Fight Aging! Newsletter, August 20th 2012

August 20th 2012

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!



- Don't Argue Incrementalism in a Time of Revolutionary Change
- Removing the Pressure of Impending Death
- A Thought on Priorities
- Discussion
- Latest Headlines from Fight Aging!
    - Everyone Suffers the Downward Spiral of Exercise Capacity
    - More Blood Vessel Engineering
    - Nanofactories to Produce and Target Drugs in the Body
    - Nanoparticles and RNA Interference Versus Cancer
    - An Improvement in Engineered Pancreatic Tissue
    - The Possibility of a Vaccine for Heart Disease
    - The Next Step in Building a Better Eye Prosthesis
    - Gadd45a Orchestrates Much of Muscle Atrophy
    - On Boredom and Radical Life Extension
    - "Not a harmless part of the aging process"


History provides us with some interesting examples of rapid technological innovation that have parallels to the present situation in biotechnology, medicine, and human longevity: steady progress is suddenly replaced with a great leap forward in capacity and quality.

"The cautious majority believes that human life span will continue to increase, but only incrementally, much as it has done for the past few decades - both life expectancy at birth and life expectancy after 60, due to the continued introduction of new medical technologies. (Which proceeds far more slowly than it could, thanks to the heavy hand of the state). One faction of epidemiologists even argues for the possibility of a dip in overall life expectancy as present trends in obesity take their toll - to their eyes the consequences of being overweight look set to outweigh modest gains due to advances in medicine.

"To my mind, arguing for incrementalism in any trend relating to medicine at the present time is choosing to go against the tide. The biotechnologies that underpin advances in medicine are going through a period of massive, revolutionary change. While it is true that organizations such as the FDA do pretty much everything short of shooting scientists to slow down and increase the cost of turning research into therapies, the rapid pace of progress in the life sciences will win through.

"Allow me to put forward a historical analogy: standing in 2012 and arguing a case for gentle future changes in life expectancy over the next few decades, based on the past few decades, is something like standing in 1885 or so and arguing that speed and convenience of passenger travel will steadily and gently increase in the decades ahead. The gentleman prognosticator of the mid-1880s could look back at steady progress in the operating speed of railways and similar improvement in steamships throughout the 19th century. He would be aware of the prototyping of various forms of engine that promised to allow carriages to reliably proceed at the pace of trains, and the first frail airships that could manage a fair pace in flight - though by no means the equal of speed by rail.

"Like our present era, however, the end of the 19th century was a time of very rapid progress and invention in comparison to the past. In such ages trends are broken and exceeded. Thus within twenty years of the first crudely powered and fragile airships, heavier than air flight launched in earnest: a revolutionary change in travel brought on by the blossoming of a completely new branch of applied technology. By the late 1920s, the aircraft of the first airlines consistently flew four to five times as fast as the operating speed of trains in 1880, and new lines of travel could be set up for a fraction of the cost of a railway. Little in the way of incrementalism there: instead a great and sweeping improvement accomplished across a few decades and through the introduction of a completely new approach to the problem.

"This is one of many historical examples of discontinuities in gentle trends brought about by fundamentally new technologies. Returning to the medicine of the present day, there are any number of lines of work we could point to as analogous to the embryonic component technologies of an aircraft in 1885. They are still in the lab, or only being trialed, or still under development - but they exist in great numbers. There are the SENS technologies; a range of advanced applications of immunotherapy; targeting methodologies to safely destroy specific cell types; organ engineering; and others. Just because we can't see the exact shape of the emerging technologies that will be constructed atop these foundations doesn't make them any less likely to be created: great changes are coming down the line in medicine. The future is not one of steady and incremental progress."


What of a world in which people are not faced by the certainty of aging to death?

"At root, medicine is driven by the urge remain alive. ... Consider a world with the means to prevent aging - say, though a package of therapies that a person undergoes every twenty years or so. Infusions of fresh stem cell populations, engineered enzymes to degrade metabolic waste products that build up in and around cells to impair their function, some form of mitochondrial DNA repair, culling excess memory T cells, and so on. These therapies prevent and reverse the build up of damage, allowing a body to continue in good health indefinitely. There is no good reason for them to be any more expensive than your average run of clinical treatments today: they would require little time from a physician, and would operate in much the same way for everyone, allowing economies of scale in production and distribution.

"In such a society, all of the pressures associated with the short span of life we presently enjoy evaporate. We are so steeped in that omnipresent pressure of time that it's somewhat hard to envisage what a society without it would look like. Every strategic decision that we make in the course of our lives is based on time - that we have ever less of it remaining, the clock is ticking, and have only a few shots at getting anything significant accomplished. It requires a decade to become truly talented in any particular profession or skill, for example, and at least a few years to figure out whether not we can follow through to that level. That is a vast investment of time when we only have a few decades in which we are at our prime. The same goes for careers and relationships of any significance. We are pressured and choices have great weight precisely because we must forever give up an ocean of possibilities in order to swim in any particular pool.

"There is a related school of thought among those opposed to engineering longevity: they say that the pressures of time created by the fact that we age to death due to our inadequate medical technology are a good thing. To me this has the look of rushing to justify what is, regardless of what might be, but they argue that the industry of individuals and humanity as a whole requires the deadline of dying; that without it, no-one would accomplish anything. They look upon the unending holocaust of death and destruction caused by aging - 100,000 lives every day, all they knew, all they could accomplish in the future, all they might have done, erased - and say it is necessary.

"This is a hideous nonsense, serving to illustrate that little but a veneer separates us from the barbarians who actively slaughtered millions in past decades. It is true that rapid progress is very necessary in today's world - but we need it because we are dying, and the only way to save ourselves is through technological progress. The faster the better, every increment of speed representing countless lives that might be saved on some future date. If more people were more aware and more interested in doing something about this, we might move faster yet towards the biotechnologies of rejuvenation. Unfortunately, for all that each and every human life is shaped completely by the foreknowledge of future disability and death, all too few are willing to help change this state of affairs.

"But so what if the medical technologies that can prevent death by aging make our societies slower-paced, more considered, less energetic? I'm not of the mind that this is a terrible thing - free-wheeling use of a resource is characteristic of wealth, and when we are wealthy in time, we will have the luxury to use it in ways that presently make little sense, or are called wasteful. Caring about waste is a sign of poverty, a sign that we don't have enough of whatever we worry about wasting, which in turn suggests we should do all we can to accumulate more of it. Besides, I don't for one moment believe that the slowing of economic engines and technological progress will in fact happen as feared by those who advocate for the continuation of mass death and suffering. There are all sorts of economic pressures upon human action that have next to nothing to do with aging and our current all-too-short span of life: consider the shifting desires for security, food, property, knowledge, and novelty, for example. The timescales on which those urges operate will not much change in an ageless society, as people will still have the same human nature as exists today. There will continue to be dynamic and ever-changing industries devoted to keeping people fed, clothed, and entertained."


It is sometimes hard to avoid idle comparisons between flows of money and time in our society:

"Let us contemplate for a moment the level of effort that people put in to just one method of papering over just one of the changes caused by aging - just to keep up appearances, and making no difference at all to the underlying processes that cause degeneration. The method I had in mind is the use of dye to camouflage the progressive graying of hair. The fading of color of hair is an early sign that stem cell populations are responding to rising levels of damage, becoming less active in maintaining tissue. For whatever reason the pigment cells that give hair its color are more sensitive than others to the accumulating cellular and molecular damage of aging. Painting your hair in brightly colored chemicals does absolutely nothing other than cover up the evidence of this process, of course. You're still degenerating underneath that dye.

"Individually, touching up graying hair isn't a great undertaking, and nor does it cost much. But when many, many people do it, that adds up. Ten years ago, hair dye was an industry with $7 billion in yearly sales worldwide - give or take. While that certainly includes the Manic Panic youth brigade, a large fraction of that commerce involves coloring gray hair. So it's not a stretch to suggest that the world's elder folk have a great enough interest in hair dye to fund the NIA several times over, or for something more constructive, provide the budget to implement the SENS vision of rejuvenation biotechnology a couple of times every year.

"This sort of comparison serves to illustrate just how small research and development expenditures in medicine are in comparison to almost any form of day to day commerce. They tell us nothing about how to change that state of affairs, however. It's already something of a mystery as to why people are so relentlessly irrational when it comes to directing resources towards actual improvements in health and longevity versus papering over the cracks with hair dye or funding culturally accepted fraud in the form of 'anti-aging' products.

"Is it the case that people decide between funding research and hiding the gray, and choose to hide the gray? Or is it that funding meaningful research doesn't really even enter that choice matrix? To reframe these questions, is the solution to adequately funding the best and most promising longevity science more a matter of persuasion or more a matter of education?"


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, August 17, 2012
Other than calorie restriction, regular exercise is the most potent presently available method available to maintain health and extend life expectancy - which is actually more of a criticism of our lack of advanced biotechnology than praise for the merits of exercise. Exercise is beneficial even for the elderly, however, and one part of the downward spiral that comes with age is that loss of strength and increasing frailty constrain the ability to exercise sufficiently vigorously to obtain its benefits. This is true even for the longest-lived humans: "Ageing is a continuum of biological processes characterized by progressive adaptations which can be influenced by both genetic and physiological factors. In terms of human maturation, physically and cognitively functional centenarians certainly represent an impressive example of successful healthy ageing. However, even in these unique individuals, with the passage of time, declining lung function and sarcopenia lead to a progressive fall in maximal strength, maximal oxygen uptake, and therefore reduced exercise capacity. The subsequent mobility limitation can initiate a viscous downward spiral of reduced physical function and health. Emerging literature has shed some light on this multi-factorial decline in function associated with aging and the positive role that exercise and physical capacity can play in the elderly. Recognizing the multiple factors that influence ageing, the aim of this review is to highlight the recently elucidated limitations to physical function of the extremely old and therefore evaluate the role of exercise capacity in the health and longevity of centenarians."

Friday, August 17, 2012
Many research groups are working on building blood vessels. Here is one: scientists "have developed [an] artificial functioning blood vessel outside of the body, made from reprogrammed stem cells from human skin. The team also saw the cells develop into a blood vessel inside the body for the first time. The new technique could have real potential to treat patients with heart disease [by] either injecting the reprogrammed cells into the leg or heart to restore blood flow or grafting an artificially developed vessel into the body to replace blocked or damaged vessels. ... this new study demonstrates that a new type of partial stem cell developed from fibroblasts (skin cells) can be reprogrammed into vascular cells before going into the body, which have no risk turning into tumours. The [team] introduced four genes to human fibroblasts in the laboratory to reprogramme them into partial stem cells so they could become vascular cells. When these newly created cells were injected into an ischemic leg (a leg with restricted blood flow) in an animal model, the function of the leg was improved. The process of developing vascular cells from skin cells took two weeks, which makes a personalised approach of turning a patient's own skin cells into vascular cells feasible for treatment of vessel-blocking related diseases. The researchers say the next step is to test this approach in cells from patients with vascular disease."

Thursday, August 16, 2012
Another branch of targeted therapies is the design of nanofactories that can be steered to specific locations in the body and there produce proteins and other drugs in response to local conditions or external commands. Early work in this field is underway: "Science is one step closer to producing drugs in the right place at the right time in the body, avoiding the collateral damage of untargeted treatments. Researchers [have] designed nanoparticles that can be stimulated via UV light to produce proteins on demand in vivo. The new method, which involves packaging the molecular machinery for making proteins into a membraned capsule, allows the researchers to spatially and temporally regulate protein production ... The scientists created the nano-sized 'protein factories' by using lipids to encapsulate polymerase and other machinery necessary for protein production from E. coli, along with a DNA plasmid containing a gene of interest. To block transcription until the right moment, they added a DNA 'photo-labile cage' to the plasmid - a small chemical that inhibits transcription but is cleaved by exposure to UV light. To test the principle in vivo, the researchers used luciferase as the reporter protein and injected mice with the nanovesicles. After zapping them with UV light at the site of injection, they were able to measure a local burst of luminescence. ... We have a long way to go still before we have a drug factory that will land in a target tissue to produce a drug of interest ... The study has proved the principle of the first step - getting the protein expressed on signal - but future research will need to ensure that the nanoparticles and the proteins they produce aren't toxic in the wrong place, and that they get to the right location. Targeting the nanoparticles to the appropriate tissues might be achieved by 'decorating' the surface of the vesicles with specific proteins."

Thursday, August 16, 2012
A novel form of targeted therapy under development in the cancer research community: "By sequencing cancer-cell genomes, scientists have discovered vast numbers of genes that are mutated, deleted or copied in cancer cells. This treasure trove is a boon for researchers seeking new drug targets, but it is nearly impossible to test them all in a timely fashion. To help speed up the process, [researchers] have developed RNA-delivering nanoparticles that allow for rapid screening of new drug targets in mice. In their first mouse study [they] showed that nanoparticles that target a protein known as ID4 can shrink ovarian tumors.What we did was try to set forth a pipeline where you start with all of the targets that are pouring out of genomics, and you sequentially filter them through a mouse model to figure out which ones are important. By doing that, you can prioritize the ones you want to target clinically using RNA interference ... researchers decided to focus on the ID4 protein because it is overexpressed in about a third of high-grade ovarian tumors (the most aggressive kind), but not in other cancer types. The gene, which codes for a transcription factor, appears to be involved in embryonic development: It gets shut down early in life, then somehow reactivates in ovarian tumors. To target ID4, [researchers] designed a new type of RNA-delivering nanoparticle. Their particles can both target and penetrate tumors, something that had never before been achieved with RNA interference. ... Within the nanoparticles, strands of RNA are mixed with a protein that further helps them along their journey: When the particles enter a cell, they are encapsulated in membranes known as endosomes. The protein-RNA mixture can cross the endosomal membrane, allowing the particles to get into the cell's main compartment and start breaking down mRNA. In a study of mice with ovarian tumors, the researchers found that treatment with the RNAi nanoparticles eliminated most of the tumors."

Wednesday, August 15, 2012
From ScienceDaily: "researchers have built pancreatic tissue with insulin-secreting cells, surrounded by a three-dimensional network of blood vessels. The engineered tissue could pave the way for improved tissue transplants to treat diabetes. The tissue [has] some significant advantages over traditional transplant material that has been harvested from healthy pancreatic tissue. The insulin-producing cells survive longer in the engineered tissue, and produce more insulin and other essential hormones ... When they transplanted the tissue into diabetic mice, the cells began functioning well enough to lower blood sugar levels in the mice. ... The well-developed blood vessel network built into the engineered tissue is key to its success, the researchers concluded. The blood vessels encourage cell-to-cell communication, by secreting growth hormones and other molecules, that significantly improve the odds that transplanted tissue will survive and function normally. ... One reason transplants fail [is] that the islets are usually transplanted without any accompanying blood vessels. ... Until the islets begin to connect with a person's own vascular system, they are vulnerable to starvation. The 3-D system developed by [the] researchers tackled this challenge by bringing together several different cell types to form a new transplantable tissue. Using a porous plastic material as the scaffold for the new tissue, the scientists seeded the scaffold with mouse islets, tiny blood vessel cells taken from human umbilical veins, and human foreskin cells that encouraged the blood vessels to develop a tube-like structure. ... The advantages provided by this type of environment are really profound ... the number of islets used to lower blood sugar levels in the mice was nearly half the number used in a typical islet transplant. Islets grown in these rich, multicellular environments lived three times as long on average as islets grown by themselves."

Wednesday, August 15, 2012
Via EurekAlert!: "Most people probably know that heart disease remains the nation's No. 1 killer. But what many may be surprised to learn is that cholesterol has a major accomplice in causing dangerous arterial plaque buildup that can trigger a heart attack. The culprit? Inflammatory cells produced by the immune system. A number of research studies have demonstrated inflammation's role in fueling plaque buildup, also known as atherosclerosis, which is the underlying cause of most heart attacks and strokes, but knowledge of which immune cells are key to this process has been limited - until now. Researchers [have] identified the specific type of immune cells (CD4 T cells) that orchestrate the inflammatory attack on the artery wall. Further, the researchers discovered that these immune cells behave as if they have previously seen the antigen that causes them to launch the attack. ... The thing that excites me most about this finding is that these immune cells appear to have 'memory' of the molecule brought forth by the antigen-presenting cells. Immune memory is the underlying basis of successful vaccines. This means that conceptually it becomes possible to consider the development of a vaccine for heart disease. [Researchers believe] the antigen involved is actually a normal protein that the body mistakes as being foreign and therefore launches an immune attack resulting in inflammation in the arteries. ... Essentially, we're saying that there appears to be a strong autoimmune component in heart disease. Consequently, we could explore creating a 'tolerogenic' vaccine, such as those now being explored in diabetes, which could induce tolerance by the body of this self-protein to stop the inflammatory attack."

Tuesday, August 14, 2012
Present prosthetic retina technology consists of an implanted electrode grid; progress is increasing the resolution by adding more electrodes to the grid. Here researchers take a different route, investigating ways to encode information such that neural cells will better process the resulting image: "More than 20 million people worldwide become blind owing to the degeneration of their retina, the thin tissue at the back of the eye that turns light into a neural signal. Only one prosthesis has been approved for treatment of the condition - it consists of an array of surgically implanted electrodes that directly stimulate the optic nerve and allow patients to discern edges and letters. Patients cannot, however, recognize faces or perform many everyday tasks. Sheila Nirenberg, a physiologist at the Weill Medical College at Cornell University in New York thinks that the problem is at least partially down to coding. Even though the retina is as thin as tissue paper, it contains several layers of nerves that seem to encode light into neural signals. 'The thing is, nobody knew the code,' she says. Without it, Nirenberg believes that visual prostheses will never be able to create images that the brain can easily recognize. Now, she and her student, Chethan Pandarinath, have come up with a code and developed a device that uses it to restore some sight in blind mice. The duo began by injecting nerve cells in the retinas of their mice with a genetically engineered virus. The virus had been designed to insert a gene that causes the cells to produce a light-sensitive protein normally found in algae. When a beam of light was then shown into the eye, the protein triggered the nerve cells to send a signal to the brain, performing a similar function to healthy rod and cone cells. Rather than feeding visual signals directly into the eye, they processed them using a code that the pair had developed by watching how a healthy retina responds to stimuli. After receiving the encoded input, the mice were able to track moving stripes, something that they hadn't been able to do before. The pair then looked at the neural signals that the mice were producing and used a different, 'untranslate', code to figure out what the brain would have been seeing. The encoded image was clearer and more recognizable than the non-encoded one. ... Nirenberg hopes to test the system in human trials soon. The encoding is simple enough to be done by a microchip, which, together with a small video camera could fit onto a pair of glasses. The camera would record a signal and the encoder would then flash it directly onto the genetically treated nerve cells in the eye."

Tuesday, August 14, 2012
An important regulatory gene for muscle atrophy is identified: "We now understand a key molecular mechanism of skeletal muscle atrophy. This finding could help us find a therapy for treating muscle atrophy in patients. ... The team has identified a single protein, called Gadd45a, and determined that it orchestrates 40 percent of the gene activity that ultimately causes skeletal muscle to atrophy. ... The researchers learned that Gadd45a affected muscles in two main ways: it instructed muscle cells to produce fewer proteins (needed to maintain muscle), and it caused proteins already existing in muscle fibers to break down. The result on both counts: muscle atrophy. The team then turned to find out how Gadd45a did its work. The nucleus of a muscle cell that is stressed changes from a cigar shape to a swollen bulb, with enlarged nucleoli (protein containers inside the nucleus). When Adams and his team injected Gadd45a into a muscle cell, the nucleus changed shape the same way as if it were stressed. ... To put this all together, it means Gadd45a is going into the muscle nucleus, and it totally changes it, so much so that the changes are visible. It's turning genes on, and it's turning genes off. It's changed the cell. ... Gadd45a changes roughly 600 genes associated with muscle atrophy, by increasing mRNAs charged either with breaking down muscle proteins or reducing muscle protein growth. ... Gadd45a is like a central switch for muscle atrophy. If you can block it, you can conceivably stunt muscle atrophy to a large extent."

Monday, August 13, 2012
Some people knee-jerk against the prospect of a greatly extended healthy life by thinking of boredom - they can't imagine what they'd do with additional time. To my mind this fits well with the demographic who are ambivalent about being alive at all. To live a longer or shorter life will always be a choice, however. You won't have to undergo the rejuvenation therapies when they are available, just as you don't have to exercise, eat less, or otherwise maintain your health today: a shorter life is right there for the taking, if you feel so inclined. Here is a piece from io9 on the subject: "Some futurists predict that we'll be able to halt the aging process by the end of this century - if not sooner. The prospect of creating an ageless society is certainly not without its critics, with concerns ranging from the environmental right through to the spiritual. One of the most common objections to radical life extension, however, is the idea that it would be profoundly boring to live forever, and that by consequence, we should not even attempt it. So are the critics right? Let's take a closer look at the issue and consider both sides. To help us make sense of the problem, we spoke to two experts who have given this subject considerable thought: Bioethicist Nigel Cameron, the President of the Center for Policy on Emerging Technologies, and philosopher Mark A. Walker, Assistant Professor and Richard L. Hedden Chair of Advanced Philosophical Studies at New Mexico State University. It was through our conversations with them that we realized how difficult this question is to answer - mostly because no one has ever lived long enough to know. But given what's at stake, it's an issue that's certainly worth considering. Now, before we get into the discussion, there are a couple of things to note. First, this is not idle speculation. An increasing number of gerontologists, biologists, and futurists are predicting significant medical breakthroughs in the coming decades that could result in so-called 'negligible senescence' - the indefinite prolongation of healthy human life. And second, this discussion is limited to the question of boredom. Clearly, there are many other serious implications to radical life extension, but those are outside the scope of this article. Okay, let's do this thing."

Monday, August 13, 2012
There is a pervasive mythology surrounding aging: that it includes many harmless changes, things that are "normal" and therefore not worthy of the attention of medicine. This is all nonsense. All changes that happen with aging are damage-driven declines, but because the overall effect is so disastrous it can be hard to pin down and separate out the lesser components. As biotechnology improves, we will see ever more pieces of aging segmented off and named as specific diseases - but in reality it's all harmful, and the full breadth of aging should be fought against: researchers "say a common condition called leukoaraiosis, made up of tiny areas in the brain that have been deprived of oxygen and appear as bright white dots on MRI scans, is not a harmless part of the aging process, but rather a disease that alters brain function in the elderly. ... In the past, leukoaraiosis has been considered a benign part of the aging process, like gray hair and wrinkles. ... [Researchers] performed functional MRI (fMRI) scans on cognitively normal elderly participants recruited from the Mayo Clinic Study of Aging between 2006 and 2010. In 18 participants, the amount of leukoaraiosis was a moderate 25 milliliters, and in 18 age-matched control participants, the amount of disease was less than five milliliters. The patients were imaged in an MRI scanner as they performed a semantic decision task by identifying word pairs and a visual perception task that involved differentiating straight from diagonal lines. ... Although both groups performed the tasks with similar success, the fMRI scans revealed different brain activation patterns between the two groups. Compared to members of the control group, patients with moderate levels of leukoaraiosis had atypical activation patterns, including decreased activation in areas of the brain involved in language processing during the semantic decision task and increased activation in the visual-spatial areas of the brain during the visual perception task. ... Different systems of the brain respond differently to disease. White matter damage affects connections within the brain's language network, which leads to an overall reduction in network activity."



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