often appears in aging research.

Nothing happens in isolation in biology. Many of these longevity-associated genes are involved in low-level processes like transcription that influence all of our biochemistry in some way or another, or take part in so many different mechanisms that it's hard to pin down their effects to some simple, clear, single outcome.

In any case, my attention was directed today to a new study in which researchers manipulate NF-κB in the brain to modestly extend life in mice. Interestingly, this also adds to the short list of interventions that can be used to move life span in either direction. Less NF-κB activity means a longer life, and more of it shortens life. In addition, the authors claim that NF-κB inhibition has a positive influence on neurogenesis in the brain, not just on the state of the immune system. The paper isn't open access, unfortunately, so you might start with this article from the science press by way of an overview:

It's all in the brain! Scientists slow down ageing in mice

The researchers said they have speeded up and slowed down the rate of ageing in laboratory mice by manipulating chemical messengers that affect the hypothalamus, which is known to play a fundamental role in growth, development, reproduction and metabolism. The [study] focused on a molecule known to be central to the many biochemical reactions involved in the process of inflammation, which is important in many age-related conditions. "As people age, you can detect inflammatory changes in various tissues. Inflammation is also involved in various age-related diseases, such as metabolic syndrome, cardiovascular disease, neurological disease and many types of cancer."

By manipulating the levels of the molecule, known as NF-κB, within the hypothalamus, the researchers were able to slow down the rate of ageing and increase longevity of mice by up to 20 per cent. The team also found that they could slow the rate of cognitive decline by up to 50 per cent, which they could measure by how easy the mice remember how to find their way out of a maze.

And here's a link to the paper:

Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH

Here we show that the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by IκB kinase-β (IKK-β), nuclear factor κB (NF-κB) and related microglia-neuron immune crosstalk.

Several interventional models were developed showing that ageing retardation and lifespan extension are achieved in mice by preventing ageing-related hypothalamic or brain IKK-β and NF-κB activation. Mechanistic studies further revealed that IKK-β and NF-κB inhibit gonadotropin-releasing hormone (GnRH) to mediate ageing-related hypothalamic GnRH decline, and GnRH treatment amends ageing-impaired neurogenesis and decelerates ageing.

In conclusion, the hypothalamus has a programmatic role in ageing development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating ageing-related health problems.

Gene therapy to remove adenylyl cyclase type 5 (AC5) was shown to increase mouse longevity a few years back, and researchers have since been working to better understand the mechanisms involved. Like many longevity mutations, this gene is involved in many crucial low-level cellular processes, and researchers are interested in producing drugs to mimic some of the effects of a full gene therapy:

G-protein coupled receptor/adenylyl cyclase (AC)/cAMP signaling is crucial for all cellular responses to physiological and pathophysiological stimuli. There are 9 isoforms of membrane-bound AC, with type 5 being one of the two major isoforms in the heart. Since the role of AC in the heart in regulating cAMP and acute changes in inotropic and chronotropic state are well known, this review will address our current understanding of the distinct regulatory role of the AC5 isoform in response to chronic stress.

Transgenic overexpression of AC5 in cardiomyocytes of the heart (AC5-Tg) improves baseline cardiac function, but impairs the ability of the heart to withstand stress. For example, chronic catecholamine stimulation induces cardiomyopathy, which is more severe in AC5-Tg mice, mediated through the AC5/SIRT1/FoxO3a pathway.

Conversely, disrupting AC5, i.e., AC5 knockout (KO) protects the heart from chronic catecholamine cardiomyopathy as well as the cardiomyopathies resulting from chronic pressure overload or aging. Moreover, AC5-KO results in a 30% increase in healthy lifespan, resembling the most widely studied model of longevity, i.e., calorie restriction. These two models of longevity share similar gene regulation in the heart, muscle, liver and brain that are both protected against diabetes and obesity. A pharmacological inhibitor of AC5 also provides protection against cardiac stress, diabetes and obesity. Thus, AC5 inhibition has novel, potential therapeutic applicability to several diseases, not only in the heart, but also in aging, diabetes and obesity.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23624627

Here is a popular science article on the many ways to extend life in laboratory mice, and the relevance of that research to human health and longevity:

Biologists have successfully extended the life spans of some mice by as much as 70%, leading many to believe that ongoing experimentation on our mammalian cousins will eventually lead to life-extending therapies in humans. But how reliable are these studies? And do they really apply to humans?

Many scientists will tell you that "mice are not people" which is true of course. It is also true that we have cured cancer many times in mice with therapies that do not work in humans, so we must be careful about saying that interventions that work in mice will be directly translatable to humans. But at the same time, functional life extension therapies in mice do hold prospects for human longevity. Extending the lifespan of a mouse that normally lives only three years to five by applying a treatment late in its life could capture the imagination of many. "In this day of the Internet, everyone would be able to view video clips of mice the equivalent of 120 human years in age - healthy, active and being social with their fellows.This would do something, I think, to the human psyche that would enable much more rapid development of interventions for humans, hence the reason for the Methuselah Mouse Prize which is designed to create this result."

Near everything demonstrated to date to extend life in mice has been a form of gene therapy or metabolic manipulation. It changes the pace of aging, but isn't rejuvenation. To create longer lives [than the present best efforts in mice], you need to work on rejuvenation attained by repairing the cell- and tissue-level damage that causes aging, not just finding ways to gently slow aging by slowing down the pace at which that damage accumulates. The future of mouse longevity is SENS (Strategies for Engineered Negligible Senescence), which is a radically different approach to any of the work currently extending life in mice.

Link: http://io9.com/do-these-startling-animal-studies-mean-your-lifespan-co-486041314