Fight Aging! Newsletter, February 4th 2013

February 4th 2013

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!



- More on the Longevity of Telomerase-Enhanced Mice
- Towards Xenotransplantation of Pig Hearts
- Learning More About SIRT3 in Aging
- Another Brief Detour into Morality
- The Damage Caused by AGEs
- Discussion
- Latest Headlines from Fight Aging!
    - A Podcast Interview With Aubrey de Grey
    - Wrapping Nanoparticles in Cell Membranes
    - Vegetarianism Associated With Lower Risk of Heart Disease
    - A Commentary on Radical Life Extension
    - The View of Mortality as Not Easily Explainable By Common Genetic Variants
    - Foundational Work For Nervous System Repair
    - Magnetic Levitation in Tissue Engineering
    - Advocating Intermittent Fasting
    - Human Brain Simulation Project Funded
    - Altering Eye Cells to Restore Vision


These past few years, researchers have produced several demonstrations of extended life and reduced cancer rates in mice through the use of various gene therapy combinations involving increased telomerase expression and extra copies of cancer suppression genes such as P53.

The latest update to arrive this month has the researchers trying out calorie restriction (CR) on their transgenic telomerase-enhanced (TgTERT) mice, with a wild-type (WT) control group. Apparently calorie restriction somewhat synergizes with the effects of additional telomerase, and thus calorie restricted TgTERT mice live longer than their ad libitum peers. Beyond that, this is also a study of how calorie restriction impacts telomere dynamics, finding that it delays the characteristic erosion of telomeres with age - which is consistent with the body of research showing calorie restriction to slow almost all other measurable aspects of aging.

The trouble with ascribing causes and mechanisms to calorie restriction is that it does change everything. So autophagy researchers see it boosting autophagy, telomerase researchers see it changing telomere dynamics, fat metabolism researchers see it affecting fat metabolism, and so forth. So far I think that autophagy has a stronger claim than any other mechanism as being the dominant cause of calorie restriction benefits to health and longevity, if only because removal of mechanisms essential to autophagy has been shown to remove those benefits in some laboratory species. But there's still plenty of room for evidence and debate.


One recent morning, a pig heart hung suspended in a clear homemade tank in the lab built for Taylor and her team. Filled with detergent, the heart had expanded to the size of a large man's fist, excess liquid dripping slowly out its sides. Once the heart is thoroughly cleaned, hard-working human stem cells - immature cells found in our organs and tissues that help repair damage on a daily basis - will bring it to life. "We can take stems cells from bone marrow, blood or fat and place them onto a heart, liver or lung scaffold," Taylor explains. "My motto for a long time has been 'Give nature the tools and get out of the way.' "

Taylor and her team will add stem cells to the heart one of two ways: by inserting a tube in the aorta and letting the cells drip inside, or by injecting the cells with a syringe through the wall of the heart. A heartbeat is perceptible after just a few days. Within a few weeks, the heart is strong enough to pump blood.

Taylor predicts that in the next two years, she and her team will approach the U.S. Food and Drug Administration and ask to do a first-in-human study with the bio-artificial hearts. "Will it be a whole heart? Probably not," Taylor says. "But it could be a cardiac patch or a valve. We might start with a piece to show the safety and efficacy of the technology."


Sirtuins have been a hot topic in aging research - largely undeservedly as it turned out - for some years, the large sums of money flowing into that field of research helping to drive enthusiasm for the slow, expensive road of slowing aging by metabolic manipulation. Most of the relevant research community, those who might be working on SENS or other rejuvenation biotechnologies if the money was there, work towards similar goals. They are producing knowledge rather than applications that can influence human lifespan, and have little expectation of producing anything more than knowledge for decades to come. Knowledge is never useless, but this path is not likely to deliver meaningful extension of human life in time to matter to us, nor is it likely to produce technologies that will help people who are already aged.

There are a number of different sirtuins, and while research initially focused on SIRT1, it is SIRT3 and SIRT6 that have generated the more interesting results in the past couple of years. SIRT3 is the topic for today, a mitochondrial protein - it is noteworthy to see just how many longevity-related genes and proteins are connected to the mitochondria in some way. Calorie restriction is noted to boost levels of SIRT3, and SIRT3 is thought to promote antioxidant activity in cells, reducing damage in the places where oxidants are produced as a side-effect of the operation of metabolism - something that you can't achieve by ingesting antioxidants, I should add.

Here, researchers demonstrate a modest reversal of one small aspect of the breadth of aging biology by boosting levels of SIRT3 in old mice:

"The researchers first observed the blood system of mice that had the gene for SIRT3 disabled. Surprisingly, among young mice, the absence of SIRT3 made no difference. It was only when time crept up on the mice that things changed. By the ripe old age of two, the SIRT3-deficient mice had significantly fewer blood stem cells and decreased ability to regenerate new blood cells compared with regular mice of the same age.

"What is behind the age gap? It appears that in young cells, the blood stem cells are functioning well and have relatively low levels of oxidative stress, which is the burden on the body that results from the harmful byproducts of metabolism. At this youthful stage, the body's normal anti-oxidant defenses can easily deal with the low stress levels, so differences in SIRT3 are less important.

"To see if boosting SIRT3 levels could make a difference, the researchers increased the levels of SIRT3 in the blood stem cells of aged mice. That experiment rejuvenated the aged blood stem cells, leading to improved production of blood cells."


Why can't we just focus on the engineering when it comes to aging and our biology? Stuff in our biology is broken, it causes tremendous pain and suffering, not to mention most of the world's deaths, so let's work on fixing it. This seems like a simple enough proposition, one that nobody has issues with when it comes to specific manifestations of aging like heart disease or Alzheimer's. Yet as soon as you talk about fixing the brokenness of aging itself, the very root causes that produce things like heart disease and Alzheimer's, suddenly half of the room wants you to know just how terribly immoral this would be.

We do not live in a rational age. Not that any of the others were any better, but still. We should be better - we have the grand sweep of recorded historical irrationality to look back on and learn from.

Throughout history people have aged and died because they had to, even as they struggled to live and railed against the inevitable, because there was nothing that could be done. Now there is something that can be done: we can build rejuvenation biotechnologies to repair the known causes of aging. That wasn't plausible centuries ago, or even three decades ago, but it's plausible now. The research and development community is not pursuing this goal in any energetic way, however, and there is no great public clamor for greater longevity through medical technology. So one might argue that the defining characteristic of this new age of ours is that its occupants, presented for the first time with the option to choose life, are instead choosing death.

They are choosing death not just for themselves, but for every future individual that might have had the choice to use rejuvenation therapies had the work started now in earnest. A day late is a hundred thousand lives short: aging produces a sweeping, staggering toll of death. More people than you will plausibly meet in a lifetime have died of aging already today. Tomorrow it will happen again, and for every new day until we choose to stop it from happening.

This is the status quo, this avalanche of funerals and pain. Yet those who tell us that it would be immoral to do anything about it often raise up the status quo, the present structure of society, the bounds of what is, as something of greater worth that must be preserved. A mighty god, the system - on a par with the environment and society when it comes to people willing to march themselves and others to death in its name. Grouping individuals and then coming to see only the group, to the point of discarding the individuals as worthless, has been all too familiar this past century - with its fervors, its global wars, and its megadeaths. I don't imagine that it'll be any easier going forward to convince people that saving tens of millions of lives every year is more important than their precious abstractions.


Advanced glycation end-products (AGEs) are perhaps the most frustrating of the mechanisms that cause aging. Frustrating because the overwhelming majority of AGEs are of the same basic type in humans - glucosepane - and all it will take to remove this contribution to aging is a designed molecule that can break down this specific compound without harming the rest of our biology. To my eyes finding that basis for therapy is a goal well within reach of a sensible, $20 million, five year program at this time, or pretty much any time over the last decade. Yet no-one is putting more than a pittance into this research, and no more than a handful of researchers pay any attention. This is why development of a glucosepane AGE-breaker therapy is low in the list of plausible near future advances in rejuvenation biotechnology. Not because it's harder than the rest, far from it, but because no-one with a large budget is trying.

AGE buildup is one of the root causes of aging. Advanced glycation end-products accumulate as a consequence of the ordinary operation of metabolism, and wherever they lurk in the body they gum up important molecular machinery, deliver harmful signals to cells that spur inflammation, and generally cause all sorts of damage and dysfunction. Aging is no more than unrepaired damage, and as you can see, a part of that stems from something that should be very easy to fix in the grand scheme of things.

Yet next to no-one is trying. The SENS Foundation is one of the few groups that does put funding into finding ways to clear glucosepane, but that is still a small amount in the grand scheme of things - certainly nowhere close to millions of dollars yet. You can read a summary at the Foundation website that discusses the science and gives an overview of the current research collaboration.


The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!



Friday, February 1, 2013
From a few weeks back, an audio interview with Aubrey de Grey of the SENS Research Foundation: "Anti-aging scientist and biogerontologist Aubrey de Grey told [the host] about his work with the SENS Foundation, an organization he founded with the purpose of defeating aging. According to him, aging is treated as a disease that should be defeated by targeting the 7 cellular activities that cause us to age. Dr. de Grey discussed the science that researchers at SENS are studying to back up the claim that we could live to 1000 years some day soon. "The problem is the funding," de Grey said. "We've been trying to fight what we've described as the pro-aging trance." The pro-aging trance, according to Dr. de Grey, is the social conception we have that death is inevitable. "No one wants to keep cancer, no one wants to keep heart disease, so what would we want to keep aging?" de Grey asks. Part of Aubrey de Grey's work is marketing his ideas and helping to diminish the acceptance society has of death. Citing his long beard which [the interviewer] said looked "like Rasputin's," de Grey said, "This is something my team and I have discussed. It's something that helps me stick in people's minds." [The interviewers] briefly talked about the social, economic, and cultural consequences of a longer life extension. When [the interviewers] pressed de Grey on these issues, Aubrey reiterated that his work is not a "longevity issue, but a health care issue, so stop thinking of it that way please." Aubrey pressed that the key for his scientific success lies in his publicity: getting more exposure and raising money through his foundation."

Friday, February 1, 2013
Here is another small step on the way towards the creation of artificial cells as medical devices. If you can wrap nanoparticles in cell membranes, then its not hard to see that disguising any arbitrary nanomachinery that way is on the agenda - such as those that can dispense or create proteins, or perform other tasks inside our tissues. " By cloaking nanoparticles in the membranes of white blood cells, [scientists] may have found a way to prevent the body from recognizing and destroying them before they deliver their drug payloads. "Our goal was to make a particle that is camouflaged within our bodies and escapes the surveillance of the immune system to reach its target undiscovered. We accomplished this with the lipids and proteins present on the membrane of the very same cells of the immune system. We transferred the cell membranes to the surfaces of the particles and the result is that the body now recognizes these particles as its own and does not readily remove them." Nanoparticles can deliver different types of drugs to specific cell types, for example, chemotherapy to cancer cells. But for all the benefits they offer and to get to where they need to go and deliver the needed drug, nanoparticles must somehow evade the body's immune system that recognizes them as intruders. The ability of the body's defenses to destroy nanoparticles is a major barrier to the use of nanotechnology in medicine. Systemically administered nanoparticles are captured and removed from the body within few minutes. With the membrane coating, they can survive for hours unharmed. "Being able to use synthetic membranes or artificially-created membrane is definitely something we are planning for the future. But for now, using our white blood cells is the most effective approach because they provide a finished product. The proteins that give us the greatest advantages are already within the membrane and we can use it as-is.""

Thursday, January 31, 2013
Vegetarianism is associated with health benefits such as reduced risk of age-related disease. It is also associated with carrying less of the visceral fat shown to cause harm to long-term health - which on balance probably means a lower calorie intake. As we all know by now, calorie intake has a disproportionate effect on measures of health. So that would seem to be a more plausible mechanism than, say, reduced dietary intake of AGEs or lower levels of methionine. Here, however, researchers are claiming that differences in body mass index - a not-so-great proxy measure for the amount of body fat - between vegetarians and non-vegetarians are not terribly important in comparison to blood pressure and cholesterol measures. That is not a particularly intuitive result: "The risk of hospitalisation or death from heart disease is 32% lower in vegetarians than people who eat meat and fish, according to a new study. "Most of the difference in risk is probably caused by effects on cholesterol and blood pressure, and shows the important role of diet in the prevention of heart disease." This is the largest study ever conducted in the UK comparing rates of heart disease between vegetarians and non-vegetarians. The analysis looked at almost 45,000 volunteers from England and Scotland enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Oxford study, of whom 34% were vegetarian. Such a significant representation of vegetarians is rare in studies of this type, and allowed researchers to make more precise estimates of the relative risks between the two groups. The Oxford researchers arrived at the figure of 32% risk reduction after accounting for factors such as age, smoking, alcohol intake, physical activity, educational level and socioeconomic background. Participants were recruited to the study throughout the 1990s, and completed questionnaires regarding their health and lifestyle when they joined. These included detailed questions on diet and exercise as well as other factors affecting health such as smoking and alcohol consumption. Almost 20,000 participants also had their blood pressures recorded, and gave blood samples for cholesterol testing. The volunteers were tracked until 2009, during which time researchers identified 1235 cases of heart disease. This comprised 169 deaths and 1066 hospital diagnoses, identified through linkage with hospital records and death certificates. The researchers found that vegetarians had lower blood pressures and cholesterol levels than non-vegetarians, which is thought to be the main reason behind their reduced risk of heart disease. Vegetarians typically had lower body mass indices (BMI) and fewer cases of diabetes as a result of their diets, although these were not found to significantly affect the results. If the results are adjusted to exclude the effects of BMI, vegetarians remain 28% less likely to develop heart disease."

Thursday, January 31, 2013
Here is a commentary I noticed recently, not entirely positive when it comes radical life extension, but the positive portion is quoted below: "Aging, along with the physical and mental deterioration that characterizes it, is undesirable. Potential economic and social difficulties notwithstanding, living longer and healthier lives is a positive and productive premise. Acceptance of the preceding premise leads to the conclusion that the technology that would facilitate radical life extension ought to be pursued. Dr. Aubrey de Grey, a [biogerontologist] with a formidable beard, offers the argument that it would be morally dubious of us not to develop these technologies and deprive future generations of the benefits therein. To have the ability to develop therapies that lead to longer and healthier lives makes it our responsibility to do so. Policy decisions concerning the adoption and implementation of the policies should be left to those generations in which they are most relevant; it is presumptuous of us to make those decisions for them by not developing these therapies. In his view, it is not only desirable but a moral imperative to give future generations the choice and allow them to decide on implementation. Our hesitation in diverting resources to the development of these therapies is actually condemning future generations to a life span that is far shorter than it could be were we to actively pursue life extension technology. Furthermore, we cannot presume to fully understand the social and political landscape of the future and their priorities - they will be best suited to make a choice and we should allow them to do so. Without going so far as to characterize those opposed to life extension technology as luddites, there is a serious risk of preventing the potential benefits of these technologies from reaching us, or our children, in time. Some people's fear of what may happen if people live ever longer lives is not a basis for pre-emptive policy decisions."

Wednesday, January 30, 2013
It is likely the case that natural variations in longevity emerge from the interaction of many, many minor genetic differences with lifestyle and other environmental factors. The majority of these contributions to longevity will be tiny, and their presence will vary widely across a population: "Twin studies have estimated the heritability of longevity to be approximately 20-30%. Genome-wide association studies (GWAS) have revealed a large number of determinants of morbidity, but so far, no new polymorphisms have been discovered to be associated with longevity per se in GWAS. We aim to determine whether the genetic architecture of mortality can be explained by single nucleotide polymorphisms (SNPs) associated with common traits and diseases related to mortality. By extensive quality control of published GWAS we created a genetic score from 707 common SNPs associated with 125 diseases or risk factors related with overall mortality. We prospectively studied the association of the genetic score with: (1) time-to-death; (2) incidence of the first of nine major diseases (coronary heart disease, stroke, heart failure, diabetes, dementia, lung, breast, colon and prostate cancers) in two population-based cohorts of Dutch and Swedish individuals (N = 15,039; age range 47-99 years). During a median follow-up of 6.3 years (max 22.2 years), we observed 4,318 deaths and 2,132 incident disease events. The genetic score was significantly associated with time-to-death. The association between the genetic score and incidence of major diseases was stronger. Associations were stronger for individuals dying at older ages. Our findings are compatible with the view of mortality as a complex and highly polygenetic trait, not easily explainable by common genetic variants related to diseases and physiological traits."

Wednesday, January 30, 2013
An example of researchers working on the tools needed to guide cell growth: "The aim of the research was to find a biomaterial able to sustain the population of neural stem cells and to generate new differentiated cells in order to start the development of an implant that allows brain regeneration. Despite recent advances in understanding the mechanisms of nerve injury, tissue-engineering solutions for repairing damage in the central nervous system (CNS) remain elusive, owing to the crucial and complex role played by the neural stem cell (NSC) niche. This zone, in which stem cells are retained after embryonic development for the production of new cells, exerts a tight control over many crucial tasks such as growth promotion and the recreation of essential biochemical and physical cues for neural cell differentiation. The team tested types of polylactic acid (PLA) with different proportions of isomers L and D/L, a biodegradable material allowing neural cell adhesion and growth, as materials for nerve regeneration. They found that one type, PLA with a proportion of isomers of 70/30, maintained the important pools of neuronal and glial progenitor cells in vitro. PLA 70/30 was more amorphous, degraded faster and, crucially, released significant amounts of L-lactate, which is essential for the maintenance and differentiation of neural progenitor cells. The results suggest that the introduction of 3D patterns mimicking the architecture of the embryonic NSC niches on PLA70/30-based scaffolds may be a good starting point for the design of brain-implantable devices. [These] will be able to induce or activate existing neural progenitor cells to self-renew and produce new neurons, boosting the CNS regenerative response in situ."

Tuesday, January 29, 2013
Researchers here demonstrate a way to use magnetic levitation to make small pieces of tissue grow more naturally, though one suspects it won't scale to much larger tissue sections. The focus here, as for much of tissue engineering at this time, is to produce tissues as close to the real thing as possible, suitable for testing and research, applications where the small amount is not an issue: "The research is part of an international trend in biomedical engineering to create laboratory techniques for growing tissues that are virtually identical to those found in people's bodies. In the new study, researchers combined four types of cells to replicate tissue from the wall of the bronchiole deep inside the lung. "One of the unique things about the magnetic levitation technology is that it allows us to move cells around and arrange them the way that we want for a particular type of tissue. This is the first time anyone has arranged these four cell types in the same way that they are found in lung tissue." The technology is said to rely on inert, non-toxic magnetic nanoparticles that are inserted into the living cells. Researchers can then use magnets to lift and suspend the cells as they grow and divide. "We conducted a number of tests, and the tissue has the same biochemical signature as native tissue. We also used primary cells rather than engineered cells, which is important for toxicological testing because primary cells provide the closest possible match to native cells." "Bronchiole tissue could solve another problem that's frequently encountered in testing the toxicity of airborne agents. With traditional 2D cultures, it is very difficult to culture cells at the air-liquid interface, which is what you'd prefer for toxicity testing. With our technology, we can easily levitate the bronchiole tissue to the air-liquid interface so that airborne toxins are exposed to the epithelial layer of the tissue, just as it would occur in the lungs.""

Tuesday, January 29, 2013
This pop-sci piece extols the virtues of intermittent fasting, though the author gives it weight over calorie restriction that it doesn't merit at this time. The evidence is much stronger for the benefits of calorie restriction, as it has been studied more extensively. The results for extended longevity in laboratory animals due to intermittent fasting remain mixed, though it certainly seems to produce health benefits: "One of the most important studies in this area was conducted just last year at Salk's Regulatory Biology Laboratory. In an experiment, biologist Satchidananda Panda and colleagues restricted the feeding of mice to - conveniently enough - an 8-hour period each day. The researchers were attempting to study whether obesity and metabolic diseases like diabetes were the result of high-fat diets, or from the disruption of metabolic cycles. To that end, Panda gave the mice lots of fat to eat. In fact, 60% of the calories consumed were derived from fat (which was meant to simulate foods like chips and ice-cream). The researchers also created a control group that ate the same thing, but these mice could eat any time they wanted (interestingly, as nocturnal creatures, they ate half their meals at night, while grazing on the remainders during the day). As for the restricted group, their 8-hour window was at night. One hundred days later, the free-for-all group was a mess. They gained weight, developed high cholesterol, high blood glucose, and experienced liver damage and diminished motor control. But as for the mice who practiced the intermittent fast, they weighed 28% less and showed no signs of adverse health."

Monday, January 28, 2013
An early step towards whole brain emulation seems to be underway, though as always funding past what is in hand now remains a question mark: "The European Commission has selected the two research proposals it will fund to the tune of half-a-billion euros each after a two-year, high-profile contest. The Human Brain Project, led by neuroscientist Henry Markram at the Swiss Federal Institute of Technology (EPFL) in Lausanne, plans to simulate everything known about the human brain in a supercomputer - a breathtaking ambition that has been met with some scepticism (See "Brain in a box"). The final winners were selected from a shortlist of six projects as being the most likely to achieve the paradigm-shifting advances they claim. They will now enter the so-called 'ramp-up' phase, each receiving €54 million over 30 months. That represents the last cash available from the EU's expiring 7th Framework Programme of Research. Subsequent phases will be supported under its successor programme, Horizon 2020, though the structure of that programme is still being negotiated and some observers fear that funds may be scaled back."

Monday, January 28, 2013
An approach to therapy for degenerative blindness that involves reprogramming existing cells rather than introducing new ones: "Doctors may one day treat some forms of blindness by altering the genetic program of the light-sensing cells of the eye. [Working] in mice with retinitis pigmentosa, a disease that causes gradual blindness, the researchers reprogrammed the cells in the eye that enable night vision. The change made the cells more similar to other cells that provide sight during daylight hours and prevented degeneration of the retina, the light-sensing structure in the back of the eye. "We think it may be significantly easier to preserve vision by modifying existing cells in the eye than it would be to introduce new stem cells. A diseased retina is not a hospitable environment for transplanting stem cells. [The] question was, when retinitis pigmentosa is caused by a mutation in a protein only active in rods, can we reduce or stop vision loss by making the cells less rod-like?" The new study focuses on a protein known as Nrl, which influences development of photoreceptors. Cells that make Nrl become rods, while cells that lack the protein become cones. Turning off the Nrl gene in developing mice leads to a retina packed with cone cells. To see if this rod-to-cone change was possible in adult mice, [researchers] created a mouse model of retinitis pigmentosa with an Nrl gene that could be switched on and off by scientists. [In] adult mice, switching off Nrl partially converts the rod cells into cone cells."



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