FIGHT AGING! NEWSLETTER
January 6th 2014
The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!
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- Looking Back at 2013
- How Can Programmed Death Be Adaptive?
- International Longevity Alliance 2013 Report and 2014 Roadmap
- A Series of Popular Press Articles on Intermittent Fasting
- Latest Headlines from Fight Aging!
- Another Study Showing Either No Effect or Reduced Life Span in Mice From Dietary Supplements
- Ellison Medical Foundation to Cease Funding Aging Research
- An Example of Engineering Bioartificial Heart Tissue
- Spurring Axon Regeneration in an Injured Spinal Cord
- The Magic Pill of Exercise
- A Little Philosophy of Mind Uploading
- Reviewing Membrane Composition and Species Longevity
- Neuropep-1 Versus Alzheimer's Disease
- A Different Approach to Designing Calorie Restriction Mimetics
- Mitochondrial DNA Damage and Stem Cell Aging
LOOKING BACK AT 2013
Another year flees past us, ever faster it seems. The past year was characterized by advocacy, shifts in publicity and organizations supporting longevity science, and community fundraising success. For example, we just finished raising $60,000 for the SENS Research Foundation in the last few days. Back in October Longecity raised $21,000 for another SENS research project: restoring function in mitochondrial mutants, an opportunity to use a pair of cell lines that suddenly became available, and would otherwise require a great deal of work to produce. The month prior, a film project on life extension raised $35,000 on Kickstarter. Publicity is good, but I can't help feeling that we have a way to go yet with our advocacy when it is easier to raise funds to talk about longevity science in fiction than it is to raise funds to actually build the technologies needed for human rejuvenation. Ah, priorities. We humans are so bad at priorities.
Alongside all of this community fundraising, the new crowdfunding models are starting to make some inroads into science - moving beyond comics and games and widgets. I see this as a promising sign. Making community fundraising for projects like the ones above, and providing better tools to help the organizers, can only lead to more projects being funded and a growth in the number of supporters.
In a similar vein the Methuselah Foundation recently officially launched the New Organ Liver Prize: $1 million for the production of a tissue engineered, functional, transplanted liver. Their fundraising proceeds apace as they continue to work on speeding up whole organ tissue engineering through a variety of avenues.
While we are on the subject of Foundations, this was the year in which the SENS Research Foundation launched their Reimagine Aging campaign, added scientific luminary George Church to their advisory board, hosted the SENS6 conference, reached a yearly budget of $4 million, filled out their YouTube channel with videos, and posted an excellent series on the work done by young molecular biologists in their intern program. The SENS research program to watch in the coming couple of years is the AGE-breaker project focused on glucosepane, I think, but you really should take a look at their annual reports to get an idea as to how the Foundation is growing, and be sure to read The Undoing of Aging. You should also absolutely catch the Ben Best interview of Aubrey de Grey from August.
Interestingly, one other noteworthy group in aging research has published their own manifesto on how to treat degenerative aging, clearly modeled on the SENS proposals. That looks a lot like victory from where I stand.
The big funding news for the year in mainstream aging research is that the Ellison Medical Foundation is exiting the arena, and the vaguely aging-related Genomics X Prize was cancelled. Meanwhile Google has created the Calico initiative with the determination to spend hundred of millions of dollars on extending healthy life. At this point I don't expect Calico to back anything so useful and ambitious as SENS - I think it will look a lot more like a backing of the slow road to nowhere of metabolic manipulation to reduce the pace of aging. No rejuvenation research there. I may be wrong, but we shall see.
Various campaigns such as the Longevity Dividend have made new publicity efforts this past year to attract more public funding to their vision of incremental slow progress towards drugs to ameliorate the effects of aging. In addition we've seen other signs of the spread of awareness of longevity science into the mainstream: a radical life extension policy wonk conference, a big well-publicized study on views of radical life extension from Pew Research, and an advertising campaign touting 150 year life spans from Prudential. There is movement: each year we come closer to mass support for the goal of longer, healthier lives, yet still much of the public seems strangely disinterested.
Telomeres have been floating around in the news in relation to longevity this year. This is largely a consequence of new services offering telomere measurement, rather than anything of greater utility. Startup companies tend to generate press as a side-effect of their existence, but that doesn't necessarily tell us anything. On the more interesting side, the teams working on life extension in mice through telomerase gene engineering published new results earlier in the year. This is one of those items that gives me pause on my opinion of telomeres: other than this, it seems very clear from the data that telomere length is a marker, a consequence of aging and not a cause. I look forward to learning more about how telomerase in mice is actually extending life.
Mitochondrially targeted antioxidants of several types have been a topic of interest for some years now. To the extent that they extend life - where normal antioxidants do no such thing, or block hormesis signaling to shorten life - this is a reinforcement of the importance of mitochondria to aging and the need for mitochondrial repair technologies. A new type of mitochondrially targeted antioxidant known as SS-31 showed up publications earlier in the year, and makes for interesting reading.
This was the year in which research into brain emulation became more serious. Very large sums and formal programs are now working on creating first simulations and later emulations of the brain. Relevant to life extension? Not directly, unless you are one of those who believe that a copy of you is still you - but this bears watching. In a related community, the 2045 Initiative held their Global Futures conference back in June. This is another initiative that is worth keeping an eye on, though I don't believe it relevant to actual progress in extending human longevity despite their claims - and for much the same set of reasons as for brain emulation. A copy of you isn't you.
There are some puzzling oddities floating around the edge of the field of aging research, made puzzling simply by virtue of the fact that all too few people are studying them. The results arrive slowly and intermittently as a result. These are items that are likely irrelevant to the future of human life extension, but that doesn't stop them from being interesting. One of the best, I think, is whether and how heavy water extends life in short-lived species.
Immune therapies are one of the more active areas of medical development at the present time. Guiding the immune system has very broad applications: treatment of cancer, removal of amyloid and other waste compounds, and reversal of age-related immune dysfunction. Even something as simple as generating enormous numbers of patient-matched immune cells and infusing them can be very beneficial for the old, a way to restore some of the immune capacity that they now lack.
Several groups of researchers are at present chewing through past claims of life extension in mice from various dietary components and supplements and disproving them one by one. This seems to be the trend: look at every such claim from the past few decades with suspicion, as they likely resulted from inadvertent calorie restriction and are now being refuted by more careful work. The present consensus is that aggressive supplementation does nothing or may even be harmful to life expectancy.
In the area of drugs to slow aging, there is some debate over whether rapamycin actually does slow aging in mice versus just reducing cancer rates. This is ongoing with some fairly energetic arguments on both sides, especially from those already fairly vested in mTOR as a target for slowing aging, given that this is becoming an area of increased fundraising. To my eyes this is all irrelevant, of course. It isn't damage repair, it's just more metabolic manipulation that is exceedingly unlikely to meaningfully extend life in humans, even though it manages 20-30% life extension in mice, about half to two thirds of the effects of calorie restriction. Think of it as version 2.0 of the hubbub over sirtuins and resveratrol - that all went nowhere, generating only new knowledge, and the same will come of this, I think.
I'm not going to talk about tissue engineering, stem cells, or regenerative medicine this year. So much is going on that it would be a very long list: body parts and their components are being made, and researchers are just hitting their stride in this arena. The 2020s are going to be very interesting, as that is when we'll start to see a fair number of people with bioartificial replacements, augmentations, organ patches, and other treatments.
On cancer, again too much to point out. I leave that to others. But I will point to news on granulocyte transplant therapies: this has been a topic in past years because it seemed so very promising. It still looks promising, but by the sound of it this has run into the wall of grinding slow progress towards application, and the discovery of previously unappreciated complexity. But on the bright side, here are two and a half other ways to cure cancer.
Programmed aging as a viewpoint seems to be on the rise. Perhaps there are more publications, perhaps I'm just noticing more publications. This might be seen to be as much a threat to future funding of rejuvenation research as the continued focus of the mainstream of the research community on either doing nothing or working only on ways to manipulate metabolism with drugs to slightly slow aging. In the programmed aging worldview we should be working to restore epigenetic patterns and other aspects of metabolism to youthful levels, as they see this change as the root cause of aging. To their eyes damage repair is a waste of time. But this focus on altering metabolism is the doomed path to nowhere if aging is accumulated damage, as in the SENS viewpoint and - largely - the present mainstream view.
This year had its usual crop of short essays, links below:
- The Fight Aging! Algorithm
- Final Complexity is Less Relevant than that of Root Causes
- Why Prioritize SENS Research for Human Longevity?
- Revisiting Audience Data for Fight Aging!: Long Tails and Bear Consumption
- Perverse Incentives in Age and Funding Longevity Research
- On Costs and Opportunity Costs of Aging
- Deploying the Argument from Authority for SENS Research
- Bracketed By Billionaires
- Civil Disobedience and DIYbio
- Costly Publicity Makes Little Sense When Research is Cheap
- SENS Research Foundation is the Watering Hole, Not the Herd
- Dear Wealthy Individual, I Have This Great Idea Regarding How to Spend Your Money in a Better Way Than You Seem to Be Managing To Date
- Extending Life By Gaining More Subjective Time
- When Will the $100 Million Donations Start to Arrive for Rejuvenation Research?
- Extending Life by Manipulating Metabolism Only Produces Dramatic Results in Short-Lived Species
I missed a hundred other interesting things in this short retrospective, of course - but that's why Fight Aging! has archives, and why you have free time.
HOW CAN PROGRAMMED DEATH BE ADAPTIVE?
Researchers who theorize that aging is the result of damage accumulation have to explain why evolutionary processes fail to select for longer lives by favoring, say, better mechanisms for damage repair. These explanations exist and are generally robust, though there is always some ongoing level of debate over details, such as why we humans live for so long in comparison to other primates or other mammals our own size. Researchers who theorize that aging is an evolved genetic program have the opposite challenge, which is to explain how evolution selects for shorter lives than would otherwise be the case: what is the value of death-assurance mechanisms? Here too explanations exist, are generally robust, and there is an ongoing level of debate over details.
The mainstream consensus of the research community supports the view of aging as damage rather than aging as a genetic program, both from the point of view of molecular biology and evolutionary considerations. It is worth noting that even in a world in which aging is damage accumulation, the world in which I believe we live in, there can still be species that appear to suffer programmed aging on top of that. Salmon are a good example: it's worth looking into what that looks like as a response to external environmental factors.
Here, as a matter of interest, is a paper on the core issue relating to the hypothetical evolution of programmed aging: how can internal death-promoting mechanisms be adaptive for a species? This paper is open access, but note that it has no abstract - you'll have to click on the "Full Text" tab to view it, or alternatively download the PDF version.
Are Internal, Death-Promoting Mechanisms Ever Adaptive?
The idea that self-inflicted organismal death could be adaptive sounds, at face value, absurd. An adaptation is a trait that is suitable (apt) for the current circumstances or environmental challenges, and archetypal examples include traits that promote survival. Natural selection is the mechanism that produces adaptations. In describing natural selection, Darwin (1859) emphasized the struggle for survival: "Two canine animals in a time of dearth may be truly said to struggle with each other which shall get food and live. But a plant on the edge of a desert is said to struggle for life against the drought......". How could an inherited trait that promotes death, rather than survival, possibly be adaptive?
Four categories encompass the major possible evolutionary explanations for the cause of death of an organism. First, death (or an increased probability of death) could inevitably occur despite the efforts or traits of the organism. Second, internal mechanisms that promote death could exist in spite of selective pressure against them. Third, death could occur as a side-effect of a mechanism within the organism that has another function or benefit. Fourth, death could occur because of a mechanism within the organism that evolved explicitly to cause death. This fourth category is the only one in which the mechanism promoting death is an adaptation for promoting death, and cases in this category can only be explained by selection at a hierarchical level other than the organism.
In all categories except the first, we can reasonably expect to see active mechanisms within an organism that promote death. This review was motivated by the observation that diverse organisms apparently have such active, internal death-promoting mechanisms and by the subtle and difficult conceptual issues that understanding the evolution of this kind of trait raises.
INTERNATIONAL LONGEVITY ALLIANCE 2013 REPORT AND 2014 ROADMAP
There has been growing interest in grassroots political organization among members of the longevity advocacy community in the past couple of years. Unlike efforts such as the Longevity Dividend, which aims at the lobbying process to direct established flows of public funding towards longevity science, the grassroots is starting with the formation of single issue political parties in different countries. As an approach to activism this has a long history in Europe, though less so in the US by virtue of the differences in electoral systems. You might look at the Green and Pirate parties as successful examples of the type.
One outcome of all this was the creation of the International Longevity Alliance a little over a year ago. This organization acts as a point of organization and coordination for various local groups in different countries, and is an umbrella for a number of lines of volunteer work, some which focus as much on science as on advocacy and politics. But take a look for yourself, as here is an annual report for the past year and roadmap looking ahead:
International Longevity Alliance (ILA) - Annual Report for 2013 - Roadmap for 2014
The ILA's mission is to to promote the advancement of healthy longevity for all people through scientific research, technological development, medical treatment, public health, education, advocacy and social activism. In the past year, ILA has grown. ILA groups now exist in over 50 countries, with unofficial membership ranging in the thousands. It is on its way to official registration in France as a "Fonds de Dotation" (Endowment Fund) and will act as an alliance of pro-longevity non-profit organizations ("NPOs") from around the world.
Officially affiliated groups already exist in Russia, France, India and Finland. Other national ILA NPOs are on their way to registration in Israel, Germany, Ukraine, Colombia, Canada, the United States and other countries. We anticipate that existing pro-longevity organizations will also join as federated members, so that by the end of 2014 ILA will become a well established network of formally registered NPOs, as well as informal groups and individuals around the world, united for the purpose of achieving healthy longevity for all.
You might also take a look at the Denigma platform that is now under the ILA umbrella. Ideally those working on it will be able to produce something as useful and well-regarded as, say, the Human Ageing Genomic Resources site at the end of the day - and this is not an unreasonable goal, considering what they have accomplished to date.
Denigma (Deciphering the Enigma of Aging), based on the Linux open-source operating system, is the main ILA IT platform to collect, hold and distribute information. In 2013, the platform was extensively developed. Deliverables produced during this year include: the building of Denigma Legacy: denigma.de; Longevity Variant Database: longevitydb.org; Denigma Destiny: denigma.org.
We have used the platform to establish molecular profiles on ageing and powerful biomarkers to accurately measure biological age and effect of anti-aging interventions (focusing on genetic targets and functional prediction on miRNAs). We have used it to analyze aging-suppressor gene activity measurements (data analysis to link levels with phenotype); to reveal the role of mitochondrial heteroplasmy and metabolic influence (link levels with phenotype); to validate the role of aging as the main cause of diseases. We have provided exact descriptions of the individual influences of aging hallmarks and created hundreds of ontologies and linked annotated data on aging.
They are also helping to set up and fund studies, though of course I'd be happier to see more SENS-like work aimed at reversal of aging and less of the drug testing with the aim of merely slowing aging. All publicity is good, and initiative in setting up studies is to be commended, but I just don't see that any great payoff is likely to result from this sort of screening work. Of course I - and other SENS supporters - are in something of a minor in holding this viewpoint:
ILA is initiating projects to test life-extending interventions in mice, other domestic animals and simpler organisms using both academic and do-it-yourself biology platforms. In 2013, we initiated a project on life-span extension in mice in cooperation with the Institute of Gerontology in Kiev, Ukraine. Test protocols have been developed for potential anti-aging drugs, as well as a plasma test for pathologies. Logistic procedures have been established. The do-it-yourself biology platform has been further strengthened to encourage testing life-extending interventions in rats and hamsters at home.
A top priority for 2014 will be to establish a screening project to test lifespan-extending interventions in mice. Funding for this large screening project will be actively sought in 2014.
So all in all there's a lot going on in that portion of the community: good news, I think, to see so much activity in comparison to the desert of past years. The European and Russian groups are really pulling together and getting stuff done - more power to them. I hope to see the ILA volunteers continue the good work, and hopefully come around to more of a SENS viewpoint in their future fundraising and scientific initiatives.
A SERIES OF POPULAR PRESS ARTICLES ON INTERMITTENT FASTING
Serious discussion about calorie restriction and intermittent fasting in the popular press is comparatively rare - anything that involves changes of diet will quickly be buried by idiocy as a general rule, if not by the author of the piece, then shortly thereafter. Dieting is just one of those topics in which rationality seems to flee the building whenever it comes up.
Both calorie restriction and intermittent fasting are shown to extend life and greatly improve health in mice and many other species, but they might not operate through exactly the same mechanisms. Intermittent fasting in which calorie intake is maintained at the same level as non-fasting rodents has been shown to produce some extension of life and health benefits in studies for example - equally other studies suggest that this might not be the case. For my money I'd wager the bulk of the effect is calorie based: intermittent fasting tends to result in a lower overall calorie intake, and we know that calorie intake has a large effect on health and longevity in comparison to everything else that you can try in mice.
There is a lot more research into calorie restriction than exists for intermittent fasting strategies such as alternate day fasting. You should bear that in mind when reading around the topic. Calorie restriction really is the gold standard for evidence when it comes to things you can do that will positively affect your health. Intermittent fasting is merely at the interesting and convincing level, worth the balance of risk and reward in my eyes, but nowhere near as well supported as, say, regular moderate exercise.
The present scientific consensus on calorie restriction is that it won't significantly extend life in humans. Perhaps 5-10% at most. This comes from a combination of evolutionary considerations and common sense. If calorie restriction could extend human life by 40%, as it does in mice, then we would have known all about this for centuries at least. Researchers believe that calorie restriction is an adaptation that allows better survival of periodic famine, something that tends to happen on a seasonal timescale - which is long for mice, but short for humans. So there is evolutionary pressure for mice to be able to extend lives considerably in response to a lack of food, but not so for humans. Apparently there is still evolutionary pressure for the creation of health benefits, however, as the short term effects of calorie restriction on the operation of metabolism and resistance to age-related disease are quite similar in both mice and humans.
When it comes to intermittent fasting there really isn't a consensus on life span effects. There isn't enough data and a big enough body of work for that to exist yet. It is generally believed to be a good thing for health, however. With that all said, take a look at this popular science series from the BBC, which examines a mild form of intermittent fasting - really just "intermittent eating somewhat less," a far cry from alternate day fasting in which practitioners only eat at all every other day.
Intermittent fasting: Trying it out for science
Curious about the scientific research that goes into devising a new diet, I decided to volunteer as a subject in a five-month clinical trial at the University of Southern California (USC). As a human guinea pig, I signed up to test a strict diet regime and subject myself to a battery of clinical tests to evaluate its effect on my body.
It involved surviving, for five consecutive days, on a narrow range of foods that contained as little as 500 calories per day - about a quarter of the average person's consumption. There was to be no cheating, no falling off the wagon and no treats. It was an opportunity to be part of study that may help scientists unravel the complex relationship between food and the human body.
The clinical trial, which is still ongoing, is designed to investigate the feasibility, safety, potential benefits and psychological changes associated with a calorie-restricted diet. It is based on previous experiments, at a number of institutions, which have shown that mice live longer and healthier lives if their food intake is cut by up to 30%.
Intermittent fasting: Enduring the hunger pangs
The limited selection of food (with no choice of flavours) means that everything has to be eaten. It's monotonous... but at least it makes meal planning easy for five days. "The reason why diets don't work is because they are very complicated and people have an interpretation problem," says Dr Valter Longo, director of the University of Southern California (USC) Longevity Institute. "The reason I think these [intermittent fasting] diets work is because you have no interpretation. You either do it or you don't do it. And if you do it you're going to get the effect."
Intermittent fasting: The good things it did to my body
During each five-day fasting cycle, when I ate about a quarter the average person's diet, I lost between 2kg and 4kg (4.4-8.8lbs) but before the next cycle came round, 25 days of eating normally had returned me almost to my original weight. But not all consequences of the diet faded so quickly. "What we are seeing is the maintenance of some of the effects even when normal feeding resumes," explains Dr Valter Longo, director of USC's Longevity institute, who has observed similar results in rodents.
Arguably, the most interesting changes were in the levels of a growth hormone known as IGF-1 (insulin-like growth factor). High levels of IGF-1, which is a protein produced by the liver, are believed significantly to increase the risks of colorectal, breast and prostate cancer. Low levels of IGF-1 reduce those risks.
"In animals studies we and others have shown this to be a growth factor that is very much associated with ageing and a variety of diseases, including cancer," says Longo. Studies in mice have shown that an extreme diet, similar to the one I experienced, causes IGF-1 levels to drop and to stay down for a period after a return to normal eating. My data showed exactly the same pattern. "You had a dramatic drop in IGF-1, close to 60% and then once you re-fed it went up, but was still down 20%," Longo told me.
LATEST HEADLINES FROM FIGHT AGING!
ANOTHER STUDY SHOWING EITHER NO EFFECT OR REDUCED LIFE SPAN IN MICE FROM DIETARY SUPPLEMENTS
Monday, December 30, 2013
There is in fact little evidence for the benefits of dietary supplementation as commonly practiced in wealthier parts of the world. Past results that suggest life extension or improved health in mice tend to vanish once researchers run more careful studies that control for calorie intake. This is taking a while to sink in, however: the supplement industry is enormous, has little incentive to give up its revenue stream or advertising programs, and that voice is much louder than the scientific community in popular culture.
Present data suggest that the consumption of individual dietary supplements does not enhance the health or longevity of healthy rodents or humans. It might be argued that more complex combinations of such agents might extend lifespan or health-span by more closely mimicking the complexity of micronutrients in fruits and vegetables, which appear to extend health-span and longevity.
To test this hypothesis we treated long-lived, male, F1 mice with published and commercial combinations of dietary supplements and natural product extracts, and determined their effects on lifespan and health-span. Nutraceutical, vitamin or mineral combinations reported to extend the lifespan or health-span of healthy or enfeebled rodents were tested, as were combinations of botanicals and nutraceuticals implicated in enhanced longevity by a longitudinal study of human aging. A cross-section of commercial nutraceutical combinations sold as potential health enhancers also were tested, including Bone Restore®, Juvenon®, Life Extension Mix®, Ortho Core®, Ortho Mind®, Super K w k2®, and Ultra K2®. A more complex mixture of vitamins, minerals, botanical extracts and other nutraceuticals was compounded and tested.
No significant increase in murine lifespan was found for any supplement mixture. Our diverse supplement mixture significantly decreased lifespan. Thus, our results do not support the hypothesis that simple or complex combinations of nutraceuticals, including antioxidants, are effective in delaying the onset or progress of the major causes of death in mice. The results are consistent with epidemiological studies suggesting that dietary supplements are not beneficial and even may be harmful for otherwise healthy individuals.
ELLISON MEDICAL FOUNDATION TO CEASE FUNDING AGING RESEARCH
Monday, December 30, 2013
The Ellison Medical Foundation has for the past fifteen years or so acted much like an extension of the National Institute on Aging, channeling philanthropic funding from Larry Ellison into investigations of the biology of aging. This has been mainstream work with little to no involvement in efforts to extend life. The Ellison Medical Foundation didn't come about because Larry Ellison has any great interest in aging research, however: the interest was in furthering molecular biology, and the study of aging just happens to be a field in which a lot of cutting edge molecular biology takes place. By the sound of it the Foundation is moving on into a new phase of existence:
Oracle Corp. founder Larry Ellison's medical foundation - one of the leading funders for research on aging over the past 15 years - has stopped making new grants and may shift its focus beyond medical research. In all, the Ellison Medical Foundation has awarded nearly $430 million in grants since its founding in late 1997. Perhaps 80 percent to 90 percent of that money went to aging researchers.
The foundation is not endowed by Ellison. Instead, Ellison varies his annual gift to the foundation, which this year will fund $53 million in new and continuing grants, the bulk of those for aging research projects. Already-awarded grants will continue to be funded, but the foundation will not make new awards. "There are some other activities planned for the foundation. It may be broader and outside the medical research sphere - not to say medical research wouldn't be a component."
The foundation's pullback from aging research is particularly perplexing, given the entrance of Calico, which is led by former Genentech Inc. chief Art Levinson, and the attention that Google's involvement has brought to the field of aging research. Some researchers have said that Calico's entré would give private foundation grants more oomph and attract other funders.
AN EXAMPLE OF ENGINEERING BIOARTIFICIAL HEART TISSUE
Tuesday, December 31, 2013
The biggest challenge in tissue engineering is still the creation of a blood vessel network sufficient to keep larger portions of tissue alive and functional. A workaround is to use decellularized donor tissues in which those blood vessels already exist: all of the cells are removed, leaving only the scaffolding of the extracellular matrix and its chemical cues, ready to be repopulated by cells derived from the recipient. As these researchers demonstrate, that donor tissue doesn't necessarily have to originate from the same organ or even the same species:
The in vitro generation of a bioartificial cardiac construct (CC) represents a promising tool for the repair of ischemic heart tissue. Several approaches to engineer cardiac tissue in vitro have been conducted. The main drawback of these studies is the insufficient size of the resulting construct for clinical applications. The focus of this study was the generation of an artificial three-dimensional (3D), contractile, and suturable myocardial patch by combining a gel-based CC with decellularized porcine small intestinal submucosa (SIS), thereby engineering an artificial tissue of 11cm in size.
The alignment and morphology of rat neonatal cardiomyocytes (rCMs) in SIS-CC complexes were investigated as well as the re-organization of primary endothelial cells which were co-isolated in the rCM preparation. The ability of a rat heart endothelial cell line (RHE-A) to re-cellularize pre-existing vessel structures within the SIS or a biological vascularized matrix (BioVaM) was determined. SIS-CC contracted spontaneously, uniformly, and rhythmically with an average rate of 200 beats/min in contrast to undirected contractions observed in CC without SIS support.
A dense network of CD31+/eNOS+ cells was detected as permeating the whole construct. Superficial supplementation of RHE-A cells to SIS-CC led to the migration of these cells through the CC, resulting in the re-population of pre-existing vessel structures within the decelluarized SIS. By infusion of RHE-A cells a re-population of the BioVaM vessel bed as well as distribution of RHE-A cells throughout the CC was achieved. Rat endothelial cells within the CC were in contact with RHE-A cells. Ingrowth and formation of a network by endothelial cells infused through the BioVaM represent a promising step toward engineering a functional perfusion system, enabling the engineering of vascularized and well-nourished 3D CC of dimensions relevant for therapeutic heart repair.
SPURRING AXON REGENERATION IN AN INJURED SPINAL CORD
Tuesday, December 31, 2013
The scientific community continues to work on ways to spur or guide nerve regeneration, something that doesn't normally occur to any great degree in human tissues. Much of that focus is on spinal injuries, and here researchers have found a way to use one cell type to guide the regrowth of others:
Transplanting self-donated Schwann cells (SCs, the principal ensheathing cells of the nervous system) that are elongated so as to bridge scar tissue in the injured spinal cord aids hind limb functional recovery in rats modeled with spinal cord injury. "Injury to the spinal cord results in scar and cavity formation at the lesion site. Although numerous cell transplantation strategies have been developed to nullify the lesion environment, scar tissue - in basil lamina sheets - wall off the lesion to prevent further injury and, also, at the interface, scar tissue impedes axon regeneration into and out of the grafts, limiting functional recovery."
The researchers determined that the properties of a spinal cord/Schwann cell bridge interface enable regenerated and elongated brainstem axons to cross the bridge and potentially lead to an improvement in hind limb movement of rats with spinal cord injury. Electron microscopy revealed that axons, SCs, and astrocytes were enclosed together within tunnels bounded by continuous basal lamina. The expression of neuroglycan (NG2; a proteoglycan found on the membrane of cells) was associated with these tunnels. They subsequently determined that a "trio" of astrocyte processes, SCs and regenerating axons were "bundled" together within the tunnels of basal lamina.
THE MAGIC PILL OF EXERCISE
Wednesday, January 1, 2014
If regular exercise were a drug, people would stampede to buy it at any price. It is more effective for prevention and treatment of near all common chronic conditions - and for healthy people too - than any presently available medical technology. The only thing to match it (and even do somewhat better) is the practice of calorie restriction. To be clear, you can't exercise your way out of aging to death on a broadly similar schedule to your peers - but exercise does correlate with a longer life expectancy, and given that we're in a race between aging and the development of rejuvenation biotechnologies to reverse aging, it would be foolish not to take every proven advantage along the way.
If there were a drug that treated and prevented the chronic diseases that afflict Americans and we didn't give it to everyone, we'd be withholding a magic pill. If this drug was free, in a country that spends more than $350 billion annually on prescription drugs, where the average 80-year-old takes eight medications, we'd be foolish not to encourage this cheaper and safer alternative as first-line treatment. If every doctor in every country around the world didn't prescribe this drug for every patient, it might almost be considered medical malpractice.
We have that drug today, and it's safe, free, and readily available.
Exercise has benefits for every body system; it is effective both as a treatment and for prevention of disease. It can improve memory and concentration, lessen sleep disorders, aid heart disease by lowering cholesterol and reducing blood pressure, help sexual problems such as erectile dysfunction, and raise low libido. Exercise does it all. Even with cancer, particularly colon and recurrent breast cancer, the data show clearly that exercise is a deterrent. Newer studies on a glycoprotein called Interleukin 6 suggests that general body inflammation, a factor in almost every chronic disease, is reduced by regular exercise.
A LITTLE PHILOSOPHY OF MIND UPLOADING
Wednesday, January 1, 2014
A great deal of philosophical and metaphysical thought is devoted to the topic of mind uploading. We are moving into an age in which the emulation of human brains in software will be possible, and clearly strong artificial intelligence will result from that work, even if not achieved through other means.
There is considerable overlap between supporters of longevity science and supporters of work on strong AI. A large contingent of people view mind uploading - making a copy of their mind and then running it in software - as a perfectly valid approach to achieving radical life extension. Look at the 2045 Initiative, for example, as a determined outgrowth of this community. This appears fine if you believe that a copy of you is you, but the problem is that this is not the case. A copy is a copy, its own entity. There are also other rather important existential issues inherent in existing as software rather than hardware: are you a continuous being, or are you just a sequence of disconnected, momentary separate beings, each destroyed an instant after its creation? A shadow of life and an ongoing atrocity of continual murder, not actual life.
So the details of implementation matter. Replace your neurons as they die, gradually, with long-lasting machinery that serves the same purpose in hardware and you are still you. Nothing is different as you transition continuously from flesh to machine. But to copy the brain and throw it away, to replace it instantly with that same end result is death. So far as I can see there is no near-future technology of gradual machine replacement that is likely to provide radical life extension on the same timeframe as work in rejuvenation medicine. Artificial neurons for gradual replacement are a long way away in comparison to implementation of the SENS vision for reversal of human aging.
In any case, here is a little philosophical reading on mind uploading, with links to much more in the way of thought on the subject. It might not be terribly relevant to our future, but that doesn't stop it from being interesting:
A couple of years ago I wrote a series of posts about Nicholas Agar's book Humanity's End: Why we should reject radical enhancement. The book critiques the arguments of four pro-enhancement writers. One of the more interesting aspects of this critique was Agar's treatment of mind-uploading. Many transhumanists are enamoured with the notion of mind-uploading, but Agar argued that mind-uploading would be irrational due to the non-zero risk that it would lead to your death. The argument for this was called Searle's Wager, as it relied on ideas drawn from the work of John Searle.
This argument has been discussed online in the intervening years. But it has recently been drawn to my attention that Agar and Neil Levy debated the argument in the pages of the journal AI and Society back in 2011-12. Over the next few posts, I want to cover that debate. I start by looking at Neil Levy's critique of Agar's Searlian Wager argument.
The major thrust of this critique is that Searle's Wager, like the Pascalian Wager upon which it is based, fails to present a serious case against the rationality of mind-uploading. This is not because mind-uploading would in fact be a rational thing to do - Levy remains agnostic about this issue - but because the principle of rational choice Agar uses to guide his argument fails to be properly action-guiding. In addition to this, Agar ignores considerations that affect the strength of his argument, and is inconsistent about certain other considerations.
REVIEWING MEMBRANE COMPOSITION AND SPECIES LONGEVITY
Thursday, January 2, 2014
Mitochondria are important in aging, and in particular their relationship to aging appears to be somewhat mediated by how resistant their membranes are to oxidative damage - the evidence and theorizing around this is known as the membrane pacemaker hypothesis. You'll recall that mitochondria are effectively the cell's power plants, generating chemical energy stores for use in many cellular processes. In the course of their operation they generate a continued flow of reactive free radicals that can cause oxidative damage - they themselves are the most likely target for that damage, but because they occupy such an important position in the cell there are ways in which their damage can lead to worse outcomes for the cell as a whole, and also for surrounding tissue. This process is one of the causes of aging, and it is why the development of mitochondrial repair technologies is important.
Here is an open access paper that reviews what is known about the link between membrane composition and longevity in various species. In general I view this as supporting evidence for the need for mitochondrial repair: I don't expect that anything of practical use in the near term can result from trying to change the composition of our mitochondrial membranes.
The appearance of oxygen in the terrestrial atmosphere represented an important selective pressure for ancestral living organisms and contributed toward setting up the pace of evolutionary changes in structural and functional systems. The evolution of using oxygen for efficient energy production served as a driving force for the evolution of complex organisms. The redox reactions associated with its use were, however, responsible for the production of reactive species (derived from oxygen and lipids) with damaging effects due to oxidative chemical modifications of essential cellular components.
Consequently, aerobic life required the emergence and selection of antioxidant defense systems. As a result, a high diversity in molecular and structural antioxidant defenses evolved. In the following paragraphs, we analyze the adaptation of biological membranes as a dynamic structural defense against reactive species evolved by animals. In particular, our goal is to describe the physiological mechanisms underlying the structural adaptation of cellular membranes to oxidative stress and to explain the meaning of this adaptive mechanism, and to review the state of the art about the link between membrane composition and longevity of animal species.
NEUROPEP-1 VERSUS ALZHEIMER'S DISEASE
Thursday, January 2, 2014
There is always something promising taking place in the lab with respect to Alzheimer's disease and other forms of age-related neurodegeneration, but all too few such line items successfully work their way through the chain to clinical application.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid beta (Aβ) deposits, hyperphosphorylated tau deposition, and cognitive dysfunction. Abnormalities in the expression of brain-derived neurotrophic factor (BDNF), which plays an important role in learning and memory formation, have been reported in the brains of AD patients. A BDNF modulating peptide (Neuropep-1) was previously identified by positional-scanning synthetic peptide combinatorial library.
Here we examine the neuroprotective effects of Neuropep-1 on several in vitro neurotoxic insults, and triple-transgenic AD mouse model (3xTg-AD). Neuropep-1 protects cultured neurons against oligomeric Aβ1-42, 1-methyl-4-phenylpyridinium, and glutamate-induced neuronal cell death. Neuropep-1 injection also significantly rescues the spatial learning and memory deficits of 3xTg-AD mice compared with vehicle-treated control group. Neuropep-1 treatment markedly increases hippocampal and cortical BDNF levels. Furthermore, we found that Neuropep-1-injected 3xTg-AD mice exhibit dramatically reduced Aβ plaque deposition and Aβ levels without affecting tau pathology. Neuropep-1 treatment does not alter the expression or activity of full-length amyloid precursor protein, α-, β-, or γ-secretase, but levels of insulin degrading enzyme, an Aβ degrading enzyme, were increased. These findings suggest Neuropep-1 may be a therapeutic candidate for the treatment of AD.
A DIFFERENT APPROACH TO DESIGNING CALORIE RESTRICTION MIMETICS
Friday, January 3, 2014
A calorie restriction mimetic - usually a drug - is a treatment that can recapture some of the same alterations to metabolism caused by the practice of calorie restriction. Since calorie restriction extends life and improves health, so should a calorie restriction mimetic. Most such work at the moment focuses on finding existing drugs that have some calorie restriction mimetic effects and side-effects that are manageable. Regulation makes it so expensive to produce new medical technologies that research and development is guided into marginal repurposing of existing drugs rather than working on better new directions.
Here is an example of the other end of the drug design spectrum, in which researchers work on identifying which epigenetic alterations should be made, and then think about how to design drugs to make those alterations. Despite the headlines none of this can turn off or reverse aging - it can only slow it down modestly, the same way that calorie restriction does. If you want rejuvenation, you have to look at the SENS approach of damage repair biotechnologies, not epigenetic manipulation.
Restricting calorie consumption is one of the few proven ways to combat aging. Though the underlying mechanism is unknown, calorie restriction has been shown to prolong lifespan in yeast, worms, flies, monkeys, and, in some studies, humans. Now [researchers] have developed a computer algorithm that predicts which genes can be "turned off" to create the same anti-aging effect as calorie restriction. "Most algorithms try to find drug targets that kill cells to treat cancer or bacterial infections. Our algorithm is the first in our field to look for drug targets not to kill cells, but to transform them from a diseased state into a healthy one."
[This] lab is a leader in the growing field of genome-scale metabolic modeling or GSMMs. Using mathematical equations and computers, GSMMs describe the metabolism, or life-sustaining, processes of living cells. Once built, the individual models serve as digital laboratories, allowing formerly labor-intensive tests to be conducted with the click of a mouse. [The algorithm, a] "metabolic transformation algorithm," or MTA, can take information about any two metabolic states and predict the environmental or genetic changes required to go from one state to the other.
Some of the genes that the MTA identified were already known to extend the lifespan of yeast when turned off. Of the other genes found, [researchers] sent seven to be tested [and] found that turning off two of the genes, GRE3 and ADH2, in actual, non-digital yeast significantly extends the yeast's lifespan. "You would expect about three percent of yeast's genes to be lifespan-extending. So achieving a 10-fold increase over this expected frequency, as we did, is very encouraging."
Since MTA provides a systemic view of cell metabolism, it can also shed light on how the genes it identifies contribute to changes in genetic expression. In the case of GRE3 and ADH2, MTA showed that turning off the genes increased oxidative stress levels in yeast, thus possibly inducing a mild stress similar to that produced by calorie restriction.
MITOCHONDRIAL DNA DAMAGE AND STEM CELL AGING
Friday, January 3, 2014
Mitochondrial DNA damage is theorized, with a great deal of evidence in support, to be one of the causes of degenerative aging. This research is somewhat relevant, but the focus on point mutations is problematic: there is other research in mice to demonstrate that point mutations in mitochondrial DNA are not all that important. The important types of damage are more severe, such as deletions in which stretches of DNA are simply dropped. The mice used here do in fact have an increased number of deletions, even though that isn't mentioned in the abstract below, so be careful of claims of associations of dysfunction with point mutations.
A decline in the replicative and regenerative capacity of adult stem cell populations is a major contributor to the ageing process. Mitochondrial DNA (mtDNA) mutations clonally expand with age in human stem cell compartments including the colon, small intestine and stomach and result in respiratory chain deficiency. Studies in a mouse model with high levels of mtDNA mutations due to a defect in the proof-reading domain of the mtDNA polymerase γ (mtDNA mutator mice) have established causal relationships between the accumulation of mtDNA point mutations, stem cell dysfunction and premature ageing.
These mtDNA mutator mice have also highlighted that the consequences of mtDNA mutations upon stem cells vary depending on the tissue. In this review we present evidence that these studies in mice are relevant to normal human stem cell ageing and we explore different hypotheses to explain the tissue specific consequences of mtDNA mutations. In addition, we emphasize the need for a comprehensive analysis of mtDNA mutations and their effects on cellular function in different ageing human stem cell populations.