An article from the New England Journal of Medicine has been doing the rounds: it looks at some of the changing causes of mortality over the past century. These changes are signs of success in the progress of medicine and technology: both might be thought of as the search for ways to prevent suffering and death - one cause at a time. With each passing generation in a time of progress, some of those causes are largely eliminated, leading to a shift in focus and new targets. The degree to which infectious disease has been tamed is very clear from the graphics in the article, though there is always much more to be done on that front:

The article itself really isn't worth reading - the authors burble about policy without really saying anything, and certainly nothing meaningful is put forward. It's exactly the sort of thing you don't want to hear from people involved in research or medicine. If you can't clearly say "it's a priority to build new and better medicine, and we're working on a portion of that goal right now," then probably best to leave the conversation about medicine to other people. Here the peanut gallery has more to offer in the way of occasional meaningful comments:

The first thing to notice here is how much our mortality rate has dropped over the course of a century, largely due to big reductions in infectious diseases like tuberculosis and influenza.

On the large scale, medicine chases the priorities of the now - and in wealthier regions of the world that has become cancer and heart disease. The size of the cancer and heart disease research communities reflects the present degree to which the two groups of conditions contribute to human mortality. What it does not yet reflect is the new and more meaningful unified way of looking at the conditions that kill the most people: that they are all caused by aging, and stem at root from a limited range of mechanisms and changes that happen over the years as a byproduct of our normal metabolism. We rust, and that rust blossoms into a thousand different failure modes. Yet medical science is still largely focused on end states, and patching over catastrophic damage rather than preventing its origins.

To keep reducing the human mortality rate, the research community has to start in on prevention in the form of repair biotechnologies - ways to halt and reverse the earliest development of the age-related conditions that kill most people. It is as much a cultural change in the life sciences as it is a technical challenge, as the path ahead is fairly clear. This is why organizations like the SENS Foundation, mixing aggressive advocacy with targeted research work where few others are making progress, are so important. It is not so much that they will get the work done by themselves, but that they will spawn a sea change in the research community, such that many, many groups will tomorrow be performing similar work with similar end goals: to to be able to treat and reverse the course of aging.

You might think of a focus on aging and its causes as the germ theory of today's medical community: a unifying set of ideas and resulting research strategies that will bring the bulk of the medical community onto a better path forward, one that will lead to a more rapid improvement in the human condition, and longer, healthier lives for all.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

It is always a good idea to learn more about how the other half of the world thinks. Most people are closer to the values of social justice than the values of libertarianism, for all that that sort of "justice" (i.e. forced redistribution and mob envy) is just as destructive of wealth and progress as communism or fascism when put into earnest practice. It becomes a tyranny of egalitarianism, a leveling down, a tearing down of the high points of society, the groups that produce advances in technology. One of the values of reading In Search of Enlightenment is seeing the thinking that leads someone enmeshed in the culture of social justice - whose members characteristically belittle or reject scientific progress and the markets that drive it - come to advocate for longevity science and the defeat of aging: "Over the past decade I have worked at the intersection of issues in political philosophy/theory and the medical sciences. I have tried to help bridge what I take to be a troublesome divide between the field most concerned with ideals of justice and equality, and scientific advances (especially in the field of biogerontology) which could profoundly improve human health and prosperity. These two things are linked in important ways, but there is very little actually written by theorists on these kinds of topics. Bridging this gap is an up-hill struggle for a variety of reasons. The theoretical concepts and normative theories developed in political philosophy over the past 4 decades either ignored the realities of morbidity (e.g. like the fact that aging is a major risk factor for disease) or just assumed people went through their complete lives as 'healthy and productive members of society'. This meant the (almost exclusive) focus of theories of distributive justice was on the distribution of wealth and income. A fair society could be measured, so went the reasoning, to a large extent by the pattern of the distribution of a society's wealth. And the extent to which theories of justice have expanded, in the last 2 decades, to tackle topics like global justice and health, they are still constrained by the original assumptions and limited perspectives/concepts with which the dominant normative theories were originally devised. In other words, taking a theory of domestic justice designed to apply to a healthy and affluent society and then trying to make a few modifications once you take disease and debt seriously is not, imho, a recipe for success."

Link: http://colinfarrelly.blogspot.com/2012/06/how-to-put-aging-and-biogerontology-in.html

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Decellularization involves stripping out the original cells from a donor organ and then repopulating it with cells grown from the recipient's tissue - thereby removing the possibility of immune rejection. One implication of this approach is that the donor doesn't necessarily have to be human: "In proof-of-concept research [a] team successfully used pig kidneys to make 'scaffolds' or support structures that could potentially one day be used to build new kidneys for human patients. The idea is to remove all animal cells - leaving only the organ structure or 'skeleton.' A patient's own cells would then be placed on the scaffold, making an organ that the patient theoretically would not reject. ... this is one of the first studies to assess the possibility of using whole pig kidneys to engineer replacement organs ... For the research, pig kidneys were soaked in a detergent to remove all cells, leaving behind the organ's 'skeleton,' including its system of blood vessels. In addition, the structure of the nephron - the kidney's functional unit - was maintained. The scaffolds were implanted in animals, where they were re-filled with blood and were able to maintain normal blood pressure, proving that the process of removing cells doesn't affect the mechanical strength of the vessels. ... It is important to identify new sources of transplantable organs because of the critical shortage of donor organs. These kidneys maintain their innate three-dimensional architecture, as well as their vascular system, and may represent the ideal platform for kidney engineering."

Link: http://www.eurekalert.org/pub_releases/2012-06/wfbm-lkp062112.php

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Crowdfunding of commercial products is having a lengthy day in the sun at the moment. It has emerged from years of great success in small markets, such as the pen and paper gaming and indie publishing industries, and people are now applying the same models to fields where much more money is involved. Quite successfully too, some raising millions in what amount to well-run and timely preorder campaigns for products yet to be built. The range of endeavors open to crowdfunding of course includes scientific research, which is why it is a topic that shows up here every now and again:

If you can raise money for books, art projects, and widgets, why not for discrete life science research projects with determined goals? The LongeCity (previously the Immortality Institute) crowd have been trying this for some years, with a great deal of success considering the limited audience of this community in comparison to the audience available through Kickstarter. It is sad but true that far more people are brought to a state of excitedly opening their wallets for the development of an iPhone widget than for any sort of biotechnology project, even one that will contribute to the reversal of aging.

If you have a dedicated community, then you want to turn that dedication into professional organizations and the funds to run them. This is always going to be a messy, organic process of development, but which perhaps may be open to improvement through the spread of a more formalized crowdfunding culture. But in any case, I wanted to expand on the point made in the quote above - that crowdfunding for scientific research is a radically different undertaking from crowdfunding for development of a commercial product. This seems worth emphasizing, given that a whole range of startups and new ventures seem to be trying to port over crowdfunding into the sciences pretty much as-is, or with just a few embellishments. Like these, for example:

• EurekaFund
• FundaGeek
• GeekFunder
• Microryza
• Petridish
• Rockethub
• Sciflies

What we can hope for from this wealth of effort is that some groups figure out the magic formula that will make science funding work in this environment - and make it work with the same degree of liquidity and interest as in commercial projects. Experimentation is clearly needed, however.

The basic point of divergence between crowdfunding a product versus crowdfunding research is that in the former case the funders are definitively buying something concrete: that is their motivation and incentive. They are putting down money in expectation that what they are doing is submitting a preorder. Variations on the preorder theme are legion, but they all boil down to paying for a definitive item, a which will usually have fairly solid delivery date. Scientific research is notoriously bad when it comes to delivering on both those points, however. The work that is most amenable to crowdfunding consists of small projects that only incrementally add value to their fields - and which may not even do that, given the necessarily high failure rate for research.

The challenge facing science crowdfunding is the same challenge faced by scientific advocates at all times: they do their part to grow communities of supporters and encourage those supporters to pay for research work. That work will give no immediate result, the eventual result may be hard for supporters to understand, it will likely not benefit them for some time, if ever, and in addition to all of that the undertaking will quite likely fail. Science is a high risk endeavor, with few short-term payoffs that people find rewarding - and thus it is a hard sell when held up against the allure of immediate gratification, candy, and shiny objects.

But technological progress is the only thing that matters, not today's pretty baubles that are made possible by past successes in science. Funding of science has to be made to work if we want to continue on this upward curve to longevity, wealth, and expansion of what it means to be human.

Despite all of the challenges, the old messy, organic way of funneling money into scientific projects does in fact make progress. People who care about the end result, something decades away, do step up to fund science. You might look at our little community of longevity science enthusiasts for example, making noise and raising somewhere north of $14 million over the past eight years for organizations and initiatives like the Methuselah Foundation, the New Organ Prize, and the SENS Foundation. Knowing that this is possible, and regardless of the fact that it is hard, very hard, to convince people to open their wallets for science, you have to look at what's happening in the crowdfunding space right now and think that fundraising for science could all be made easier - if someone just goes about it in the right way, builds the right tools, hits the right business model, pulls together the right sort of seed community.

And maybe so. I've watched most of a decade of a small community funding research, and the cryonics advocates have watched much the same thing for far longer, but I don't have any good answers - and I'm not sure that they do either. So it is a good thing that a number of venture funded and bootstrapped groups are working on this; they'll have a few years of runway to work on finding the key to the problem, and we'll all benefit should one of them come up with a good way forward.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Crowdfunding of commercial products is having a lengthy day in the sun at the moment. It has emerged from years of great success in small markets, such as the pen and paper gaming and indie publishing industries, and people are now applying the same models to fields where much more money is involved. Quite successfully too, some raising millions in what amount to well-run and timely preorder campaigns for products yet to be built. The range of endeavors open to crowdfunding of course includes scientific research, which is why it is a topic that shows up here every now and again:

If you can raise money for books, art projects, and widgets, why not for discrete life science research projects with determined goals? The LongeCity (previously the Immortality Institute) crowd have been trying this for some years, with a great deal of success considering the limited audience of this community in comparison to the audience available through Kickstarter. It is sad but true that far more people are brought to a state of excitedly opening their wallets for the development of an iPhone widget than for any sort of biotechnology project, even one that will contribute to the reversal of aging.

If you have a dedicated community, then you want to turn that dedication into professional organizations and the funds to run them. This is always going to be a messy, organic process of development, but which perhaps may be open to improvement through the spread of a more formalized crowdfunding culture. But in any case, I wanted to expand on the point made in the quote above - that crowdfunding for scientific research is a radically different undertaking from crowdfunding for development of a commercial product. This seems worth emphasizing, given that a whole range of startups and new ventures seem to be trying to port over crowdfunding into the sciences pretty much as-is, or with just a few embellishments. Like these, for example:

• EurekaFund
• FundaGeek
• GeekFunder
• Microryza
• Petridish
• Rockethub
• Sciflies

What we can hope for from this wealth of effort is that some groups figure out the magic formula that will make science funding work in this environment - and make it work with the same degree of liquidity and interest as in commercial projects. Experimentation is clearly needed, however.

The basic point of divergence between crowdfunding a product versus crowdfunding research is that in the former case the funders are definitively buying something concrete: that is their motivation and incentive. They are putting down money in expectation that what they are doing is submitting a preorder. Variations on the preorder theme are legion, but they all boil down to paying for a definitive item, a which will usually have fairly solid delivery date. Scientific research is notoriously bad when it comes to delivering on both those points, however. The work that is most amenable to crowdfunding consists of small projects that only incrementally add value to their fields - and which may not even do that, given the necessarily high failure rate for research.

The challenge facing science crowdfunding is the same challenge faced by scientific advocates at all times: they do their part to grow communities of supporters and encourage those supporters to pay for research work. That work will give no immediate result, the eventual result may be hard for supporters to understand, it will likely not benefit them for some time, if ever, and in addition to all of that the undertaking will quite likely fail. Science is a high risk endeavor, with few short-term payoffs that people find rewarding - and thus it is a hard sell when held up against the allure of immediate gratification, candy, and shiny objects.

But technological progress is the only thing that matters, not today's pretty baubles that are made possible by past successes in science. Funding of science has to be made to work if we want to continue on this upward curve to longevity, wealth, and expansion of what it means to be human.

Despite all of the challenges, the old messy, organic way of funneling money into scientific projects does in fact make progress. People who care about the end result, something decades away, do step up to fund science. You might look at our little community of longevity science enthusiasts for example, making noise and raising somewhere north of $14 million over the past eight years for organizations and initiatives like the Methuselah Foundation, the New Organ Prize, and the SENS Foundation. Knowing that this is possible, and regardless of the fact that it is hard, very hard, to convince people to open their wallets for science, you have to look at what's happening in the crowdfunding space right now and think that fundraising for science could all be made easier - if someone just goes about it in the right way, builds the right tools, hits the right business model, pulls together the right sort of seed community.

And maybe so. I've watched most of a decade of a small community funding research, and the cryonics advocates have watched much the same thing for far longer, but I don't have any good answers - and I'm not sure that they do either. So it is a good thing that a number of venture funded and bootstrapped groups are working on this; they'll have a few years of runway to work on finding the key to the problem, and we'll all benefit should one of them come up with a good way forward.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

To go along with a recent post on cell therapies for nerve regeneration, here researchers investigate a different set of mechanisms: "A protein required to regrow injured peripheral nerves has been identified by researchers. ... The finding, in mice, has implications for improving recovery after nerve injury in the extremities. It also opens new avenues of investigation toward triggering nerve regeneration in the central nervous system, notorious for its inability to heal. ... scientists show that a protein called dual leucine zipper kinase (DLK) regulates signals that tell the nerve cell it has been injured - often communicating over distances of several feet. The protein governs whether the neuron turns on its regeneration program. ... How does an injured nerve know that it is injured? How does it take that information and turn on a regenerative program and regrow connections? And why does only the peripheral nervous system respond this way, while the central nervous system does not? We think DLK is part of the answer. ... If an axon is severed somewhere between the cell body in the spinal cord and the muscle, the piece of axon that is no longer connected to the cell body begins to disintegrate. Earlier work showed that DLK helps regulate this axonal degeneration. And in worms and flies, DLK also is known to govern the formation of an axon's growth cone, the structure responsible for extending the tip of a growing axon whether after injury or during development. The formation of the growth cone is an important part of the early, local response of a nerve to injury. But a later response, traveling over greater distances, proves vital for relaying the signals that activate genes promoting regeneration. This late response can happen hours or even days after injury. But in mice, unlike worms and flies, [DLK] is not involved in an axon's early response to injury. Even without DLK, the growth cone forms. But a lack of DLK means the nerve cell body, nestled in the spinal cord far from the injury, doesn't get the message that it's injured. Without the signals relaying the injury message, the cell body doesn't turn on its regeneration program and the growth cone's progress in extending the axon stalls. ... A neuron that has seen a previous injury now has a different regenerative program than one that has never been damaged. We hope to be able to identify what is different between these two neurons - specifically what factors lead to the improved regeneration after a second injury. We have found that activated DLK is one such factor. We would like to activate DLK in a newly injured neuron to see if it has improved regeneration."

Link: http://www.sciencedaily.com/releases/2012/06/120620132926.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Here is another paper suggesting that resveratrol isn't necessarily a great place to be spending hundreds of millions of dollars on research and development, given the poor results in studies that evaluate its effects. In an ideal world this money that would go towards improving biotechnology rather than the old-school approach of mining the natural world for compounds that maybe do more good than harm: "Resveratrol has shown evidence of decreasing cancer incidence, heart disease, metabolic syndrome and neural degeneration in animal studies. However, the effects on longevity are mixed. We aimed to quantify the current knowledge of life extension from resveratrol. We used meta-analytic techniques to assess the effect resveratrol has on survival, using data from 19 published papers, including six species: yeast, nematodes, mice, fruitflies, Mexican fruitflies and turquoise killifish. Overall, our results indicate that resveratrol acts as a life-extending agent. The effect is most potent in yeast and nematodes, with diminished reliability in most higher-order species. Turquoise killifish were especially sensitive to life-extending effects of resveratrol but showed much variation. Much of the considerable heterogeneity in our analysis was owing to unexplained variation between studies. In summary, we can report that few species conclusively show life extension in response to resveratrol. As such, we question the practice of the substance being marketed as a life-extending health supplement for humans."

Link: http://dx.doi.org/10.1098/rsbl.2012.0316

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A fellow that you met today will, forty years from now, have an entirely artificial immune system. It is an early model, a prosthetic replacement that is a mix of synthetic cells and less organic medical nanomachines, and requires frequent work and an open data channel to keep in line. Obtaining it wasn't a choice - it is a new treatment for a small class of acquired autoimmune conditions that somehow manage to persist through complete removal and replacement of immune cell populations. It works; he doesn't get sick, at all. Ever.

Nonetheless, you shook this man's hand today. That future lies in waiting.

Earlier you passed by a kid who will outlive you, your plans, your memory, your immediate descendants, and the first phase of terraforming to take place on Mars. The young have it good these days: a solid eighty years of probable-worst-case life expectancy at birth that will take them well into the first age of radical life extension - and that even if the next twenty years take us through a miserable economic depression coupled with a spread of repressive regulatory regimes that effectively stifle life science research and its application. Many of the youngest children of today will live for centuries, and many of those will go on to live for thousands of years.

You walked right by that kid. In fairness, he doesn't know either, of course.

Then there's that new face at the office, fresh out of college: by the 2070s she'll be a shell of the person she was. A happy shell, however, the original exterior polished up by gene, cell, and enzyme therapies to minimize the changes of aging in skin and musculature, but all of the interior organs below the neck new from labs in Thailand and Vietnam over the years, grown from her own genetic material. That took money, even though it's second string organ biotechnology by that time - but the sharp average worker you can save enough to afford that sort of thing over a lifetime. It's not as though she'll be retiring any time soon, and better low on funds than living like a 80-year old from a century past.

That probably didn't cross your mind today when the two of you happened to be in the same meeting.

The point here is this: the next half century is shaping up to be a transformation to match the last, but this time in biotechnology and medicine as well as in computing. These little snapshot nascent futures are no different than my 1960s analog describing to you the future of a then-20-something-and-now-70-something individual: surrounded by monitors; in touch with distant corners of the world at the click of a button; the world's encyclopedias and research institutions available at a moment's notice; living drenched in a wealth of knowledge, and connected to half the world's population in near-instant communication; possessing such massive reserves of computation power that enormous multi-machine simulations run for little more than entertainment value; connected to this web of knowledge and communication by radio, microwave, and pocket-devices that can be used near anywhere; amidst a sea of surging culture, charged by a hundred million voices all talking at once.

This is an age of change, and much lies ahead of us. The potential for what sounds like science fiction - radical life extension, artificial organs and bodily systems, the defeat of disease and aging - lies nascent and dormant, awaiting those who will carve it from the passage of time, who will do the work to make these dreams a reality.

This is the time for it.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

You might recall the species of clam that can live for at least four centuries. Similarly, you might also recall the membrane pacemaker hypothesis that explains differences in longevity between species in terms of the resistance of cell membranes - and especially mitochondrial membranes - to damage. Here, the two topics are linked: "The deleterious reactive carbonyls released upon oxidation of polyunsaturated fatty acids in biological membranes are believed to foster cellular aging. Comparative studies in mammals and birds have shown that the susceptibility to peroxidation of membrane lipids (peroxidation index, PI) is negatively correlated to longevity. Long-living marine molluscs are increasingly studied as longevity models, and the presence of different types of lipids in the membranes of these organisms raises questions on the existence of a PI-longevity relationship. We address this question by comparing the longest-living metazoan species, the mud clam Arctica islandica (maximum reported longevity = 507 y) to four other sympatric bivalve molluscs greatly differing in longevity (28, 37, 92, and 106 y). We contrasted the acyl and alkenyl chain composition of phospholipids from the mitochondrial membranes of these species. The analysis was reproduced in parallel for a mix of other cell membranes to investigate if a different PI-longevity relationship would be found. The mitochondrial membrane PI was found to have an exponential decrease with increasing longevity among species and is significantly lower for A. islandica. The PI of other cell membranes showed a linear decrease with increasing longevity among species and was also significantly lower for A. islandica. These results clearly demonstrate that the PI also decreases with increasing longevity in marine bivalves and that it decreases faster in the mitochondrial membrane than in other membranes in general. Furthermore, the particularly low PI values for A. islandica can partly explain this species' extreme longevity." This emphasizes the importance of mitochondrial damage in aging and longevity, and thus the importance of research into mitochondrial repair biotechnologies for humans.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22708840

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

There's a fair amount of evidence implicating cytomegalovirus (CMV) in immune system decline, rhe theory here being that the immune system devotes ever more of its fixed resources to dealing with the largely harmless variants of this virus that it cannot clear. Here researchers argue against that view: "Aging is accompanied by the development of low grade systemic inflammation, termed 'inflammaging', characterised by raised serum C-reactive protein (CRP) and pro-inflammatory cytokines. Importantly, inflammaging is implicated in the pathogenesis of several of the major age-related diseases including cardiovascular disease, type 2 diabetes and dementia and is associated with increased mortality. The incidence of infection with the persistent herpes virus cytomegalovirus (CMV) also increases with age. Cross-sectional studies have proposed CMV infection as a significant driver of inflammaging, but a definitive case for CMV as a causative agent in inflammaging has not yet been made. We studied longitudinally 249 subjects (153 men, 96 women) who participated in the Hertfordshire Ageing Study at baseline (1993/5, mean age 67·5 years) and at 10 year follow up. At both times [subjects] provided blood samples for analysis of inflammatory status and CMV seropositivity. In the cohort as a whole, serum CRP and pro-inflammatory cytokines [were] increased between baseline and follow up ... These changes to cytokine status over time occurred equally in the 60% of subjects who were seropositive for CMV at baseline and follow up, the 8% who were CMV negative at baseline but who became CMV positive by the 10 year follow up, and also in the 32% who were CMV seronegative throughout. We conclude that CMV infection is not a primary causative factor in the age-related increase in systemic inflammation."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22708923

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm