Fight Aging!

We humans are stuck with bodies that are far from the ideal of regenerative prowess: we are very frail in comparison to a great many other species. We don't regrow limbs or organs to any meaningful degree, we scar, lose functions, and die to a range of injuries that are easy enough to fall into. Break that poorly protected sack of innards and you won't be around for long enough to greatly regret it. So all told, evolutionary success is something of a low bar when it comes to resilience to wear, tear, and aging - and as a recent popular science article reminds us.

"The trouble is that humans and other mammals do not have a very good means of responding to loss of heart muscle. They cannot repair the heart as other creatures, such as zebrafish, can. There is no intrinsic mechanism to get cells to migrate into the heart to replace those that have been killed off by a heart attack."

Fortunately, we will soon be able to work around or remove human limitations of this nature through the application of biotechnology. Evolutionary pressure has done little for our robustness, but technology can do much more in the decades to come:

Unlike the approach taken by the team led by Paul Riley, which is concentrating on trying to simulate a patient's own stem cell population, Emanueli is working on techniques to deliver stem cells derived from other sources. The ultimate aim is to find a way to create sets of cells that can be put inside heart attack patients in order to stimulate the growth of new blood vessels. These cells are known as vascular endothelial cells and vascular smooth muscle cells and both play a crucial role in the construction of blood vessels that are destroyed in the heart in the wake of a myocardial infarction.

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By contrast, Dr Anastasis Stephanou, at University College Hospital, London, is using a grant from the BHF to work - with his colleague Suwan Jayasinghe - on a technique aimed at "patching-up" a damaged heart. Their work exploits a form of spray technology that allows them to impregnate sheets of protein with biological material including aerosol suspensions of cells. The protein acts like a skeleton in which the cells can settle.

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Several research groups round the world have recently reported success in using stem cell technology first to isolate fibroblast cells found in the skin and then to transform these into cardiac cells using various chemical interventions. "We envisage a person going into a hospital and being diagnosed with a serious heart problem. Once a diagnosis is made, a section of his or her skin would be removed and its fibroblast cells would be isolated. These cells would then be treated with chemicals and transformed into cardiac cells which can be used to create one of our sheets. This in turn would be taken by a surgeon and inserted into the damaged part of the patient's heart in the expectation that cardiac cells will be taken up and the heart's function restored."

These are small steps, but there are many different similar lines of work for the heart, and again more groups working on regeneration of other organs. Ultimately, this will all lead in to ways to address the damage of aging at earlier stages than a heart attack - incrementally restoring and maintaining the heart such that it never comes to that point of catastrophic failure, and doing the same for other organs and biological systems in the body.

An article on the work of Aubrey de Grey and the SENS Foundation: "In the simplest of terms, SENS is about combating ageing, which according to de Grey is in essence, damage on the molecular and cellular levels caused by the metabolism. The SENS model breaks aging down to 7 major classes of damage; cancer-causing nuclear mutations, Mitochondrial mutations, intracellular junk, extracellular junk, cell loss and atrophy, cell senescence and extracellular crosslinks. ... In the SENS Foundation research center we currently focus on two major projects. Two of our senior postdoctoral fellows are working on a project to make mitochondrial mutations harmless, by putting modified copies of the mitochondrion's DNA into the cell nucleus. Mitochondrial mutations are one of the seven key types of damage that are described in SENS, and this is the most complete way to address it. ... The second project which is currently pursued by another senior postdoc in de Grey's staff deals with the accumulation of molecular 'garbage' which de Grey says our bodies are not built to dispose of. ... back in 2006, de Grey outlined the SENS research being conducted and was received with positive reviews from the attendees. Back then, de Grey predicted that with this research, if enough funding and attention was drawn to it, could see direct benefits being applied to people alive today. He believes the first human to reach the age of 300, if given the treatment before ageing does too much damage, may have already been born. The first human to live to a thousand would only be a decade younger. Unfortunately, the economic crisis plaguing a large portion of the globe means funding for research becomes tighter and tighter. De Grey remains optimistic however, as he believes that 'the financial crisis has probably slowed things down a little, but not massively.' ... I think 20 years is optimistic, but I still think we have a 50 percent chance of getting there within 25 years. However, that all assumes that we make rapid progress in persuading the public, especially wealthy people, that this is a really important mission. Our research is indeed going really well. It's still at an early stage, that's for sure, but we're making progress all the time. Also, I should mention that we're focusing on the very hardest parts of SENS; there are easier parts, already being pursued by others, and those are going extremely well too."

Link: http://bikyamasr.com/46685/scientists-combat-aging-report-measurable-progress/

Another step on the way to regenerative medicine that can repair and rebuild specific tissues: "Stem cell therapies hold enormous potential to address some of the most tragic illnesses, diseases, and tissue defects world-wide. However, the inability to target cells to tissues of interest poses a significant barrier to effective cell therapy. To address this hurdle, [researchers] have developed a platform approach to chemically incorporate homing receptors onto the surface of cells. This simple approach has the potential to improve the efficacy of many types of cell therapies by increasing the concentrations of cells at target locations in the body. ... While conventional cell therapies that include local administration of cells can be useful, they are typically more invasive with limited potential for multiple doses. ... You can imagine, that when the targeted tissue is cardiac muscle, for example to treat heart attacks or heart failure, injecting the cells directly into the heart can be an invasive procedure and typically this approach can only be performed once. ... Using the platform the researchers created, the cells are prepared to travel directly to the area of interest after being injected through a common and much less invasive intravenous infusion method. ... the approach can be used to systemically target bone producing cells to the bone marrow to treat osteoporosis, cardiomyocytes to the heart to treat ischemic tissue, neural stem cells to the brain to treat Parkinson's disease, or endothelial progenitor cells to sites of peripheral vascular disease to promote formation of new blood vessels. The researchers concluded that, as the understanding of the mechanisms of cell trafficking grows, the ability to improve homing to specific tissues through engineered approaches should significantly enhance cell therapy."

Link: http://www.eurekalert.org/pub_releases/2011-10/bawh-pct102711.php

Here's a question for you: why does the triumvirate of astrophysics, astronomy, and cosmology get such good press and widespread public approval in comparison to, say, the fundamental life sciences? I have to think it has something to do with the succession of scientists who evolved into successful media figures, educators, and advocates for their field, such as Carl Sagan, the present day Neil deGrass Tyson, or Patrick Moore - and I'm probably dating myself here by knowing of the existence of the latter. If asked to name noted scientists who went on to become media figures, off the cuff, I think I'd be hard pressed to quickly come up with more than one or two who didn't come from an astrophysical or similar background (right now my brain is delivering Attenborough, Dawkins, and blank). So clearly there's been a lot of groundwork accomplished over the past decades: bringing the broad field of physics and cosmology to the masses, and along the way gaining public support for the ongoing and often thankless work of understanding the universe and its myriad components.

A cynic might think that that having a massive government agency like NASA floating around for a good number of decades and spending lavishly on flashy programs intended in part to assure its own popularity might have something to do with it. I'd be that cynic, but it seems to me that most of the comparatively less popular and less beloved fields of scientific research are also ridden by large government agencies in the US - big budgets and just as much need for popular support. So I do think that there's something interesting going on here in that small sliver of the media spectrum that scientists have colonized. Something we can learn from.

To be a media figure of this sort is a career path option that's certainly open to researchers who garner either sufficient fame or media experience across the years, but for best effect it requires you to remove yourself from the business of science. The scientific community tends to behave like an aggravated immune system when confronted with someone who is both a media figure and actively publishing scientific research. Throughout history a great many people have subverted the scientific method for personal gain, using influence, fame, money, and other forms of corruption - and the modern media is all that rolled up into one neat package. Taking your work to the press before taking it to your peers is thus a grand heresy in modern science, one which leads to harsh judgement and excommunication. Consider what happened to the reputations of Pons and Fleischmann, for example. From that, all things associated with the mass media come to be eyed with suspicion by the rank and file scientists: publicizing a field is very welcome, but even the slightest hint of use of position to influence matters of publication is going to stir up wrathful mutterings at the very least.

So the scientist turned media figure must feel strongly enough about his field to want to be an advocate and educator, but must also essentially give up his work in favor of talking about what he used to do. Not, I think, the easiest of paths for someone who truly enjoys the scientific life.

Regardless, the future of longevity science - or the foundations of rejuvenation biotechnology, or SENS-like research, or whatever you want to call it - must come to include scientist-educators in the media. A Carl Sagan for this presently minor field must eventually arise: to my mind that will be one of the signs of growth and progress, meaning that it will happen as a matter of course along with (a) the expansion of the community of researchers actively working on ways to repair the damage of aging, and (b) increasing public awareness. But sooner is always better than later.

The opening up of information, communication, and organization brought by the internet is changing business as normal in every field, making it far easier for ideas on the edge to gain support and activity. This is important for the development of rejuvenation biotechnology, as the changing nature of scientific work can speed the move to the mainstream, and allow for far more useful progress to be achieved while the flow of funding is still comparatively small: "our entire model of education and what it means to be a 'trained professional' is shifting. There's a hell of a lot of resistance from the status quo - which makes it difficult and inconvenient for rapid progress - but it isn't enough to stop it from happening. ... When the university system and the current PhD paradigm was invented, it was a different time. ... If you wanted to study advanced topics, or apprentice under someone famous to learn from their expertise, you needed to go to a university. But things are different now. Technology allows us access to some of the leading minds of our age [making] proximity to a university campus nearly irrelevant in order to meet other students and benefit from valuable peer-to-peer discussions. With the world's information available on the web, and with all of these advances in technology allowing for rapid data sharing and collaboration, how much value is there in the Ivory Tower? We are becoming a society of autodidacts, with information at our fingertips 24/7. Citizen Science is a natural consequence of that. Have an interesting scientific inquiry? Get on the web and investigate it. Learn from the millions of sources out there. Crowdsource some ideas, generate some hypotheses. Have discussions with others. Make a plan. Get your equipment. The scientific method is in-progress. Science is free for all to explore. Why waste time jumping through bureaucratic hoops when you can begin investigating what you want, when you want? Need to fund your research? Crowdsourced methods of funding, such as Kickstarter, are becoming more popular for these types of endeavors. Instead of 100 scientists chasing the same grant, why not go to the public and let them fund what they think is valuable? I think we'll be seeing a lot more of this in the future."

Link: http://ieet.org/index.php/IEET/more/4935

Another review of Sonia Arrison's 100+: "I have to congratulate Sonia Arrison on putting together a book that is both highly accessible to newbies with no prior background in transhumanist thinking or longevity research, and also richly interesting to those of us who have playing in these regions of conceptual space for a long time. The main concepts in the book are indeed things I've been familiar with for a long time: (a) There is a host of rapidly accelerating technologies with the apparent capability of dramatically extending human healthspan, (b) Most likely, human psychology and society will adapt to dramatically increased human healthspan as it occurs, so that it will be experienced primarily as a Good Thing rather than as something traumatic or troublesome However, the book is packed with a sufficient number of interesting informational tidbits, that I found it well worth reading in spite of my general familiarity with the biology, psychology and sociology of radical longevity. ... Arrison reviews the key technological streams leading us toward radically increased healthspan - including gene therapy, stem cell therapy, Aubrey de Grey's SENS concept, artificial organs, tissue regeneration, the potential application of advanced AI to longevity research, and so forth. Both current research and envisioned future advances are considered. Then, in what is probably the greatest strength of the book, she considers the potential psychological and social impact of progressively increasing healthspan: the effects, as the book's subtitle indicates, on personal life, family relationships, marriage, careers and the economy etc. Combining common sense with appropriate invocations of rigorous research and statistics, Arrison provides the most systematic refutations I've seen of the standard anti-longevity arguments - 'death gives life meaning', 'overpopulation will starve or bankrupt us all', and so forth. Step by step, and in an invariably good-natured and friendly way, she demolishes these arguments, making a solid case that increased healthspan is likely improve rather than degrade our emotional health and family lives and enhance our careers and economies."

Link: http://hplusmagazine.com/2011/10/26/sonia-arrisons-100-plus-book-review/

The cancer stem cell hypothesis suggests that a majority of cancers are driven and supported by a small population of errant stem cells, and that these cells are characteristic in ways allowing them to be identified and destroyed. Without the cancer stem cells, a cancer would whither. In other words, cancer stem cells offer the hope that there are in fact broad commonalities in the mechanisms of different forms of cancer, and that this fact will lead to a unified, single technology platform and robust cures for even late-stage cancers.

The existence and universality of cancer stem cells is a hotly debated topic in medical research, and rightly so for the reasons given above. Good evidence and arguments can be found on either side. Is cancer something that can be solved through a single mechanism or group of very similar mechanisms? Or only some cancers? Or only few cancers? These are important questions, and the answers, when they arrive, will tell us whether the prospects are for many cures arriving soon or for a slow and incremental flow of therapies over decades.

Today I noticed a good introductory popular science article that walks through the present state of research and scientific thought on this topic, and provides copious references along the way. You might find it interesting:

Take some cells from a tough-to-treat tumor, sort them, and inject each fraction into a different immunodeficient mouse, and only a small percentage of those cells will thrive and form tumors. This sort of experiment illustrates a concept that has been gaining traction within the cancer research community. Tumors contain a diverse mixture of cells, and only a handful of them can bounce back after treatment. That deadly minority can reproduce indefinitely and differentiate into a wide variety of cell types, just like stem cells. And often they express many of the same genes that are active in induced or embryonic stem cells and inactive in mature tissue.

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The logic of pursuing therapies that might zero in on cancer stem cells is compelling to many. But the methods to evaluate such therapies' effectiveness, or to personalize cancer treatments according to stem cell markers, are not nearly as well developed. Without an array of proper markers, it's hard to tell whether drugs that target cancer stem cells are working as intended. ... Things are looking up for genetic analysis, but the poor reliability of cancer stem-cell-surface markers remains a confounding problem. For nearly a decade, biologists have known that antigens such as CD133 can be found on the surfaces of cancer stem cells. But these markers are not particularly specific.

...

But for solid tumors, which account for about 85% of all cancer diagnoses, the search for such stem-cell-surface markers is still in the early days. In such [cancers] cell-surface markers can vary from one type of cancer to another or even from one cell within a tumor to another. Until better markers are discovered [the] cancer stem cell field will remain somewhat embryonic.

A number of different research teams have recently demonstrated epigenetic markers that can be used to establish chronological age or predict life expectancy to various degrees. Here is another: "Aging has been associated with accumulation of cellular defects such as DNA damage and telomere shortening. On the other hand, there is accumulating evidence that aging rather resembles a developmentally regulated process which is tightly controlled by specific epigenetic modifications. ... All tissues of the organism are affected by aging. This process is associated with epigenetic modifications such as methylation changes at specific cytosine residues in the DNA (CpG sites). Here, we have identified an Epigenetic-Aging-Signature which is applicable for many tissues to predict donor age. ... This Epigenetic-Aging-Signature was tested on a validation group of eight independent datasets corresponding to several cell types from different tissues. ... The average absolute difference between predicted and real chronological age was about 11 years. ... It has to be noted, that chronological age is not identical with biological age and it is conceivable that some of the discrepancy between predicted and real age can be attributed to this difference - further research might facilitate determination of the biological age for personalized medicine."

Link: http://impactaging.com/papers/v3/n10/full/100395.html

There are a number of different lines of research focused on developing artificial blood or culturing blood to order from stem cells: "Clinical trials using blood created from adult stem cells are set to begin within the next two or three years, raising the prospect it could soon become routinely used where real blood is unavailable. Scientists are also developing alternative bloodlike substances which could be injected into the body as a 'stopgap' until an actual blood transfusion could be performed. ... modern doctors have minimised the risk of patients receiving infections such as Hepatitis A and C during transmission [but] blood produced from stem cells would avoid these risks and could be manufactured as type 'O-negative', which is produced by just 7 per cent of the population but is suitable for use in into up to 98 per cent of patients. ... It could also be used in certain hospital situations, for example in elective surgery, and save hundreds of thousands of lives in parts of the world where blood banks are not available. [Researchers have] developed a method of taking adult stem cells from bone marrow and growing them in the laboratory to produce cells which look and act almost identically to red blood cells. Once their technique is fine-tuned the team may consider using stem cells taken from embryos, or reprogrammed skin cells, instead of adult cells because although the end product does not mimic red blood as closely, they can be grown in much greater quantities in the lab. ... A more radical solution, which [researchers] say could be perfected within five to 10 years, is to develop a completely artificial alternative to blood which performs the same key functions and would be safe to use in patients of every blood type. This could involve packing haemoglobin - which carries oxygen around the body - into a synthetic cell-like structure, or using a chemical to hold the haemoglobin together so that it can be injected without the need for red blood cells."

Link: http://www.telegraph.co.uk/science/science-news/8850684/Artificial-blood-could-be-used-within-next-decade.html

SENS Foundation co-founder Aubrey de Grey recently presented at a meeting of the MIT Club of Northern California, and a two-part video record of the event was uploaded for those of us too distant in time and space to be there:

Join us for a fascinating discussion with Dr. Aubrey de Grey, Chief Science officer of the SENS Foundation (SENS stands for "Strategies for Engineered Negligible Senscence"), on the topic of "Regenerative Medicine Against Aging."

Dr. de Grey has been a provocative and polarizing figure in the scientific and medical communities' dialogue on the topic of life extension, and the approaches that will
lead to dramatic increases in quantity and quality of life.

According to Dr. de Grey, "the first human who will live up to 1,000 years is probably already alive now, and might even be today between 50 and 60 years old."

You might look back into the archives for an explanation of the 1,000 year life span: this is an estimated life expectancy for someone who does not age to death, thanks to a rolling series of advances in rejuvenation medicine that eventually add more than a year of additional life with each passing year of research and development. If you examine mortality rates due to other causes projected out over time, you see that an effectively ageless person will live for at least a millennium under the mortality rates of today, not considering any future reductions in the rate of death by accident thanks to advances across the board in technology.

The SENS Foundation has published a series of posts over the past year or so that follow progress in the development of immunotherapies to remove the age-related buildup of amyloid in the brain - much of it intended as treatments for Alzheimer's disease. Success here will, however, lead to a broader technology platform that might ultimately be turned against any damaging aggregate that builds up in the body with age. These aggregates contribute to aging itself, and so removing them is one necessary part of any comprehensive rejuvenation biotechnology package: "soluble and insoluble aggregates of beta-amyloid protein (Aß) and other malformed proteins accumulate in brain aging and neurodegenerative disease, leading progressively to neuronal dysfunction and/or loss. These have long been widely accepted to be drivers of Alzheimer's disease (AD) and other age-related dementias and neurological disorders such as Parkinson's disease, and it has recently become increasingly clear that neuronal protein aggregates are the main driver of 'normal' cognitive aging. To prevent and reverse the course of neurodegenerative disease and age-related cognitive dysfunction, the regenerative engineering solution is therapeutic clearance of extracellular aggregates (such as Aß plaques) and intracellular aggregates (such as soluble, oligomeric Aß). Immunotherapeutic Aß clearance from the brain is a very active field of Alzheimer's research, with at least seven passive, and several second-generation active, Aß vaccines currently in human clinical trials. ... . We now have a published report of preliminary findings from the first Phase I trial in an Aß-targeting vaccine with novel properties, and with the benefit of preliminary findings of outcomes that have only emerged with the experience of its forerunners in previous clinical trials."

Link: http://sens.org/node/2437

Via ScienceDaily: "Exceptional cognitive and physical function in old age leaves a tell-tale immunologic fingerprint, say researchers ... Likewise, older adults who have mild impairments bear a distinct immunologic pattern, too. ... Our study indicates that getting older does not necessarily mean that the immune system gets weaker, as many of us assumed. The immune system is dynamic, and the changes it undergoes over time very much influence function. ... For the project, the team collected blood samples from 140 participants who had been followed in the Cardiovascular Health Study (CHS) for nearly two decades and were 78 to 94 years old. With only two participants younger than 82, the average age of the group was 86. The team also gathered information about the participants' health and function, medical history and hospitalizations, and self-rated health, and assessed their cognitive and physical function using standard tests. Previous research has shown that with age, immune cells called T-cells become more like natural killer (NK) cells, which typically target tumor cells and virus-infected cells ... A closer look in the new study shows that participants who were most physically and cognitively resilient had a dominant pattern of stimulatory NK receptors on the T-cell surface, and that these unusual T-cells can be activated directly through these NK receptors independently of the conventional ones. The functionally resilient elders also have a distinct profile of blood proteins called cytokines that reflect an immune-enhancing environment. ... Conversely, the group that showed mild health impairment had a dominant pattern of inhibitory NK receptors on their T-cells, and they have a cytokine profile indicating a pro-inflammatory environment. Both of these immunologic features could suggest a greater susceptibility to illness."

Link: http://www.sciencedaily.com/releases/2011/10/111021125808.htm

The present work on tissue engineering of large structures, such as printing blood vessels and organs, or creating patient-specific organs for transplant using decellularization, will produce end results that rely on surgery - major surgical procedures in the case of organ transplants.

The trouble with surgery is that it is risky: major, involved surgeries bear a non-trivial risk of death even in the most advanced clinical surroundings, and that risk grows with age. Old people suffer a general frailty due to the damage of aging that makes it progressively less likely for them to survive any given surgical procedure. When you consider that every major organ is going to have issues if we live long enough without access to general biological repair technologies that remove the cellular and molecular damage that lies at the root of tissue dysfunction in aging, that's a bunch of major surgeries to look forward to.

So I believe we should look on the forthcoming phase of tissue engineering as a transitional period: organs will be built from scratch and transplanted until such time as the state of the art allows our existing organs to be incrementally repaired and rebuilt in situ instead. Eliminating the need for surgery is a big deal, and so in the long term I think that the future belongs to the branch of regenerative medicine that delivers populations of tailored stem cells into damaged tissue. As the research community becomes every better at precisely controlling the behavior and activities of cells, even that step of delivering new cells into the body may go away, to be replaced with adaptive drug-like therapies that issue commands to the body's existing cells through signaling pathways or induced epigenetic alterations, and which react to guide the ongoing state of repair.

Either way, surgery is not a desirable outcome - it's a least worst path at the best of times. In the future of medicine and aging, everything that can be achieved without surgery should be achieved without surgery, and we'll all be better off for it.

Work on sirtuins as longevity genes hasn't exactly shown promise, but there are still interesting things to be learned from the work taking place, as this open access paper shows: "One fundamental observation in cancer etiology is that the rate of malignancies in any mammalian population increases exponentially as a function of age, suggesting a mechanistic link between the cellular processes governing longevity and carcinogenesis. In addition, it is well established that aberrations in mitochondrial metabolism, as measured by increased reactive oxygen species (ROS), are observed in both aging and cancer. In this regard, genes that impact upon longevity have recently been characterized in S. cerevisiae and C. elegans, and the human homologs include the Sirtuin family of protein deacetylases. Interestingly, three of the seven sirtuin proteins are localized into the mitochondria suggesting a connection between the mitochondrial sirtuins, the free radical theory of aging, and carcinogenesis. Based on these results it has been hypothesized that Sirt3 functions as a mitochondrial fidelity protein whose function governs both aging and carcinogenesis by modulating ROS metabolism. Sirt3 has also now been identified as a genomically expressed, mitochondrial localized tumor suppressor."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189778/

The degree to which progressive mutation of nuclear DNA causes aging is debated, but here is some work on the mechanisms: "Genetic damage through mutations and genome rearrangements has been hypothesized to contribute to aging. The specific mechanisms responsible for age-induced increases in mutation and chromosome rearrangement frequencies and a potential causative role for DNA damage in aging are under active investigation. Retrotransposons are mobile genetic elements that cause insertion mutations and contribute to genome rearrangements through nonallelic recombination events in humans and other organisms. We have investigated the role of endogenous Ty1 retrotransposons in aging-associated increases in genome instability using the Saccharomyces cerevisiae chronological aging model. We show that age-induced increases in loss of heterozygosity and chromosome loss events are consistently diminished by mutations or treatments that reduce Ty1 retrotransposition. Ty1 mobility is elevated in very old yeast populations, and new retromobility events are often associated with chromosome rearrangements. These results reveal a correlation between retrotransposition and genome instability during yeast aging. Retrotransposition may contribute to genetic damage during aging in diverse organisms and provides a useful tool for studying whether genetic damage is a causative factor for aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22021441

Folk from the Russian side of the longevity advocacy and transhumanist communities have initiated a range of interesting ventures and perspectives in the past few years. Take KrioRus, for example, or the work of the Science for Life Extension Foundation. Following in the same vein, I see that at the recent Singularity Summit the founder of an interesting new initiative called Russia 2045 presented his view on the best path for longevity science, mixed in with a heady brew of can-do Russian sci-tech nationalism - an attitude that might instill a certain nostalgia for the recent past of American technological exceptionalism in the older readers here.

We believe that it is possible and necessary to eliminate aging and even death, and to overcome the fundamental limits of the physical and mental capabilities currently set by the restrictions of the physical body. ... We believe that this country still possesses the necessary scientific and technical potential that will allow us to embody such a lofty objective. Such a project will turn Russia into the world's ideological leader and will revive the leadership status of our country in many different scientific and technical areas.

Willingness to get up and try is the first necessary step on any path, and a great deal of the work at present in advocacy for rejuvenation biotechnology lies in drumming up the will to try to extend human life at all. All too few people think about it or even much care, sad to say. If Russian scientific pride - something that I think isn't all that unreasonable, given the achievements made by that community under the circumstances forced on them by history - makes a difference, then I'm all for it.

To my eyes, the most interesting aspect of this Russia 2045 initiative is that, unlike any other serious proposal I'm aware of, their focus is on getting out of biology and into machine bodies as rapidly as possible. Bear in mind that in the long term every plan for radical life extension ends up with we humans changing out our biological parts for machinery - but that is generally proposed to happen somewhere past the point at which nanotechnology supersedes biology in terms of effectiveness, when there is increasingly little difference between biological and nanoscale machine systems. Both operate on the scale of single molecules, but the artificial system will be much better at it than the natural system - because it will be designed rather than evolved. We will replace our biology with machinery because the machinery will ultimately get the job done much more effectively.

Until that time arrives, however, much of the longevity science movement focuses on biotechnology, medicine, and the development of other ways to keep the biology we have repaired and in good shape. Not so for Russia 2045, however. The early parts of their plan look much like this:

• Develop an electromechanical body-shaped chassis.
• Develop a robust, lightweight life support system for the brain.
• Decant the brain into the life support system, and place the system in the body-chassis.
• Focus on biotechnologies to sustain the aging brain.
• Develop ways to replace the brain as the substrate of the mind, such as by uploading or slowly replacing brain cells with nanomachine brain cell emulators.
• Lastly, incrementally improve the body-chassis to better serve its role as a mind carrier.

In essence, this is a course to throw away as much of the body as possible as soon as possible - a path based on a different set of preconceptions about difficulty and efficiency on the road leading to an artificial brain hosting a once-biological human mind. If aiming for life spans of thousands of years, this is the exactly same place we'll get to in the end even if we start out by maintaining our biological bodies and brains for as long as possible through rejuvenation biotechnologies. I'll point you to an article entitled The Million Year Life Span or back into the archives for a piece on whole brain emulation if you're interested in thinking about the stage of replacing the biological brain with a machine brain - I won't talk about that today. It's certainly a long way off in comparison to a range of more important first steps on the road to greatly extending healthy human life.

Instead, let's consider how the next twenty years of "robot body as fast as possible" might unfold, and what advantages and disadvantages that might incur in comparison to a strategy that focused instead on rejuvenation biotechnology and keeping our fleshy bodies. I would hope that we can all agree that efficient humanoid artificial bodies will be realized in this time frame: between the robotics and the powered exoskeleton industry (both for military use and as a replacement for wheelchairs for the disabled), a lot of people are already working on this. The real challenges here are:

• A reasonably complete, safe, and reliable neural-computer interface
• A robust and safe life support system for a disembodied brain

I don't think that either of these can be seen as much off the starting blocks at this point - it's still the case that every small advance in working with neural interfaces is widely touted, and in the grand scheme of things those advances are not all that impressive. Researchers remain a long way away from being able to provide good images to the brain, or correctly identifying general intent and language use from brain activity. Without progress in a general neural interface to allow communication and action, I can't see much impetus in the scientific community for building a brain life support system - the ethics groups would shut that down pretty quickly.

Thus my wild stab in the dark guesstimate is that the research community is at this time better placed to realize SENS than it is to build a full neural interface. Other folk may know better than I on that front. Either way, this isn't a critique of plausibility regarding the technology; building these systems is a very plausible long-term goal. There's no strong objection from physics or physiology, but both are very hard tasks. In taking this path, research and development groups would be substituting the difficulties of much of rejuvenation biotechnology with the difficulties of electromechanical systems and brain-machine interfaces.

The first objection that came to mind after looking over the Russia 2045 vision is much the same as my objection to WILT: in ideal circumstances, it will lead to extended life, but only for so long as you have access to a technology base capable of maintaining your (bio)technologies. If you fall off the wagon and out into the wilderness for a few decades, then you will probably die, or at least suffer a greatly raised risk of death and serious systems failure. There are certain advantages to an approach to longevity based as much as possible on repairing the biology we have: we know that what we have is fairly robust.

In any case I encourage you to look over the Russia 2045 website. Progress towards any given goal depends on a healthy competition between different practical methodologies, and the "straight to the machine body" school of thought hasn't gathered as much support as it might in recent years, and nor has a body of work accumulated to explain exactly how the next twenty to thirty years would run under this scenario. I look forward to seeing that change.

A layperson's explanation of the theorized role of mitochondria in driving aging can be found at h+ Magazine: "Aging is a complex process that, by nearly all educated accounts, appears to involve multiple different interacting processes. Aubrey de Grey has sought to break down the causes of aging into seven categories; others have presented different understandings. One perspective on aging broadly recognized as important, however, is the mitochondrial theory - tying aging to changes in the function of mitochondria, the energy powerhouses of the cell. This article reviews the mitochondrial theory of aging, with an aim of describing enough of the science to give the lay reader a real sense of what the theory is about. ... In the mid-1950s, Denham Harman proposed that aging results from accumulated damage inflicted by free radicals - atoms or molecules possessed of a sole unpaired electron in their outer shells. ... In 1972 Harman proposed the Mitochondrial Theory of Aging (MTA), which is considered an extension of the free radical hypothesis. According to this theory, aging is due to the cumulative effects of damage wrought by free radicals on the mitochondrial DNA and function. ... Taken together, data derived from several thousand studies largely supports the MTA. Mitochondrial fee radicals damage the mitochondrial DNA, causing mitochondrial dysfunction with lowered ATP production, cellular energy depletion and death, resulting in aging."

Link: http://hplusmagazine.com/2011/10/21/the-mitochondrial-theory-of-aging/

From Singularity Hub: "scientists, engineers, futurists, and other forward-thinkers converged for Singularity Summit 2011. ... In this first part of three [we'll] highlight the speakers who discussed the various aspects of health related to the singularity. This includes life extension and regenerative medicine as well as the implications of these new technologies. ... Hands down, one of the most exciting talks of the first day. Dr. Stephen Badylak was able to wow the crowd with his work on regenerative medicine ... Working at the McGowan Institute for Regenerative Medicine at the University of Pittsburgh, Badylak and his team have been experimenting with what's known as the extracellular matrix (ECM), the structural component in animal tissue outside of the cells. Research has found that besides providing support for cells, the ECM acts as a 'information superhighway', allowing cells to communicate with each other. Part of this communication involves molecular signals that recruit stem cells after injury and indeed, grafting pig ECM at sites of human injury have been shown to work better at regenerating tissue than injecting stem cells directly. ... Dmitry Itskov presented on a new movement that he has founded to tackle the issue of human immortality. Itskov gave a somewhat nationalistic presentation, touching on many aspects of why Russia is poised to become the leader in the area of longevity. He described the work of famous Russian scientists that are the intellectual grandfathers of this movement and gave an open invitation to anyone who wanted to help grow it. As was a common theme throughout the 2-day summit, Itskov doesn't think that the breakthroughs in the technology to bring radical life extension to market will necessarily come from government. Instead, he advocates grass-roots movements [that] assemble the necessary scientists, thinkers, and financiers to see it through."

Link: http://singularityhub.com/2011/10/10/singularity-summit-2011-a-state-of-the-future/

Xenotransplanation is the use of animal organs, possibly genetically modified, in place of human organs for transplantation in cases of organ failure or damage. This is one of the developing technologies that will compete with electromechanical or bioartificial organs and tissue engineering of whole organs to make organ replacement a far more viable, effective, and low-cost prospect than it is today. To my eyes xenotransplantation was always going to be a transitional technology, economically viable for a period of years in which tissue engineering was still finding its feet, but the development of decellularization has made animal organs look like a far more interesting long term source of raw materials.

a valve from a human or animal donor is removed of all cells using tissue engineering, so that only its outer framework remains. This valve matrix is then colonised with cells that have been obtained from the blood of the recipient and propagated. Within a few weeks, a quasi-natural heart valve then emerges in this bioreactor, that exhibits no rejection response or other faults, but instead grows with the patient after the implantation. ... Recellularization makes xenotransplantation a much more viable technology to fill the tissue engineering gap prior to the ability to grow complex organs from scratch.

The use of the patient's own cells in a donor scaffold removes issues of immune rejection, wherein the patient's immune system attacks and destroys the donor organ. When immune rejection is removed from the equation, not only does the entire process become much safer and cheaper, we are left with the extracellular matrix organ scaffold as the actual raw material required. A full organ scaffold is presently too complex for researchers to construct from scratch, and even when this can be done at some point in the next decade or two, it will be expensive for a time thereafter. Obtaining the decellularized scaffolds from human organs puts you right back to where you started with the difficulties of sourcing donor human organs when needed, but using animal organs can work around that issue.

I noticed a recent article that discusses the timelines for present work on xenotransplanation without decellularization, which is largely focused on transferring cells and small sections of tissue rather than whole organ structures. Organs are clearly on the agenda, however:

During the past decade xenotransplantation, the use of animal organs, tissues or cells in humans, has made great advances. Due to the fact that more and more genetically modified pigs are available with genes to protect them from human immune response, has alleviated earlier problems in helping humans to accept such transplants. ... at this time the longest time of survival for pig organs in non-human primates varies from a few days in lung transplants to approximately 6-8 months in hearts transplants. Although research is still years away from conducting human trials of solid organ transplants of this nature, lifesaving transplants of a pig heart or liver could pose as an alternative solution until a human organ becomes available. At present researchers are investigating strategies to incorporate human anticoagulant or antithrombotic genes into genetically modified pigs, and additional genes to regulate the human inflammatory response.

...

The authors also discussed in terms of organs, that stages of other strategies are currently more advanced than xenotransplantation, such as left ventricular assist devices for cardiac support. However, they agree that given time, transplanting a pig's heart will prove to be the better option compared to using a mechanical device.

...

Although remaining issues are delaying clinical implementation, experimental results obtained with pig islet, neuronal-cell, and corneal xenotransplantation have been encouraging. With new genetically modified pigs becoming available that are likely to improve the outcome of cellular and corneal xenotransplantation further, we believe that clinical trials will be justified within the next 2-3 years. No safety concerns that would prohibit such clinical trials have been reported...With regard to pig tissues and cells, as opposed to organs, it would seem that clinical xenotransplantation could soon become a reality.

Another group working on machinery to produce tissue engineered blood vessels: "German researchers have been working at growing tissue and organs in the laboratory for a long time. These days, tissue engineering enables us to build artificial tissue, although science has still not been successful with larger organs. Now researchers at the Fraunhofer group of applied research institutes are applying new techniques and materials to come up with artificial blood vessels in their BioRap project that will be able to supply artificial tissue and, perhaps, even complex organs in the future. ... The aim of tissue engineering is to create organs in the laboratory for opening up new opportunities in the field. Unfortunately, researchers have still not been able to supply artificial tissue with nutrients because they do not have the necessary vascular system. Five Fraunhofer institutes joined forces in 2009 to come up with biocompatible artificial blood vessels. It seemed impossible to build structures such as capillary vessels that are so small and complex and it was especially the branches and spaces that made life difficult for the researchers. But production engineering came to the rescue because rapid prototyping makes it possible to build workpieces in line with any complex three-dimensional (3D) model. Now scientists at Fraunhofer are working on transferring this technology to the generation of tiny biomaterial structures by combining two different techniques: 3D printing technology established in rapid protoyping and multiphoton polymerisation developed in polymer science."

Link: http://www.engineeringnews.co.za/article/when-ink-becomes-an-artificial-vessel-system-2011-10-21

A look at what comes after merely targeting cancer cells: "Several decades from now we hope to have sophisticated medical nanorobots, produced by molecular manufacturing, that can enter cells, analyze the state of the cell, and initiate appropriate therapy, such as killing cancer cells. A team of scientists [has] taken an important step in that direction by demonstrating a synthetic circuit that, when incorporated into a cell, detects the presence or absence of five specific small RNA molecules,processes that information, and then, based upon that result, either kills or does not kill the cell. ... [The] long-term goal is to construct biocomputers that detect molecules carrying important information about cell wellbeing and process this information to direct appropriate therapeutic response if the cell is found to be abnormal. ... The researchers constructed what they describe as a 'classifier' gene circuit that is transiently expressed inside a cell and then integrates information from five molecular markers to determine the state of the cell, and then produces a protein that sets off the cellular suicide cascade if the cell is determined to be cancerous. The DNA circuit they constructed contains numerous control sequences chosen from standard genetic engineering toolkits that respond to specific miRNAs such that only the combination that identifies the particular cancer cell line used in the experiments activates the circuit and triggers the onset of cellular suicide. The results presented do show some false positives and some false negatives, so further optimization of the genetic circuit would be needed. Nevertheless, the results are impressive. Also, in principle, this method could be adapted to different cell types by choosing the combination of miRNAs appropriate to distinguish that cancerous cell from neighboring cells."

Link: http://www.foresight.org/nanodot/?p=4813

Much as none of us like to think about it, we all have an ongoing, changing mortality risk - the flip side of the statistics of life expectancy at any given age. This largely involves cars in younger years, but then goes on to be dominated by the unpleasant and varied consequences of aging to death. I have no sage advice when it comes to cars, but I can point out the science that backs up the idea that we have a modest degree of control over our risk of death at any given age, and hence over our life expectancy.

There are three line items here:

• Exercise
• Calorie restriction
• Working to speed development of rejuvenation biotechnology

I don't expect to see significant additions to this list become widely available for another twenty years or so. Aside from the fact that we can do a great deal to speed up the advent of ways to repair the cellular and molecular damage of aging - which is a very big deal - the healthy person interested in putting a thumb on the scales of mortality risk is presently stuck with much the same narrow array of methods as our immediate ancestors. There's an anti-aging marketplace shouting loudly that they have plenty of new things to try, but their marketing folk are largely lying through their teeth, hyping things with no scientific basis, or selling goods that have statistically negligible effects in comparison to exercise and calorie restriction.

But so it goes - there are always people who want answers now, and never mind whether they are the right answers, and so there will always be other people selling immediate answers. Fools and their money, and so forth.

By way of following on from yesterday's post on exercise, mortality, and medical costs, I thought I'd point out a couple of other recent items that clearly point to the obvious ways in which the vast majority of us can adjust our own life expectancy.

Early mortality risk reduced up to 40 percent through increased physical activity and sports:

The researchers identified about 7,000 potentially relevant reports, of which a total of 80 cohort studies with more than 1.3 million study participants from Europe, Canada, United States, and Asia fulfilled the strict inclusion criteria. At study onset participants had to be free of cardiovascular disease, cancer and other chronic conditions. Study participants were followed up by a median of 11 years. 'The results of the included studies were combined and controlled for other potential influential factors, e.g. cigarette smoking, alcohol uptake, body mass index, blood pressure, nutrition, education and social factors,' explained Guenther Samitz.

...

For light- to moderate intensity activities of daily living, e.g. housework, gardening, stair climbing, walking and bicycling for transportation, an increase of one hour per week compared to no physical activity was associated with a reduction in mortality of four percent. Dr. Samitz said that with moderate-intensity leisure activities (e.g. Nordic walking, hiking, social dance) the risk reduction increased to six percent, and with vigorous-intensity aerobic activity or sports (e.g. jogging, bicycling (>10 miles per hour), tennis, ball sport), the reduction in all-cause mortality was even nine percent per one hour increment per week. Meeting the WHO´s recommended level of 150 minutes per week of moderate physical activity of daily life or during leisure was associated with a reduction in mortality risk by ten percent. For vigorous exercise and sports the reduction in mortality risk was more than twofold higher (22 %).

High to moderate levels of stress lead to a higher mortality rate:

A new study concludes that men who experience persistently moderate or high levels of stressful life events over a number of years have a 50 percent higher mortality rate. ... This is the first study to show a direct link between stress trajectories and mortality in an aging population. Unlike previous studies that were conducted in a relatively short term with smaller sample sizes, this study was modified to document major stressors - such as death of a spouse or a putting a parent into a retirement home - that specifically affect middle-aged and older people.

You might look back in the Fight Aging! archives for more on the material links between psychological stress and biomarkers of health, such as telomere length in immune cells.

An open access review paper: "In tissue engineering fields, recent interest has been focused on stem cell therapy to replace or repair damaged or worn-out tissues due to congenital abnormalities, disease, or injury. In particular, the repair of articular cartilage degeneration by stem cell-based tissue engineering could be of enormous therapeutic and economic benefit for an aging population. ... Many people over the age of 40 suffer from degeneration or injury of their cartilage, leading to a reduced workforce and increased medical expenses. Thus, improvements in cartilage repair using a cell-based tissue engineering approach will greatly benefit public health and the economy. Personalised cell therapy for cartilage repair using cell-based tissue engineering technologies would provide clinically practical methods for producing a cartilage tissue equivalent. A number of biomaterials are available as scaffolds, and research continues to help us understand more details about how tissues develop and which cell type should be applied. These studies have provided details of how tissues grow in vitro and in vivo, but clinical applications depend on working with surgeons and the translation of these materials and technologies to in vivo models that are more relevant to patients. When cell-based cartilage tissue engineering technologies are applied to new animal models, we attempted to find better functional compositions for successful applications than were observed in previous studies. Although stem cell-based cartilage tissue engineering systems may demonstrate success even in animal models, there are a number of new challenges when the technologies are applied to humans. Further research on in vivo application must address immunological issues, integration of host and stem cell-based engineered cartilage, and the variability of tissue development in an in vivo environment, depending on surrounding disease processes, age, or physical activity. Therefore, interdisciplinary studies are not only necessary but crucial before cell-based cartilage tissue engineering can reach its full potential in cartilage repair and regeneration."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191858/

Researchers investigating calorie restriction have noticed that its effects on longevity can be inherited through epigenetic variations - which makes sense, given the reasons why individual longevity variations in response to available food evolved in the first place. If it is advantageous for a given individual at a given time to shift metabolism into a mode that allows it to live longer due to a decline in available food, then it's probably also advantageous for the children to do that from birth as well: "The tiny soil-dwelling worms C. elegans, when given mutations that make them live longer, transmit that trait even when their progeny don't inherit the life-extending mutations. ... Although much more research remains to be done, the new study raises the tantalizing possibility that if Grandma practiced caloric restriction - which affects the expression of longevity-enhancing genes - her descendants might reap the benefits. The inheritance occurs through "epigenetics": alterations not in the coding sequence of DNA (those ubiquitous A's, T's, C's, and G's) but in chemical changes that affect whether genes are expressed. ... [A] protein complex called ASH-2 [alters] histones in C. elegans, reconfiguring the histone-DNA complex into an 'open' state that promotes gene expression. Deficiencies in ASH-2 extend the worm's life span by as much as 30 percent. ... [researchers] blocked the three key proteins that make up the ASH-2 complex by mutating their genes. As expected, the worms lived longer - typically, an extra seven days beyond their lab life span of 20. [Researchers] bred the mutated worms with normal worms until their descendants no longer had the mutations. Nevertheless, the progeny still lived longer, as did their own descendants: even though their genes for the key proteins were normal, an epigenetic memory of longevity persisted."

Link: http://www.technologyreview.com/biomedicine/38943/

One longevity-related line item that doesn't come up often enough in discussion is the matter of the expected state of your wallet as you move through life. Given that you have a fair degree of control over your long-term health, do you also have the same degree of control over the funds needed for future medical treatment? Reliability theory, a consideration of aging as damage, suggests that the only paths to a longer life are those which reduce or repair the accumulated biological damage that leads to aging. Reliability theory also tells us that this will lead to a lower chance of systems failure - which we might interpret as a lower chance of the need for medical intervention at any given time.

Thus it makes sense to look at the foreseeable biotechnologies of enhanced longevity as a way to reduce long term expenditures on medicine, on average, for individuals. One might hope that everyone - and not just those who have nursed an aging car through its last years - understands the difference in maintenance costs for a well-repaired machine versus one that's showing all the signs of accumulated wear and tear. Damaged machines spiral down into ever more expensive breakdowns, and that's just as true of people as it is of the things people build. Yet much of the public debate over medicine seems to focus on the idea that living longer implies greater medical expenditure - possibly another aspect of the Tithonus Error, the naive belief that living longer though biotechnology means being old for longer rather than being young for longer.

(As an aside, unrelated to the present point, the prospects for greater expenditure in the field of medicine would be a sign for rejoicing in a sane world. It would mean an industry primed for growth, needing more workers, gathering funds for investment in new ways to serve the growing number of customers, and so forth. No-one complains when the demand for cars, shoes, or shiny internet sharing widgets increases. Yet because medicine is so completely socialized in countries like the US, you see the inevitable spiral towards rationing, rejection of expenditures, and decay of new development rather than a healthy, competitive industry).

The tools for personal longevity will, I think, remain crude for the next couple of decades. Essentially, exercise, calorie restriction, and the avoidance of sharp things. Amazing things are happening in the labs, and we can clearly see how to extend life - but amazing in the lab doesn't yet translate to available in the clinic, and won't for a while. But even with these crude tools, barring genetic bad luck (or any of the other fatal forms of bad luck), the vast majority of us have a fair degree of control over our future health and medical budget. You might look at this open access paper, for example:

The authors followed up 27,738 participants aged 40-79 years and prospectively collected data on their medical expenditure and survival covering a 13-year-period. Participants were classified into those walking <1 and ≥1 h per day.

...

The present results indicate that the multiadjusted lifetime medical expenditure from the age of 40 years for those who walked ≥1 h per day was significantly lower by 7.6% in men and non-significantly lower by 2.7% in women than for those who walked <1 h per day. This decrease in lifetime medical expenditure was observed in spite of a longer life expectancy (1.38 years for men and 1.16 years for women) among those who walked ≥1 h per day. Thus, a healthy lifestyle not only extended longevity but also decreased the amount of lifetime medical expenditure, especially men.

It would be interesting to see the results on medical expenditure in a similarly large study that focused on deliberate exercise as opposed to time spent walking - but I think this illustrates the point, even with the smaller differences in life expectancy and health than are typically seen in studies that compare sedentary people with those who exercise regularly.

The response of metabolism to lowered methionine intake appears to be a major component of the mechanisms of calorie restriction: "Methionine dietary restriction (MetR), like dietary restriction (DR), increases rodent maximum longevity. However, the mechanism responsible for the retardation of aging with MetR is still not entirely known. As DR decreases oxidative damage and mitochondrial free radical production, it is plausible to hypothesize that a decrease in oxidative stress is the mechanism for longevity extension with MetR. In the present investigation male Wistar rats were subjected to isocaloric 40% MetR during 7 weeks. It was found that 40% MetR decreases heart mitochondrial ROS production at complex I during forward electron flow, lowers oxidative damage to mitochondrial DNA and proteins, and decreases the degree of methylation of genomic DNA. ... These results indicate that methionine can be the dietary factor responsible for the decrease in mitochondrial ROS generation and oxidative stress, and likely for part of the increase in longevity, that takes place during DR. They also highlight some of the mechanisms involved in the generation of these beneficial effects."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22006472

An example of present work in growing skin from stem cells: scientists "are participating in research to study how to make use of the potential for auto regeneration of stem cells from skin, in order to create, in the laboratory, a patient's entire cutaneous surface by means of a combination of biological engineering and tissue engineering techniques. Skin is a tissue that naturally renews itself throughout our lives thanks to the existence of epidermic stem cells. ... We have found that this regenerative potential can be preserved in vitro (in the laboratory) if the cells are joined and become part of generated skin using tissue bioengineering techniques. ... The researchers have already been able to join together these epidermic stem cells into skin created by means of bioengineering, and they have observed that the cells preserve the regenerative potential that they normally have in our skin. That is, using a small biopsy from a specific patient, they can generate almost the entire cutaneous surface of that individual in the lab. ... The regenerative capacity of epidermic stem cells in these conditions is overwhelming, and it leads to the possibility of using these cells as a target for even more complex protocols, such as gene therapy. ... In fact, these researchers have already demonstrated, at the pre-clinical level, that it is possible to isolate epidermic stem cells from patients with different genetic skin diseases, cultivate them and, using molecular engineering as a first step, incorporate the therapeutic genes into each patient's genome to take the place of the one that the patient does not have or that functions abnormally. Afterwards, in the second step, the stem cells would be assembled into patches ready to be transplanted onto the patients."

Link: http://www.physorg.com/wire-news/80303525/bioengineering-to-repair-and-generate-healthy-skin.html

There's an article over at Reason Magazine today that calls out one example in a pattern of abuse of meaning that I've long found threatening. Attempts to fundamentally rework the meaning of a basic and important word are one of those little fragments of 1984 that manage to drift into the real world, an unsavory activity in which the meaning of the word is both kept and entirely inverted at the same time. I think the following quote captures the essence of this particular case:

Lawler, a member of President George W. Bush's controversial Council on Bioethics, tried to make the case that using technology to radically extend human lifespans, and boost human intellectual, emotional, and physical capacities, will end in coercion. Those who don't want to take advantage of the kinds of enhancements that biotechnology, nanotechnology, and cognitive technology will offer, argues Lawler, will ultimately not have a choice about using them. ... But is that so? If anyone should be concerned about coercion, it is the transhumanists who rightly fear that bioconservatives like Lawler will try to use the power of the state to halt the research that would lead to the development of enhancements would enable them to improve their life chances and those of their children.

Shades of Freedom is Slavery march through all too many minds, methinks. That is a real threat, as halting and slowing research in the life sciences is something that the bureaucrats of the modern state are very good at indeed. That people carefully try to invert the word "coercion" to mean "the existence of freedom of choice that I personally do not approve of" is also a threat, as freedom of choice and freedom from coercion are the deep roots of wealth and technological progress. Without them, you end up living in something akin to the backward ruins and ruined, predatory culture of the final years of the Soviet Union.

Freedom is fundamental to transhumanist ideals - such as developing the means to greatly extend youthful life span through biotechnology. Freedom is vital for the research and research community needed to open these new doors:

Freedom of research is, in essence, economic freedom, which is no different from personal freedom - the freedom to invest and work in whatever arrangements you can freely agree upon with other people. The most rapid progress occurs in free marketplaces, free for the exchange of ideas, free for association with others for mutual benefit, free for the exchange of goods. Any and all interference by centralized entities - such as governments - is inefficient and serves only to slow things down, make goods more expensive, and ensure that some research never happens at all.

Further, freedom is the very essence of transhumanism itself, which is no more than the human imperative to create new choices where before there was nothing. Having a choice today in an area where there was no choice yesterday is an increase in your freedom, and building those new choices - these new freedoms - is exactly what humanity achieves through technology:

Transhumanism, make no mistake, is just a fancy name for common sense. Change for the better is good, right? Common sense. It's what we humans do in our scattered finer moments - we work to change things for the better. It's common sense to fetch in the harvest on wheels rather than on foot, and it's common sense to repair the biomolecular damage of Alzheimer's before the mind begins to rot. It's common sense to build perfect immune systems from nanomedical robots, and it's common sense to develop the technologies of regenerative medicine to their logical end. It takes work, but what is work compared to a world of suffering? Choosing not to attain these goals makes about as much sense as standing out in the rain to spite yourself.

The Soviet Union may be gone in all but the longer memories, but there is no shortage of people who would strive to rebuild it again, today, in their country, one piece at a time. There are so many petty would-be totalitarians in this world, each laboring under the belief that central control of the matters they care about will work - this time! - if it is just done their way. The real danger of centralized government is that sooner or later, those would-be totalitarians get their hands on their ability to do real harm by attempting to enact their visions.

From MSNBC: "The latest science and schemes for achieving long life and the "singularity" moment of smarter-than-human intelligence came together at the Singularity Summit held [in New York] October 15-16. Some researchers explored cutting-edge, serious work about regenerating human body parts and defining the boundaries of consciousness in brain studies. ... The most immediate advances related to living longer and better may come from regenerative medicine. Pioneering physicians have already regrown the tips of people's fingers and replaced cancer-ridden parts of human bodies with healthy new cells. ... Success so far has come from using a special connective tissue - called the extracellular matrix (ECM) - to act as a biological scaffold for healthy cells to build upon. Badylak showed a video where his team of surgeons stripped out the cancerous lining of a patient's esophagus like pulling out a sock, and relined the esophagus with an ECM taken from pigs. The patient remains cancer-free several years after the experimental trial. The connective tissue of other animals doesn't provoke a negative response in human bodies, because it lacks the foreign animal cells that would typically provoke the immune system to attack. It has served the same role as a biological foundation for so long that it represents a 'medical device that's gone through hundreds of millions of years of R&D'. ... If work goes well, Badylak envisions someday treating stroke patients by regenerating pieces of the functioning human brain."

Link: http://www.msnbc.msn.com/id/44938297/ns/technology_and_science-innovation/

Researchers report another longevity gene: "Scientists have previously found mutations that extend fruit fly lifespan, but this group of genes is distinct because it acts specifically in muscles. The findings could help doctors better understand and treat muscle degeneration in human aging. [Researchers] started investigating a pair of genes called "p38 MAP kinase" in fruit flies with the expectation that they could play a role in learning and memory. Along the way, they discovered that mutations in these genes speed up the process of aging and make the flies more sensitive to oxidative stress. ... It was really just dumb luck, because we found a mutant that had almost completely lost gene activity, but had enough activity to be born. ... If both genes are defective in the same fly, the flies die very early. ... The experiment that made us nervous was when we asked whether having more p38 could increase lifespan. You can make flies sick and shorten their lives in a hundred different ways easily, but finding one gene that makes a big change in lifespan is more significant. ... Fruit flies normally live about fifty days in [this] laboratory, depending on temperature and conditions. Some strains of fly that overproduce p38 MAP kinase live on average about 75 days, 50 percent longer than regular flies ... For this effect, it is sufficient that p38 is overproduced in muscles only. ... a protein that protects cells against oxidative stress that is found in mitochondria, superoxide dismutase (MnSOD), is responsible for at least some of p38 MAP kinase's effects on aging." That last point makes this look rather like the mouse studies in which life span was extended by genetic engineering to boost levels of natural antioxidants present in the mitochondria.

Link: http://www.eurekalert.org/pub_releases/2011-10/eu-mta101711.php

It's good to be living at a time in which we can seriously discuss in some detail exactly how an ultimate cure for cancer would in fact be built: what biotechnologies are needed, how our biology would have to be changed. While we might all wish our births to have slid at least a few decades into the future to benefit from what will come, being here now puts us in a far better position than that of our immediate ancestors. Personally, I'd settle for the greatly improved odds of survival imparted by a very robust suite of cancer cures - and that is exactly what will emerge with the next generation of targeted cancer therapies that use some combination of immunotherapy and nanoscale engineering. Cancer doesn't worry me anywhere near as much as other aspects of aging, given the way the odds look to be shaping up. If you're two to three decades away from the prime years for cancer, then you should probably feel the same way.

In any case, one of the longer term research projects that is a part of the Strategies for Engineered Negligible Senescence (SENS) is the technical basis for what might be described as the ultimate cure for cancer. It goes by WILT, or Whole-body Interdiction of Lengthening of Telomeres. The short version of the idea is to turn off the ability of the human body to do the one thing that all cancers depend upon, which is lengthening telomeres beyond their normal limits. Telomeres are the protective caps at the end of chromosomes that progressively shorten with each cell division: one of their functions is to prevent runaway division of cells (i.e. cancer), but that roadblock can be evaded by a cancer that evolves any one of a number of ways to abuse mechanisms that the body normally uses to repair and lengthen telomeres in the few cell populations that need it.

The not inconsiderable downside of WILT is that a person who has undergone this treatment will have a reduced life span without access to procedures for regularly replacing their entire stem cell populations - turning off telomere lengthening will kill the possibility of cancer, but also put a short timer on the stem cells that need that process in order to keep repairing the body and replenishing cells. To my eyes this seems like an unnecessary risk when balanced against the future robustness of cancer therapies under development - but it's hard to argue against WILT as an ultimate cancer therapy.

That is, provided all of the scientific assumptions about WILT are correct. For example, that we know all of the biological processes by which telomeres can be lengthened, and that shutting them all down doesn't cause any other harm beyond the loss of stem cell longevity. So there is a certain amount of groundwork to be done to seal the case for WILT as ultimate-cancer-therapy-with-big-but-possibly-acceptable-downside, and the SENS Foundation has been funding some of it, whilst keeping an eye on other related research already ongoing. Here is an outline of one recent advance in knowledge:

To develop an unbreachable defense against cancer, SENS Foundation is pursuing the WILT (Wholebody Interdiction of Lengthening of Telomeres, or OncoSENS) strategy of preemptively deleting genes essential to the cellular telomere-maintenance mechanisms (TMM) from all somatic cells ... The strongest challenge to this approach, granting the periodic replenishment of somatic stem-cell pools with autologous but OncoSENS-ready stem cells, has been the possible existence of functions of TERT (telomerase reverse transcriptase - the catalytic subunit of telomerase), other than the lengthening of telomeres itself.

...

A careful test of the development of [mice engineered to lack TERT] would be expected to provide strong evidence on the subject one way or the other, provided that telomere lengths did not shorten excessively. Nobel laureate Dr. Carol W. Greider, whose career in telomerase research and path to the Nobel prize began when she first identified the enzyme in 1984, has finally carried out such a test, and she and her collaborators have generated results that strongly support the safety of this element of WILT.

...

This little-heralded, meticulous investigation into the effects of ablation of the telomerase catalytic subunit in mice with human-like telomeres provides us with strong reassurance that, should it prove to be the preferred approach for implementing the OncoSENS strategy, the effects of knocking out TERT would be limited to those dictated by the loss of telomere-lengthening per se, and would not lead to an unintentional loss of some essential but hitherto-unknown physiological function.

Researchers are spending more time these days on the mechanisms by which stem cell populations decline with age - understanding the controlling processes that stop stem cells from working so well in later life will be the key to restoring their effectiveness. For example; "The aging process decreases tissue function and regenerative capacity, which has been associated with cellular senescence and a decline in adult or somatic stem cell numbers and self-renewal within multiple tissues. The potential therapeutic application of stem cells to reduce the burden of aging and stimulate tissue regeneration after trauma is very promising. Much research is currently ongoing to identify the factors and molecular mediators of stem cell self-renewal to reach these goals. Over the last two decades, fibroblast growth factors (FGFs) and their receptors (FGFRs) have stood up as major players in both embryonic development and tissue repair. Moreover, many studies point to somatic stem cells as major targets of FGF signaling in both tissue homeostasis and repair. FGFs appear to promote self-renewing proliferation and inhibit cellular senescence in nearly all tissues tested to date. ... The effects of FGF signaling can be in part attributed to the stimulation of self-renewal in endogenous somatic stem cells within these organs, but there is also much evidence that FGF signaling also plays a role in the concomitant inhibition of cellular senescence in stem cell. The evidence presented here also suggests a role of FGF signaling in the more committed cells downstream of stem cells, a role that appears to stimulate differentiation. Moreover, in most cell types studied, FGF seems to play a permissive role rather than a direct inductive or instructional role, usually by modifying the responsiveness of the cells to other factors or by potentiating and synergizing with other signals. That seems to hold true in both stem cells self-renewal and differentiation of more committed cells."

Link: http://www.impactaging.com/papers/v3/n10/full/100369.html

The idea that you can do something positive for long term health by consuming presently available antioxidant supplements is a myth, not backed up by scientific evidence at all: "A study of vitamin E and selenium use among 35,000 men found that the vitamin users had a slightly higher risk of developing prostate cancer ... A separate study of 38,000 women in Iowa found a higher risk of dying during a 19-year period among older women who used multivitamins and other supplements compared with women who did not ... The findings are the latest in a series of disappointing research results showing that high doses of vitamins are not helpful in warding off disease. ... You go back 15 or 20 years, and there were thoughts that antioxidants of all sorts might be useful. There really is not any compelling evidence that taking these dietary supplements above and beyond a normal dietary intake is helpful in any way, and this is evidence that it could be harmful. ... Everyone needs vitamins, which are essential nutrients that the body can't produce on its own. But in the past few years, several high-quality studies have failed to show that high doses of vitamins, at least in pill form, help prevent chronic disease or prolong life." Antioxidants specifically targeted to the mitochondria have been shown to produce benefits to health and life span in mice, but running out to eat antioxidants from a bottle because of that is nothing more than magical thinking. In the case of currently available antioxidant supplements, there is every reason to think that they interfere with the beneficial mechanisms of exercise, causing a net loss in long term health.

Link: http://well.blogs.nytimes.com/2011/10/11/more-evidence-against-vitamin-use/

An unfortunate fact of life for anyone engaged in trying to persuade the world to adopt a new point of view - that crash development of rejuvenation biotechnology is a good and plausible idea, for example - is that people who are skeptical or only vaguely interested in your ideas don't tend to be vocal or engaged. So it's hard to assess their views in comparison to those people who have already been won over. This is simply a matter of priorities: when people take the time to publish their thoughts and lucid arguments, they tend to do so for their own causes, for the ideas they agree with. Time is, after all, fleeting - there are only so many blog posts and essays that can be written in any one life.

So as an advocate or activist, one has to pay attention to this hole in awareness; it's one of the things that makes advocacy a challenge. You're often none the wiser as to exactly how or why vast swathes of the population manage to be unresponsive to your message and outreach efforts. They know, but getting them to tell you is like blood from a stone.

On this topic, I see that Aubrey de Grey of the SENS Foundation recently gave a talk in Baltimore on SENS and the path to rejuvenation biotechnology. One of those attending was Kavan Peterson, a writer from ChangingAging, which is something of a pro-aging organization - both in the sense of empowerment and opposition to ageism, which are noble causes, but also in the less desirable sense of apologism for aging. There are already far too many talking heads trying to persuade the world that progressively accumulating pain, suffering, and loss of function are just fine and dandy. In any case Peterson, unlike most skeptics, took the time to write. So we should take the time to learn from that:

The Immortal Life? An Evening With Aubrey de Grey

I am skeptical of de Grey's work and I'll use his own introduction to explain why: "It may seem premature to be discussing the elimination of human aging as a cause of death, when so little progress has been made in even postponing it says Aubrey de Grey." That's right - despite all the marvels of modern medical science, there is absolutely zero evidence that any known treatment has ever extended human life by a single day. Immortality is as fantastical an idea today as it was in ancient times.

My Evening With Aubrey de Grey

I'd like to think of ChangingAging.org as the preeminent pro-aging blog so it was a great opportunity to talk to the world's leading anti-aging advocate. And surprisingly I came away with the impression that although our rhetoric is wildly divergent - as divergent as anti- vs pro-aging rhetoric can be - we share similar goals.

First, where we diverge - as our masthead says, we look at human aging "as a strength, rich in developmental potential and growth." De Grey argues aging is "obviously, unequivocally humanity's worst problem."

That's a big difference. But lets look at our goals.

You should read the rest of it; this is an example of the type of person we'd like to persuade to support SENS and the broader field of work on repair-based strategies to reverse aging. Separately, I noticed another blog post from a different attendee, one who falls into the category of peripherally interested, I believe. She made this remark:

I asked the question: "There are assumptions in your theory, that the patient will get to the doctor on time, that the doctor is well trained in this new technology, and that the insurance companies will pay for these services." His answer was that his main focus is on the biological aspect and that these issues will come up and will need to be addressed at some point.

Also worth learning from.

This is an open access report in book format that delves into the factors that cause regional variations in life expectancy and rates of age-related disease - and thus longevity - in the first world. Given its origins, don't expect to see much on the stifling regulation that raises prices and reduces quality and innovation in medicine, but most of the other important contributing factors are addressed: "Over the past 25 years, life expectancy has been rising in the United States at a slower pace than has been achieved in many other high-income countries. Consequently, the United States has been falling steadily in the world rankings for level of life expectancy, and the gap between the United States and countries with the highest achieved life expectancies has been widening. International comparisons of various measures of self-reported health and biological markers of disease reveal similar patterns of U.S. disadvantage. The relatively poor performance of the United States with respect to achieved life expectancy over the recent past is surprising given that it spends far more on health care than any other nation in the world, both absolutely and as a percentage of gross national product. Motivated by these concerns, the National Institute on Aging requested that the National Research Council convene a panel of leading experts to clarify patterns in the levels and trends in life expectancy across nations, to examine the evidence on competing explanations for the divergent trends, and to identify strategic opportunities for health-related interventions to narrow this gap."

Link: http://www.ncbi.nlm.nih.gov/books/NBK62369/

From Next Big Future: "The [SENS5] conference itself was high quality - many of the scientists that I describe in my book, 100+, were there. Hearing about the tangible progress that these researchers are continually making was very exciting. I noticed that there were many companies that attended this conference, which is an indication that extending health span is a prospect which is starting to garner serious consideration. ... There are a large and growing number of corporations which, although not explicitly focused on anti-aging, are developing treatments and drugs related to longevity. Gene therapy and personalized medicine are the future, and these companies know that. ... The field of regenerative medicine is getting substantial resources. That includes tissue engineering, which is essentially growing organs. The recent successes with growing and implanting human tracheas are exciting. ... The most common concern is that increased life spans will lead to overpopulation. This fear rests on the false Malthusian idea that population grows faster than our ability to provide for ourselves. We haven't run out of resources as population has grown because humans are a resource themselves, providing problem-solving ideas. Also, fertility and world population growth rates are on the decline. ... Perceptions [of longevity science] have changed. The term health extension is actually less controversial than life extension, since everyone wants robust health. There is little resistance to treatments designed to keep people healthy."

Link: http://nextbigfuture.com/2011/10/is-longevity-research-speeding-up.html

Research into calorie restriction has, as I'm sure you know, been picking up in pace and breadth over the past decade or so. The drug industry is interested in trying to replicate the end results without the dietary changes, which should ensure continuing funds and interest for the foreseeable future. Lowering calorie intake while still obtaining optimal levels of micronutrients is a practice that, much like regular exercise, has long term beneficial effects on health and longevity in healthy animals and people. These benefits are very reliable and exceed those that can be provided by any presently available medical technology - they also exceed the results of many of the interesting ways to extend healthy life in laboratory animals. This state of affairs won't last, given the pace of progress in biotechnology, but based on the present landscape for medical development we should expect calorie restriction and exercise to remain the best available tools for most of us for a good twenty years yet.

I noticed a good open access review paper today (the full thing is in PDF format only) that covers all of what has been learned of calorie restriction (CR) in the past decade or two. That includes the results of a fair number of human studies, what is now known of the underlying biochemistry and mechanisms, differences between intermittent fasting versus constant dietary restriction (DR), and more:

CR has been demonstrated to extend the maximal lifespan of a diverse group of species. This extension of life is maximized when: 1) the magnitude of CR is elevated to the highest possible value before inducing malnutrition and 2) the duration of CR is maximized. Animals on CR regimens exhibit a variety of improvements in overall health in general and cardiovascular health in particular. Unfortunately, the likelihood of discovering whether or not CR extends human life is rather remote due to the ethical and logistical limitations of research design. The optimal magnitude and duration of CR for humans will also likely never be known for the same reason. Nonetheless, many human CR studies have noted favorable changes in biomarkers related to cardiovascular and glucoregulatory function, which likely relate to quality of life and may relate to longevity.

...

Regarding DR, neither carbohydrate restriction nor lipid restriction extend life. However, protein restriction appears to extend maximum lifespan by 20%. Recent findings suggest that methionine restriction may be the single cause of life extension observed in protein restriction studies. Future studies should examine the effects of different magnitudes of methionine restriction on life extension.

It's pessimistic to think that optimal calorie restriction practices will not be uncovered for humans, however. Scientists can measure changing levels in biomarkers over years of calorie restriction, so identifying optimal practices really rests on the larger area of work that relates to linking biomarkers with aging and longevity. If measurable aspects of our biology can be firmly linked to future life expectancy - and there is no reason to think that the development of such biomarkers is implausible - then a whole range of medical and health practices become open to far greater optimization than is presently possible.

Via EurekAlert!: "As a person ages, the ability of their beta cells to divide and make new beta cells declines. By the time children reach the age of 10 to 12 years, the ability of their insulin-producing cells to replicate greatly diminishes. If these cells, called beta cells, are destroyed - as they are in type 1 diabetes - treatment with the hormone insulin becomes essential to regulate blood glucose levels and get energy from food. Now, [researchers] have identified a pathway responsible for this age-related decline, and have shown that they can tweak it to get older beta cells to act young again - and start dividing. ... a protein called PDGF, or platelet derived growth factor, and its receptor send beta cells signals to start dividing via an intricate pathway that controls the levels of two proteins in the beta cell nucleus, where cell division occurs. Working with young mice, [researchers] found that PDGF binds to its receptor on the beta cell's surface and controls the level of these regulating proteins allowing cells to divide. However, in older mice, they discovered that beta cells lose PDGF receptors, and that this age-related change prevents beta cells from dividing. [Researchers] further found that by artificially increasing the number of PDGF receptors, they can restore the ability of the beta cell to divide and generate new cells. ... By understanding what genes are turned on and off in a young beta cell, we can try to recreate that genetic environment in older beta cells such that they divide in a desirable, controlled manner."

Link: http://www.eurekalert.org/pub_releases/2011-10/jdrf-rmo101211.php

Sequencing of the genome of the long-lived naked mole rat was announced earlier this year, but here's more: "Scientists have sequenced the complete genome of the naked mole rat, a pivotal step to understanding the animal's extraordinarily long life and good health. A colony of more than 2,000 naked mole rats at The University of Texas Health Science Center at San Antonio contributed to the findings ... If we understand which genes are different or are expressed differently in naked mole rats - compared to short-lived mice that clearly have poor defenses against aging and cancer - we might find clues as to why the naked mole rat is able to extend both health span and longevity, as well as fight cancer, and this information could be directly relevant and translatable to humans. ... The mouse-sized naked mole rat is the longest-lived rodent known, surviving up to 31 years in captivity. This is much longer than its laboratory rodent relatives, and the naked mole rat maintains good health and reproductive potential well into its third decade. Naked mole rats live underground in large family groups, like termites and bees, with only a single breeding female. These social rodents are extremely tolerant of life in low oxygen and high levels of carbon dioxide."

Link: http://www.eurekalert.org/pub_releases/2011-10/uoth-big101211.php

From where I stand, it looks much like the equities market has given the sign of doom over the past couple of months. The view of the next couple of years I subscribe to is that equities will fall dramatically some more very soon, then there will be a variety of massive government intervention timed to influence the presidential elections in 2012. The markets will then rise much as they did after the last massive intervention, but fail to regain the highs of this year, and thereafter fall into the pit through 2013. All of these equity market gyrations, like those of the past couple of years, are just a symptom of the deep underlying economic malaise in what was formerly a grand economic powerhouse - though malaise is probably the wrong word, as it suggests something that just happened, faultlessly. This is very much a state of affairs created through the actions of a comparatively small number of people in positions of power - evenly distributed between government and financial industries in a symbiotic state of regulatory capture - and then again by the actions of the rest of us in letting them do what they do, in failing to understand enough of economics to see cause and effect, and in failing to act to stop this process.

It's no great secret that the US is decaying; this is history unfolding as a procedural. The US is ever more rapidly becoming just another Europe, Japan, or pick your dysfunctional fascist-leaning (per the dictionary definition) economy of choice. The ending of empires that centralize economic and legislative power, develop a ruling class, grow their military, and debase their currency is pretty much written in stone - it's the details of the move from wealth enjoyed in freedom to authoritarian poverty that will surprise people in their nature and timing.

But in any case, what does the sign of doom in the markets mean for the next few years of research funding, and especially speculative research funding for efforts such as SENS? In my experience it means much the same as it does for raising funds to launch startup companies. This is to say that when the economy is in the doldrums, raising funds is very challenging - especially when the equity markets have just started on their way down in earnest and fear is rife. Funding agencies and investors pull back, either because they've suffered losses or because they have the luxury of waiting for a few years for better times.

To my eyes that makes the next few years the time to double down on raising funds from high net worth philanthropists. These are people who will be slowing their normal flow of deals and investment, but who have most likely not suddenly lost wealth in any meaningful way. There is an argument to be made that investments in early stage research made in the shadow of a falling market and economic destruction will be more effective on a dollar for dollar basis: there may be greater access to researchers and resources at lower prices due to a downturn in the normal state of their employment, for example.

One rather important item to take away from all this is that, like everyone else, I'm wrong about the market at least half the time. The fundamentals underlying modern national economies, and the US in particular, are truly terrible, however. If markets are up, it's because they're being propped up by the Federal Reserve, most recently by an uncharacteristically direct process that amounts to devaluation of the dollar and pumping newly created-from-nothing money into equities. I consider these large-scale manipulations to be something that cannot continue forever: the only goals they achieve are (a) political, keeping one faction or another in favor by providing the modern equivalent of bread and circuses in the form of high equities prices, and (b) personal in the sense that some of the ruling class become very wealthy in the course of carrying out these activities. They don't create wealth in any meaningful sense, only the hollow illusion of it. Eventually the cards must come crashing down and the hole will grow too large to be filled in by the standard model of government bailout. As they say, the trouble with other people's money is that you eventually run out of it.

So maybe the next few years will see the US equities indexes much lower than they are now, and the fundraising scene a desert. Maybe not, but I think it more likely than the alternatives. If you're in the business of raising funds, now is the time to be stacking away for the coming winter, and finalizing all the deals you can.

Following on from an earlier consideration of state of the mind and how that may interact with the operation of metabolism over the long term to affect aging, here is a very readable open access paper that tries to draw lines between longevity, psychological factors, and mitochondrial biochemistry: "A central question concerning longevity remains: Why do some people live long whereas others die early? Another equally critical question concerns morbidity: Why is aging associated with a greater incidence of almost every categorized disease - including degenerative, metabolic, and malignant disorders? Since disease incidence, mortality, and longevity are all associated terms in the same aging equation, a more general question may be posed: What are the pathways that impact individuals' rate of aging? ... Compelling evidence suggests that both biological and psychosocial factors impact the process of aging. However, our understanding of the dynamic interplay among biological and psychosocial factors across the life course is still fragmentary. For example, it needs to be established how the interaction of individual factors (e.g., genetic and epigenetic endowment and personality), behavioral factors (e.g., physical activity, diet, and stress management), and psychosocial experiences (e.g., social support, well-being, socioeconomic status, and marriage) in perinatal, childhood, and adulthood influence health across the aging continuum. This paper aims to outline potential intersection points serving as an interface between biological and psychosocial factors, with an emphasis on the mitochondrion."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180824/

An accumulation of advanced glycation endproducts (AGEs) is one of the changes thought to be a root cause of aging. The research quoted below is only a correlation, but there is plenty more where this came from to back up the viewpoint of AGEs as a contributing cause of aging: "Several studies report that diabetes increases risk of cognitive impairment; some have hypothesized that advanced glycation end products (AGEs) underlie this association. AGEs are cross-linked products that result from reactions between glucose and proteins. Little is known about the association between peripheral AGE concentration and cognitive aging. ... We prospectively studied 920 elders without dementia, 495 with diabetes and 425 with normal glucose (mean age 74.0 years). Using mixed models, we examined baseline AGE concentration, measured with urine pentosidine and analyzed as tertile, and performance on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and repeatedly over 9 years. ... Older adults with high pentosidine level had worse baseline DSST score but not different 3MS score. On both tests, there was a more pronounced 9-year decline in those with high and mid pentosidine level compared to those in the lowest tertile ... [Thus] high peripheral AGE level is associated with greater cognitive decline in older adults with and without diabetes."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21900628

Somewhere in the world, someone today pushed out the boundaries of what can be done with stem cells in medicine. The field is now so large and well funded that noteworthy advances are rolling in every week, and for each incremental step forward that you read about in the popular science press there are another half a dozen more behind the scenes, achieved without much commentary outside the scientific community. This is what a healthy field of research and development looks like: a lot of movement, a great deal of progress. Here are pointers to a few recent items, representative of what is taking place day in and day out around the world:

New Transplant Method May Eliminate Need for Lifelong Medication

The study found that a combination of two drugs lengthened survival time and prevented liver rejection in rodents. One drug was a low dose of tacrolimus, which prevented immediate rejection of the transplant, and the other was plerifaxor, which freed the recipient's stem cells from the bone marrow. The bone marrow cells freed by plerifaxor then traveled to the damaged liver and repopulated it with the recipients' own cells, replacing the donor cells that cause rejection. The stem cells also appeared to control immune response by increasing the amount of regulatory T-cells. Essentially, the scientists said they transformed the donor liver from a foreign object under attack by the immune system into an organ tolerated by the body within three months of the surgery. And - the rats only had to take the medications for one week after the transplant.

100-fold increase in efficiency in reprogramming human cells to induced stem cells

Researchers from the Wellcome Trust Sanger Institute have today announced a new technique to reprogramme human cells, such as skin cells, into stem cells. Their process increases the efficiency of cell reprogramming by one hundred-fold and generates cells of a higher quality at a faster rate. Until now cells have been reprogrammed using four specific regulatory proteins. By adding two further regulatory factors [retinoic acid receptor gamma (RAR-γ) and liver receptor homolog (Lrh-1)], Liu and co-workers brought about a dramatic improvement in the efficiency of reprogramming and the robustness of stem cell development. The new streamlined process produces cells that can grow more easily.

Regenerating eyes using cells from hair

Limbal stem cell deficiency (LSCD) [is] a condition which causes the cornea to become cloudy and develop a rough surface causing pain and leading to blindness. Currently, treatments focus on harvesting limbal cells from a patient's healthy eye or from cadaveric tissue. In her pioneering research, Dr. Meyer-Blazejewska considered the potential use of stem cells harvested from hair follicles to reconstruct damaged tissue for patients who suffer from LSCD in both eyes. ... Dr. Meyer-Blazejewska's team demonstrated that in the right microenvironment stem cells from hair follicles do have the capacity for cellular differentiation, the process whereby a less specialized cell becomes a more specialized cell type, in this case the cells of the corneal epithelial phenotype. The team's results showed an 80% rate of differentiation in mouse eyes following a cell transplant highlighting the promising therapeutic potential of these cells.

Stem-Cell Clinical Trials Move Debate Beyond Labs

Next year, Pfizer Inc. and a clutch of British scientists hope to join a small but growing group of researchers conducting the first clinical trials in one of the more contentious areas of science: medical treatments derived from human embryonic stem cells. Pfizer and its partners at University College London's Institute of Ophthalmology are awaiting regulatory permission to begin a human study in the U.K. of a possible treatment for age-related macular degeneration, a common disorder in the elderly that can cause blindness.

The constant hum of progress from the field of stem cell science and development is what we'd like to see emerging from work on aging and longevity science - and needless to say we don't. There are not enough researchers, and there is not enough funding, and there is not enough popular support to build this sort of pace of progress at the present time. That is what we must strive to change.

An open access paper: "Age-related changes in innate immune function and glial-neuronal communication are early and critical events in brain aging and neurodegenerative disease, and lead to a chronic increase in oxidative stress and inflammation, which initiates neuronal dysfunction and reduced synaptic plasticity, and ultimately disruption in learning and memory in the aged brain. Several lines of evidence suggest a correlation between adult neurogenesis and learning. It has been proposed that a decline in hippocampal neurogenesis contributes to a physiologic decline in brain function. Recently, new and important insights relating to the production of new neurons affecting hippocampal-dependent memory ability have been provided. A multitude of factors have been shown to regulate the production of new neurons in the adult hippocampus, many of which change as a result of aging. Yet, the potential importance of neurogenesis in some affective and cognitive behaviors, as well as endogenous tissue repair mechanisms, makes further investigation of neurogenic regulators warranted. We have recent evidence that key regulators of communication between neurons and microglia are disrupted in the aged brain and may be one of the factors that precedes and initiates the observed increase in chronic inflammatory state. In this review the role of dysfunction in these neuronal-glial communication regulators underlying age-related impairments in cognition and hippocampal neurogenesis will be discussed. An understanding of these mechanisms will lead to the development of preventive or protective therapies."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180926/

From the New Scientist: "Beta cells in the pancreas produce insulin, which regulates glucose levels. People with diabetes either have type 1, in which native beta cells are destroyed by the immune system, or type 2, in which beta cells cannot produce enough insulin. To replace lost or malfunctioning beta cells, [researchers] turned to neural stem cells in the brain. First, they extracted a tiny amount of tissue from the rats' olfactory bulb, the part of the brain which deals with smell, or from the hippocampus, involved in memory. Each area is accessible through the nose, both in rats and humans. Next, the team extracted neural stem cells from the tissue and exposed them to Wnt3a - a human protein that switches on insulin production - and to an antibody that blocks a natural inhibitor of insulin production. After multiplying the stem cells for two weeks, they placed them on thin sheets of collagen which act as a removable scaffold. This allowed the team to lay the sheets incorporating the cells on top of the rats' pancreas without harming the organ itself. Within a week, concentrations of insulin in the blood of both type 1 and type 2 rats that had received treatment matched those in non-diabetic rats. Elevated blood glucose concentrations also returned to normal."

Link: http://www.newscientist.com/article/dn21019-diabetic-rats-cured-with-their-own-stem-cells.html

Research into the physiology of psychological stress - how it changes the operation of metabolism and seems to accelerate some measures of aging - opens the door to asking whether other states of mind or character traits can affect human health and longevity in measurable ways. The difficulty of establishing measures of mental states makes this an unpopular topic for discussion in some reaches of the scientific community, and I'd be the first to say that a great deal of what passes for soft science these days is a waste of time and money. But there are physiological links between metabolism, aging, and the physical structure that forms the mind, so in the long run there should be some way to measure, assess, and correlate these links.

One thorny problem in this endeavor is that people don't conveniently live in laboratory tanks, and the choices they make in lifestyle and use of medical services throughout their free-range lives have a large impact on health and longevity. It's not hard to find studies that show strong correlations for longevity that might be traced back to people who are more conscientious in taking care of their health, or greater wealth and access to medicine, or greater access to knowledge that in turn leads to better healthcare and bodily maintenance. And so forth.

That all said, here's an open access paper that looks at a narrow range of character traits and their effects on survival rates of older people:

The just world hypothesis and how it may relate to health and longevity is easily stated. Individuals have a strong need to believe that they live in a world where people generally get what they deserve. The belief that the world is just enables the individual to confront his/her physical and social environment as though they were stable and orderly. Without such a belief, it would be difficult for the individual to commit himself/herself to the pursuit of long-range goals or even to the socially regulated behavior of day-to-day life.

Since the belief that the world is just serves such an important adaptive function for the individual, people are very reluctant to give up this belief, and they can be greatly troubled if they encounter evidence that suggests that the world is not really just or orderly after all. According to Lerner and Miller's just-world theory, people who believe that the world treats them fairly may plan confidently for their future, expecting their lives to be orderly, meaningful, and controllable, foreseeing a positive future or viewing one's living situation as justly deserved and hence fair. In turn, this expectation promotes mental health, meaning that the belief in a just world (BJW) can be seen as a "positive illusion". Indeed research links BJW to many indices of subjective well being including a greater purpose in life and commitment to planned healthy survival. There is empirical evidence showing that individuals who strongly believe in a just world have been seen to experience less stress and more positive affect than individuals with a weaker BJW.

The authors pull in data gathered from hundreds of study participants across the better part of a decade to support their hypothesis for this trait and a few others - including levels of distrust and the degree to which individuals see an open and expansive future ahead of them. The authors see definitive correlations between these comparatively narrow traits and mortality rates, and we might make guesses as to the mechanisms by which these correlations are established. Mechanisms similar to those linking stress with our biology, or more to do with the practice of good health over the years? The paper makes for interesting reading no matter your thoughts on whether this sort of research has any real merit.

An open access review paper that covers some of the ground leading into the need for mitochondrial repair therapies to be a part of any comprehensive biotechnology toolkit capable of reversing aging: "Aging is an intricate phenomenon characterized by progressive decline in physiological functions and increase in mortality that is often accompanied by many pathological diseases. Although aging is almost universally conserved among all organisms, the underlying molecular mechanisms of aging remain largely elusive. Many theories of aging have been proposed, including the free-radical and mitochondrial theories of aging. Both theories speculate that cumulative damage to mitochondria and mitochondrial DNA (mtDNA) caused by reactive oxygen species (ROS) is one of the causes of aging. Oxidative damage affects replication and transcription of mtDNA and results in a decline in mitochondrial function which in turn leads to enhanced ROS production and further damage to mtDNA. In this paper, we will present the current understanding of the interplay between ROS and mitochondria and will discuss their potential impact on aging and age-related diseases."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184498/

The largest, most vocal and organized opposition to engineered longevity emerges from the environmentalist movement and their misguided view of resources and overpopulation. Here is a modest answer to those viewpoints: "Increased health and life spans may be a dream come true, but many worry that it could turn nightmarish owing to problems like overcrowding, resource depletion, and greater pollution. Living a long time might be wonderful on an individual basis, but if many people can do it, would the world still be a place in which we would want to reside? ... Consider the idea that more people automatically means less food for everyone. In reality, as population grew, so did our ability to produce food. Today, many around the world are struggling with obesity, or the consumption of too much food, all while the world's population has been growing. Since 1800, the price of wheat has been steadily declining and the daily intake of calories per capita in both the developed and developing countries has been on the rise. Though it may seem counterintuitive, greater numbers of humans do not necessarily translate to fewer available resources. A key reason for this is that the more people there are, the more ideas there are, and more ideas lead to new and better ways of producing the things that we need. Fiber optic cables, which turned out to be superior to copper as a conduit for data communications, were invented in response to prohibitively high copper prices. Analogous innovations have been engineered in the food industry, such as high-yield dwarf wheat that has saved countless lives in India and Pakistan, and crops that can flourish in areas with less pure or plentiful water. As the innovations driving the longevity revolution improve the length and quality of our lives, concurrent improvements in the environment can be expected. Numerous studies have shown that the less people have to focus their energy on survival and meeting their basic needs, the more they care about making their environment cleaner. This pattern has occurred, and continues to occur, in developed countries like the United States and is now beginning in developing countries."

Link: http://volokh.com/2011/10/07/can-the-earth-survive-the-longevity-revolution/

Just as the research community is sifting the world for correlations between variations in the human genome and variations in human longevity, so too are scientists beginning to pay greater attention to the role of the epigenome. The DNA in every one of our cells is better thought of as a whirling, dynamic machine rather than a static blueprint. It is in motion, a blur, a thousand thousand feedback loops involving the production of proteins that selectively alter the process of producing proteins. The amount of any one specific protein in a given cell produced from its DNA blueprint rises and falls dynamically, in response to environmental conditions, time of day, status of the cell's internal machinery, and a million other variations tuned by evolution. The epigenome is this dynamic partner to the static genome, a catalog of how genes become tagged and the changes that result from those tags. Epigenetics is the study of how DNA interacts with the machinery of protein construction to selectively modify the output in response to circumstances - and what that then means for cells, organs, and the operation of the body as a whole.

Just as there are genetic variations that subtly contribute to human longevity, we should expect there to be equally subtle epigenetic variations - though more complex, and harder to uncover. Research here contributes to the grand debate over the degree to which aging is programmed: is the epigenetic contribution to aging a matter of growing disarray in the processes of tagging and correcting levels of protein production, arising due to damage, or are there signs of programmed changes in levels of protein production that cause damage and dysfunction?

A paper from earlier this year claims epigenetic biomarkers of longevity in nematode worms, a much simpler animal to study than we mammals:

Why do some individuals live longer than others? ... Inter-individual variation in human longevity has not been found to be under substantial genetic control, with heritability generally between 15% and 30% ... The situation is thrown into relief in studies of C. elegans, in which genetically identical siblings reared in identical environments usually experience different lifespans. In this work, we show that physiological differences between identical animals begin to appear relatively early in life and that markers of ill health in young adulthood presage shorter lifespans.

Using fluorescent markers to examine the level of activation of several genes, we found three regulatory microRNA genes [in] which early-adulthood expression patterns individually predict up to 47% of lifespan differences. Though expression of each increases throughout this time, mir-71 and mir-246 correlate with lifespan, while mir-239 anti-correlates. Two of these three microRNA "biomarkers of aging" act upstream in insulin/IGF-1-like signaling (IIS) and other known longevity pathways, thus we infer that these microRNAs not only report on but also likely determine longevity. Thus, fluctuations in early-life IIS, due to variation in these microRNAs and from other causes, may determine individual lifespan.

The educated guess at this point is that the way in which natural, unmodified life span emerges depends a little on the DNA blueprint, a lot on the environment, but just as much on chains of chaotic happenstance in the enormously complex operations of metabolism. We might consider that last line item a form of stochastic accumulation of molecular damage to cells: even with all other things being equal, individuals will age at somewhat different rates because initially small, localized differences in biological damage snowball over time into widely diverging system-wide outcomes.

Interestingly, it looks like there are good signposts on that road; we shall no doubt see how good or useful epigenetic biomarkers turn out to be in humans. Certainly a large community of researchers are hotly engaged in trying to uncover truly reliable biomarkers that measure aging or predict longevity, so if there is something to be found in the epigenome they will eventually find it.

It is the common wisdom that retirement from active work speeds the process of decline - and there are all sorts of reasonable explanations as to why this might be the case, but insofar as actual supporting evidence goes you're not going to find much of a consensus. That said, here is an unusual paper amongst those in search of a correlation between retirement and a shorter remaining life span: "Mortality hazard and length of time until death are widely used as health outcome measures and are themselves of fundamental demographic interest. Considerable research has asked whether labor force retirement reduces subsequent health and its mortality measures. Previous studies have reported positive, negative, and null effects of retirement on subsequent longevity and mortality hazard, but inconsistent findings are difficult to resolve because (1) nearly all data confound retirement with unemployment of older workers, and often, (2) endogeneity bias is rarely addressed analytically. To avoid these problems, albeit at loss of generalizability to the entire labor force, I examine data from an exceptional subgroup that is of interest in its own right: U.S. Supreme Court justices of 1801-2006. Using discrete-time event history methods, I estimate retirement effects on mortality hazard and years-left-alive. ... Estimates by all these methods are consistent with the hypothesis that, on average, retirement decreases health, as indicated by elevated mortality hazard and diminished years-left-alive. These findings may apply to other occupational groups characterized by high levels of work autonomy, job satisfaction, and financial security."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21948108

Extreme Longevity notes an Italian study: "Sardinia [is] especially rich in male centenarians. The present study was undertaken to quantify and determine which particular lifestyle and nutritional variables endemic to Sardinia males accounted for their extreme longevity. The authors point out that no genetic differences have been found between Sardinian males and less long-lived males found elsewhere in Italy so they reasoned lifestyle choices were more likely causative of their longevity than genetic factors. The researchers specifically compared the frequency of several dietary choices and lifestyle factors between men of Sardinia and Italian men not from Sardinia. It was particularly surprising that diet alone didn't account for the differences. The frequency of meat, cheese, wine, grain and nut consumption was identical in the two groups. Total daily caloric intake was slightly but insignificantly lower in the Sardinian men. The most significant difference found was in the distance to work and average slope of the terrain between the men of Sardinia and those from other regions. The researchers conclude it is likely the large amount of daily physical exercise required to walk long distances up steep mountain climbs that has led to the increased longevity of Sardinian males. They point out the effect of physical exercise on extending longevity is becoming widely recognized, appearing at the conclusion of many scientific articles."

Link: http://extremelongevity.net/2011/10/04/vigorous-daily-exercise-linked-to-extreme-male-longevity/

As I might have remarked upon back in the Fight Aging! archives, there is something about the idea of greatly extending human life through medical technology that sends otherwise sane people off the deep end. Mention the topic and you'll hear screeds on class warfare, relinquishment of progress in medicine, death before inequality, and visions of immortal tyrants lording it over mortal serfs. Nonsense, the lot of it, all utterly divorced from the history that shows us time and again exactly how change, even radical change, progresses in a technological society - but people say this stuff anyway.

there are a great many unrealistic viewpoints in the world that would hinder or halt longevity research, either directly or indirectly. Viewpoints like "the more regulation the better", "prove that you will do no harm at all before we'll let you move forward," or "let us redistribute all property and remove incentives for success and progress, for inequality for any is worse than death for all" spring to mind. In this latter context, "social justice" is a particularly pernicious phrase, being a shorthand for forceful redistribution of wealth by government fiat - institutionalized theft, aimed exactly at the point at which it will do the greatest damage to progress by removing incentives for success.

The world works this way: we can labor and trade to move everyone ahead, benefits for all and inequalities for all, or we can redistribute what presently exists - which at best leads to stagnation and no progress, and at worst becomes a repetition of Soviet era Russia and Eastern Europe. In both cases, inequality will be there - you can't kill it. The choice is whether it's inequality in comparative wealth or inequality in poverty, disease and rubble. Progress is absolutely dependent on freedom and the incentives of wealth earned through hard work and invention.

People react to the prospect of rejuvenation biotechnology in ways that are completely different from their reactions to, say, the highly effective next generation of cancer therapies. You don't hear people declaring that late stage treatments for cancer will split the world into warring factions of haves and have nots, or that all development must be halted until it can be offered to everyone. If you walk through all the varied nonsense spouted on the topic of society and radical life extension, and replace rejuvenation with stem cell heart therapies, or cures for cancer, or organs such as blood vessels grown to order - then you might start to see just how nutty it sounds. Medical technologies just as revolutionary have emerged in the past, and will continue to do so without being hoarded, restricted to the rich, tearing the world asunder, turning brother against brother, and causing cats to lie with dogs.

But aging and longevity has a lot of baggage, it seems. So I see that Sonia Arrison, blogging on radial life extension at the Volokh Conspiracy, took some time early on to address the standard nonsense on class warfare and social justice style "equality":

Could class conflict or even warfare break out over life-extension technologies? It is true that technology is rarely adopted by everyone at the same time, and when life-extending science hits the market, it will almost certainly be used by the wealthy first. ... New technologies are almost always adopted by the rich first, but over time they eventually reach everyone, and the historical record shows that the distribution of new technology is speeding up, not slowing down. For instance, it took forty-six years for one-quarter of the population to get electricity and thirty-five years for the telephone to get that far. It took only sixteen years, however, for one-quarter of American households to get a personal computer, thirteen years for a cell phone, and seven years for Internet access. A more vital example may be AIDS drugs which started off costing about $30,000 per patient per year 15 years ago. Now, better drugs are available and cost $100 per patient. ... The fact that the first users of life-extending technologies will tend to be wealthy increases the chances that the technologies will thrive and eventually reach everybody. Without private investors who believe in the value of a new product and want to support its development, many great ideas would be stillborn. History bears this out, from Queen Elizabeth owning some of the first silk stockings, to wealthy New Yorkers paying $20 in 1915 for a three-minute phone call to San Francisco.

I've long thought it rather sad that so much of our society is bludgeoned into the chattering classes' view of everything laid out in terms of class, conflict, redistribution, forced organization in a top-down fashion, and all the other unfortunate ideals that come with strong centralization of power. Their viewpoints are completely divorced from any sensibility as to how progress actually occurs, or how wealth is in fact created. They are thus one of the first barbarians hammering at the gate: people ignorant of the causes of the success of their society, yet still wealthy enough to be somewhat shielded from the immediate consequences of such ignorance. It never lasts forever, of course: in the end this will come to the same sorry end as Rome or the British Empire, and the US will become a shell of what it once was, a population living amidst the ruins of past grandeur, so constrained by their government as to have forgotten how to achieve greatness and prosperity once again.

The only silver lining is that scientific knowledge is no longer lost alongside the roots of wealth and prosperity; the world has become too small for that, and knowledge will move to the places where it can be best preserved. So those glories, at least, will continue even when the research community that produced them can no longer be sustained.

Researchers continue to explore what stem cells might be able to achieve for the regeneration of serious injuries: "adult human mesenchymal stem cells may have an important role in the treatment and repair of spinal cord injuries. Mesenchymal stem cells (MSCs) are found mainly in the bone marrow and are the focus of many clinical trials that investigate potential methods of neurological repair and other regenerative applications. ...Although mesenchymal stem cells are widely known to be used in replacing damaged tissue, these stem cells may also recruit endogenous cells (those made within the body) to help accelerate the repair process. ... For the first time, [researchers] examined the use of human MSCs to prompt repair of spinal cord injuries in transgenic (genetically engineered or altered) zebrafish embryos. Zebrafish are especially valuable to researchers due to invertebrate characteristics that are similar to those of humans, the transparency of their bodies and their ability to initiate regeneration of damaged tissue. The study demonstrates that human MSCs affix to the injury site and influence spinal cord cells to accelerate the repair process. ... Our results indicate that MSC therapy not only augments recovery after spinal cord injury, but also accelerates the recovery time"

Link: http://www.newswise.com/articles/research-indicates-that-adult-human-mesenchymal-stem-cells-may-be-viable-treatment-for-spinal-cord-injury-repair

Via ScienceDaily: "Glioblastoma is one of the most aggressive forms of brain cancer. Rather than presenting as a well-defined tumor, glioblastoma will often infiltrate the surrounding brain tissue, making it extremely difficult to treat surgically or with chemotherapy or radiation. ... [scientists] developed a method to combine a tumor-homing peptide, a cell-killing peptide, and a nanoparticle that both enhances tumor cell death and allows the researchers to image the tumors. When used to treat mice with glioblastoma, this new nanosystem eradicated most tumors in one model and significantly delayed tumor development in another. ... This is a unique nanosystem for two reasons. First, linking the cell-killing peptide to nanoparticles made it possible for us to deliver it specifically to tumors, virtually eliminating the killer peptide's toxicity to normal tissues. Second, ordinarily researchers and clinicians are happy if they are able to deliver more drugs to a tumor than to normal tissues. We not only accomplished that, but were able to design our nanoparticles to deliver the killer peptide right where it acts - the mitochondria, the cell's energy-generating center. ... In this study, our patients were mice that developed glioblastomas with the same characteristics as observed in humans with the disease. We treated them systemically with the nanoparticles. Once the nanoparticles reached the tumors' blood vessels, they delivered their payload (a drug) directly to the cell's power producer, the mitochondria. By destroying the blood vessels and also some surrounding tumor cells, we were able to cure some mice and extend the lifespan of the rest,"

Link: http://www.sciencedaily.com/releases/2011/10/111003151828.htm

Long-standing businesses must index everything they do to the changing - almost always falling - value of their regional currency, but very few smaller businesses do this in any sort of a deterministic way. Your average talented and determined fellow willing to start a company knows a lot about the business itself, but generally isn't very knowledgeable regarding currencies, inflation, finance, and so forth. That sort of expertise doesn't emerge in a company as a matter of course until it becomes much larger. So smaller businesses deal with the falling value of money by raising their prices as best they can on an ad hoc basis, but this is ever a challenge for products that involve very long memberships. Trying to raise rates on existing customers is, frankly, one of the hardest things a business can do. But raise rates they must, as modern paper currencies have long been set on a relentless spiral of devaluation.

This happens because politicians and government bureaucrats can use the strategic devaluation of their national fiat currency as a way to generate significantly more revenue for a given level of public upheaval than can be achieved through direct taxation - so of course they tend to do exactly that. This is why inflation exists, and is arguably why fiat currencies continue to enjoy such wide, legally-enforced use. So fiat currencies are somewhat systematically, somewhat opportunistically devalued over time in ways that result in a transfer of wealth from the public at large and into the control of politicians, bureaucrats, and their close supporters.

This is one of a number of processes that make long-term prognostication on future costs a challenge. Others include assumptions on the economies of scale that will emerge with success in development, or success in popularity of a product - successful products invariably become much cheaper as they become more widespread. This happens because competitors figure out more effective means of building the product, and because it is usually cheaper on a per-unit cost to build a hundred widgets rather than ten widgets.

The cryonics industry is presently running into a number of these issues. It offers products that are commonly paid for over decades, or where decades might elapse between the ink drying on a contract and the actual provision of service. The industry is decades old, but never grew to the point at which experience in managing the consequences of currency devaluation and other long-term strategic issues would naturally emerge amongst the major players in a field. At Alcor, this manifests as a growing underfunding issue, and to the credit of the present management they are openly publishing their current thinking on the matter:

The cryonics economies anticipated by Robert Ettinger in 1965 were never realized. By the 1970s, the cost of whole body cryopreservation as offered by TransTime and Soma (the for-profit arm of IABS, which later merged with Alcor) was $60,000. As shown in Fig. 1, the nominal dollar cost of cryonics has risen steadily with Consumer Price Index (CPI) inflation since then. By 2011, the minimum funding for whole body cryopreservation with Alcor was $200,000. Even this large number has not kept pace with inflation, so another increase will be necessary soon.

Whenever Alcor has increased cryopreservation minimums, it has traditionally only required new members to meet new minimum funding requirements. Existing members were "grandfathered," and allowed to remain members even if their cryopreservation funding fell below new minimums. This was and is believed to be important for members who due to age or disability become uninsurable, and would otherwise have to leave Alcor after many years of supporting the organization. ... However the main way that Alcor coped with grandfathering was by just taking the loss on what was historically a small number of underfunded cases. There was never a quantitative analysis of the impact of grandfathering, or a specific financial plan for dealing with it. ... The sustainability of this has been questioned on numerous occasions.

You should read the whole thing; it outlines the problem, puts numbers to it to show the size, and presents a range of possible solutions, along with discussion of their merits.

The bottom line is that businesses must act like businesses, even when they have their roots in the non-profit space, research, advocacy, and saving the world, as is the case for most of the ongoing cryonics concerns. There's no such thing as a free lunch, and the cost of providing a service has to be met somehow - if it isn't, then the whole product structure and relationship with the customer has to be rethought. The challenges of managing business agreements across decades have to be addressed by cryonics providers one way or another, such as by continually and clearly indexing against inflation for customers, or by using specialized financial instruments akin to futures contracts, as is the practice in many industries that have to make very long-term commitments and want to shield their customers from the complexity inherent in doing that.

In practice, things are always more complicated and intricate than the sweeping statements I give above, but I think an organization willing to put out a document that talks through their issues in this way is an organization with the right mindset to come to a solution. Openness is a virtue in this modern world, and I think that it is a very beneficial approach to customer relations when those relations have to extend across decades. Many of the most successful companies can be said to have communities as much as they have customers, and I don't see that as being a bad thing for the cryonics industry.

MItochondrial function, structure, and damage are clearly important to longevity, both within and between species, so it should be no surprise to find mitochondrial DNA haplogroups associated with variations in human longevity: "Human longevity is a complex heritable genetic trait. Based on substantial evidence from model organisms, it is clear that mitochondria play a pivotal role in aging and lifespan. However, the effects that mitochondrial genome variations have upon longevity and longevity-related phenotypes in Zhuang people in China have yet to be established. By genotyping 15 variants for 10 haplogroups in 738 Zhuang subjects, including 367 long-lived individuals and 371 controls, we found that haplogroup F was significantly associated with longevity in females of Zhuang population of China. Additionally, haplogroup F was related to higher HDL levels in long-lived individuals. Further analysis suggests that the non-synonymous variant m.13928G>C in haplogroup F was also associated with longevity in female Zhuang Chinese which might account for the beneficial effect of F."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21945877

The Volokh Conspiracy on the correlations between health and wealth in a region, a connection with compelling evidence both before and after the Industrial Revolution: "for most of history, gains in human life expectancy were made at the beginning, not the end of life. It is true that older people have always been part of society, but they were less numerous and more weathered than today's seniors. ... But that is not the end of the story. Rather, it is the beginning of a new chapter where humanity takes on ill health and death at later ages. Indeed, those efforts have already had an impact on the growth of life expectancy. ... For many years, it's been clear that there is a positive correlation between health and wealth, but it was most commonly thought that wealth creates health. While it is certainly true that the rich can afford to take better care of themselves, it is now known that health also begets wealth. Put another way, poor health causes a decline in productivity for the simple reason that it's very difficult to work effectively when you're in ill health, thereby increasing the chances of falling into poverty. ... based on the available research, if there are 'two countries that are identical in all respects, except that one has a 5 year advantage in life expectancy,' then the 'real income per capita in the healthier country will grow 0.3-0.5% per year faster than in its less healthy counterpart.' While these percentages might look small, they are actually quite significant, especially when one considers that between the years of 1965 to 1990, countries experienced an average per capita income growth of 2% per year. When countries only have an average growth of 2%, an advantage of 0.5% is quite the boost. Now, those numbers are based only on a 5 year longevity advantage. What if a country had a 10, 20, or 30 year advantage? The growth may not continue on a linear basis, but if the general rule holds - a jump in life expectancy causes an increase in economic growth per capita - then having a longer-lived population would facilitate enormous differences in economic prosperity."

Link: http://volokh.com/2011/10/04/healthier-and-wealthier/

I stumbled upon a series of open access review papers today, entitled "The Changing Understanding of Aging," written by a veterinarian for an audience of practitioners largely unfamiliar with the history and present state of aging research. As a consequence it's very readable for the layperson, and it really doesn't matter that the papers are as much focused on the animal kingdom as on human research: at the high level much of what is the case for the mammals we keep as pets is also the case for humans - the same theories apply. Only the details of our biochemistries are different, which does lead to greatly differing life spans and rates of aging, but all proceeding according to much the same fundamental mechanisms.

Part 1: Evaluating ageing theories and studies (Full PDF)

This is the first of three discussions on emerging views of ageing, its derivation, and ageing-related diseases. To offer a context for the series, this first report briefly reviews several major early and recent theoretical debates. Arguments for and against several well-known ageing theories are presented for their veterinary relevance, including mutation, pleiotropy, reproduction-longevity trade-offs, oxygen metabolism and ageing as a genomically programmed product of natural selection. ... Central ideas of these discussions include why post-reproductive life span is relatively common among animals, the nature of age-related diseases relative to stochastic or programmed origins and the disease-related implications.

Part 2: Body composition, metabolism and cell death (Full PDF)

This second of three discussions about ageing biology and diseases continues at the level of the organism, examining the relationship among body composition, late life and diseases. ... Sarcopenia is declining mass and strength of skeletal muscle during aging. Healthy humans experience a 20%-40% reduced physical strength during decades 7 and 8. In one study, prevalence of sarcopenia among 883 elderly persons ranged from 13%-24% over the ages 65 to 70 and >50% after the age of 80. ... It is disconcerting that investigators have identified early skeletal muscle mass decline in some humans, with substantial change by decade five. Potential life span implications for individuals in this category need to be monitored by primary care and specialist physicians, and not just by geriatricians. Additional implications are that new studies need to be conducted to establish whether or how subtle mid-life changes in muscle mass and strength can be observed across animal species and what concerns accrue for their health and longevity.

Part 3: Diseases of ageing (Full PDF)

A contentious debate revolves around whether ageing is purely a combined effect of stochastic events on residual programming relating to reproductive robustness, or whether ageing itself is programmed by natural selection. Emerging data indicate that the influence of genetic programming on specific late-life diseases, and even individual tissue pathologies, will probably need to be reconsidered in the light of newer theoretical possibilities.

An unpleasant conjecture outlined via EurekAlert!: "The brain damage that characterizes Alzheimer's disease may originate in a form similar to that of infectious prion diseases such as bovine spongiform encephalopathy (mad cow) and Creutzfeldt-Jakob, according to newly published research ... Our findings open the possibility that some of the sporadic Alzheimer's cases may arise from an infectious process, which occurs with other neurological diseases such as mad cow and its human form, Creutzfeldt-Jakob disease. The underlying mechanism of Alzheimer's disease is very similar to the prion diseases. It involves a normal protein that becomes misshapen and is able to spread by transforming good proteins to bad ones. The bad proteins accumulate in the brain, forming plaque deposits that are believed to kill neuron cells in Alzheimer's. ... Researchers injected the brain tissue of a confirmed Alzheimer's patient into mice and compared the results to those from injected tissue of a control without the disease. None of the mice injected with the control showed signs of Alzheimer's, whereas all of those injected with Alzheimer's brain extracts developed plaques and other brain alterations typical of the disease. ... We took a normal mouse model that spontaneously does not develop any brain damage and injected a small amount of Alzheimer's human brain tissue into the animal's brain. The mouse developed Alzheimer's over time and it spread to other portions of the brain. We are currently working on whether disease transmission can happen in real life under more natural routes of exposure." It's probably best not to get too worked up about this sort of thing, concerning though it is. Many conditions can be made to be transmissible through the intervention of biotechnology, but that doesn't mean they are normally so in any meaningful way, and the prion diseases are not easy to transmit. The assumption at this point, based on the weight of evidence, should still be that Alzheimer's is something that in the vast majority of cases your body does on its own, and you bear a level of risk strongly associated with your lifestyle choices.

Link: http://www.eurekalert.org/pub_releases/2011-10/uoth-uam100311.php

From FuturePundit: "Myelin is insulation around nerves and is essential for the conduction of impulses along nerves. The ability to grow pure populations of cells that make myelin brings us closer to effective treatments for multiple sclerosis and other diseases characterized by the loss of myelin. ... Scientists [found] a way to rapidly produce pure populations of cells that grow into the protective myelin coating on nerves in mice. Their process opens a door to research and potential treatments for multiple sclerosis, cerebral palsy and other demyelinating diseases afflicting millions of people worldwide. ... These results matter to us all. Why? We all suffer from a demyelinating disease called aging. One of the reason older folks have harder times with memory recall, coordination, and other mental tasks is that myelin deteriorates with age. The ability to restore myelin is an essential rejuvenation therapy. Therefore the pursuit of effective treatments for MS and other demyelinating diseases will yield useful therapies for brain rejuvenation. Just about any therapy aimed at repairing damage caused by a specific disease will also be useful for rejuvenation. Aging causes very diffuse damage to all the tissues in the body. When enough of that damage accumulates in a single organ or structural element disease emanating from a specific location emerges. But the localized disease is really just part of a bigger pattern of damage accumulation. So therapies aimed at repair of specific locations in the body will have a great deal of overlap with therapies aimed at full body rejuvenation."

Link: http://www.futurepundit.com/archives/008312.html

People who make decisions involving very large amounts of money are not necessarily right any more often than the rest of us, but they do put in a great deal more groundwork and research in the course of making these decisions. In the gargantuan life insurance and pensions marketplace, where the long-term success of multinational conglomerates rests on good predictions of life expectancy, that amounts to a lot of time spent thinking about the near future of human longevity and medical technology.

The results of that work are not terribly secret. Industry mouthpieces update and publish the present consensus expectation for human life expectancy, as well as the consensus on the chances of that expectation being wrong, and the consensus on how large the errors might be. Then there are other analysts who watch the actions of various insurance and pensions giants in order to decide how that relates to what will happen to human life spans in the decades ahead - and on top of that, there are a whole range of big financial institutions that offer forms of insurance and risk management for the life insurance and pensions industry, trying to make money by better guessing the risk of error than other specialists.

I look on all this activity in two ways: firstly, it is a useful pathway for wider education on longevity science. The actuaries are aware of research and its implications long before the general public, and they are also hooked into business machinery that widely publishes their analysis and viewpoints. As a result, many people will be convinced about the prospects for engineered human longevity by the materials produced by the financial industry rather than those produced by patient advocates, scientists, and the medical industry.

Secondly, the work and publications of actuaries are a barometer for how compelling and widespread the arguments have become for significantly extending healthy human life through biotechnology. In this, I tend to pay attention to the pace at which their estimates are changing rather than the estimates themselves - it is my opinion that great financial upheaval lies ahead as sudden, large, and uncertain gains in life expectancy for older people are unlocked by advances in biotechnology. Present estimates are rather tied to the slow model of incidental life extension rather than the far more uncertain timeframe for the arrival of ways to achieve deliberate slowing and reversal of aging.

You might have a look at this recent article as an example of the sort of thing that catches my eye; the bigger picture of comparatively rapid changes in actuarial assessments is a good thing. It means that more people are paying attention to what is going on in the laboratory, and thinking clearly about what that means for the future.

The [UK's] biggest firms have increased their pensioner longevity assumptions for the fifth year running in a move which has added about 1% to scheme liabilities, Mercer says. Research from the consultant found FTSE100 companies had increased their UK longevity assumptions by about three months for current pensioners and by about five months for future retirees compared to the previous report in December 2009. It said, on average, male scheme members aged 65 are projected to live until 87.2, while those currently aged 45 who survive until 65 are expected to live until 89.2. Mercer said this represented an increase of about two years in life expectancy from its 2006 report - which means companies believe life expectancy has improved faster than previously expected, which has added to pension bills.

My suspicion is that anyone taking a large financial position that in effect depends on today's average 45-year-old dying on time in 2055 stands a good chance of losing their shirt. The guesstimate technologies of that decade veer into places that are hard to predict; it should be past the first business cycles of molecular manufacturing, for example, and at the same time benefit from fully mature technologies based on regenerative medicine, organ regrowth, and other forms of control over the body's cells and their state.

An increasing weight of evidence links ongoing to damage to blood vessels in the brain with loss of cognitive ability as people grow older. Here is another example: "Cerebral microbleeds (MBs) are an important indicator of cerebral small-vessel disease, and their prevalence increases with increasing age. Little is known about the functional consequences of MBs in the aging population. In this study we investigated whether the presence and location of MBs are associated with cognition in the PROSPER study. ... For 439 subjects the number and location (cortico-subcortical, deep white matter, basal ganglia, and infratentorial) of the MBs was recorded. Difference in cognitive performance between subjects with and without MBs was calculated by entering the variables sex, age, white matter hyperintensity volume, infarction, and MBs in a linear mixed model. Differences in cognition between subjects with and without one or more MBs at different anatomic locations were assessed using the same model. ... We found that after correction for sex, age, white matter hyperintensity volume, and infarction, subjects with infratentorial MBs had a significantly lower score on the Immediate Picture-Word Learning test, Delayed Picture-Word Learning, and Instrumental Activities of Daily Living. ... Our data demonstrate that in elderly individuals at increased vascular risk, infratentorial MBs are associated with loss in cognitive functioning." The only practical, widely available ways to slow down blood vessel aging at the present time are exercise and calorie restriction, but future therapies - such as those built upon the SENS platform - will have to do better and actually reverse damage in the old.

Link: http://www.ncbi.nlm.nih.gov/pubmed/21956727

Here's a popular press article that discusses the concept of actuarial escape velocity: "Someone you know could live to be 1,000 years old, according to Aubrey de Grey ... Even for people in good health, cells become damaged through the course of a human life, de Grey said. It's a solvable problem, he said, by providing maintenance to damaged cells. He cited stem cell research and using bacteria as possible means of restoring cells to their youthful state, which would lengthen life - perhaps infinitely. 'It's all about restoring organs and tissue to the way it was before it suffered some sort of damage,' he said, comparing the process to the maintenance that can keep cars running for decades.The research that could lead to these techniques is further along than most people realize, de Grey said, and could begin providing therapies within the next 25 years. Or not, he added, but the possibility exists that today's 20-somethings could be alive in 3011. Not only would they be alive, but they'd be able to live well, he said. The progress toward treatments that can provide such longevity will be incremental, though. The therapies that might exist in 25 years may restore a 90-year-old's body to a 60-year-old's health, but would not extend life indefinitely, he said. The key is reaching what de Grey called 'longevity escape velocity' - the rate of aging combined with the rate of the medical advancements that will prolong life to before-unthinkable lengths. An 80-year-old in 2011 hasn't much hope of living forever, he said, but the younger a person is, the better their chances of living in an age when drastically age-prolonging therapies exist."

Link: http://www.courier-journal.com/article/20110924/NEWS01/309240053