Fight Aging!

That was 2012: another year closer to both the grave and the rejuvenation biotechnology to keep us out of it. This is very much a race, but one in which we can all do our part to help the right horse win. Research runs on money and popularity - but mostly money. Every little bit helps.

Conferences, as usual, abounded this past year. Noting only a few, there was the Alcor 40 conference, the Eurosymposium on Healthy Aging, Humanity+ conferences in Melbourne and San Francisco, the Singularity Summit, and the International Conference on the Genetics of Aging and Longevity.

The cryonics community has, pleasantly, continued with the trend of receiving better and more positive coverage in the press, as well as from the medical community. Another of the original leaders of the US cryonics community was cryopreserved earlier in the year, while the establishment of a new cryonics provider in Australia appears to be moving ahead. On the scientific side of things, the Brain Preservation Foundation's research prize is beginning to generate concrete results.

This has been in year in which the longevity science community over in Europe and Russia have set themselves to form single-issue political parties, a strategy for advocacy that has seen some success for other causes. An International Longevity Alliance umbrella organization was formed, and we should no doubt expect to see more on this front over the next few years.

Speaking of Russia, there has been more press this past year for the ongoing 2045 initiative, including an interview with the wealthy founder. We shall see where this all goes, but to my mind the best thing that could happen here is for the fellow to change his mind about strategy and begin to put his weight behind SENS research rather than the current robotics and mind-machine interface approach. Time is too short to make the latter work rapidly enough.

The wave of Kickstarter clones has led to many organizations that are trying to bring crowdsourced funding to scientific research. I applaud this goal, and have absolutely no idea how they are going to make it work - I hope that someone cracks the code and finds a good general, supportive methodology that can lead to better results in funding for research projects like SENS, or organizations like the Methuselah Foundation, or for community initiatives like those at Longecity. If it's going to happen, it will happen in 2013 or 2014 - if not by then, I think these scientific crowdfunding initiatives will die back for a decade before someone tries again.

The Glenn Foundation expanded its ongoing support for mainstream longevity science this year, establishing labs at Princeton and the Albert Einstein College of Medicine.

The SENS Foundation released their 2011 annual report and research report, building on the impressive 2010 progress. Research on the foundations of rejuvenation biotechnology is progressing, and we can hope that the larger philanthropic and institutional fundraising efforts continue to expand alongside their growing Academic Initiative. On the scientific side, new results were published a few months back for LysoSENS bioremediation research - finding bacterial enzymes that can safely break down harmful metabolic byproducts that build up in cells. Co-founder and scientist advocate Aubrey de Grey participated in a number of noteworthy events in 2012, such as the Oxford University Science Society public debate, and a seminar chaired by Peter Singer that later led to a fairly favorable article by that bioethicist. De Grey also put forward some updated cost and time estimates for the SENS program as presently envisaged.

The Methuselah Foundation has focused on tissue engineering and the New Organ Prize, continuing their establishment of a crowdsourced fundraising initiative to speed development of organs produced to order from a patient's own cells. You might take a look at an interview with David Gobel from ealier in the year, or swing by the New Organ website to see the latest.

Autophagy, the collection of recycling mechanisms that help keep cells undamaged and working well, continues to be a focus of research into aging and longevity. I'm not aware of anything truly new and exciting that has emerged this year, but the goal of therapies that can boost autophagy and thereby slightly repair and slightly slow aging continues to look plausible. Here's a review paper, a second review paper, and research that provides more compelling data on autophagy as a mechanism linking exercise to increased longevity.

A possible game-changing advance for mitochondrial repair was presented earlier this year. The hope is that it will greatly speed progress towards the ability to either fix damaged mitochondrial DNA or make the damage irrelevant.

Tissue engineering continues to go from strength to strength. Several clinical research groups are hitting their stride and carrying out numerous procedures in which large chunks of tissue in patients are replaced with new, engineered structures grown from their own cells. One of these is led by Paolo Macchiarini and has been in the news here and there over the past year. That is the more visible end of a great deal of equally important ongoing work, some of which does not make the popular press.

Following on from last year's demonstration of the benefits of selectively destroying senescent cells, this year researchers presented the basis for a more practical targeting mechanism. This is an important field, one in which useful results may happen sooner rather than later, so keep an eye on it.

One of the interesting, if not immediately applicable, consequences of ongoing research into stem cells and regeneration is that scientists are finding that some tissue is more capable of regeneration than was thought. It wasn't all that long ago that the dominant paradigm was the neurons were not created in the adult brain, for example. But this year researchers found out that podocytes in the kidney renew throughout life too. There will undoubtedly be other revisions in the years ahead, and this is creates hope that greater regeneration for much of the body will involve turning up the volume dial rather than creating a process that doesn't already exist.

Of course this research also turns up some challenges in the other direction: some parts of our biology never change. We don't just have the very same cells we were born with, some of the protein molecules in those cells are the very same protein molecules that were in place on day one. No recycling going on there at all - which means no native process of repair, either. That poses some interesting long-term challenges, looking out past the days in which the first generation rejuvenation therapies grant additional decades of life.

An an unrelated note, researchers have finally figured out a way to accurately determine lobster age. Given a few years, expect to see some sort of final determination on the degree to which lobsters suffer degenerative aging, and what their maximum life span actually is.

The genetics of human longevity are not producing earth-shaking results these days, and it looks very much like that will continue to be the case. It is a field in the midst of a long run of hard work to fill in gaps and find linkages. It is generally accepted that there will be many, many genetic contributions to longevity, varying by population, and most of which have only a tiny effect. Only in the very old are signs of correlation between longevity and genetics easier to come by, suggesting that the importance of genes grows with age - but it's still the case that this is a forest of many small trees. Researchers face decades of work ahead just to build a decent map.

Telomere length is a growth field, however. Commercial ventures have launched of late to provide clinical tests of telomere length based on research techniques from recent years. When it comes to what telomere length can be used for today on an individual rather than statistical basis, however, researchers are still trying to produce better data - such as that produced in a recent study showing a correlation between shorter telomeres and a higher risk of heart attack. Other results published in the past year include life span correlations in finches, a similar study in warblers and suggestions that measuring changes in the fraction of short telomeres is far better than simply taking the average.

More evidence arrived this year to suggest that early life circumstances greatly influence the later progression of aging. From a reliability theory perspective this fits: more damage at the outset means the expectation of a shorter life. But it works the other way too, thanks to hormesis - if you suffer just enough damage to kick your repair systems into activity, you can come out ahead and live longer as a result.

This year saw the normal brace of new methods for extending life in various different species of laboratory animal. These new discoveries are almost beneath public notice now, and most don't show up in the popular press. Some examples:

• Heterochromatin Levels in Flies Can Raise and Lower Lifespan
• DGAT1: Another Mouse Longevity Mutation
• Ethanol and Nematode Lifespan
• A Modest Sample of the Flood of Longevity Genes
• VANG-1: Another Longevity Gene in Nematodes
• SIRT6 and Mouse Longevity
• Pten: A Cancer Suppression Mutation That Also Extends Life
• Telomerase Gene Therapy Extends Life, Eliminates Cancer in Adult Mice
• Extending Life in Flies via Pink1 Overexpression
• Overexpression of FGF21 Extends Life in Mice
• Dihydrolipoamide Dehydrogenase as Longevity Gene
• Increased Longevity in Mice by Removing Cardiotrophin 1
• Less BubR1 Accelerates Aging, But More BubR1 Appears to Slow the Progression of Aging

Scattered in among the year's posts you'll find the occasional short essay in place of links to research and other matters scientific. Here are a few of those that I think hold up reasonably well:

• One Wealthy Zealot Would Make a 20 Year Difference
• The Three Types of Research Into Aging and Longevity
• The Future Awaits Its Makers
• The World of Aging Science Must Up-End, Change, Renew Itself
• An Outline of Progress in Longevity Science
• Removing the Pressure of Impending Death
• Don't Argue Incrementalism in a Time of Revolutionary Change
• The Weight of the Inheritors
• Personal Survival and Swimming Against the Cultural Currents
• Putting Aside What You'd Rather Do Because You're Dying
• A Speculative Order of Arrival for Important Rejuvenation Therapies
• Where to Find Data on Aging Research?
• Breaking the Wheel of Time
• Is Funding the Only Roadblock Standing in the Way of Greatly Extending Healthy Human Life Spans?

Lastly: are the Strategies for Engineered Negligible Senescence still the only plausible way out of degenerative aging, the most unpleasant and harmful part of the human condition? Yes, yes they are.

From earlier this month, something to think about in the context of reliability theory and life span:

Manipulating growth rates in stickleback fish can extend their lifespan by nearly a third or reduce it by 15 percent. [Researchers] altered the growth rate of 240 fish by exposing them to brief cold or warm spells, which put them behind or ahead their normal growth schedule. Once the environmental temperature was returned to normal, the fish got back on track by accelerating or slowing their growth accordingly. However, the change in growth rate also affected their rate of ageing.

While the normal lifespan of sticklebacks is around two years, the slow-growth fish lived for more than 30 percent longer, with an average lifespan of nearly 1000 days. In contrast, the accelerated-growth fish had a lifespan that was 15% shorter than normal. These effects occurred despite all fish reaching the same adult size, and were even stronger when the rate of growth was increased by artificially manipulating the length of daylight the fish were exposed to, 'tricking' their bodies into growing faster to reach their target size before the start of the breeding season.

The results of the study are striking. It appears that bodies which grow quickly accumulate greater tissue damage than those that grow more slowly and their lifespan is substantially reduced as a result. The study also demonstrates the surprising ways in which a slight change in environmental conditions in early life can have long-term consequences.

These findings are likely to apply to many other species, including humans, since the manner in which organs and tissues grow and age is similar across very different kinds of animal. It has already been documented in humans, for example, that rapid growth in early childhood is associated with a greater risk of developing ailments later in life such as cardiovascular disease in middle or old age, possibly because of the way in which the tissues of a fast-grown heart are laid down.

Link: http://phys.org/news/2012-12-slower-longer-growth-lifespan.html

Muscle mass and strength diminish with age, and researchers are making steady progress into understanding exactly why this is the case. Rejuvenation biotechnologies of the sort proposed in the SENS plan should reverse this decline, but most researchers are looking more narrowly at intervening in secondary mechanisms - patching the problem rather than attacking aging at its roots.

Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging.

In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.

Link: http://dmm.biologists.org/content/6/1/25.long

Organovo is the organ printing company that was partially funded in the early days with an investment from the Methuselah Foundation - an investment that the Foundation has done well by so far. In turn, the Organovo founders are noteworthy supporters of the crowdfunded New Organ Prize that the Foundation is working on these days.

Organovo has engineered a good position for itself even though the technologies it works on will take another decade or two to arrive at maturity. The research community won't be printing organs next year, but between here and the arrival of printed organs somewhere in the 2020s there are many commercially viable products that build upon one another: tissue for research, machinery for laboratories, and so forth.

Wired is running an article that notes some of the recent progress at Organovo:

While this all sounds awesome, the big question remains "When can I print a spare kidney?"

The answer is unsatisfying. Even moderately complex structures, like patches of heart muscles to repair damage from heart attacks are decades out. Still, progress is still being made. "One of the dramatic things we did was to make blood vessels made from a patient's own cells, comprised entirely of human cells, that expand and contract as expected and have reached a strength that's implantable, though they are not yet implanted." says Murphy.

The first "apps" on the Organovo platform will be simple tissues which could be ready for clinical trials in just 5 or 6 years. This is an eternity in smartphone cycles, but is a breakneck pace in healthcare. Until then, Organovo will continue to serve researchers at pharma companies that give the public 3-D printer company a steady stream of revenue, a fact Murphy says is a "fairly novel thing for an early stage life science company."

Organovo also has a strong academic track record including partnerships with Stanford and Harvard along with a string of published papers that have the biomedical community abuzz. Ultimately, Murphy's primary goal is getting more people experimenting. "For me it's allowing greater access to our platform. The bottom line is it needs to be more accessible, faster to more people."

The Wired article is, I think, overly pessimistic on timelines. Yet there is still a great need for projects like the New Organ Prize, greater fundraising, and faster progress.

Here is a review paper that looks back at the recent history of biogerontology as a field of study, noting the struggle with long-held perceptions of fraud associated with the intersection of aging and medicine:

Through archival analysis this article traces the emergence, maintenance, and enhancement of biogerontology as a scientific discipline in the United States. At first, biogerontologists' attempts to control human aging were regarded as a questionable pursuit due to: perceptions that their efforts were associated with the long history of charlatanic, anti-aging medical practices; the idea that anti-aging is a "forbidden science" ethically and scientifically; and the perception that the field was scientifically bereft of rigor and scientific innovation.

The hard-fought establishment of the National Institute on Aging, scientific advancements in genetics and biotechnology, and consistent "boundary work" by scientists, have allowed biogerontology to flourish and gain substantial legitimacy with other scientists and funding agencies, and in the public imagination. In particular, research on genetics and aging has enhanced the stature and promise of the discipline by setting it on a research trajectory in which explanations of the aging process, rather than mere descriptions, have become a central focus. Moreover, if biogerontologists' efforts to control the processes of human aging are successful, this trajectory has profound implications for how we conceive of aging, and for the future of many of our social institutions.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23264719

Looking back at past commercial development in medicine is a fair way to manage expectations for present efforts to bring therapies to the clinic. The short version of the story is that there are certainly cycles in which expectations outpace results, but those results arrive in the end:

Like many advanced technologies, the field of regenerative medicine has gone from boom to nearly bust to boom again in the span of just 30 years. Today, there are over 55 regenerative medicine products on the market focused on diverse therapeutic areas, including repair of skin/soft tissue, wound care, cardiology, oncology, and diabetes. Thirty years in, regenerative medicine has truly "come of age," the result of a tenacious pursuit to translate groundbreaking research into therapeutic products and overcome initial setbacks that almost derailed this critical new medical approach.

Yet while the past decade's focus on scientific advances and business fundamentals has propelled regenerative medicine forward, I believe this is just the start. By reflecting on the successes and lessons learned over the past three decades, we can begin to chart a roadmap for the future that will help to ensure that regenerative medicine continues to deliver important new treatments for patients, while creating sustainable value for shareholders.

From its origins in the mid-1980s, regenerative medicine was greeted with the kind of extreme excitement that has accompanied other potential breakthroughs, including monoclonal antibodies and RNA interference. By the year 2000, more than a decade after the first companies were formed, regenerative medicine companies were valued at over $2.6 billion, TIME named tissue engineering one of the hottest jobs for the 21st century, and Barron's predicted it would become a $100 billion industry. A few years later, the bubble had burst, and company valuations plummeted to a tenth of their year 2000-high.

Several factors contributed to these setbacks. First, like many new medical advances, expectations far exceeded reality. Investors and the media saw incredible promise in early research, and unrealistic timelines were set for when a product could be on the market. Second, the initial regenerative medicine products to reach the market had limited commercial success, as the few companies in the space had not yet understood all that was required to achieve both clinical and commercial success. From a scientific perspective, the field was poised to deliver, but it had not yet developed the regulatory, business, and commercial expertise required for long-term success.

In the wake of these setbacks, there came a clear understanding of what was needed to propel regenerative medicine forward and strike the appropriate balance between promise and reality. When I joined Organogenesis in 2003, the company was emerging from bankruptcy and a dissolved commercial partnership with big pharma. In the decade since, I have experienced firsthand the rebirth of our company, and on a larger scale, of the regenerative medicine field itself. Our path over the past decade has taught us several lessons about what it will take to succeed in this space going forward.

Link: http://www.genengnews.com/gen-articles/regenerative-medicine-engineering-its-continued-success/4653/

Stephen Valentine is the architect on the ofttimes seemingly dormant Timeship project, which drifted back into the news recently. It was suggested at the time that the goal is less to build something for the cryonics industry and more to provide a tax shelter for those who seek to take advantage of cryonics, which might explain some otherwise puzzling aspects of the initiative. Cryonic providers are not at the vanguard of a wealthy industry by any means, and the Timeship seems out of place in in scale and goals when compared to the ongoing, practical work of small foundations and businesses in this narrow marketplace.

In any case, here's an article that includes thoughts from Valentine:

No one's claiming that human reanimation is within our grasp yet, although the Cryonics Institute claims that insects, vinegar eels and human brain tissue (not to mention human embryos, as shown by the growing success of IVF treatment) have been stored at liquid nitrogen temperature, at which point all decay ceases, and then revived fully.

"No one's saying, 'Hey, we cryopreserved a dog and brought it back,'" says Stephen. "The breakthroughs come at a slow, slow pace, but the advantage with being cryopreserved is that you have time. If they can work it out in 100 or 200 years, you're not going anywhere. You're on ice for a while..."

The early part of the procedure is now certainly feasible, thanks to a process called vitrification. Before, one of the main stumbling blocks to freezing bodies was the damage caused to tissue by ice crystals (think about how inferior a steak that's been in the freezer tastes: that's because of molecular damage caused by crystallisation).

Not surprisingly, Stephen is optimistic. "Many scientists are saying that this is going to be considered the century of immortality," he says. [Meanwhile], he insists that life-preservation is not just for the elite few. "This is no exclusive club," he says. "It's affordable to anybody, because it can be paid for through life insurance. Most people around the world can do it if they want."

Irritated that doubters still see life extension as a crackpot notion, Stephen points out that every major scientific breakthrough in history was once deemed unthinkable. "When Christiaan Barnard did the first heart transplant in 1967 in South Africa, they thought the guy was an unethical monster," he says. "Today, thousands of heart transplants take place every year and - rightly - no one questions the moral or ethical issues of it."

The international cryonics community certainly has no shortage of widely celebrated scientists on its side. Marvin Minsky, the pioneer of artificial intelligence, is a supporter; Ray Kurzweil, the author and inventor, has signed up with for preservation with Alcor; molecular nanotechnologist K Eric Drexler is an advocate; as are prominent stem-cell researcher Michael West and Aubrey de Grey, a prominent gerontologist (the scientific study of ageing).

Mitochondria are the power plants of your cells, responsible for creating the energy stores that are used to power cellular operations. Mitochondrial composition is an important determinant of longevity, and accumulating mitochondrial damage - self-inflicted in the course of the operation of metabolism - is one of the root causes of aging. Here researchers review what is know of mitochondrial decline in aging, and the ways in which mitochondrial function can be altered to extend life in laboratory animals:

For decades, aging was considered the inevitable result of the accumulation of damaged macromolecules due to environmental factors and intrinsic processes. Our current knowledge clearly supports that aging is a complex biological process influenced by multiple evolutionary conserved molecular pathways. With the advanced age, loss of cellular homeostasis severely affects the structure and function of various tissues, especially those highly sensitive to stressful conditions like the central nervous system.

In this regard, the age-related regression of neural circuits and the consequent poor neuronal plasticity have been associated with metabolic dysfunctions, in which the decline of mitochondrial activity significantly contributes. Interestingly, while mitochondrial lesions promote the onset of degenerative disorders, mild mitochondrial manipulations delay some of the age-related phenotypes and, more importantly, increase the lifespan of organisms ranging from invertebrates to mammals.

Here, we survey the insulin/IGF-1 and the TOR signaling pathways and review how these two important longevity determinants regulate mitochondrial activity. Furthermore, we discuss the contribution of slight mitochondrial dysfunction in the engagement of pro-longevity processes and the opposite role of strong mitochondrial dysfunction in neurodegeneration.

Link: http://www.frontiersin.org/Genetics_of_Aging/10.3389/fgene.2012.00244/full

Failing neural plasticity, the ability of the brain to adapt and continue creating new neurons, seems to be important in aging. Here researchers investigate the ability of some forms of stem cell transplant to boost the pace of neurogenesis, the creation of neurons:

Neurogenesis occurs throughout life but significantly decreases with age. Human umbilical cord blood mononuclear cells (HUCB MNCs) have been shown to increase the proliferation of neural stem cells (NSCs) in the dentate gyrus (DG) of the hippocampus and the subgranular zone of aging rats, but it is unclear which fraction or combination of the HUCB MNCs are responsible for neurogenesis.

To address this issue, we examined the ability of HUCB MNCs [to] increase proliferation of NSCs. [We] injected HUCB cells intravenously in young and aged [rats] and examined proliferation in the DG at 1 week and 2 weeks postinjection. HUCB-derived [cells] increased NSC proliferation at both 1 and 2 weeks while also enhancing the density of dendritic spines at 1 week and decreasing inflammation at 2 weeks postinjection. Collectively, these data indicate that a single injection of HUCB-derived T cells induces long-lasting effects and may therefore have tremendous potential to improve aging neurogenesis.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23263793

Back in the Fight Aging! archives, you'll find a post on breaking out historical data on increases in human longevity into two components: firstly an increase in the average years lived, and secondly a reduction in early mortality - that more people are reaching ever closer to the average. This second statistical behavior is often presented as compression of morbidity, with the goal being to reduce the time spent in ill health at the end of life.

There is some debate over whether compression of morbidity is in any way a realistic or even useful goal for medical science, as opposed to aiming for increased human longevity through repair and reduction in the ongoing damage that causes aging. If you consider aging in terms of reliability theory, for example, it seems dubious that one could engineer the machineries of human life to last a set time and then fall apart very rapidly at the end - at least not without deliberately making it fall apart at the end. If all you are doing is consistently removing damage, then you extend the length of life, but don't do much about the time taken to fall apart when you stop repairing damage.

In any case, here is a recent paper that revisits this structural decomposition of increased longevity. The researchers here suggest that it is longevity, not compression of morbidity, that is the important factor.

The contribution of rectangularization to the secular increase of life expectancy: an empirical study

In low-mortality countries, life expectancy is increasing steadily. This increase can be disentangled into two separate components: the delayed incidence of death (i.e. the rectangularization of the survival curve) and the shift of maximal age at death to the right (i.e. the extension of longevity).

We studied the secular increase of life expectancy at age 50 in nine European countries between 1922 and 2006. The respective contributions of rectangularization and longevity to increasing life expectancy are quantified with a specific tool.

For men, an acceleration of rectangularization was observed in the 1980s in all nine countries, whereas a deceleration occurred among women in six countries in the 1960s. These diverging trends are likely to reflect the gender-specific trends in smoking. As for longevity, the extension was steady from 1922 in both genders in almost all countries. The gain of years due to longevity extension exceeded the gain due to rectangularization. This predominance over rectangularization was still observed during the most recent decades.

Disentangling life expectancy into components offers new insights into the underlying mechanisms and possible determinants. Rectangularization mainly reflects the secular changes of the known determinants of early mortality, including smoking. Explaining the increase of maximal age at death is a more complex challenge. It might be related to slow and lifelong changes in the socio-economic environment and lifestyles as well as population composition. The still increasing longevity does not suggest that we are approaching any upper limit of human longevity.

There are two ways to think of upper limits on human longevity. One is that there may exist a distinct process of damage accumulation that eventually claims even the most hardy survivors, and which is not yet greatly affected by modern medicine. One candidate is TTR amyloidosis, based on autopsies of supercentenarians.

The second way of looking at limits on longevity is that there are no limits. Or rather, the only limits are those imposed by the lack of biotechnologies to circumvent them. Heart disease used to be a death sentence, for example, and now it is not. The same goes for all of the low-level mechanisms that drive aging and create conditions like heart disease - we are limited because, while we know how to go about repairing these forms of damage, we do not yet have the means in hand to do so.

One important outgrowth of stem cell research is the search for ways to manipulate existing cell populations into greater feats of regeneration. Eventually, it would be hoped, the research community can gain sufficient control over cells in the body so as not to need stem cell transplants at all. Meanwhile scientists are uncovering advances such as this one:

Researchers have pinpointed a molecular mechanism needed to unleash the heart's ability to regenerate, a critical step toward developing eventual therapies for damage suffered following a heart attack.

Researchers found that hearts of young rodents mounted a robust regenerative response following myocardial infarction, but this restorative activity only occurs during the first week of life. They then discovered that a microRNA called miR-15 disables the regenerative capacity after one week, but when miR-15 is blocked, the regenerative process can be sustained much longer.

Further research will be needed to optimize the ways in which medical scientists, and eventually clinicians, may be able to control this regenerative process. "This may well be the beginning of a new era in heart regeneration biology. Our research provides hope that reawakening the regenerative capacity of adult mammalian hearts is within reach."

Link: http://www.eurekalert.org/pub_releases/2012-12/usmc-rpk121912.php

Therapies for several forms of degenerative blindness have been under development for some years. Here is news of progress towards trials for two of them:

Two recent experimental treatments - one involving skin-derived induced pluripotent stem (iPS) cell grafts, the other gene therapy - have been shown to produce long-term improvement in visual function in mouse models of retinitis pigmentosa (RP).

Researchers tested the long-term safety and efficacy of using iPS cell grafts to restore visual function in a mouse model of RP. [The] cells were administered, via injection directly underneath the retina, when the mice were five days old. The iPS cells assimilated into the host retina without disruption, and none of the mice receiving transplants developed tumors over their lifetimes, the researchers reported. The iPS cells were found to express markers specific to retinal pigmented epithelium (the cell layer adjacent to the photoreceptor layer), showing that they had the potential to develop into functional retinal cells. Using electroretinography, a standard method for measuring retinal function, the researchers found that the visual function of the mice improved after treatment and the effect was long lasting.

In the [other] study, the [researchers] tested whether gene therapy could be used to improve photoreceptor survival and neuronal function in mice with RP caused by a mutation to a gene called phosphodiesterase-alpha (Pde6α) - a common form of the disease in humans. To treat the mice, the researchers used adeno-associated viruses (AAV) to ferry correct copies of the gene into the retina. The AAV were administered by a single injection in one eye, with the other eye serving as a control.

When the mice were examined at six months of age (over one-third of the mouse lifespan), photoreceptor cells were found in the treated eyes but not in the untreated eyes, the researchers reported. More important, the treated eyes showed functional visual responses, while the untreated eyes had lost all vision.

Link: http://www.eurekalert.org/pub_releases/2012-12/cumc-tnt122012.php

A couple of recent opinions from the Russian end of the longevity science advocacy community - the second edited somewhat to remove the standard set of automated translation artifacts. Machine translation is improving, but still somewhat slowly at this point.

We Have to Have More Courage to Insist Aging is Accepted as a Disease

Right now one can't come to the hospital and say, "doctor, I've got a problem, I am aging." People would laugh at such a patient, however this is the best kind of patient, the smartest one, one who cares about his future and wants to prevent the upcoming illnesses and frailty.

How to start a conversation about life extension?

Let's say you touched the light of truth and decide to convince people of the need to spend their resources on radical life extension. First, please accept my admiration - what you think - is the most important task for you, for me and for all the people on the planet. Now your goal is to convey a simple message to your buddies to live - good and bad die. Here you will find a shock, most people do not agree with this rather obvious postulate. The overwhelming majority stand against their own immediate death, but insist on the fact that the after-life is beautiful and that man should not argue with nature in the matter of aging. Why should I have to argue with this sort of person? It may be worthwhile to wish them a speedy dispatch to their forefathers, such that they stop creating negative public opinion about the radical life extension, thus helping to kill you by making progress a little less likely.

There is another school in transhumanism, which states that people need to talk about a more moderate view of prevention of age-related diseases and healthy aging, and then most people will agree to help. In my view, this agreement is not worth anything, because for one it has not yet gained any great success, but more importantly it does not lead to scientific experiments aimed at radical life extension. I believe that you first need to attract people who want to live a long time, who want to live come what may. Then you deliver the motivation, a way to wake up such a man. You have the most wonderful news for him that ever he heard: "You have a chance not to die!"

Those who regularly write on the topic of aging research and longevity science are a diverse bunch, but not yet a large enough group to find any two who completely agree with one another on all points. Pick any of those I link to or quote on a regular basis here at Fight Aging!, and I doubt that we overlap on even a majority of positions when it comes to the details.

Last month the popular press was doing its normal breathless job of failing to adequately understand and present the facts in relation to research into aging and longevity. In this case it related to recent research into hydra. These small water creatures may be ageless, or at least age very slowly, and are certainly very competent when it comes to regeneration from injury, but that's about as far as it goes - it seems unlikely that profound advances immediately applicable to humans lurk in hydra biology. Instead this is the standard slow gathering of new knowledge, adding to the grand picture of the evolution of aging, longevity, and the plethora of individual mechanisms that contribute to these traits.

Here is a short open access commentary on the recent hydra research:

Clues to the role of FOXO3A in controlling longevity may be available through the comparative study of organisms which show no sign of aging. One of the very few examples of animals which appear to be truly immortal is the freshwater polyp Hydra. Much of Hydra's remarkable immortality can be traced back to the asexual mode of reproduction by budding which requires a tissue consisting of stem cells with continuous self-renewal capacity. [Hydra's] stem cells indeed continuously proliferate and generate eternal lineages. How? This question has been plaguing some of us since the late 1980s.

In the new study, a literally immortal model organism was induced to both stem cell senescence and immune senescence by altering the expression level of a single gene, the longevity factor FoxO. The data suggest that FoxO has ancient roles in controlling stem cell behavior that may underlie longevity.

The findings have captured the imagination of the popular press, and raised the skeptic's eyebrows. What lessons can actually be learned from the Hydra study? What does this mean for understanding human longevity? First, the Hydra results have moved the longevity-enabling FOXO3A gene from reported association to possible functions, corroborating and extending beyond previous observations in C. elegans and Drosophila. Second, the link between FoxO and components of the innate immune system is of particular interest since aging processes in humans are known to result in impairment of both innate and adaptive immunity ("immunosenescence") as well as in a pro-inflammatory status ("inflammaging"). Third, the Hydra study strengthens the earlier described role of FOXO3A in human stem cell maintenance and regulation. This hypothesis warrants further investigation and indicates another plausible mechanism through which FOXO3A variation may exert its effect on longevity. Attempts to extend the lessons learnt from Hydra to more complex organisms including humans will be challenging. However, the recent study is a proof of principle that investigations in Hydra stem cells hold promise. The more we learn about the role of FoxO in Hydra, the better we will understand how the gene and its variants contribute to longevity in humans.

Link: http://www.impactaging.com/papers/v4/n11/full/100510.html

Inflammation is an important process in the progression of Alzheimer's disease, and researchers have been turning their attention to ways to manipulate inflammation as a form of treatment:

The complex named "NLRP3 inflammasome" is composed of several proteins and plays a key role in the immune system. It resembles a fire alarm sensor that triggers a chain reaction when activated. As a result, immune cells are mobilized and substances that foster inflammation are released. This process can be triggered by infections, which are subsequently suppressed by the immune response. However, in the case of Alzheimer's disease, the activation of the molecular alarm may have negative consequences: nerve cells are damaged and die. Ultimately, this leads to the loss of brain function and mental capabilities in humans.

The researchers collected a comprehensive chain of evidences: they examined both the brains of deceased Alzheimer patients and of mice who exhibited behavioural disorders that are typically associated with Alzheimer's disease. The researchers found an activated form of the NLRP3 inflammasome in both cases.

Looking at another group of mice, the scientists examined possibilities for suppressing inflammatory reactions. To achieve this, they removed the genes that trigger production of the NLRP3 inflammasome. Therefore, these mice were no longer able to synthesize the protein complex. As a result, the animals developed only relatively mild symptoms of the disease. Moreover, their brains showed only reduced amounts of the damaging plaques.

Link: http://www.eurekalert.org/pub_releases/2012-12/haog-adc121912.php

Life is a sequence of decisions involving time and resources: how much, how long, now, or later? Everything from choosing a career to deciding whether to reach for the salt passes through the engine in your mind that weighs costs and time. In this, helping to further the advance of longevity science is the same as any other human endeavor. We choose when to support research, we try to pick the best research to support based on likely outcomes, and we choose how much support to give.

I've debated the money axis ad nauseam, so let us do something different and look at the time axis for a change. You could choose to donate resources today to an organization like the SENS Research Foundation, one that funds the most promising projects in the laboratory, or you could wait to donate in some future year. Some arguments to either side:

Donating Later

On balance, I am likely to have more resources to donate later. If I soundly invest what I would have donated now, it will most likely be worth more in later years. This is not a certainty, but a reasonable expectation.

The cost of life science research is falling dramatically. If I donate the same amount later, more can be accomplished, and more rapidly, than now.

Donating Now

Work that isn't accomplished today will have to be accomplished tomorrow. It may be faster and cheaper to complete that research project if we start twenty years from now, but what if we could be long done by then, even though today's progress is slow and expensive by comparison? Every year shaved from the time taken to develop new medicines means many lives saved.

If you don't use money when you have it, it has a way of vanishing amid life's slings and arrows. Not donating today easily turns into not donating at all. Just as "paying yourself first" is the way to enforce savings in spite of your worse nature, so maintaining a steady stream of donations today is the way to ensure that you actually make a difference.

Without providing support now, a range of researchers and organizations that can make best use of your resources will not emerge to accept later donations. Growth in the sciences is as much about establishing institutions that have authority and continuity as anything else. Funds here and now are needed for all of their functions: drawing new researchers into the field; bringing respect to the field; communicating to the public; educating students. No great research community, dedicated to a cause, arises spontaneously from nothing. Years or decades of steadily increasing funds and incremental progress are required.

Donating now encourages other people to donate very soon. It is a form of persuasion, granting legitimacy in other people's eyes to the project you favor. When you do not donate now, you miss the chance to persuade others now.

In Conclusion

Donate now. Unless you find yourself in the rare and envious position of knowing in certainty that a stupendous pile of money will fall upon your bank account in years to come. In which case, donate both now and after that fortunate event.

Over the years I have watched many people churning their way through the energetic startup community of the US West Coast, putting off many things in their lives because of the conviction that they would have time and much money to deal with them later. Among the ways to wealth, it is true that doing a good job of starting a company (and a good job of being networked while doing it) is the best shot at success - but best is a far way from a sure thing, or even a good chance. I can assure you that most of the people involved in that world do not end up wealthy enough to have justified putting off anything.

The same, at a more sedate pace, applies to the rest of us. Tomorrow is what we build today. If we set down no bricks, there will be no wall.

Here is an example of a stem cell therapy that is just a little advanced over established medical techniques - in effect just a more sophisticated and cost-effective version of a tissue transplant:

A variety of things can cause [corneal limbal stem cell deficiency], including chemical and thermal burns to the corneas, which are the glass "domes" over the coloured part of our eyes. But it's also thought that microbial infections and wearing daily wear contact lenses for too long without properly disinfecting them can lead to the disease, too.

Since a corneal transplant was not an option for Binns, his doctors at Toronto Western Hospital proposed something new: a limbal stem cell transplant. The limbus is the border area between the cornea and the whites of the eye where the eye normally creates new epithelial cells. Since Binns' limbus was damaged, doctors hoped that giving him healthy limbal cells from a donor would cause healthy new cells to grow over the surface. While the treatment is available in certain centres around the U.S., Binns became the first patient to try the treatment at a new program at Toronto Western Hospital. Though Binns knew he'd need to take anti-rejection drugs, he decided the procedure was worth a try.

Just like with an organ transplant, Binns' doctors had to find a healthy match. It turned out his younger sister, Victoria, was the ideal candidate for the job. In the operating room, doctors removed the scar tissue on Taylor's eyes, then took some healthy stem cells from Victoria's eyes and stitched them to the surface of Binns' eyes. "Within a month he could see 20/40. His last visit he was 20/20 and 20/40."

Researchers are also working on using stem cells from deceased donors and even using limbal stem cells from a patient's own eyes. While that would require growing the cells in a lab to force them to multiply, it would also mean that patients might be able to skip anti-rejection drugs.

Link: http://www.ctvnews.ca/health/ontario-man-s-sight-restored-with-help-of-stem-cells-1.1088888

The Health Extension salons are an ongoing series of meetups in the Bay Area for people interested in supporting and advancing longevity science, associated with the energetic technology entrepreneur community there. This sort of initiative is important, as grassroots efforts associated with this community have a way of growing and getting things done.

There are a number of presentation videos at the meetup site from previous events, and you might consider helping out if you are in the area:

The Health Extension community is committed to information sharing and collaborative action to extend healthy and happy human lifespans to 123 years and beyond. Our members are scientists, entrepreneurs and social influencers dedicated to fixing the degenerative cellular processes that cause deadly human diseases.

This community began in early 2012 as informal meet-ups in the home of Joe and Lisa Betts-La Croix. Our 100+ members now meet monthly at Y Combinator HQ in Mountain View, California with plans to launch salons and other projects in Los Angeles and New York in 2013.

Link: http://healthextension.co

Perhaps I'm just paying greater attention to the topic of late, but it seems like a fair number of large statistical studies that correlate exercise with increased life expectancy have shown up in the past couple of years - more than I recall prior to that. A few examples from the archives:

• Exercise, Longevity, and Long Term Medical Costs
• The Power of Moderate Exercise
• Another Study Suggests that Sedentary Behavior Adds Up

Here is a newly published study on this topic that pulls from a data set of around 95,000 people. It is presently open access, which is not usually the case for the journal in question, so take advantage of it while it lasts:

Years of Life Gained Due to Leisure-Time Physical Activity in the U.S.

Data from the National Health and Nutrition Examination Survey (2007-2010); National Health Interview Study mortality linkage (1990-2006); and U.S. Life Tables (2006) were used to estimate and compare life expectancy at each age of adult life for inactive (no moderate to vigorous physical activity); somewhat-active (some moderate to vigorous activity); and active ([more] moderate to vigorous activity) adults. Analyses were conducted in 2012.

Somewhat-active and active non-Hispanic white men had a life expectancy at age 20 years that was ∼2.4 years longer than that for the inactive men; this life expectancy advantage was 1.2 years at age 80 years. Similar observations were made in non-Hispanic white women, with a higher life expectancy within the active category of 3.0 years at age 20 years and 1.6 years at age 80 years. In non-Hispanic black women, as many as 5.5 potential years of life were gained due to physical activity. Significant increases in longevity were also observed within somewhat-active and active non-Hispanic black men; however, among Hispanics the years-of-life-gained estimates were not significantly different from 0 years gained.

The estimates in the present study for non-Hispanic white men aged 20 years [suggest] that 2.6 hours [of overall life expectancy] are gained per hour of moderate activity and 5.2 hours were gained per hour of vigorous activity accrued in adulthood.

The effects of exercise on general health over the long term are possibly more striking. You can't exercise your way out of aging, but you can laze your way into a much more unpleasant and expensive later life. Exercise, calorie restriction, and the like are small stopgap measures, the poor and miserable best we can do right now in order to gain a better chance of being alive and in good health to great the arrival of rejuvenation biotechnologies - therapies that will repair and reverse the cellular and molecular damage that drives aging.

We need those biotechnologies to get out of this hole alive. They are the most important goal - don't lose sight of that behind the constant deluge of data on health, life expectancy, and how we can presently modestly adjust the pace at which we're aging to death.

The Eurosymposium on Healthy Aging took place in Brussels earlier this month, a gathering of researchers and advocates for longevity science. The presentations were recorded and videos have been posted to Youtube. I encourage you to browse. Here is a report on the event:

Theoretical questions of longevity were covered in the first day, including such themes as the general overviews of ageing theories, molecular damage in ageing, mitochondria and autophagy. The general panel on causes, mechanisms, and interventions in aging, featured Drs. Aubrey de Grey, David Gems, Kris Verburgh, and Diana Van Heemst, and was moderated by Sven Bulterijs of HEALES.

The second day featured an inspiring plethora of promising potential interventions for increasing healthy longevity: genetics of aging and centenarians research, nutritional and pharmacological interventions in aging, biomedical interventions such as repair of damaged mitochondria, destruction of senescent cells, use of telomerase to extend health span, remediation of the Alzheimer's disease, and regenerative medicine, including both cell material and computational aspects.

The main subject of the third day was the political and social promotion of research into the biology of aging and healthy longevity. Discussion groups were formed and tentative suggestions made for increasing funding for life extension research, improving public opinion of life extension, and scientific positioning of life-extension.

Link: http://hplusmagazine.com/2012/12/19/the-brussels-summit-of-longevity-activists/

A successful demonstration of a novel form of immune therapy is noted in this article, and described in a recently published paper:

An experimental "Trojan-horse" cancer therapy has completely eliminated prostate cancer in experiments on mice. [The] team hid cancer killing viruses inside the immune system in order to sneak them into a tumour. [After] chemotherapy or radiotherapy is used to treat cancer, there is damage to the tissue. This causes a surge in white blood cells, which swamp the area to help repair the damage. "We're surfing that wave to get as many white blood cells to deliver tumour-busting viruses into the heart of a tumour."

[Researchers] blood samples and extract macrophages, a part of the immune system which normally attacks foreign invaders. These are mixed with a virus which, just like HIV, avoids being attacked and instead becomes a passenger in the white blood cell. In the study, the mice were injected with the white blood cells two days after a course of chemotherapy ended. At this stage each white blood cell contained just a couple of viruses. However, once the macrophages enter the tumour the virus can replicate. After about 12 hours the white blood cells burst and eject up to 10,000 viruses each - which go on to infect, and kill, the cancerous cells.

At the end of the 40-day study, all the mice who were given the Trojan treatment were still alive and had no signs of tumours. By comparison, mice given other treatments died and their cancer had spread.

Link: http://www.bbc.co.uk/news/health-20795977

I noticed a good, comprehensible open access paper today: a review that summarizes what is known of the biology of the most common type of long-lived genetically engineered mouse species, those with disrupted or suppressed growth hormone (GH) activity. These include Ames dwarf mice, Snell dwarf mice, and growth hormone receptor knockout (GHRKO) mice. The present record for mouse longevity is held by the results of a GHRKO study, some of the mice involved living more than 60% longer than peers.

If you'd like to better understand how this all fits together under the hood and how it relates to other areas of study where metabolism, genetic engineering, and aging overlap - such as calorie restriction - then take a look:

Metabolic characteristics of long-lived mice

The remarkable extension of longevity in mice lacking GH or GH receptors appears to be due to multiple interacting mechanisms including reduced activation of growth-promoting pathways, greater stress resistance, reduced inflammation, increased reservoir of pluripotent stem cells, and improved genome maintenance.

Data summarized in this article indicate that alterations in energy metabolism and improved insulin control of carbohydrate homeostasis have to be added to this list. In fact, these metabolic adaptations may represent key features of the "longevous" phenotype of these animals and important mechanisms of the extension of both healthspan and lifespan in GH-related mutants.

Importantly, many of the metabolic features of long-lived mutant mice described in this article have been associated with extended human longevity. Comparisons between centenarians and elderly individuals from the same population and between the offspring of exceptionally long-lived people and their partners indicate that reduced insulin, improved insulin sensitivity, increased adiponectin, and reduced pro-inflammatory markers consistently correlate with improved life expectancy.

Many of the early forms of stem cell therapy involve cell transplants, and seem to produce benefits without those transplanted cells creating replacements for lost native cells. Instead the newcomers are improving the local environment and issuing signals that allow greater survival and repair among the native cell populations. Here is an example of the type:

Promising new research provides evidence that amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, may be treatable using neural stem cells. A consortium of researchers at multiple institutions [have] shown that neural stem cells, when transplanted into the spinal cord of a mouse model with familial ALS, slow disease onset and progression while improving motor function, breathing and survival time compared to untreated mice.

Neural stem cells are the precursors of all brain cells. They can self-renew, making more neural stem cells, and differentiate, becoming nerve cells or other brain cells. These cells can also rescue malfunctioning nerve cells and help preserve and regenerate brain tissue. But they've never before been studied extensively in a good model of adult ALS.

In 11 independent studies [researchers] transplanted neural stem cells into the spinal cord of a mouse model of ALS. The transplanted neural stem cells benefited the mice with ALS by preserving the health and function of the remaining nerve cells. Specifically, the neural stem cells promoted the production of protective molecules that spared remaining nerve cells from destruction. They also reduced inflammation and suppressed the number of toxin-producing and disease-causing cells in the host's spinal cord.

Link: http://www.eurekalert.org/pub_releases/2012-12/uomm-tns121912.php

Improving the ability of cells to clear out garbage is a potential therapy for a wide range of conditions - probably including aging itself, as the failure of garage clearance mechanisms related to the lysosome contributes to degenerative aging. In past years researchers have noted that calorie restriction seems to boost garbage clearance and the cellular recycling known as autophagy, while making autophagy more efficient has been used to rejuvenate liver function in old mice.

Here researchers are tinkering with garbage clearance in the brain as a way to treat neurodegenerative conditions, many of which seem to involve a buildup of unwanted and harmful compunds inside cells:

[Researchers] found that the issue in amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) is the inability of the cell's protein garbage disposal system to "pull out" and destroy TDP-43, a powerful, sometimes mutated gene that produces excess amounts of protein inside the nucleus of a nerve cell, or neuron.

The way to rev up protein disposal is to add parkin - the cell's natural disposal units - to brain cells. In this study, [researchers] demonstrated in two animal experiments that delivering parkin genes to neurons slowed down ALS pathologies linked to TDP-43. [The] study further demonstrates that clumps known as "inclusions" of TDP-43 protein found inside neuron bodies in both disorders do not promote these diseases, as some researchers have argued.

What happens in both diseases is that this protein, which is a potent regulator of thousands of genes, leaves the nucleus and collects inside the gel-like cytoplasm of the neuron. In ALS, also known as Lou Gehrig's disease, this occurs in motor neurons, affecting movement; in FTD, it occurs in the frontal lobe of the brain, leading to dementia.

"Our study suggests TDP-43 in the cell cytoplasm is deposited there in order to eventually be destroyed - without contributing to disease - and that TDP-43 in the nucleus is causing the damage. Because so much protein is being produced, the cell can't keep up with removing these toxic particles in the nucleus and the dumping of them in the cytoplasm. There may be a way to fix this problem."

[Researchers] found that parkin "tags" TDP-43 protein in the nucleus with a molecule that takes it from the nucleus and into the cytoplasm of the cell. "This is good. If TDP-43 is in the cytoplasm, it will prevent further nuclear damage and deregulation of genetic materials that determine protein identity, We think parkin is tagging proteins in the nucleus for destruction, but there just isn't enough parkin around - compared with over-production of TDP-43 - to do the job."

Link: http://www.eurekalert.org/pub_releases/2012-12/gumc-rp121712.php

It looks like the SENS Foundation is now the SENS Research Foundation; a good name change, I think. The Foundation's year end newsletter arrived today:

Dear friends and supporters,

SENS Research Foundation's mission is to transform the way the world researches and treats the diseases of aging. As another holiday season approaches, we would like to share the progress that we have made with you. Our projects on lysosomal aggregates and mitochondrial mutations at our Mountain View, California research center have advanced steadily over the last year. We have also launched a major new project on the alternative lengthening of telomeres.

Meanwhile, we continued to expand our extramural programs, conducted in collaboration with such elite university partners as Harvard, Yale, Cambridge, and Berkeley. Our development work has also made great strides. You will soon see the results of a complete logo and website design overhaul, and the world-class animations that we have commissioned to visualize the individual strands of SENS.

All that said, you can be sure that the challenge we face remains daunting. Not a single one of the conditions that cause so much suffering and claim so many lives across the world - Alzheimer's, heart disease, and diabetes, to name a few - has yet been cured. We believe that the greatest promise to not simply treat but eradicate age-related disease lies in the use of regenerative medicine: the rejuvenation biotechnology approach. Unfortunately, despite the increasingly large amount of data indicating the effectiveness of this approach, research on "damage repair" therapies remains largely neglected.

As a nonprofit research charity, we depend on your generosity to drive this critical work. Our level of funding determines how many new scientific projects we can sponsor, how loudly we can broadcast our message, and how many students we can educate about the SENS platform. We have come a long way with your help so far, and have many more steps that we can take. In 2013, we will:

• Host SENS6, the next in our series of biennial conferences at Cambridge University, to bring together the scientists making the greatest breakthroughs in rejuvenation.
• Hold a summit for leaders in industry and academia to discuss the future of aging and the importance of an interdisciplinary approach.
• Grow our talented staff by hiring new postdoctoral-level researchers to head our in-house LysoSENS and OncoSENS projects.
• Fund new projects with partner universities and research centers.
• Dramatically extend the size and scope of our outreach efforts.
• Expand our summer internship program for student researchers to multiple campuses.

While we are proud of what we have achieved so far and optimistic about the future, we understand that a great deal of work remains to be done. Our vision -- a world free of age-related disease -- remains just that: a vision. With your support, we can keep on bringing it closer to a reality.

Warmest wishes,

Mike Kope, CEO
Aubrey de Grey, CSO
Tanya Jones, COO
and the rest of the SRF Team

Change is coming, more of it in the next few decades than has taken place in the past few centuries: progress is accelerating. We are the species that builds and changes - but inside we still carry the evolved instincts of the ape, and he greatly dislikes change, no matter whether or not it is positive. How much of opposition to human life extension is predicated on fear of change?

"Wouldn't you eventually get bored?" Like clockwork, the question arises when I tell someone quixotically, arrogantly, that I plan on living forever. From the limited perspective of 20 years, even the prospect of living another six or seven decades in full color can be impossible to envisage. Hedging, I answer that assuming a world where radical life extension is possible, there will be no telling as to how different the human experience will be from what we know.

Returning to the original question - in essence: "Why choose to live forever if forever really just means eternal boredom and senescence?" - it's apparent that living forever would mean something other than continuing as our current selves. Technology futurists are reasonably certain that at some point in the next century, we'll be enmeshed in networks of artificial intelligence, bodily modified beyond immediate recognition, and confronted with a new set of identity questions, societal challenges, and existential ambitions.

If I'm fortunate enough to make it to 150, I expect to find a world where caring about ethnic politics in the Middle East, wearing university colors, impressing girls, and investigating my ancestral origins won't be of much, if any, use. In other words, I expect that I'll need to invent a new self for a radically new world. More than anything I can imagine, it'll be a tall order. We have good evolutionary reason to love ourselves to death rather than contemplate being completely reconfigured. It's a daunting prospect to imagine, but it's anything but boring.

Link: http://www.thecrimson.com/column/dining-on-sacred-cow/article/2012/12/17/lipson-life-after-death/

In the past I've discussed whether or not we are obliged to future generations, morally bound to work on making their world a better place by producing rejuvenation biotechnologies. Here, it is suggested that we are obliged to past generations - that we owe much to their efforts to improve the human condition and should thus continue to do the same, as a sign of respect at the very least:

Humanity has braved the weather many times over the millennia, surviving long enough to invent language, an earth-shattering breakthrough in their time. Language to them was as big of a game changing breakthrough than the internet is to the world now. We pushed on through famines and wars, the cold, the heat, the wild. We figured out how to harness fire. We learned how to farm so we could live in greater abundance. That gave rise to more free time to invent and explore, and led us through progressions like the bronze and iron ages. This in turn enabled so many other things eventually leading up through times like the great industrial age. Humanity exponentially shifted a gear soon after, and moved on through the technology revolution.

The struggle and strife and hardship and toil that has been gone through to get us here is deeper than I can imagine. I try sometimes, as many of you might also, and its horrifying. The world is filled with graveyards; the soil is drenched in blood, sweat and tears. The dreams realized and the dreams shattered echo across the millennia and eons. If we could have collected all the hardship on video to play it in a huge montage then I imagine it might kill us from strife. We owe this to them, we owe the creation of indefinite life spans to them. They have brought us through all that to this great cusp of destiny.

We grab the baton, on the ground work that our ancestors put down for us, with their blood coursing through our veins. [They] had to die for us to be here. They had to give us all that they did and then die so that we may have what we have. We don't have what we have because it magically appeared here. We have it because they toiled and died for us to have it. We cannot pilfer it and waste the opportunity, we have to keep pioneering existence, we have to keep building, we have to keep pushing the boundaries, because that is the wage they earned.

Link: http://transhumanity.net/articles/entry/we-owe-pursuit-of-indefinite-life-extension-to-our-ancestors

This turned up from the Methuselah Foundation in my in-box today, and I thought I'd share. Remember that their donation page is just a click away, as is the fundraising challenge at the New Organ Prize:

Dear Friend,

In the spirit of the season, we've been looking back on the last year at Methuselah Foundation and appreciating everything we have to be thankful for. And we want you to know that you're at the top of the list. Without our many donors, colleagues, partners, and friends, we could never do what we do. We're so grateful for your ongoing support, and we'd like to thank you for believing so fervently, like we do, in the enormous promise of regenerative medicine for extending healthy human life.

2012: Year in Review

Thanks to your generosity, Methuselah made significant progress in 2012 on our flagship project, the New Organ Prize. We launched a beta website at neworgan.org and kicked off our first campaign to raise $100,000 and inspire 100 people to become "New Organizers." We quadrupled the size of our online community at facebook.com/neworganprize. We're collaborating with the gifted filmmaker Michael Marantz (The Future is Ours) on a video highlighting regenerative medicine as a lasting solution to the organ crisis. We've been working with tissue engineering pioneers like Dr. Anthony Atala, Dr. Paolo Macchiarini, and Dr. Gabor Forgacs to beging shaping prize rules and criteria. And as we enter December, we're only $20,000 away from reaching our $100,000 goal for New Organ in 2012.

Investing in the Future

This year, we also located a beautiful piece of land in the U.S. Virgin Islands for our long-planned monument to the Methuselah 300. One of the promising young companies we've invested in, Organovo, has been making a splash, going public in record time, winning a critical patent, and appearing on Technology Review's list of the 50 Most Innovative Companies of 2012. Another young company we've invested in, Silverstone Solutions, also made headlines this year by enabling several life-saving paired kidney transplants at California Pacific Medical Center in San Francisco using their sophisticated kidney-matching software powered by cloud computing, saving at least 50 lives. We continue to scour the landscape for disruptive longevity advancing companies, and expect great things from Organovo and Silverstone in 2013.

Looking Forward Together

The field of regenerative medicine is truly coming of age, with growing public interest and more press coverage during the past six months than at any time we can remember. We even saw a Nobel Prize in Medicine this year for Dr. Shinya Yamanaka and Dr. John Gurdon's work on pluripotent stem cells.

From all of us at the Methuselah Foundation, happy holidays, and thank you once again for everything you do. We're looking forward to sharing an even brighter 2013 with you.

Warm regards,

David Gobel
Methuselah CEO

Cancer immunotherapy technology demonstrations continue to roll in. This one is representative of what is taking place in many laboratories these days:

Using an artificial protein that stimulates the body's natural immune system to fight cancer, a research team [has] engineered a lethal weapon that kills brain tumors in mice while sparing other tissue. If it can be shown to work in humans, it would overcome a major obstacle that has hampered the effectiveness of immune-based therapies.

The protein is manufactured with two arms - one that exclusively binds to tumor cells and another that snags the body's fighter T-cells, spurring an attack on the tumor. In six out of eight mice with brain tumors, the treatment resulted in cures.

"This work represents a revival of a somewhat old concept that targeting cancer with tumor-specific antigens may well be the most effective way to treat cancer without toxicity. But there have been problems with that approach, especially for brain tumors. Our therapeutic agent is exciting, because it acts like Velcro to bind T-cells to tumor cells and induces them to kill without any negative effects on surrounding normal tissues. One of the major advantages is that this therapy can be given intravenously, crossing the blood-brain barrier. When we gave the therapy systemically to the mice, it successfully localized to the tumors, treating even bulky and invasive tumors in the central nervous system."

Link: http://www.eurekalert.org/pub_releases/2012-12/dumc-dmn121412.php

If you remove germ cells from nematode worms or flies they live longer. Researchers continue to investigate the mechanisms involved:

The gonad is well known to be important for reproduction but also affects animal life span. Removal of germ cells - the sperm and egg producing cells - increases longevity of the roundworm Caenorhabditis elegans. However, the underlying molecular mechanisms were a mystery. [The] roundworm Caenorhabditis elegans is a commonly used model organism in the field of ageing research. It develops from an egg to adult through four larval stages. These developmental stages are controlled by a developmental clock.

[Researchers] used a laser to remove the germ cells. They found that the remaining gonadal cells trigger production of a steroid hormone called dafachronic acid. Dafachronic acid activates so-called microRNAs, which work as tiny molecular switches causing changes in gene expression that promote longevity. Interestingly, this same steroid hormone-microRNA switch was previously shown [to] be part of the developmental clock. Thus, the loss of the germ cells ultimately causes the worm to use developmental timers to put in motion a life-prolonging programme.

Link: http://www.mpg.de/6696558/reproduction-lifespan

There are a range of mouse laboratory species genetically engineered to age more rapidly than usual. Reduction in the cost and time taken for studies is the impetus in some cases, a bet that the economic benefits will outweigh any uncertainty introduced by differences in these species. Other accelerated aging species were created to study processes of aging, DNA repair, or other important mechanisms.

One of these species is the BubR1 mutant, noted here at Fight Aging! back in 2004. Interestingly, this was the species used in last year's demonstration that (accelerated) aging can be slowed by removal of senescent cells. There are the usual cautions about extrapolating from work in accelerated aging mice, but at this point people expect to see much the same result in mice that age normally: better health, extended life.

But back to BubR1. If there is too little of it, accelerated aging results, as described in 2004. Researchers have now shown that boosting levels of BubR1 seems to slow aging, placing it into a small and select category of genetic or metabolic alterations that can be reversed to either speed or slow aging. Here's an article and the release:

Revved-Up Protein Fights Aging

Biologists report that genetically engineered mice that make extra BubR1 are less prone to cancer. For example, they found that when they exposed normal mice to a chemical that causes lung and skin tumors, all of them got cancer. But only 33% of those overexpressing BubR1 at high levels did. They also found that these animals developed fatal cancers much later than normal mice - after about 2 years, only 15% of the engineered mice had died of cancer, compared with roughly 40% of normal mice.

The animals that overexpressed BubR1 at high levels also lived 15% longer than controls, on average. And the mice looked veritably Olympian on a treadmill, running about twice as far - 200 meters rather than 100 meters - as control animals. All of this left [researchers] thinking that BuBR1's life-extending effects aren't due to only its ability to prevent cancer, although that's not yet certain.

Mayo Clinic study unmasks regulator of healthy life span

"We've known for some time that reduced levels of BubR1 are a hallmark of aging and correspond to age-related conditions, including muscle weakness, cataract formation and tumor growth. Here we've shown that a high abundance of BubR1, a regulator of chromosome segregation during mitosis, preserves genomic integrity and reduces tumors, even in the face of some genetic alterations that promote inaccurate cell division. Our findings suggest that controlling levels of this regulator provides a unique opportunity to extend healthy life span."

Researchers studied two lines of transgenic mice, one with moderate expression of BubR1 and the other with high expression. Outcomes of a series of experiments showed that mice with high expression of the gene were dramatically effective in preventing or limiting age-related disease compared to those with moderate expression and especially to wild type mice.

The findings were significant. Only 33 percent of these high expressing mice developed lung and skin tumors compared to 100 percent of the control group. BubR1 overexpression markedly reduced aneuploidy (a state of having an abnormal number of chromosomes), which causes birth defects. Other results showed these mice were protected from muscle fiber deterioration, that they were better performers in treadmill tests, that they had much reduced levels of renal sclerosis, intestinal fibrosis and tubular atrophy - all signs of aging. They also showed higher cardiac-stress tolerance and resistance to age-related retinal atrophy.

Mice, it should be recalled, are little tumor factories. Anything that can reduce cancer rates will likely extend their lives somewhat - but these results have a slew of other measures to go with that, making the effect look more general than just cancer resistance. I'd say it's all fuel for the debate over the degree to which DNA damage is a significant cause of aging versus just a significant cause of cancer.

The published paper for this BubR1 work is available online if you wish to dig deeper, but sadly not open access.

This past year, efforts have started in the longevity science community to form single-issue political parties in Russia and some European Union countries. This is a long-standing form of advocacy in that part of the world, where political systems are structured in such a way that having a formal party - even if small - opens the door to reaching more people with your message. Successful examples from past years include the Green Party and the Pirate Party.

The various newly-founded longevity party initiatives have a unified banner organization called the International Longevity Alliance. That group recently launched their website:

The International Longevity Alliance promotes the social struggle against the deteriorative aging process and for healthy and productive longevity for all, through scientific research, technological development, medical treatment, public health and education measures, and social activism.

We believe that this goal can be achieved through broad public cooperation and support, from all nations and all walks of life. Hence, the International Longevity Alliance promotes the creation and international cooperation of social activist and advocacy groups from across the world.

Advocacy Groups within the International Longevity Alliance have been initiated in more than 30 countries. Currently we are in the process of official registration as a non-profit, non-governmental international public association. Several options for registration are considered, mainly in the US and EU, that would ensure the optimal and egalitarian international cooperation. Petitions in support of research of aging and longevity are being promoted in the EU, US and Russia.

Link: http://longevityalliance.org

Researchers demonstrate the ability to guide heartbeats by introducing pacemaker cells:

A human heart is made up of billions of cells, but researchers say fewer than 10,000 are responsible for controlling the heartbeat. Age and disease can lead to problems such as the heart pumping too fast or too slow - and it can even stop completely, in what is known as a cardiac arrest.

A team of [researchers] tried to restore the heart's own ability to dictate the beat by creating new pacemaker cells. They used a virus to infect heart muscle cells with a gene, called Tbx18, which is normally active when pacemaker cells are formed during normal development in an embryo. When heart cells were infected with the virus they became smaller, thin and tapered as they acquired the "distinctive features of pacemaker cells."

When the virus was injected into a region of the hearts of seven guinea pigs, five later had heartbeats which originated from their new pacemaker. [Researchers expect] the same method to work in the human heart as they used a human gene, Tbx18, to generate the effect.

"It opens up the tantalising possibility of using cell therapy to restore normal heart rhythm in people who would otherwise need electronic pacemakers. However, much more research now needs to be done to understand if these findings can help people with heart disease in the future."

Link: http://www.bbc.co.uk/news/health-20713986

You might recall past studies of elite atheletes that showed a sizable correlation with increased life expectancy:

• Atheletes Live Longer, Probably the Exercise
• Putting Upper Bounds on Longevity Derived From Exercise

Exercise and physical fitness are obviously things to point to here. Causation is harder to pin down in human studies: for example, we might ask to what degree competitive athletes are drawn their line of work because they are more robust than the average individual - and thus capable of living longer anyway. While it's certainly the case that a mountain of studies show causation for health benefits deriving from moderate exercise, there isn't as much to point to when it comes to the same for human life expectancy. There is certainly a lot of correlation in published research, however.

There are any number of other significant factors at play here when you look at statistical differences of a few years up or down in human life expectancy. For example, wealth: successful professional athletes are wealthier than the average fellow. To what degree is their longer life expectancy the result of the broad array of benefits that come with being wealthier? Easier access to medicine; more personal connections where it matters; greater likelihood of education or other access to knowledge that helps with taking advantage of medicine; and so forth.

Here is another study that shows a longevity advantage for athletes, but which unfortunately doesn't help much with questions of causation:

Olympic medalists stay alive longer, study finds

Athletes who win at the Olympics may bring home more than just a medal: They could add a few years to their life spans, scientists have found. Winners of a gold (or silver or bronze) medal lived almost three years longer on average than their country's general population - when matched for age, gender and birth year - according to a study [that] examined some 15,174 Olympic medalists.

"Some elite sportspeople may be influenced by fame and glory, which could confer longevity through increased affluence," said an editorial accompanying the research, "unless undermined by excessive partying and hazardous risk-taking behaviors."

Alternatively, survival edges could simply be due to more healthful lifestyles and physical fitness. [Researchers] said it wasn't possible to examine the longevity fates of those who competed in the Olympics but did not win a medal because records for non-winners weren't nearly as complete as those for winners.

The study is open access and very readable, so head on over and have a look at the published paper. It isn't the first to suggest that high intensity regular exercise is either no more beneficial than moderate regular exercise or no more correlated with longevity:

Our results show that former Olympic athletes who engaged in disciplines with high cardiovascular intensity had similar mortality risks to athletes from disciplines with low cardiovascular intensity. This would indicate that engaging in cycling and rowing (high cardiovascular intensity) had no added survival benefit compared with playing golf or cricket (low cardiovascular intensity).

MIT news here looks at the present state of tissue engineering, with a focus on work that is taking place at their own institution:

In the 1970s and 1980s, tissue engineers began working on growing replacement organs for transplantation into patients. While scientists are still targeting that goal, much of the tissue engineering research [is] also focused on creating tissue that can be used in the lab to model human disease and test potential new drugs.

Another near-term goal for tissue engineers is developing regenerative therapies that help promote wound healing. [Healthy cells] sitting adjacent to diseased tissues can influence the biology of repair and regeneration, [which might be achieved via] implantable scaffolds embedded with endothelial cells, which secrete a vast array of proteins that respond to injury. Endothelial cells, normally found lining blood vessels, could help repair damage caused by angioplasty or other surgical interventions; smoke inhalation; and cancer or cardiovascular disease. The implants are now in clinical trials to treat blood-vessel injuries caused by the needles used to perform dialysis in patients with kidney failure.

One major challenge for designing implantable organs is that the tissues need to include blood vessels that can connect to the patient's own blood supply. [Researchers] are working on inducing blood vessels to form by growing cells on nanopatterned surfaces, [and] recently developed 3-D liver tissues that include their own network of blood vessels. Though still a long-term goal, being able to regenerate new organs could have a great impact on the future of health care. "It's the kind of thing that can transform society. You can't have a drug that will grow a new liver or a new heart, so this could be huge."

Link: http://web.mit.edu/newsoffice/2012/engineering-health-tissue-engineering-growing-organs-1214.html

Previous estimates of ongoing gains in life expectancy at birth put it at around a fifth of a year every year. Life expectancy at 60 rises at about half that pace - a tenth of what is needed for actuarial escape velocity. This has been incidental life extension, achieved without any deliberate attempt to tackle aging.

New data suggests a slightly higher pace for gains in life expectancy at birth, with a decade gained since 1970. This is probably largely driven by increased wealth and accompanying reductions in childhood mortality:

In the first Global Burden of Disease Study 2010 paper [the] authors present new estimates of life expectancy for the last four decades in 187 different countries. While overall life expectancy is increasing globally, the gap in life expectancy between countries with the highest and lowest life expectancies has remained similar since 1970.

The new estimates show that, globally, in 2010 a man's average life expectancy at birth had increased by 11.1 years (19.7%) since 1970, from 56.4 years in 1970, to 67.5 years in 2010. For women, life expectancy increased by 12.1 years (19.8%) during the same period, from 61.2 years in 1970, to 73.3 years in 2010. Deaths in children under five years old have declined by almost 60% since 1970, from 16.4 million deaths in 1970 to 6.8 million in 2010.

Link: http://medicalxpress.com/news/2012-12-world-population-gains-decade-life.html

We possess a very large and diverse set of bacteria inside our bodies, and they play a vital role in process such as digestion. In effect they are the first link in the chain that leads from diet to metabolism to the pace of aging: a large portion of how environment influences natural variations in life expectancy. Researchers are still only in the very early stages of gaining a complete picture of human aging in terms of metabolism, genes, gene expression, and cellular mechanisms. It is enormously complex, but very little of this ongoing work has anything to do with our symbiotic bacteria - so by comparison next to nothing is known about how the intestinal microbiome fits into the big picture, and not much of a grasp on how important it might be in aging.

(As an aside: as soon as the research community can develop medical technologies like those envisaged in the Strategies for Engineered Negligible Senescence (SENS), natural aging and ways to influence it become a quaint old-time sideshow. We will be able to reverse the progression of aging, so why bother with those small details? To my mind that means we should all treat these discussions like a quaint old-time sideshow today, and focus more on how to make SENS happen faster).

But back to the plot: think about calorie restriction and the degree to which it (a) affects health and longevity, and (b) seems to hinge on levels of certain essential amino acids transported to cells. In that context, it seems likely that changes or differences in gut microbe populations - some of which are preprocessing your dietary intake - could have some influence. But again, there isn't much to go on in terms of solid data in comparison to research aimed at figuring out our own cells. You might look at these posts from the archives as a starting point:

• Investigating Intestinal Bacteria and Aging in Nematodes
• Becoming Aware of the Influence of Bacteria Upon Aging and Longevity
• Aging and Bacteria in the Body
• Intestinal Bacteria and Ageing

My attention was caught today by a post on changes in our gut microbiome over the past century - they have been very large indeed, now matter which causative mechanism you think might be the likely culprit:

Too Many Antibiotics? Bacterial Ecology That Lives On Humans Has Changed in Last 100 Years

[Researchers] analyzed microbiome data from ancient human fecal samples collected from three different archaeological sites in the Americas, each dating to over 1000 years ago. In addition, the team provided a new analysis of published data from two samples that reflect rare and extraordinary preservation: Otzi the Iceman and a soldier frozen for 93 years on a glacier.

"The results support the hypothesis that ancient human gut microbiomes are more similar to those of non-human primates and rural non-western communities than to those of people living a modern lifestyle in the United States. From these data, the team concluded that the last 100 years has been a time of major change to the human gut microbiome in cosmopolitan areas."

The past hundred years has also been a time of greatly increased life span expectancy, both at birth and adult life expectancy at any age. There are plenty of obvious candidate mechanisms to point to when explaining these gains: control of infectious disease; improved medical technology across the board; rapidly increasing wealth and all the benefits that brings to the individual.

So there is no great incentive or missing cause that might drive one to go digging around in the microbiome of the gut in search of the degree to which changes there might influence life span. But it is interesting to speculate on that topic in advance of the studies that might provide an answer one way or another - which I would expect to require a great deal of time and work, given that the effects of medicine and wealth are comparatively large. Teasing out smaller effects from population studies is a challenging task.

A review paper here looks over the biochemistry, similarities, and differences between embryonic stem cells and induced pluripotent stem cells, both of which are presently used in the development of new therapies, but the former is far more limited by regulation than the latter:

Embryonic stem cells (ESCs) are derived from the inner cell mass of the blastocysts and are characterized by the ability to renew themselves (self-renewal) and the capability to generate all the cells within the human body. In contrast, inducible pluripotent stem cells (iPSCs) are generated by transfection of four transcription factors in somatic cells. Like embryonic stem cells, they are able to self-renew and differentiate. Because of these features, both ESCs and iPSCs, are under intense clinical investigation for cell-based therapy.

Since the first isolation of human Embryonic Stem Cells (ESCs) huge interest has developed in the scientific and clinical communities and in the public in general because of their therapeutic potential. In particular, attention has focused on their potential use in cell-based therapy for diseases that are refractory to conventional treatments, such as neurodegenerative diseases and immunodeficiency, because of their ability to be programmed into new mature differentiated cells of all lineages.

Although our knowledge of the molecular mechanisms that control the self-renewal and differentiation of stem cells has grown considerably during the past decade, we still need more basic research in order to understand the molecular mechanisms that regulate proliferation, survival and differentiation of stem cells particularly after transplantation and in the pathological environment.

Link: http://impactaging.com/papers/v4/n12/full/100513.html

An open access review of the New England Centenarian Study:

The New England Centenarian Study (NECS) was founded in 1994 as a longitudinal study of centenarians to determine if centenarians could be a model of healthy human aging. Over time, the NECS along with other centenarian studies have demonstrated that the majority of centenarians markedly delay high mortality risk-associated diseases toward the ends of their lives, but many centenarians have a history of enduring more chronic age-related diseases for many years, women more so than men. However, the majority of centenarians seem to deal with these chronic diseases more effectively, not experiencing disability until well into their nineties.

Unlike most centenarians who are less than 101 years old, people who live to the most extreme ages, e.g., 107+ years, are generally living proof of the compression of morbidity hypothesis. That is, they compress morbidity and disability to the very ends of their lives. Various studies have also demonstrated a strong familial component to extreme longevity and now evidence particularly from the NECS is revealing an increasingly important genetic component to survival to older and older ages beyond 100 years. It appears to us that this genetic component consists of many genetic modifiers each with modest effects, but as a group they can have a strong influence.

Link: http://www.frontiersin.org/Genetics_of_Aging/10.3389/fgene.2012.00277/full

The year heads towards its close again, and it seems somewhat traditional for people to make charitable 501(c)3 or equivalent donations around this time. I was asked for recommendations a few times in the past month, and here they are:

1) SENS Foundation

At the head of my list is the SENS Foundation, the best organized and most central of the small number of groups working on ways to rejuvenate the old by repairing the cellular and molecular damage that causes aging. The SENS Foundation is a research organization: they put money to work in the laboratory. Given that rejuvenation of the old is the goal, the Strategies for Engineered Negligible Senescence (SENS) is far more attractive as a charitable cause when compared to most aging research. The vast majority of researchers in the field of aging and longevity aim at best to modestly slow aging, if they are even working on the basis for therapies. If we want to see significant progress towards engineered human longevity in our lifetimes, it is very important to support work that credibly aims to do more than simply slow the degenerations of aging a little.

At this point in the ebb and flow of advocacy and research programs, SENS would benefit from a more rapid flow of tangible research results, preferably attractive and easily comprehended by the public at large. Bootstrapping from modest funding to grand funding is a matter of side-by-side progress in advocacy on the one hand and results in the lab on the other - neither can really move too far ahead of the other. The best way to help progress at this time is to donate and persuade others to donate, as money creates results. The SENS Foundation is a very efficient engine for turning philanthropic funds into progress in the best sort of longevity science.

If you know enough about the work under development and which approaches you favor you might even consider calling the SENS Foundation folk to talk about more directed donations - for example, if you are intrigued by the UK-based work on breaking down glucosepane. But for most of us the reason to donate to a trusted organization staffed by smart and knowledgeable folk is because they can do a better job of directing funds to the goal of engineered longevity than we can: they know the researchers, are familiar with who is doing what in which laboratories, and all the tricks of the trade when it comes to stretching funds as far as they can go.

The SENS Foundation donation page can be a little hard to find, so here is a link. Have at it. You are not going to find a better place to put money if progress towards therapies of human rejuvenation is your goal.

2) New Organ Prize

The New Organ initiative is driven by the folk at the Methuselah Foundation, in alliance with tissue printing company Organovo and a range of other advocates. They are building a crowdsourced research prize to speed development in tissue engineering of complex organs. As you might know, the Methuselah Foundation runs the Mprize for longevity science, and was the umbrella organization for SENS research prior to the formation of the SENS Foundation.

It will likely require decades to move from present day technology demonstrations in growing small amounts of structured tissue to the ability to print functional hearts, livers, and lungs to order. There is plenty of room to accelerate that process - and research prizes have shown their worth in this and many other fields of human endeavor. The faster it goes, the more lives can be saved.

Research prizes offer a purse for specific goals in development, and tend to encourage far more activity in a field than would otherwise take place. A well run prize acts as incentive, beacon, watering hole, loudspeaker, and clearing house for research and development - enlivening the field, drawing attention and funding. If you recall the way in which the Mprize for longevity science grew back when it was the Methuselah Mouse Prize - well, the New Organ Prize something like that, but with the benefit of social networks, modern online donation management services, and a focus on tissue engineering and organ printing.

To donate and set up your own fundraising page, see the New Organ 100 instructions.

The results from this paper suggests that efforts to find any correlation between fertility and longevity in humans will be challenging, as in most data sets it will be swamped by associations with wealth, use of medical technologies to control fertility, and so forth:

The disposable soma theory proposes a trade-off between fertility and longevity but existing findings on this association have been mixed. This study used data from 15,622 twins born between 1901 and 1925 ascertained from the population-based Swedish Twin Registry to test the child-longevity association and whether it is accounted for by individual-level factors or by genetic and environmental factors shared by family members.

Based on survival analysis, both women and men with children had significantly longer survival relative to the childless, with a slightly higher relative advantage in men. Adjustments for demographic factors and cotwin fertility did not mediate the parenting-survival association, indicating that this association is attributable to individual-level factors associated with fertility rather than family-level environmental or genetic factors shared by cotwins. These results, derived from a large, population-based sample, are inconsistent with the disposable soma theory as applied to modern human populations.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23213027

Senescent cells accumulate with age, disrupting the tissues they are in, promoting inflammation, and undertaking a range of other bad behavior. Their presence is one of the causes of degenerative aging, and thus targeting them for destruction or reversal of their senescent state is a priority in longevity science:

Research has revealed that the presence of senescent cells is worse than one might think. These cells assume a special secretory form (SASP) in which they release various chemical signals that harm the health of nearby cells. In a domino effect they then damage their neighbors further accelerating the aging process.

A breakthrough study earlier this year showed that using specialized genetic methods to remove senescent cells throughout the lifespan of rats reduced signs of aging in the animals.

The current state of the science review article [is] written by two of the scientists who performed that study. In the paper they describe how senescent cells lead to aging in many tissues in the body. They further point out that aging of tissue is the reason for the development of diseases. "Therapeutic intervention in normal aging may prevent comorbidity and delay mortality in the elderly," they write. "In this way, targeting of senescent cells during the course of normal aging would be a preventative strategy rather than a treatment."

It is also pointed out that senescent stem cells may poison stem cell niches reducing the ability to regenerate and rejuvenate tissue so that removing them there could have diffuse age reducing benefit. Of course the big question is how senescent cells could be regularly removed from all over and within the human body other than embedding programmable genes before birth like was done in lab rats. The answers remain vague but the authors offer an idea, and some hope: "If a common signature is identified for senescent cells in vivo, strategies to alleviate these effects with compounds or drugs, whether by dampening the SASP profile or by completely removing the senescent cells, can begin to be elucidated."

Link: http://extremelongevity.net/2012/12/10/targeting-senescent-cells-to-reduce-human-aging/

Last month I pointed out an interesting article on regeneration in the zebrafish brain. Zebrafish, like a number of lower animals, have far greater regenerative abilities than we mammals. They can regrow fins and even large portions of some of their major organs. As is the case for salamanders, there is a research community working on understanding the mechanisms of this regeneration, with an eye to seeing whether it can be brought to humans anytime soon. One school of thought suggests that we and other mammals still possess the necessary biological machinery for regeneration of limbs and organs, but it is buried and inactive - after all, just like the fish, we grow from embryos. So there is at least one program for growing limbs and organs hidden in there somewhere.

Nonetheless, it remains to be seen whether it is in fact the case that a mammal can be made to regrow major body structures by following this path of salamanders and fish: there are reasonable arguments to be made for both yes and no, and it's still too early to say which it will turn out to be. There is no necessary reason for limb regeneration in one species to be in any way present but dormant in another, and there is no necessary reason for limb regeneration to be some form of re-running of the initial program of embryonic growth. These could all be different, distinct processes - and for that matter, there could be distinct, different processes of regrowth in different species with these strong regenerative abilities. Biology is always more complex than you'd like it to be.

Putting all this to one side, there is another interesting reason to study regeneration in zebrafish - their ability to regrow tissue and heal wounds doesn't decline all that much with age. See this open access paper, for example:

Life-long preservation of the regenerative capacity in the fin and heart in zebrafish

The zebrafish is a widely used model animal to study the regeneration of organs, such as the fin and heart. Their average lifetime is about 3 years, and recent studies have shown that zebrafish exhibit aging-related degeneration, suggesting the possibility that aging might affect regenerative potential. In order to investigate this possibility, we compared regeneration of the fin and heart after experimental amputation in young (6-12 month old) and old (26-36 month old) fish.

Comparison of recovery rate of the caudal fin, measured every two or three days from one day post amputation until 13 days post amputation, show that fins in young and old fish regenerate at a similar rate. In the heart, myocardium regeneration and cardiomyocyte proliferation occurred similarly in the two groups.

Moreover, neo-vascularization, as well as activation of fibroblast growth factor signaling, which is required for neo-vascularization, occurred similarly. The epicardial tissue is a thin layer tissue that covers the heart, and starts to express several genes immediately in response to injury. The expression of epicardial genes [in] response to heart injury was comparable in two groups. Our results demonstrate that zebrafish preserve a life-long regenerative ability of the caudal fin and heart.

More or less everything I said above about limb regrowth applies to the preservation of regenerative capacity with aging. Perhaps there is something here that can be brought to humans in the next few decades, or perhaps not and these are such different biological systems that there is little to be done with the knowledge that will be gained - it is too early to say which way that will go.

Here is one research result among the many generated by scientists investigating the biochemistry of calorie restriction, seeking after a greater understanding of how it improves health and extends life:

[Researchers] examined the role of the compound β-hydroxybutyrate (βOHB), a so-called "ketone body" that is produced during a prolonged low-calorie or ketogenic diet. While ketone bodies such as βOHB can be toxic when present at very high concentrations in people with diseases such as Type I diabetes, Dr. Verdin and colleagues found that at lower concentrations, βOHB helps protect cells from "oxidative stress" - which occurs as certain molecules build to toxic levels in the body and contributes to the aging process.

"Over the years, studies have found that restricting calories slows aging and increases longevity - however the mechanism of this effect has remained elusive. Here, we find that βOHB - the body's major source of energy during exercise or fasting - blocks a class of enzymes that would otherwise promote oxidative stress, thus protecting cells from aging."

The researchers found that calorie restriction spurs βOHB production, which blocked the activity of a class of enzymes called histone deacetylases, or HDACs. Normally HDACs keep a pair of genes, called Foxo3a and Mt2, switched off. But increased levels of βOHB block the HDACs from doing so, which by default activates the two genes. Once activated, these genes kick-start a process that helps cells resist oxidative stress.

Link: http://www.sciencedaily.com/releases/2012/12/121206142025.htm

The visible signs of skin aging are reflected by a similar loss of elasticity and function in important tissues inside the body, driven by declining function in stem cells that support these tissues, a steep growth in the number of senescent cells that hamper maintenance of tissue integrity, the accumulation of AGEs - largely glucosepane - and the other mechanisms that cause aging.

These root causes must be dealt with, but comparatively few scientists are trying to tackle them directly. The more usual research focuses on ways to try to patch over consequences by making use of other mechanisms - somewhat akin to trying to deal with a broken dam by bailing rather than fixing the holes. Here researchers manage to reverse a fraction of the effects of skin aging:

[The] extracellular matrix, or ECM, acts like the scaffold that skin cells roost in. It's made of tiny fibrils of collagen, produced by the cells (fibroblasts). Over time, as skin ages, the ECM becomes fragmented, which causes cells to lose their connections to that scaffold - and the lack of support accelerates their decline further. The same thing may happen in other types of tissue.

[Scientists] injected the skin of 21 volunteers in their 80s with a filler often used cosmetically to reduce facial wrinkles. The filler bolsters the ECM, filling in the spaces left by aging. The researchers did not receive funding from the product's manufacturer, nor did they get input on the design or results from the company. Rather, they were using the product as a way to increase the mechanical forces within the volunteers' skin. The result: over three months, the fibroblasts began expressing collagen-related genes, producing more collagen, and connecting better to the ECM. The entire layer of skin grew thicker, and more blood vessels, which nourished the cells were seen.

"Fragmentation of the extracellular matrix plays an important role in skin aging, but by altering the matrix using an external filler and increasing the internal pressure, we've shown that we can essentially trigger a signal for cells to wake up. This shows that skin cells in elderly people have the capacity to respond robustly in a very positive way to alterations in the mechanical property of their environment. We still need to know more about how cells sense their environment, but in general it appears we have made a real difference in the structural integrity of skin."

Link: http://www.sciencedaily.com/releases/2012/12/121210101351.htm

Earlier this year, bioethicist Peter Singer chaired a seminar on "The Science and Ethics of Eliminating Aging" at which Aubrey de Grey of the SENS Foundation put forward his vision for rejuvenation biotechnology: building ways to reverse the root causes of aging, fixing cellular and molecular damage so as to extend healthy life spans, prevent aging in the young, and rejuvenate the elderly.

It has to be said that I'm not in favor of bioethics as a profession - medical ethics, its predecessor, has in recent decades has lost its way and evolved into an institution that stands opposed to its original goals. Medical ethicists tried to make medicine better, aiming to obtain, on average, better outcomes from the many unpleasant and difficult circumstances that can occur in the practice of medicine. Bioethicists, on the other hand, nowadays seek to empower themselves as general naysayers, able to put barriers in place of the path of development and invention. Thus they are incentivized to slow or block the progress needed to build better medicine: they can only justify their institutional positions by finding ever more reasons not to move ahead with new technologies.

Incentives of this nature are fundamentally corrosive, leading to people and organizations that are little more than parasites, consuming resources that might have been used for productive work, while laboring to harm their own field of science. One might argue that the rise in bioethics has come about because of rampant growth in regulation of medical research and development. Bureaucrats of the FDA have their own incentives to block and slow new medical technologies, and these regulators need institutions that can be used to justify the increasing costs placed on the process of building new medicine.

All that to one side, I noticed that a short article written by Peter Singer on the topic of radical life extension seems to have resulted from the seminar I mentioned at the start of this post. But consider the incentives of the bioethicist while reading it:

Should We Live to 1,000?

Aubrey de Grey, Chief Science Officer of SENS Foundation and the world's most prominent advocate of anti-aging research, argues that it makes no sense to spend the vast majority of our medical resources on trying to combat the diseases of aging without tackling aging itself. [In] developed countries, aging is the ultimate cause of 90% of all human deaths; thus, treating aging is a form of preventive medicine for all of the diseases of old age. Moreover, even before aging leads to our death, it reduces our capacity to enjoy our own lives and to contribute positively to the lives of others.

On the other hand, we still need to pose the ethical question: Are we being selfish in seeking to extend our lives so dramatically? And, if we succeed, will the outcome be good for some but unfair to others? People in rich countries already can expect to live about 30 years longer than people in the poorest countries. If we discover how to slow aging, we might have a world in which the poor majority must face death at a time when members of the rich minority are only one-tenth of the way through their expected lifespans.

Whether we can overcome these objections depends on our degree of optimism about future technological and economic advances. De Grey's response to the first objection is that, while anti-aging treatment may be expensive initially, the price is likely to drop, as it has for so many other innovations, from computers to the drugs that prevent the development of AIDS. If the world can continue to develop economically and technologically, people will become wealthier, and, in the long run, anti-aging treatment will benefit everyone. So why not get started and make it a priority now?

De Grey has set up SENS Foundation to promote research into anti-aging. By most standards, his fundraising efforts have been successful, for the foundation now has an annual budget of around $4 million. But that is still pitifully small by the standards of medical research foundations. De Grey might be mistaken, but if there is only a small chance that he is right, the huge pay-offs make anti-aging research a better bet than areas of medical research that are currently far better funded.

That annual budget figure sounds closer to the SENS Foundation expenditures plus directly related research funded from other sources - the Foundation's budget itself is somewhat smaller than that per the last annual report. There's a long way to go yet in the fundraising stakes.

The next generation of cancer therapies will involve ways to target and destroy cancer cells with far greater precision than is possible through presently available treatments, leading to highly effective therapies with few side effects. One branch of this research and development effort involves targeting cells by characteristic differences in surface chemistry, but there are many others. This is one recent example:

In a series of experiments in mice with cancer and in cancer cells, [researchers] have shown that they can block the process by which leukemia stem cells repair themselves by targeting a particular protein, RAD52, which the cells depend on to fix genetic mistakes. The findings may lead to a new strategy to help overcome drug resistance that hinges on cancer stem cells gone awry.

In chronic myeloid leukemia (CML), an enzyme called ABL1 goes into overdrive because of a chromosomal mix-up that occurs in bone marrow stem cells that are responsible for the generation of all blood components. The genes ABL1 and BCR become fused and produce a hybrid BCR-ABL1 enzyme that is always turned on. This overactive BCR-ABL1 protein drives the excessive production of white blood cells that is the hallmark of CML.

In CML cells, the BCR-ABL1 protein shuts down the main DNA repair system and leukemia cells have to rely on a backup pathway for repair. Previous experiments in mice bone marrow cells lacking RAD52, a key protein in the backup system, showed that its absence abrogated the development of CML, proving that CML DNA repair depended on RAD52.

[Researchers] then used an "aptamer," a peptide that mimicked the area where the RAD52 protein binds to DNA, to see the effects of blocking RAD52 from binding to DNA. The investigators found that when the aptamer was added to BCR-ABL1-positive bone marrow cells, RAD52 was prevented from binding to DNA and the leukemic bone marrow cells accumulated excessive double-strand breaks and eventually died. The aptamer had no effect on normal cells.

"With this treatment in hand, we eventually hope to generate a small molecule inhibitor with which we will be able to target leukemia patients based on their oncogenic profiles. We've started to use microarrays to look at the expression profiles of the DNA repair genes in other cancers, and based on these profiles, predicted if they would be sensitive to [this] approach."

Link: http://www.eurekalert.org/pub_releases/2012-12/tuhs-tst120612.php

The positive results of a cancer immunotherapy trial are noted here:

Nine of twelve leukemia patients who received infusions of their own T cells after the cells had been genetically engineered to attack the patients' tumors responded to the [therapy]. Two of the first three patients treated with the [protocol] remain healthy and in full remissions more than two years after their treatment, with the engineered cells still circulating in their bodies. The findings reveal the first successful and sustained demonstration of the use of gene transfer therapy to turn the body's own immune cells into weapons aimed at cancerous tumors.

The protocol for the new treatment involves removing patients' cells through an apheresis process similar to blood donation, and modifying them in [a] vaccine production facility. Scientists there reprogram the patients' T cells to target tumor cells through a gene modification technique using a HIV-derived lentivirus vector. The vector encodes an antibody-like protein, called a chimeric antigen receptor (CAR), which is expressed on the surface of the T cells and designed to bind to a protein called CD19.

The modified cells are then infused back into the patient's body following lymphodepleting chemotherapy. Once the T cells start expressing the CAR, they focus all of their killing activity on cells that express CD19, which includes [tumor] cells, and normal B cells. All of the other cells in the patient that do not express CD19 are ignored by the modified T cells, which limits systemic side effects typically experienced during traditional therapies.

In addition to initiating the death of the cancer cells, a signaling molecule built into the CAR also spurs the cell to produce cytokines that trigger other T cells to multiply - building a bigger and bigger army until all the target cells in the tumor are destroyed.

Link: http://www.eurekalert.org/pub_releases/2012-12/uops-lpr120712.php

The modern age of antibiotics didn't do a great deal to combat the inexorable processes that contribute to tooth decay and gum disease, as it things turned out. One might have thought so at the outset: bacteria in the mouth are causing issues, we're developing all sorts of enormously improved methods of killing bacteria, ergo tooth decay and commonplace gum disease like gingivitis and should soon be a thing of the past. Alas not so, however - nothing is straightforward in the world of medicine. As one consideration, many of the hundreds of bacterial species in the mouth are actually beneficial.

In recent years, there has been some progress towards more sophisticated solutions. These include methods of sabotaging key mechanisms in problem bacterial species so as to leave other bacteria unharmed, or of targeting bacteria by their surface chemistry or other markers. For example:

• The End of Tooth Decay Looms Large
• The Possibility of Eliminating Tooth Decay
• Progress Towards Cavity Vaccines

I noticed another line of work in this field; here researchers are sabotaging the progression of gum inflammation caused by bacteria:

Penn-Led Research Suggests a New Strategy to Prevent or Halt Periodontal Disease

Porphyromonas gingivalis, the bacterium responsible for many cases of periodontitis, acts to "hijack" a receptor on white blood cells called C5aR. The receptor is part of the complement system, a component of the immune system that helps clear infection but can trigger damaging inflammation if improperly controlled. By hijacking C5aR, P. gingivalis subverts the complement system and handicaps immune cells, rendering them less able to clear infection from the gum tissue. As a result, numbers of P. gingivalis and other microbes rise and create severe inflammation. According to a study published [last year], mice bred to lack C5aR did not develop periodontitis.

[The] researchers synthesized and administered a molecule that blocks the activity of C5aR, to see if it could prevent periodontitis from developing. They gave this receptor "antagonist," known as C5aRA, to mice that were then infected with P. gingivalis. The C5aRA injections were able to stave off inflammation to a large extent, reducing inflammatory molecules by 80 percent compared to a control, and completely stopping bone loss. And when the mice were given the antagonist two weeks after being infected with P. gingivalis, the treatment was still effective, reducing signs of inflammation by 70 percent and inhibiting nearly 70 percent of periodontal bone loss.

I suspect that the next generation will very rarely visit dentists, as much of the need for regular dental services will be removed by products based on this and similar sorts of research.

Researchers have found a number of potential ways to spur growth of muscle tissue, and some of these might be used in attempts to fend off the loss of muscle mass and strength that occurs with aging - not by fixing the root causes, but by trying to compensate through another mechanism. Here is a recent example:

The protein is an isoform, or slight variant, of PGC-1 alpha, an important regulatory of body metabolism that is turned on by forms of exercise, such as running, that increase muscular endurance rather than size. [A rise in] PGC-1 alpha-4 with exercise increases activity of a protein called IGF1 (insulin-like growth factor 1), which facilitates muscle growth. At the same time, PGC-1 alpha-4 also represses another protein, myostatin, which normally restricts muscle growth. In effect, PGC-1 alpha-4 presses the accelerator and removes the brake to enable exercised muscles to gain mass and strength.

Several experiments demonstrated the muscle-enhancing effects of the novel protein. The investigators used virus carriers to insert PGC-1 alpha-4 into the leg muscle of mice and found that within several days their muscle fibers were 60 percent bigger compared to untreated mice. They also engineered mice to have more PGC-1 alpha-4 in their muscles than normal mice who were not exercising. Tests showed that the treated mice were 20 percent stronger and more resistant to fatigue than the controls; in addition, they were leaner than their normal counterparts.

Link: http://www.sciencedaily.com/releases/2012/12/121206121728.htm

It should be noted that, on balance, everything except physical health becomes better with age. Outside of degenerative aging, becoming older is so good that people are driven to apologism for the fact that aging cripples and kills them - they conflate being old and being aged, seeing two very different things as one, and a certain confusion arises after that point.

Consider how much better it will be to be older once we start being able to treat the root causes of the degenerative medical condition called aging. If you're not there yet, consider just how good being older must be in order for people to be able to say they are well off even while their health is crumbling:

The SAGE study included adults between the ages of 50 and 99 years, with a mean age of just over 77 years. In addition to measures which assessed rates of chronic disease and disability, the survey looked at more subjective criteria such as social engagement and participants' self-assessment of their overall health.

Participants were asked to rate the extent to which they thought they had "successfully aged," using a 10-point scale and using their own concept of the term. The study found that people with low physical functioning but high resilience, had self-ratings of successful aging similar to those of physical healthy people with low resilience. Likewise, the self-ratings of individuals with low physical functioning but no or minimal depression had scores comparable to those of physically healthy people with moderate to severe depression.

"It was clear to us that, even in the midst of physical or cognitive decline, individuals in our study reported feeling that their well-being had improved with age."

Link: http://www.eurekalert.org/pub_releases/2012-12/uoc--poa120312.php

The latest supplement from Nature contains a collection of articles on the topic of aging, largely from the mainstream research community viewpoint that centers on modestly slowing aging as a goal rather than anything more ambitious:

Humans are the longest lived primates, with life expectancy in some developed nations surpassing 80 years. Of course, that doesn't stop us wanting more time. Research into the mechanisms of ageing is yielding insights, many of them diet-related, into how we might not only live longer but also stay healthier as we do.

I'll point you to a couple of the more interesting pieces, which review some of the knowledge gained in recent years:

Comparative biology: Looking for a master switch

Comparative studies are beginning to give clues to the cellular and molecular mechanisms that enable some species to live longer than related species. Miller's team, for example, cultured skin cells from nine rodent species and exposed them to various stresses, including cadmium, hydrogen peroxide and heat. Similar experiments involved skin cells from 35 different bird species. Both studies showed that cells from long-lived animals are more resistant to stresses than those of short-lived species, says Miller.

Similar research also suggests one possible reason why birds tend to live longer than mammals of similar size, Miller adds. "Bird cells tend to be three- to ten-fold more resistant to many of these stresses than cells from rodents of the same size. We can't prove that's why birds live a long time, but it's a good guess."

Interventions: Live long and prosper

While researchers wait for statistical proof of the diet's effects in primates, some people have elected to go on the diet anyway. CRONies - the label adopted by those on a diet of Caloric Restriction with Optimal Nutrition - voluntarily eat 30% fewer calories than recommended by the US Department of Agriculture. That can be as low as 1,400 calories a day for men, and 1,120 for women.

Fontana, who studies the CRONies, says most of the health benefits seen in animals on the caloric restriction diet also appear in humans. He says that people who started caloric restriction in middle age and stayed with the regimen for eight years have a "fantastic" cardiometabolic profile. He adds that he has seen subjects in their late 70s with the blood pressure of teenagers.

Stem cells: Repeat to fade

As with so much else, stem cells in an older person are not the same as those in someone younger. They tend to be less productive and less reliable, and become slower and less predictable when it comes to replenishing cells affected by injury, illness or senescence - and the tissues they serve become less healthy and vital. In other words, stem cells are prominent in the fundamental biology of ageing. If stem cells in older people could be made to retain their effectiveness, perhaps broken bones and skin wounds could be made to heal faster and, with time, we might be able to treat the conditions of old age, such as dementia and heart disease.

Retinal implants are currently in their earliest stage of development: comparatively crude electrode arrays that provide an alternative to vision rather than restoring it. From here the path to ever more sophisticated systems seems assured, however:

A coming generation of retinal implants that fit entirely inside the eye will use nanoscale electronic components to dramatically improve vision quality for the wearer, according to two research teams developing such devices.

Current retinal prostheses, such as Second Sight's Argus II, restore only limited and fuzzy vision to individuals blinded by degenerative eye disease. Wearers can typically distinguish light from dark and make out shapes and outlines of objects, but not much more. The Argus II, the first "bionic eye" to reach commercial markets, contains an array of 60 electrodes, akin to 60 pixels, that are implanted behind the retina to stimulate the remaining healthy cells. The implant is connected to a camera, worn on the side of the head, that relays a video feed.

A similar implant, made by Bionic Vision Australia, incorporates just 24 electrodes. With so few electrodes, the amount of visual information transmitted to the brain is limited: text, for example, is difficult to read. Second Sight recently announced a method by which Argus II wearers are able to visualize Braille instead of traditional text.

Recognizing this limitation, both Second Sight and Bionic Vision Australia have announced that they are developing next-generation devices with 200-plus electrodes. But arrays of nanoscale electrodes, which are currently being incorporated into new retina devices, could someday give blind people 20/20 vision.

Link: http://www.technologyreview.com/news/508041/vision-restoring-implants-that-fit-inside-the-eye/

One of a number of methods under development to regenerate or rebuild the cornea is outlined here:

Using a combination of techniques known as microstereolithography and electrospinning, the researchers are able to make a disc of biodegradable material which can be fixed over the cornea. The disc is loaded with stem cells which then multiply, allowing the body to heal the eye naturally. "The disc has an outer ring containing pockets into which stem cells taken from the patient's healthy eye can be placed. The material across the centre of the disc is thinner than the ring, so it will biodegrade more quickly allowing the stem cells to proliferate across the surface of the eye to repair the cornea."

A key feature of the disc is that it contains niches or pockets to house and protect the stem cells, mirroring niches found around the rim of a healthy cornea. Standard treatments for corneal blindness are corneal transplants or grafting stem cells onto the eye using donor human amniotic membrane as a temporary carrier to deliver these cells to the eye. For some patients, the treatment can fail after a few years as the repaired eyes do not retain these stem cells, which are required to carry out on-going repair of the cornea. Without this constant repair, thick white scar tissue forms across the cornea causing partial or complete sight loss. The researchers have designed the small pockets they have built into the membrane to help cells to group together and act as a useful reservoir of daughter cells so that a healthy population of stem cells can be retained in the eye.

"Laboratory tests have shown that the membranes will support cell growth, so the next stage is to trial this in patients in India. One advantage of our design is that we have made the disc from materials already in use as biodegradable sutures in the eye so we know they won't cause a problem in the body. This means that, subject to the necessary safety studies and approval from Indian Regulatory Authorities, we should be able to move to early stage clinical trials fairly quickly."

Link: http://www.eurekalert.org/pub_releases/2012-12/uos-ntt120512.php

Every cell has its herd of mitochondria. They are the cell's power plants, the descendants of symbiotic bacteria that possess their own DNA and perform a range of vital functions. Unfortunately mitochondria are fragile in comparison to other cellular components and they can cause themselves lasting harm in the course of their normal operation: some forms of damage cannot be repaired by existing cellular processes, and indeed will even spread throughout a cell's herd of mitochondria, causing the entire cell to become dysfunctional. This happens more and more often as the years tick by, and such self-inflicted mitochondrial damage is one of the root causes of aging.

Methods of repair or prevention are under consideration, or their component parts under research, but they don't exist yet, more is the pity. But we know how to remove this contribution to aging - if the funding sources and research community would just step up the pace to get the job done.

So mitochondria are important. They are important, and their ability to function well critical, because they sit right in the middle of many fundamental, vital processes in metabolism. Arguably the most vital of these is managing the transformation of nutrients into chemical energy stores that can be used throughout the cell to power its activities. There is much going on under the hood when it comes to how mitochondria respond to varying nutrient levels, for example. Investigations into the biological mechanisms by which calorie restriction alters the function of metabolism, improves health, and extends life span have resulted in many lines of research that examine protein machinery in mitochondria or the regulation of mitochondrial activity.

To pull one paper at random for the sake of giving some context to that remark, consider research into sirtuins. At least a billion dollars has vanished into sirtuin research over the past decade, in search of ways to recreate at least some of the beneficial effects of calorie restriction without actually restricting dietary intake:

Mitochondrial metabolism, sirtuins, and aging

The sirtuins are a family of proteins that act predominantly as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases. In mammals seven sirtuin family members exist, including three members, Sirt3, Sirt4, and Sirt5, that localize exclusively within the mitochondria. Although originally linked to life-span regulation in simple organisms, this family of proteins appears to have various and diverse functions in higher organisms.

One particular property that is reviewed here is the regulation of mitochondrial number, turnover, and activity by various mitochondrial and nonmitochondrial sirtuins. An emerging consensus from these recent studies is that sirtuins may act as metabolic sensors, using intracellular metabolites such as NAD and short-chain carbon fragments such as acetyl coenzyme A to modulate mitochondrial function to match nutrient supply.

To expand upon this, here is an open access paper that reviews mitochondrial biology and function within the surrounding context of nutrients; even if you only skim it, scroll to the end for the diagram.

Nutrient availability links mitochondria, apoptosis, and obesity

Mitochondria are the dominant source of the cellular energy requirements through oxidative phosphorylation, but they are also central players in apoptosis. Nutrient availability may have been the main evolutionary driving force behind these opposite mitochondrial functions: production of energy to sustain life and release of apoptotic proteins to trigger cell death. Here, we explore the link between nutrients, mitochondria and apoptosis with known and potential implications for age-related decline and metabolic syndromes.

Although ad libitum feeding is standard laboratory practice, it is unlikely to reproduce animals' natural food intake, which is probably nearer to a regimen of calorie restriction (CR). In this regard, since mitochondria evolved to coordinate energy production with food availability, their optimum performance coincides with CR, whereas excess of food intake will compromise mitochondrial energetic capacity.

Thus, we might envisage a scenario where mitochondria are susceptible to apoptosis as their efficiency of energy production, which is linked to nutritional status, declines. In other words, excess food intake will impair respiratory capacity and prime mitochondria for apoptosis, increasing cellular susceptibility to additional stress.

In summary, the nutritional imbalance in western diets leads to mitochondrial dysfunction and higher susceptibility to apoptosis with dramatic consequences for metabolic syndromes such as insulin resistance and liver steatosis. It is already known that caloric restriction protects from several stresses, and it would be interesting to investigate whether cells isolated from mice on different diets show different susceptibilities to apoptotic cell death via the intrinsic pathway and whether this correlates with the mitochondrial respiratory rate. In particular, adult stem cells could be intriguing candidates for further studies, as they show a particular sensitivity to nutrient availability, and their loss contributes to aging.

Since clinical trials for comparatively simple forms of stem cell therapy seem to be today's topic, here is another example:

Cardio3 BioSciences (C3BS) announced it has received authorization from the Belgian Federal Agency for Medicines and Health Products (FAMHP) to begin its Congestive Heart failure Cardiopoietic Regenerative Therapy (CHART-1) European Phase III trial.

[The] therapy, called C3BS-CQR-1, involves taking stem cells from a patient's own bone marrow and [re-programming] those cells so that they go onto becoming heart cells. The cells, known as cardiopoietic cells, are then injected back into the patient's heart through a minimally invasive procedure using a catheter, [with] the aim of repairing damaged tissue and improving heart function and patient clinical outcomes.

The trial will recruit a minimum of 240 patients with chronic advanced symptomatic heart failure. The primary endpoint of the trial is a composite endpoint including mortality, morbidity, quality of life, Six Minute Walk Test and left ventricular structure and function at 9 months post-procedure. Studies in additional countries will commence once national regulatory approvals have been received.

Link: http://www.science20.com/news_articles/phase_iii_clinical_trial_regenerative_medicine_heart_failure-96950

Stem cell therapies based on comparatively uncomplicated transplants of cells - either grown from the patient's own tissue or from donors - are still working their way through trials in the more regulated parts of the world, and will be for years yet. For wider access to these therapies, one has to look to medical tourism and reputable clinics overseas. So far these therapies usually result in modest or better improvements over presently available treatment options. Here is an example:

Critical limb ischemia (CLI) is a vascular disease affecting lower limbs, which is going to become a demanding challenge because of the aging of the population. Despite advances in endovascular therapies, CLI is associated with high morbidity and mortality. Patients without direct revascularization options have the worst outcomes. To date, 25%-40% of CLI patients are not candidates for surgical or endovascular approaches, ultimately facing the possibility of a major amputation.

This study aimed to assess the safety and efficacy of autologous bone marrow (BM) [stem cell] transplantation performed in "no-option" patients, in terms of restoring blood perfusion by collateral flow and limb salvage. A multicenter, prospective, not-controlled phase II study for no-option CLI patients was performed. Patients were subjected to intra-arterial infusion of autologous bone marrow and followed for 12 months after the treatment.

Sixty patients were enrolled and treated with BM transplantation, showing improvement in objective and subjective measures of perfusion. Furthermore, survival analysis demonstrated improved amputation-free survival rates at 12 months after the treatment.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23197862

A couple of months back, I pointed out the first pair of posts in a series entitled "the Duty to Extend the Biological Warranty Period." The series looks at the moral imperative to work on rejuvenation biotechnology from a social justice perspective. While this is not a viewpoint I agree with in any way, it is nonetheless interesting to watch folk on that side of the fence trying to construct a self-consistent argument for support of engineered longevity research. After all, most of their fellow travelers are, in public at least, opposed to anything that might be construed as building greater privilege for the wealthy - though medical progress is no different from any form of progress in technology when it comes to how much it costs, who gets access to it, and how those line items change over time.

In any case, here's the full series. Beyond matters related to redistribution of property and the role of government in society, you'll see that there is the usual broad swathe of common ground:

• The Duty to Extend the "Biological Warranty Period" (Part 1)
• The Duty to Extend the "Biological Warranty Period" (Part 2)
• The Duty to Extend the "Biological Warranty Period" (Part 3)
• The Duty to Extend the "Biological Warranty Period" (Part 4)
• The Duty to Extend the "Biological Warranty Period" (Part 5)

For over the past decade now I have taught undergraduate and graduate students on ethical issues pertaining to life extension and aging and I am always struck by how easily and quickly intelligent people can convince themselves that it is better to accept the rate of aging selected for by the blind process of evolution through natural selection than by a rate humans consciously influence to expand the opportunities for health by reducing and delaying many of the afflictions of senescence.

The objections I have heard over the years range from a concern that reducing mortality could reduce our appreciation of life, to concerns that it would be boring to be married to the same person for longer and a concern that promoting the health of the elderly would make things worse for the employment of younger generations (a sentiment I find is more common among my undergraduate students who have anxieties about finding employment and paying off their student debts).

Most of these objections can be dispensed with when one makes the benefits of age retardation more concrete. Adding 2 or 3 decades to the human lifespan, for example by a pill that mimics the effects of caloric restriction, would mean a delay of cancer, heart disease, stroke, AD, etc. When framed in that light the concerns typically raised against life extension begin to sound less compelling, even ridiculous. Would living with a lower risk of death from cancer, stroke or heart disease decrease our appreciation of living? If so, then is that a reason to promote smoking, obesity and an inactive lifestyle? Is it desirable that we increase the job prospects of today's younger adults by ensuring their parents' generation are afflicted with stroke or heart disease a decade or two earlier? Is increasing the risk of morbidity and mortality a fair and reasonable strategy for tackling societal problems like unemployment? No, of course not. But much work must be done to persuade people to think rationally about such issues rather than be governed by their knee jerk reactions to such cases.

Most people instinctively view the world in the light of the broken window fallacy - the economic concerns noted above are a good example of that. We are hardwired to see zero-sum games where there is only open and mutually beneficial trade, and to believe destruction of value is beneficial. It takes a moment's effort to step beyond what your gut tells you (wrongly) about the way the world works, but all too few people are prepared to make that leap.

Advanced glycation end-products (AGEs) are a form of metabolic byproduct that build up with age, causing increasing damage through their effects on cellular machinery, which ultimately manifest in harmful conditions such as reduced elasticity in blood vessels and skin. Ways to safely break down the most important forms of AGE would be greatly beneficial - but research aimed at achieving that goal is unfortunately very sparse and poorly funded.

Here researchers show that some of the mechanisms of heart failure and decline in heart function correlate with the level of AGEs in the body:

Aging is accompanied by increased vascular and ventricular stiffness, diastolic dysfunction and an increased risk of heart failure. Heart failure, with either reduced or preserved ejection fraction, is associated with abnormalities of myocardial structure and microvasculature including increased fibrosis, cardiomyocyte hypertrophy and reduced microvascular density, and animal models suggest that these abnormalities precede the development of heart failure in older age.

In addition, advanced glycation end-products (AGEs) are proposed to contribute to the increased myocardial stiffening of aging by cross-linking collagen and elastin and promoting collagen accumulation, and by promoting inflammation and oxidative stress mediated by the receptor for AGEs (RAGE). Moreover, plasma AGE levels correlate with the severity and prognosis of heart failure and predict all-cause and cardiovascular disease mortality in older adults.

We investigated the hypothesis that diastolic dysfunction of aging humans is associated with altered myocardial structure and plasma AGE levels. [We found that] diastolic dysfunction of aging was independent of myocardial structure but was associated with plasma AGE levels.

Link: http://dx.doi.org/10.1371/journal.pone.0049813

Igor Artyukhov of the Institute of Biology of Aging is director of research for Russian cryonics provider KrioRus, and here is interviewed by Pravda:

Pravda: If you live forever, then you stop rushing somewhere. You can always take time because it would seem that you will always have time for everything, that you can do everything later.

Igor Artyukhov: If you know you'll die anyway, you do not rush either. And most of us, by the way, live by this principle. Few people can write a book, trying to finish it before the end of life. Most of us just live. You can not bring the meaning of life from the outside. People set all goals themselves. If life is long, they will be able to set a lot of goals and reach them. If life is short, people just die. Imagine how much Galois could do, who at age 20 proved an important mathematical theorem. Let us understand one simple thing - there is nothing good either about aging or death. This is something that we have imposed on us by nature, events, our lifestyle. We do not know any laws of nature that could make aging and death inevitable. If we can cope with aging, then we should do it. Many say that it is not like this, they say that it is contrary to the laws of nature. This is incorrect. They mention the second law of thermodynamics, which has nothing to do with aging. Moreover, it turns out that there are ageless creatures in the world. The naked mole rat revealed no signs of aging. This is a tiny animal, the size of a mouse. Maybe we will be able to make man ageless too.

Pravda: Old age - this is still weakness. Imagine how young people will suffer, when they are forced to endure endless moods.

Igor Artyukhov: Depression is one of the manifestations of senile debility, when a person wants to die soon. It happens that people commit suicide at this age. But this is a manifestation of aging, and we want to fight with it. If we can push aging away, elderly people would stay longer in sober mind, they would feel useful to society.

Pravda: How can we make old age not feeble and horrible, but joyful and fulfilling?

Igor Artyukhov: Well, you first need to make it come as late as possible. In the words of biologist Ashley Montague, "I want to die young as late as possible." From my point of view, if it were possible not to die, it would be better to do without it. If this is impossible, then we must find a way to postpone death. My mission is to extend the active period of life in perpetuity.

Link: http://english.pravda.ru/society/stories/03-12-2012/123012-aging_death-0/

I was asked this question a few weeks back: is money the only real obstacle standing between us and good odds of greatly extending the healthy human life span within the next 20-30 years? The answer I gave was this: yes, yes it is is. A hundred times yes - a shortage of money is the central and only limiting factor to progress in slowing and reversing aging.

The world as a whole does not suffer from a shortage of money, of course. (If anything, the situation quite the opposite, sadly). When I say that money is a challenge, I mean that at present only a tiny faction of the optimal - or even somewhat adequate - research funds flow into the best projects in aging and longevity science. The field of aging research is as a whole underfunded in comparison to its importance, and a great deal of that funding is consistently misallocated - at least when seen from the perspective of someone who wants to produce concrete results in terms of years gained and lives saved. Very little of it goes to longevity science.

Nonetheless, clear research plans exist to address aging, such as the Strategies for Engineered Negligible Senescence (SENS) that aims to reverse its causes. The way ahead is known in great detail, the root causes of aging at the cellular and molecular level are so well specified at this point that proof or disproof by example lies within a handful of years, were suitable research programs funded. By that I mean go ahead and reverse or repair a root cause of aging in mice, then see what happens. That, however, takes money. Perhaps a billion dollars of it and ten years if a crash program was put together.

There are of course any number of other challenges I could point to - goals and line items that lie between the present and a possible future in which we will all live far longer in good health. For example, take the need to grow a longevity research community to rival the cancer research institution in energy and fundraising prowess. Or the need for SENS and related work on rejuvenation to win dominance over slowing aging by metabolic manipulation as the approach most favored by biogerontologists. Or the need to attract high net worth philanthropic donors and conservative funding institutions to the field. Or the need to make the public more aware of what progress could be achieved, and more demanding of that progress. I could go on. Yet these all boil down to money: sufficient funding will solve all of these challenges, as they will be flattened beneath a weight of money.

Consider this: if a few hundred million dollars fell upon the SENS Foundation today, and was spent aggressively, in five years the Foundation could be the leading US center for aging research. (For comparison, note that the Buck Institute draws an annual budget of a little less than $40 million, and the NIH itself budgets around $2.5 billion dollars a year, mostly spent on matters that have little to no impact on extending human life). That much money attracts more funding, opens doors, draws researchers, provides a megaphone for public speaking, and shifts the balance of interest and strategy in the way research is conducted in the field.

The bottom line: a section of the research community knows how to go about creating a good shot at reversing aging within a few decades. Only a trickle of money is flowing in their direction, and it is that level of funding that limits their progress. So the bootstrapping approach continues: get a little money, do the work, show positive results, leverage those results to gain more interest and more funding, repeat. This is a slow business, however, and will remain so until greater funding and interest in longevity science is achieved.

So money matters, is the limiting factor to progress, and will continue to be so until it is not.

Since we're talking about money, I should note that the year is coming to a close. This is traditionally a time to make charitable donations. If you want to have an impact on the future, then consider donating to help fund the active development of rejuvenation biotechnology or advocacy for longevity science. See the Take Action! page here at Fight Aging! for suggested charitable causes, such as the SENS Foundation, Methuselah Foundation, or New Organ initiative.

Researcher have been examining the role of NF-κB in accelerated aging conditions such as Hutchinson-Gilford Progeria Syndrome, and believe that the findings may also be relevant as a basis for therapies to slow the ordinary progression of degenerative aging:

NF-κB transcription factors respond to a large variety of external and internal stress signals, having essential roles in development and tissue https://en.wikipedia.org/wiki/Homeostasis>homeostasis maintenance. The in vivo monitoring of NF-κB activity by using a reporter-based assay revealed that this pathway was constitutively hyperactivated in progeroid mice. Further experiments allowed us to unveil the molecular pathway involved in this aberrant activation.

[Our] results indicate that these findings can be extended to normal aging, suggesting that a common accumulation of genetic damage and nuclear envelope alterations with age could be responsible, at least in part, of the abnormal NF-κB activity reported in tissues from advanced aged donors. The accumulation of senescent cells together with the decline in adult stem cell function is a primary cause of the compromise of tissue homeostasis during aging. The primary function of NF-κB activation in this context could be related to the prevention of apoptosis of damaged cells, so that chronic activation of this pathway with the subsequent immunological decline could preclude a proper clearance of senescent and damaged cells.

[Experimental data] confirm that NF-κB signaling is active during normal aging, its hyperactivation is associated with the development of accelerated aging and its amelioration retards the aging process. These characteristics support the use of strategies aimed at controlling NF-κB related inflammation as putative rejuvenation strategies during both normal and pathological aging.

Link: http://impactaging.com/papers/v4/n11/full/100502.html

Since online databases on aging research have been a recent topic, here is an open access paper that discusses a set of such databases:

The Human Ageing Genomic Resources (HAGR) is a freely available online collection of research databases and tools for the biology and genetics of ageing. HAGR features now several databases with high-quality manually curated data: (i) GenAge, a database of genes associated with ageing in humans and model organisms; (ii) AnAge, an extensive collection of longevity records and complementary traits for more than 4000 vertebrate species; and (iii) GenDR, a newly incorporated database, containing both gene mutations that interfere with dietary restriction-mediated lifespan extension and consistent gene expression changes induced by dietary restriction.

Since its creation about 10 years ago, major efforts have been undertaken to maintain the quality of data in HAGR, while further continuing to develop, improve and extend it. This article briefly describes the content of HAGR and details the major updates since its previous publications, in terms of both structure and content. ... Altogether, we hope that through its improvements, the current version of HAGR will continue to provide users with the most comprehensive and accessible resources available today in the field of biogerontology.

Link: http://dx.doi.org/10.1093/nar/gks1155