Fight Aging! Newsletter, October 20th 2014

October 20th 2014

Herein find a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress on the road to bringing aging under medical control, the prevention of age-related disease, and present understanding of what works and what doesn't when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Fundraising Update: Thousands Donated, and More Yet Needed to Hit the Target
  • Resetting Tissue GHK Levels to Provide Benefits to the Old
  • Proposing Aging as an Evolutionary Strategy to Extend Life in a High Mortality Environment
  • Stroke as a Consequence of Immune Dysfunction
  • A Glance at the Present State of Limb Prosthetics
  • Latest Headlines from Fight Aging!
    • Claiming Confirmation of the Amyloid Hypothesis in Alzheimer's Disease
    • Discussing the Path to a Tissue Engineered Liver
    • Obesity Accelerates Aging of the Human Liver
    • Aging: Humanity Faces a Major Problem
    • Success in Cell Therapy for Degenerative Blindness
    • A Device to Clear Pathogens from Blood to Treat Sepsis
    • An Update on a Trial of Chimeric Antigen Receptor Methods of Targeting Cancer Cells
    • Investigating a Repair Mechanism for Stroke Damage
    • A New Discovery Relating to Heat Shock Factors and Longevity
    • Factor Magazine on SENS Rejuvenation Biotechnology


On October 1st we kicked off this year's grassroots matching fundraiser in support of SENS Research Foundation programs. Earlier this year a group of us raised a large matching fund to encourage donations: each $1 donated to the SENS Research Foundation before the end of the year draws an additional $2 from the fund. The Foundation is a 501(c)(3) charity, and your tax-deductible donations help to expand ongoing research programs that aim to produce the necessary foundation biotechnologies for therapies to repair the causes of degenerative aging. We have a chance at avoiding frailty and age-related disease, but if we want to attain that goal in time enough to matter then we must all do our part. New medical technologies don't fund themselves, and the future we get is the future we choose to invest in.

As of Friday 10th more than 200 people from the futurist and broader longevity science community stepped up to donate thousands. With matching from our fund these first donors have ensured that three times that amount will go to support rejuvenation research organized by the Foundation in 2015. We have a way to go yet to draw down the rest of the fund, however - and all help is appreciated.

A big part of this process is people and discussion, not money. It is about building a larger community of supporters, reaching new audiences who have yet to give serious thought to just what might be accomplished in the next twenty years if the right approach to therapies for aging wins out. To most people rejuvenation is an impossible pipe dream, but then most people don't pay any attention to the ins and outs of medicine in practice, let alone medical research still in progress, until they need to. We must do our part to change this state of affairs, to make aging research more like cancer research in the public eye: support, a clear vision for a cure, and an eagerness for progress.

To implement a comprehensive suite of first generation rejuvenation treatments in mice, of the damage repair variety as outlined in the SENS proposals, the research community will need a large amount of resources, perhaps as much as Big Pharma devotes to guiding a single new drug through research and development. That funding largely arrives from institutions and companies with millions to spend on each grant or project, but they never become involved in any line of research that lacks prototype treatments resulting from early stage research, and widespread recognition and support.

The way you raise tens of millions or more for medical research from a few select groups is by first raising tens of thousands from hundreds of grassroots supporters, while thousands more are talking about your work, and tens of thousands are reading about it in the press. You use that modest funding to conduct the low-cost early stage research to produce prototypes and prove your case: producing clinical treatments remains very expensive, but progress in the tools of biotechnology has made early stage medical research very cheap in comparison to past decades.

That is how bootstrapping works, whether for research, biotech startups, or any human endeavor for that matter. But can we do it for SENS rejuvenation research? Of course we can. In fact, we've done it already: SENS started out fifteen years ago or so with a few tens of thousands of dollars here and there raised from hundreds of supporters. As those numbers grew, deeper pockets then provided most of the probably $20-30 million devoted to SENS research programs to date. They did this only because crowds were already making modest donations and talking in support of SENS. The overall funding for SENS is a number hard to pin down nowadays: there is a fair amount of relevant work taking place that is not funded by the SENS Research Foundation or even coordinated by the Foundation, and in some cases it's a tough call as to whether to include it or not in any estimate.

So what are we doing here with this fundraiser? The answer to that question is this: the same proven-to-work strategy, except with more money and faster progress than the early days. The grassroots who make modest donations are the very people who lead the way and light the path for later large-scale funding, and when the grassroots grows that funding will be larger than the present support for SENS. You can help us to make this happen by reaching out to the communities you know: people that haven't heard from us. It's a simple message:

  • Do you want to grow sick and frail with age, or for that to happen to your friends and parents? We don't.
  • We live in an age of science and progress. Medical researchers can now work to prevent the disability and degeneration of aging, with your support.
  • The pains and suffering of aging are not inevitable forever. All ill health was once incurable, but cures were made by dealing with the root causes of ill health. The same can can also be accomplished for the frailty and sickness of old age.
  • The state of research and the detailed knowledge of what must be done is presently much more advanced than you might imagine.
  • If supporting cancer research looks good, why not also give to support research to treat the root causes of all age-related disease?
  • It makes sense. Later, when we are old, we will get the medicine that we supported today.


The aging research community might be divided into two camps. The much larger camp sees aging as a process of damage accumulation and reactions to that damage. There is a lot of argument over which forms of damage are more important and how they lead to the observed age-related changes in biochemistry, but the primary forms of damage are well described and that list has existed in its present form for more than thirty years. The smaller camp in the research community sees aging as an evolved genetic program of changes that cause damage. So we have a cart and a horse and debate over which is which. For my part I see the balance of evidence as leaning strongly towards aging as damage.

It can be the case that researchers well understand the fundamental damage of aging but yet argue over whether it is a cause or a consequence because metabolism - the day to day operation of our biochemistry, and the way in which it reacts to circumstances - is fantastically complex. Even in this age of advanced biotechnology and large-scale computation we stand a long, long way from a full model of its operation. So it seems likely that settling the debate over aging as damage versus aging is program will occur when the first damage repair treatments are rolled out and trialed in mice. They should be very effective if aging is in fact the results of damage. If aging is a program, well, they will be much less effective and the results transient. The cost of performing this grand experiment is very low in comparison to the cost of trying to build a complete understanding of metabolism. At this point in time it requires hundreds of millions of dollars and a decade of work to chase down answers in the roles of just a few genes and proteins out of the thousands of noteworthy types of molecule involved in metabolism: just look at sirtuin research as an example. In the world of SENS rejuvenation research, hundreds of millions of dollars would buy most of a rejuvenation toolkit for laboratory mice and the proof as to whether it works or not.

We live in a world that isn't all that rational, however, as illustrated by the fact that damage repair approaches like SENS are not well funded. Despite the fact that a majority in the research community work from the hypothesis that aging is caused by cellular and molecular damage in tissues, they work on treatments that make much more sense for the programmed aging school of thought. Generally research focuses on the end stages of age-related conditions, working backwards to identify proximate causes of pathology. Scientists identify the next to last changes before the end, which of course are very rarely the same thing as the primary forms of damage that are thought to cause aging. Only in some diseases, such as macular degeneration, is there a very short chain of steps from fundamental damage (build up of metabolic waste products called lipofuscin) to disease process (death of retinal cells), and that chain is well understood.

So instead of root causes, researchers are far more often studying the details of metabolic disarray in late stage disease. Simple causes spiral out into highly complex dysfunction in a system, our metabolism, that is researchers are still figuring out piece by piece as they go. Since genetic and epigenetic studies are becoming popular - they are newly cheap and funding is easily raised - the proximate causes latched onto are often epigenetic changes. These are consequences, reactions to damage, if you think that aging is damage, and primary causes of damage if you think that aging is programmed. So we have researchers who are firmly in the aging as damage camp nonetheless working hard to create treatments that should, by their own hypotheses, have only marginal benefits. Treatments that won't in any way deal with the underlying problem, but rather are attempts to force a dysfunctional metabolism to work better under a high load of damage. This is patching the problem, and will be expensive and provide little in comparison to the results that damage repair could achieve.

But anyway, there are plenty of examples to point out. Most research into treating aging is as I've described above, and the "repair the damage" approach of SENS is still the disruptive minor newcomer. It's strange, given that the majority of the field considers aging to be a process of damage. Here is one example in which researchers pick out an epigenetic change that occurs in aging, resulting in altered levels of one particular protein, and discuss the prospects for altering it in order to adjust the operation of metabolism. Read the open access paper, and bear in mind that this is what the ultimately futile path looks like, the way forward that will not greatly help us when we are old:

GHK and DNA: Resetting the Human Genome to Health

During human aging there is an increase in the activity of inflammatory, cancer promoting, and tissue destructive genes plus a decrease in the activity of regenerative and reparative genes. The human blood tripeptide GHK possesses many positive effects but declines with age. It improves wound healing and tissue regeneration (skin, hair follicles, stomach and intestinal linings, and boney tissue), increases collagen and glycosaminoglycans, stimulates synthesis of decorin, increases angiogenesis, and nerve outgrowth, possesses antioxidant and anti-inflammatory effects, and increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells.

GHK was discovered during studies comparing the effect of human plasma from young persons (age 20-25) to plasma from older persons (age 50-70) on the functioning of incubated slices of human hepatic tissue. The younger plasma more effectively induced a profile associated with youth by suppressing fibrinogen synthesis. The active factor was found to be GHK. Since then numerous studies over the course of four decades demonstrated that this simple molecule improves wound healing and tissue regeneration.

Even though numerous and diverse beneficial effects of GHK have been known for decades, it was not clear how one simple molecule could accomplish so much. The use of gene expression data greatly extends our understanding of GHK's effects and its potential treatments of some of the diseases and biochemical changes associated with aging. As a potential therapeutic agent GHK has a clear advantage over many other active chemicals that may also show promising results in gene profiling experiments, its gene modulating effects correspond to findings from in vivo experiments. When GHK is administered internally to an animal, it induces actions throughout the body.

There is still not enough information to translate gene profiling data into biological effects. However, based on the documented activity of GHK in vivo, we can predict [various] beneficial actions from our gene profiling data. Most current theories and therapies to treat disease tend to target only one biochemical reaction or pathway. But for human aging, our data suggests that we must think of simultaneously resetting hundreds to thousands of genes to protect at-risk tissues and organs. GHK may be a step towards this gene resetting goal.


There are traditional wisdoms in the study of the evolutionary origins of aging. For example that greater extrinsic mortality due to predation or an otherwise harsh environment selects for shorter life spans, producing species whose individual members are optimized to reproduce rapidly and age rapidly, as health assurance mechanisms that create longer reproductive and overall life spans are either lost or never evolve in the first place. This and other consensus theories initially emerged from simple models that have nonetheless largely continue to do fairly well over the years, but all simple models are eventually challenged. With the falling cost and vast increase in available computing power ever more sophisticated evolutionary modeling has taken place, and researchers are finding that there can be exceptions to almost every hypothesis in the field.

Here is an interesting paper in which researchers propose that under some circumstances high extrinsic mortality can result in species with longer lives, not shorter lives, and further that aging may have evolved because it actually increases lifespan in a species living in a high mortality environment. These are not the only researchers producing models in which this sort of thing happens. The argument here is that aging and improved youthful ability are linked: the evolution of capabilities that improve survival and reproductive success in the face of adversity in early life goes hand in hand with an inability to maintain tissues and metabolism over the long term. Thus individuals better survive their hostile environment and live longer on average, but age as a consequence.

Interaction Mortality: Senescence May Have Evolved because It Increases Lifespan

Given an extrinsic challenge, an organism may die or not depending on how the threat interacts with the organism's physiological state. To date, such interaction mortality has been only a minor factor in theoretical modeling of senescence. In general, it holds that mortality does not affect evolution if it affects all organisms equally. The intuitive reason for this is that evolution favors a phenotype (strategy) if it is better at propagation than other strategies. If all strategies are affected equally, no strategy improves relative to others, and selection gradients remain unchanged.

Mortality that does not distinguish between individuals is often called 'extrinsic mortality' and modeled as an age-independent parameter in the mortality function of age-structured models. In these models, extrinsic mortality is a discounting factor in the survival function that cannot be molded in any way by the (fictitious) organism that is studied. However, whether environmental threats result in mortality depends on the interaction of those threats with an organism's physiological state. By adjusting its state, an organism can influence death from environmental causes.

To investigate mortality-environment interactions from a theoretical perspective, we model a trade-off between an age-independent and an age-dependent mortality term. As an example of a biological rationale for such a model, [it has been] suggested that it could be beneficial from an evolutionary standpoint to attain a state that is unmaintainable by its very nature, causing mortality to be low at young ages, but to increase over time [as senescence takes hold]. As a result, death can be postponed to later ages, depending on the magnitude of initial reduction relative to the ensuing increase in mortality with age.

We find that depending on the physiological constraints, any outcome is possible in any environment, be it 'no senescence' or 'high rate of senescence'; that the highest optimal rate of senescence emerges for an intermediate physiological constraint; and that the optimal rate of senescence as a function of the environment is driven by the way the environment changes the effect of the organism's state on mortality. We conclude that predicting the outcome requires knowledge about the interaction of the environment and the organismal physiology: separately, these have little predictive power.

We propose, perhaps paradoxically, that senescence may have evolved because it extends lifespan. Lifespan is equal to the inverse of average mortality. If mortality increases over age, but [for a senescent species] starts off from a much lower level than would otherwise be the case [for a non-senescent species], average mortality may go down, implying lifespan extension.


To suffer a stroke is one the uglier and more abrupt system failures of aging. A vital blood vessel in the brain is either blocked by the biological debris of clots and fatty deposits on blood vessel walls, or more rarely the blood vessel suffers a structural failure of its walls due to forms of cellular and molecular damage that weaken, restructure, and stiffen this tissue. The higher blood pressure that accompanies age, for a collection of reasons that are only mostly avoidable, raises the odds of disaster. Thus a part of the brain is either deprived of oxygen or flooded with blood, and in either case cells die and a fragment of the brain - and the mind it hosts - is lost or greatly impaired, often permanently.

The ultimate objective of rejuvenation biotechnology after the SENS model of is to remove the root causes that lead to stroke, as for all age-related conditions. Break down the metabolic waste that stiffens blood vessels and indirectly raises blood pressure; restore stem cell populations to more aggressive repair of failing tissues; and more besides. Among the "more besides," is it the case that stroke has immune dysfunction among its noteworthy contributing causes? The immune system fails in characteristic ways with aging, among them a growth in chronic inflammation: even as the immune system becomes unable to adequately police the body in search of pathogens and rogue cells, it is constantly overactive, in a state of inflammation. This progression towards dysfunction is termed inflammaging, but there may be comparatively straightforward ways to turn it back at least some of the way. This might be achieved by crudely rebalancing the internal configuration of the immune system, destroying one class of cells that serve little useful purpose, but have grown too numerous. Their numbers block the generation of effective new immune cells, but if winnowed that would change.

Open access papers in the latest issue of Aging and Disease argue for the immune dysfunction contribution to stroke, mediated by inflammation:

Ischemic Stroke: A Consequence of a Diseased Immune System?

Stroke is a leading cause of long-term disability and the second leading cause of death globally. Approximately 795,000 strokes are reported each year in the US, 87 percent of which are ischemic. The direct medical cost associated with stroke in 2009 was approximately $22.8 billion, with an additional $13.8 billion in indirect costs associated with lost productivity, unemployment, rehabilitation, and follow-up care.

It is interesting to consider whether a common mechanism of immune dysfunction underlies many complex diseases, such as stroke, heart disease, myocardial infarction, and atherosclerosis. While it is possible that the immune system is similarly altered, gene-environment interactions may control the timing or severity of the dysfunction, and epigenetic modifications may provide a common molecular mechanism to link the immune response among different disease states. Our knowledge of the epigenetic control of the immunological consequences of ischemic stroke is limited and requires a new approach to clinical and pre-clinical studies.

The Immune Response to Acute Focal Cerebral Ischemia and Associated Post-stroke Immunodepression: A Focused Review (PDF)

It is currently well established that the immune system is activated in response to transient or focal cerebral ischemia. This acute immune activation occurs in response to damage, and injury, to components of the neurovascular unit and is mediated by the innate and adaptive arms of the immune response. The initial immune activation is rapid, occurs via the innate immune response and leads to inflammation. The inflammatory mediators produced during the innate immune response in turn lead to recruitment of inflammatory cells and the production of more inflammatory mediators that result in activation of the adaptive immune response.

Under ideal conditions, this inflammation gives way to tissue repair and attempts at regeneration. However, for reasons that are just being understood, immunosuppression occurs following acute stroke leading to post-stroke immunodepression. This review focuses on the current state of knowledge regarding innate and adaptive immune activation in response to focal cerebral ischemia as well as the immunodepression that can occur following stroke.

Cytokines: Their Role in Stroke and Potential Use as Biomarkers and Therapeutic Targets (PDF)

The complex, multifaceted cascade of events that results from brain deprivation of oxygen, glucose, and other essential nutrients to the brain causes dysfunction. During ischemia, glutamate stored within brain cells is released when cells are hyperactive or die. Furthermore, brain and immune cells produce reactive oxygen species (ROS), and restoration of blood flow in the occluded vessel generates additional ROS. ROS activate endothelial cells and cause oxidative stress. Oxidative stress and the induction of the inflammatory cascade leads to the breakdown of the blood-brain barrier allowing activated blood-borne immune cells such as neutrophils and T-cells to infiltrate and accumulate in the ischemic brain tissue. Along with the accumulation of activated immune cells, microglia in the brain become activated after cerebral ischemia. Activated microglia secrete pro-inflammatory mediators such as cytokines.

As cells die and brain tissue is damaged, molecular danger signals further potentiate the inflammatory response by activating more microglia and infiltrating leukocytes in a feed-forward response producing more deleterious pro-inflammatory cytokines. These inflammatory changes after ischemia lead to an increase in neuronal cell death resulting in a larger infract volume and worse neurological outcome. Inflammation is a key player in brain damage during cerebral ischemia; however, inflammation aiding in repair and recovery after cerebral ischemia can be beneficial.

It is clear that cytokines play an important role in the pathophysiology of stroke, and the loss in balance between pro-inflammatory and anti-inflammatory cytokines after stroke affects infarct size and functional outcome. Thus, focusing on one cytokine only as a potential biomarker or a therapeutic target likely will not be advantageous in stroke. Future work needs to elucidate the temporal profile of cytokines in the periphery in human and experimental stroke studies to determine which cells contribute to the elevation of cytokines in the brain and blood and to understand how they work in concert to provide neuroprotection or increase neurotoxicity.

The crosstalk between the immune system and the brain is still not well understood. Using cytokines as biomarkers or therapeutic targets may be beneficial to understand the post-ischemic immune response and its effects on outcome clinically and to modulate the post-ischemic immune response to limit tissue damage. However, modulation of the immune response can also be detrimental after stroke; thus, it is imperative that further clinical and experimental studies be pursued to better understand the complex interaction between the immune system and the brain after stroke.


The body is a life support system, carriage, and collection of useful accessories for the brain. Insofar as you as an individual are concerned, you are your brain. The rest of the body is only indispensable because we don't have other ways to provide the same capabilities. That will change, though likely not in any easily predicted way: the decades ahead are a time of great uncertainty in technological details because the pace of change is so rapid. Small differences in research today are magnified over the years leading up to future applications of that science. We might set out to draw a smooth line of progression between today's prosthetics - artificial limbs with simple nervous system interfaces, bioartificial dialysis devices, vision substitutes for the blind via implanted electrode grids, and so forth - and the integrated artificial brain carriage of tomorrow, a collection of technologies and capabilities that will bear roughly the same relationship to the natural human body and biological systems as a car bears to a horse. Some people, such as those involved in the 2045 Initiative see this as a goal to be pursed more aggressively and directly than is presently the case. But I suspect that the line will be anything but smooth and direct.

Prosthetics are just one approach to tackling the results of disability, disease, and the damage of aging, after all. If the goal is function where function is lost, then prosthetics are in competition with regenerative medicine. The two sides will tend to ebb and flow in funding for any of the thousands of potential applications as they do better or worse than one another in providing the ability to regain what was lost. My suspicion is that prosthetics will fade as as an active line of development in the decades ahead due to progress in tissue engineering and regenerative medicine. Artificial limbs, perhaps the least complex of all possible prosthetics, will soon be potentially better than the real thing in a range of capabilities. Yet I imagine that the average fellow short a limb would nonetheless jump at the chance of regrowing a biological replacement in the fashion of a salamander if that was a possibility, as it may well be twenty years from now.

Meanwhile, however, it is interesting to watch progress in this field. Some of the work on prosthetics is potentially applicable to augmentation devices such as wearable exoskeletons that might provide the frail elderly with far greater freedom of action. But again, this is no substitute for the creation of repair biotechnologies that might restore lost capabilities and health. Much of today's prosthetics development is a matter of substitution and compensation; increasingly useful, and the only game in town until there is more progress in medicine, but a phase of technology that will pass, or transition to augmentation of those without disability. Perhaps it will return in earnest at the end of the biological period of medicine when "prosthetics" will mean producing discrete systems of diamondoid nanomachinery to replace slices of our biology: artificial immune cells; artificial oxygen stores in blood; artificial ATP-producing nanofactories to augment mitochondria. All of these are machines that we can consider and design in theory today, and that might be hundreds of times more efficient than our evolved biology. Building an industry to create and maintain such things lies a few steps beyond present endeavors in medicine and materials science, however. It or something similar might be the new new thing for the 2040s and later.

Returning to the present day, here are a few articles noting the present state of work on limb prosthetics. Perhaps the most interesting aspect of this is work on integration with the nervous system. That is a technology that has wide-ranging applications beyond prosthetics, and we'll be seeing a lot more of in the years ahead.

Is This the Future of Robotic Legs?

"When you view the human being in terms of its locomotory function, some aspects are quite impressive," Herr said. "Our limbs are very versatile: We can go over very rough terrain, we can dance, we can stand still. But...our muscles, when they do positive work, 75 percent is thrown out as heat and only a quarter is mechanical work. So we're pretty inefficient, we're pretty slow and we're not terribly strong. These are weaknesses we can fix."

The next frontier for bionics, Herr believes, is neurally controlled devices. For now, the BiOM [prosthetic foot] works independently from the brain, with an algorithm and a processor governing the prosthetic's movement. But Herr is working on sensors that can tap into the body's nervous system - eventually we could see a prosthetic controlled by the brain, muscles and nerves.

Mind-controlled prosthetic arms that work in daily life are now a reality

The novel osseointegrated (bone-anchored) implant system gives patients new opportunities in their daily life and professional activities. "We have used osseointegration to create a long-term stable fusion between man and machine, where we have integrated them at different levels. The artificial arm is directly attached to the skeleton, thus providing mechanical stability. Then the human's biological control system, that is nerves and muscles, is also interfaced to the machine's control system via neuromuscular electrodes. This creates an intimate union between the body and the machine; between biology and mechatronics."

The patient is also one of the first in the world to take part in an effort to achieve long-term sensation via the prosthesis. Because the implant is a bidirectional interface, it can also be used to send signals in the opposite direction - from the prosthetic arm to the brain. This is the researchers' next step, to clinically implement their findings on sensory feedback.

"Reliable communication between the prosthesis and the body has been the missing link for the clinical implementation of neural control and sensory feedback, and this is now in place. So far we have shown that the patient has a long-term stable ability to perceive touch in different locations in the missing hand. Intuitive sensory feedback and control are crucial for interacting with the environment, for example to reliably hold an object despite disturbances or uncertainty. Today, no patient walks around with a prosthesis that provides such information, but we are working towards changing that in the very short term."

Amputees discern familiar sensations across prosthetic hand

The system, which is limited to the lab at this point, uses electrical stimulation to give the sense of feeling. But there are key differences from other reported efforts. First, the nerves that used to relay the sense of touch to the brain are stimulated by contact points on cuffs that encircle major nerve bundles in the arm, not by electrodes inserted through the protective nerve membranes. Second, to provide more natural sensations, the research team has developed algorithms that convert the input from sensors taped to a patient's hand into varying patterns and intensities of electrical signals. The sensors themselves aren't sophisticated enough to discern textures, they detect only pressure.

The different signal patterns, passed through the cuffs, are read as different stimuli by the brain. The [researchers believe] that everyone creates a map of sensations from their life history that enables them to correlate an input to a given sensation. "I don't presume the stimuli we're giving is hitting the spots on the map exactly, but they're familiar enough that the brain identifies what it is."


Monday, October 13, 2014

Most of the research community proceeds under the assumption that amyloid, deposits of misfolded proteins that form in tissues, is a causative agent in Alzheimer's disease. Amyloid levels rise with age, probably due to progressive failure of clearance mechanisms. Definitive proof of the role of amyloid has been slow in coming, however, for all that the weight of evidence is strong. From a biochemical point of view Alzheimer's is a very complex condition, and there has been plenty of room for alternate theories to flourish, especially given the slow progress towards meaningful treatments based on removing amyloid.

Researchers are here claiming confirmation of the amyloid hypothesis, which is news, though that might be overstating the case:

An innovative laboratory culture system has succeeded, for the first time, in reproducing the full course of events underlying the development of Alzheimer's disease. Using the system they developed, [investigators] now provide the first clear evidence supporting the hypothesis that deposition of beta-amyloid plaques in the brain is the first step in a cascade leading to the devastating neurodegenerative disease.

"Originally put forth in the mid-1980s, the amyloid hypothesis maintained that beta-amyloid deposits in the brain set off all subsequent events - the neurofibrillary tangles that choke the insides of neurons, neuronal cell death, and inflammation leading to a vicious cycle of massive cell death. One of the biggest questions since then has been whether beta-amyloid actually triggers the formation of the tangles that kill neurons. In this new system that we call 'Alzheimer's-in-a-dish,' we've been able to show for the first time that amyloid deposition is sufficient to lead to tangles and subsequent cell death."

[The researchers] realized that the liquid two-dimensional systems usually used to grow cultured cells poorly represent the gelatinous three-dimensional environment within the brain. Instead the [team] used a gel-based, three-dimensional culture system to grow human neural stem cells that carried variants in two genes - the amyloid precursor protein and - known to underlie early-onset familial Alzheimer's Disease (FAD).

After growing for six weeks, the FAD-variant cells were found to have significant increases in both the typical form of beta-amyloid and the toxic form associated with Alzheimer's. The variant cells also contained the neurofibrillary tangles that choke the inside of nerve cells causing cell death. Blocking steps known to be essential for the formation of amyloid plaques also prevented the formation of the tangles, confirming amyloid's role in initiating the process. The version of tau found in tangles is characterized by the presence of excess phosphate molecules, and when the team investigated possible ways of blocking tau production, they found that inhibiting the action of an enzyme called GSK3-beta - known to phosphorylate tau in human neurons - prevented the formation of tau aggregates and tangles even in the presence of abundant beta-amyloid and amyloid plaques.

Monday, October 13, 2014

An interesting interview with a tissue engineer can be found at the Methuselah Foundation blog. It covers one view of the path from today's research to the clinical availability of complete engineered livers constructed to order, among other subjects:

[The most significant challenge] definitely has to do with scaling up our cell sources, because the liver is such a large organ, and you just need an enormous volume of cells. We can take fat-derived bone marrow stem cells and turn them into pretty much any cell that we want, but we need such large quantities that we may have to combine cells from different populations in order to get enough. [So] we're going back to how we tackled it for the small bowel, which was to use clusters of cells known as organoid units rather than single cells alone. For the bowel, what that cluster looks like is an epithelial cell - the specialized stem cell of the intestine - with a little ball of cells gathered around it. One of the beauties of these organoid units is that because all of the cells are together, they've already got their natural architecture in place. When you're working with single cells, they have the unfortunate habit of changing into other cells that you don't want. And the more you can keep them together, the happier they are. So these already existing cell architectures turned out to be very useful to us.

Likewise, with the liver, rather than using single cells alone and therefore having to figure out how to mass produce them in order to get enough, we're exploring whether or not we can use these organoid units instead and get them to expand and coalesce into functional tissue. It's kind of like giving the whole process a head start. Instead of saying, "Okay, two cells need to get together and start talking," we're saying, "Can we put 10 cells together and get them to talk to another 10 cells?"

Down the line, we're still going to have to figure out where these cells will come from. With pigs, I can take the liver from one pig and turn it into a scaffold, and then take another pig and break down its liver in order to get a bunch of little organoid units out of it, which I can then seed back into the scaffold. That's great, but it's not clinically translatable. I can't really go to a human patient and just take out little bits of their liver and start chopping them up, because they need their liver to survive. So it's a bit of a Catch-22 at the moment.

In the end, I wonder whether we may have to figure out how to harvest a smaller portion of organoid units from small biopsies of a patient's liver, seed them into a scaffold alongside other stem cells, and then somehow get those organoid units to turn the adjacent stem cells into liver cells. We do have a little bit of lab evidence that this could work, because we've taken bone marrow stem cells, co-cultured them together with epithelial cells from the bronchi, and these stem cells have shown signs of turning into epithelial cells themselves. But this still needs to be explored in a lot more detail.

In general, we'd eventually like to be able to say to you, "Here's a fully seeded new liver, and you can have a full transplant." Before we get to that point, however, it may also be possible to use a partial tissue-engineered liver to make some kind of dialysis machine, much like we do for the kidney. This would give us the opportunity, step by step, to offer an intermediate form of treatment that would give your liver a chance to regenerate a little bit and regain some of its function.

Based on the work we're doing now, I think we'll need another four to five years at least before we're ready to find our first human patient and do a serious pre-clinical GLP study, which is the completely audited study that the regulators would approve of. And that's for the dialysis treatment. Once you got the dialysis up and running, from there it may just be a case of scaling it up to full engineered organ transplants. I don't know how long that will take.

Tuesday, October 14, 2014

It was only comparatively recently that researchers developed a potential measure of biological age using patterns of DNA methylation, a collection of epigenetic alterations that are in some cases similar between different individuals of the same age. It makes sense that there should be age-related patterns to find in our biochemistry, as we all age due to the same root causes: degenerative aging is the consequence of a few forms of cellular and molecular damage, and since the damage is the same, some of the reactions to that damage should also be the same.

Researchers have now had enough time to apply the new DNA methylation measure in larger studies and process the data. I imagine we'll be seeing more results like this one over the next few years. In this case the data adds to the voluminous support for the negative impact of excess fat tissue on long-term health:

Scientists have found, for the first time, that obesity significantly quickens the aging process of the liver and have revealed that carrying excessive weight can negatively impact certain human tissues. The researchers used an 'epigenetic clock' [based on] a naturally occurring process called methylation, which is a chemical modification of the DNA molecule. To reach their findings in this study and examine the connection between increased body weight and epigenetic acceleration, the [scientists] worked with and used [the] aging clock method on almost 1,200 human tissue samples, 140 of which were liver samples.

The researchers found that the aging clock was quite accurate and was able to match the biological age with the chronological age of liver tissue samples taken from subjects with little body fat. On the other hand, the scientists found that liver tissues taken from subjects who were obese had a tendency of having a higher biological age than their chronological age. While they found that obesity has no affect the epigenetic age of human tissues such as fat, muscle or blood, [the] epigenetic age of the liver, on average, increased by 3.3 years for every 10 units of Body Mass Index (BMI). "This does not sound like a lot, but it is actually a very strong effect. For some people, the age acceleration due to obesity will be much more severe, even up to 10 years older."

Tuesday, October 14, 2014

The cost of aging is enormous, far greater than any other single cause of pain, suffering, and death. Approximately two thirds of all deaths are due to aging and its consequences: more than 100,000 lives are lost to aging each and every day. These are rarely pleasant or easy ends. Aging progressively raises the chance of suffering a range of fatal or disabling medical conditions: cardiovascular disease, amyloidosis, dementia, and many others. Hundreds of millions of people live with ever worsening chronic pain, disability, and suffering as a result of aging.

The overwhelming majority of all medical expenditure goes towards treating the consequences of aging or providing palliative care for the aged. Further, there is an enormous opportunity cost to aging: those who become frail and unable to work might have otherwise gone on to continue earning and creating value. The amounts involved are staggering: the cost of the most common chronic medical conditions in the US alone amounts to ~$280 billion in expenditures and ~$1 trillion in lost productivity each and every year. The overwhelming majority of that is due to aging.

Yet it remains unusual for anyone to point out that this is happening, or that we need to address it by striking at the root cause of all this pain, suffering, death, and loss:

Humanity faces a major problem (what I refer to here simply as the Problem) this century. And given the nature of the Problem it will most likely be a significant problem for all future generations as well, unless we seriously tackle this problem. The Problem is one of the most significant problems we have ever faced. Sadly not very many people realize how big of a problem the Problem is, and few believe there is anything we can do to remedy the Problem. Thus people do not pressure their governments to take action to address the Problem.

There is an extremely strong scientific consensus concerning the likelihood that the Problem will impose unprecedented levels of suffering, disease and disability on people in both rich and poor countries. Indeed this is a certainty if we do nothing to prevent the Problem. Furthermore, the Problem threatens to undermine the economic prosperity of all nations, rich and poor alike. So if you hadn't yet guessed it, the Problem is global aging. Civilization has become so successful at preventing early and mid-life mortality - thanks to public health measures like the sanitation revolution, immunizations, antibiotics, changes in behaviour and increases in material prosperity - that our populations now age.

Some claim we should just focus on "adaptation" to minimize the harms of the Problem. Those taking this position doubt we can do anything to directly alter the certainty and severity of the problem. And yet many of the scientists with expertise on the nature of the Problem believe we can directly manipulate the factors responsible for the Problem. Numerous scientific experiments have demonstrated that the biological processes involved in senescence (aging) can be modulated, thus slowing down the rate of molecular and cellular decline.

Given the rapid rise of chronic disease that has already occurred, and will dramatically rise this century as populations age, what can be done? The strategy of adaptation is one that simply takes the biology of aging we have inherited from our species life and evolutionary history as a given, and looks for ways to minimize the harmful effects of aging. So promoting exercise, or tackling specific diseases of aging by funding medical research on cancer or Alzheimer's disease, or redesigning cities to better promote the mobility of aging populations.

A more ambitious and rational strategy would be to aspire to modulate aging itself. Retarding human aging could dramatically increase the health span and reduce the period of time humans will suffer chronic disease. Such an intervention could be something all future generations benefit from as well. There are hardly any global problems as pressing and significant as tackling aging is today.

Wednesday, October 15, 2014

There are signs of progress in the use of cell therapies to restore vision. A small trial involving patients suffering from forms of degenerative blindness caused by loss of retinal cells is reporting better results than expected:

The study involved patients suffering from age-related macular degeneration and Stargardt's macular dystrophy, the two leading causes of adult and juvenile blindness in the developed world. The diseases destroy a person's central vision. Working with Advanced Cell Technology Inc. [researchers] took human embryonic stem cells and turned them into the kind of cells that are killed by these diseases - retinal pigment epithelial cells. Then, they infused between 50,000 and 150,000 cells into the retinas of the patients. "What we did is put them into patients who have a disease where those particular cells are dying; and we replaced those dying tissues with new tissue that's derived from these stem cells. In a way it's a retinal transplant."

No one expected the cells to help any of these patients see better, because the study was designed mostly just to see if doing this was safe. Researchers were concerned the cells could destroy whatever vision was left or lead to tumors in the volunteers' eyes. So [they] picked patients whose eyes were so far gone that they weren't risking losing any vision. That also meant that there was little hope the cells could help either.

Surprisingly, many of the patients did start to see better. Ten of the 18 patients can see significantly better. One got worse, but the other seven either got better or didn't lose any more vision. The researchers stress that the findings must be considered preliminary because the number of patients treated was relatively small and they have only been followed for an average of less than two years. But the findings are quite promising. The patients had lost so much vision that there was no expectation that they could benefit.

Wednesday, October 15, 2014

Sepsis is a serious threat to the old, but researchers are developing new forms of blood cleansing devices that more effectively target the causes of this condition by removing pathogens from the blood. Looking ahead, one can imagine an evolution of this technology into long-term implants that could augment immune system function for everyone, providing far greater resistance to many threats to health:

A microfluidic device filled with magnetic nanometer-sized beads that bind a plethora of pathogens and toxins was able to clear these invaders from the blood of rats with sepsis, improving their outcomes. The design of the extracorporeal device was inspired by the small vessels and sinusoids within the spleen, through which blood "trickles slowly, almost like in a wetlands, efficiently capturing pathogens".

The device has two interconnected channels, one for the flowing blood and another containing a saline solution that traps and removes the pathogens. Magnetic nanobeads coated with a genetically engineered version of the mannose binding lectin (MBL) protein - which has a natural proclivity for foreign toxins and bugs, and normally functions as part of the mammalian innate immune system - are injected into the flowing blood before it enters the device.

Extracorporeal blood cleansing is not a novel concept for treating sepsis. An antibiotic-coated column called Toraymyxin that is approved in Japan and Europe - currently in a Phase 3 clinical trial in the U.S. - can remove endotoxins from the blood and has been shown to improve outcomes for sepsis patients. Other dialysis-like devices have been developed to mitigate the symptoms of sepsis, and these have included hemofiltration of the inflammatory molecules that are the root of the so-called cytokine storm that spurs organ damage in sepsis patients. But previous approaches did not target the cause of the storm - pathogens.

"Some already available blood-cleansing technologies have negative side effects like depletion of platelets, white blood cells, or other proteins along with the deleterious elements. What I like a lot about this approach is that it appears safe and there is no blood coagulation or altering of the blood composition - that is really important."

Thursday, October 16, 2014

A trial has been running in leukemia patients using immune cells modified to express a variety of chimeric antigen receptors. This allows the immune cells to recognize and attack cancer cells with a high degree of specificity, and the early results in the trial were impressive. Here is a more recent update:

The blood cells of cancer patients, reprogrammed by doctors to attack their leukemia and re-infused back into the patients' veins, led to complete remissions in 27 of 30 people. That's especially exciting because those patients had failed all conventional treatments. Not all of the remissions lasted. Nineteen patients in the study remain in remission 2 to 24 months later, and 15 of them didn't need any additional treatment. Seven patients relapsed between 6 months and 9 months after their infusion; those included three people whose cancers spread beyond the blood cells the new treatment targets. Five patients left the study for alternative therapy. The numbers are remarkable because these patients had cancer return as many as four times before they joined the study, including some whose cancer had returned after stem cell transplants.

For this method, the researchers harvest a patient's T cells using a process like blood transfusion. Then the lab [performs] a gene transfer, to teach the T cells to target a protein found on the surface of B cells, another type of blood cell that's affected in leukemia. The T cells are then transplanted back into the patient, where they hunt and kill anything with the protein attached to it. That means all B cells, not just the cancerous ones, are killed. Tests of all treated patients showed that their normal B cells had been killed along with the tumors. Because B cells are responsible for creating antibodies, which hunt any viruses or bacteria circulating in the blood stream, the solution isn't ideal; patients usually receive immunoglobulin replacement to help boost their immune systems to healthy levels. Living without B cells isn't perfect, but it's better than dying of cancer.

Absence of B cells is a situation that should be possible to fix with today's cell technologies. In past years researchers have destroyed and recreated the immune system in patients with autoimmune disease, so repopulating B cells should be a very plausible goal.

Thursday, October 16, 2014

The brain attempts to repair itself following damage such as that caused by a stroke, and researchers continue to discover more about these processes, many of which are still comparatively poorly understood. The near term goal here is to manipulate the underlying biochemistry in order to spur much greater regeneration, possibly not just following injury, but also as a way to offset some of the impact of aging on the brain:

A previously unknown mechanism through which the brain produces new nerve cells after a stroke has been discovered. A stroke is caused by a blood clot blocking a blood vessel in the brain, which leads to an interruption of blood flow and therefore a shortage of oxygen. Many nerve cells die, resulting in motor, sensory and cognitive problems. The researchers have shown that following an induced stroke in mice, support cells, so-called astrocytes, start to form nerve cells in the injured part of the brain. Using genetic methods to map the fate of the cells, the scientists could demonstrate that astrocytes in this area formed immature nerve cells, which then developed into mature nerve cells.

The scientists could also identify the signalling mechanism that regulates the conversion of the astrocytes to nerve cells. In a healthy brain, this signalling mechanism is active and inhibits the conversion, and, consequently, the astrocytes do not generate nerve cells. Following a stroke, the signalling mechanism is suppressed and astrocytes can start the process of generating new cells. "Interestingly, even when we blocked the signalling mechanism in mice not subjected to a stroke, the astrocytes formed new nerve cells. This indicates that it is not only a stroke that can activate the latent process in astrocytes. Therefore, the mechanism is a potentially useful target for the production of new nerve cells, when replacing dead cells following other brain diseases or damage."

"One of the major tasks now is to explore whether astrocytes are also converted to neurons in the human brain following damage or disease. Interestingly, it is known that in the healthy human brain, new nerve cells are formed in the striatum. The new data raise the possibility that some of these nerve cells derive from local astrocytes. If the new mechanism also operates in the human brain and can be potentiated, this could become of clinical importance not only for stroke patients, but also for replacing neurons which have died, thus restoring function in patients with other disorders such as Parkinson's disease and Huntington's disease."

Friday, October 17, 2014

The heat shock factor HSF-1 is involved in the processes of cellular maintenance relating to ensuring correct protein folding and clearing out misfolded proteins. Protein shape is vital to the operation of cellular machinery, and the presence of misfolded proteins should be considered a form of damage. It has been demonstrated that more HSF-1 extends life and improves tolerance to damage-inducing stress in laboratory animals, and thus a number of research groups are interested in producing treatments based on this effect.

For 35 years, researchers have worked under the assumption that when cells undergo heat shock, as with a fever, they produce a protein that triggers a cascade of events that field even more chaperones to refold unraveling proteins that could kill the cell. The protein, HSF-1 (heat shock factor-1), does this by binding to promoters upstream of the 350-plus chaperone genes, upping the genes' activity and launching the army of chaperones, which originally were called "heat shock proteins."

Injecting animals with HSF-1 has been shown not only to increase their tolerance of heat stress, but to increase lifespan. Because an accumulation of misfolded proteins has been implicated in aging and in neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases, scientists have sought ways to artificially boost HSF-1 in order to reduce the protein plaques and tangles that eventually kill brain cells. To date, such boosters have extended lifespan in lab animals, including mice, but greatly increased the incidence of cancer.

[Researchers] found in experiments on the nematode worm C. elegans that HSF-1 does a whole lot more than trigger release of chaperones. An equal if not more important function is to stabilize the cell's cytoskeleton, which is the highway that transports essential supplies - healing chaperones included - around the cell. "We are suggesting that, rather than making more of HSF-1 to prevent diseases like Huntington's, we should be looking for ways to make the actin cytoskeleton better."

[The researchers compare] a cell experiencing heat shock to a country under attack. In a war, an aggressor first cuts off all communications, such as roads, train and bridges, which prevents the doctors from treating the wounded. Similarly, heat shock disrupts the cytoskeletal highway, preventing the chaperone "doctors" from reaching the patients, the misfolded proteins. "We think HSF-1 not only makes more chaperones, more doctors, but also insures that the roadways stay intact to keep everything functional and make sure the chaperones can get to the sick and wounded warriors." The researchers found specifically that HSF-1 up-regulates another gene, pat-10, that produces a protein that stabilizes actin, the building blocks of the cytoskeleton. By boosting pat-10 activity, they were able to cure worms that had been altered to express the Huntington's disease gene, and also extend the lifespan of normal worms.

Friday, October 17, 2014

Here is a short article from earlier this month in a popular science magazine. SENS, the Strategies for Engineered Negligible Senescence, is a research and development program that aims to repair aging by reverting the known root causes. These are forms of cellular and molecular damage cataloged by the research community over the past century; it has been three decades since the last was discovered, so there is a fair degree of confidence that the list is completely enough for now. For each of these types of damage there is a clear path towards the production of treatments:

Aubrey de Grey wants to save lives. He wants to save as many as he possibly can, as soon as he can, and to do it he is going to fix ageing. The prominent scientist and futurologist is on a crusade to beat ageing and when he does it will mean that we stay healthy and live longer - possibly for up to hundreds of years. But, as de Grey emphasises, his primary goal is not just making people live longer; he wants us to live healthily, he wants to restore us to a state of health that is "fully functional in every way". The ability to live for hundreds of years is just a side effect. The work carried out by de Grey and his colleagues at the SENS Research Foundation will ultimately raise new challenges that need to be tackled, both in medicine and society, but there is no scientific reasoning why the body, with the right treatment, cannot be healthy for much longer.

The idea of treating disease and the disabilities of old age will not be treated by one breakthrough de Grey says. It has to be broken down into a series of manageable tasks. "We don't really think there is going to be one particular technique that will do the job. We believe that the process of ageing has to be recognised as a chaotic somewhat uncoordinated set of processes such that a truly effective treatment of it is going to involve a divide and conquer approach, essentially sub-dividing the problem into a variety of types of damage that accumulate and figuring out therapies that can address each of them."

In a world where getting old is no longer an issue, concerns will arise about population levels and resources that the planet can provide. But this view does not give credit to other technologies that are developing at a faster implementation rate than anti-ageing, and people can have a blinkered view about this. "They just don't look at the problem properly, so for example one thing that people hardly ever acknowledge is that the other new technology is going to be around a great deal sooner than [SENS rejuvenation biotechnology], or at least sooner than [SENS] will have any demographic impact. For example we will have [a much lower] carbon footprint because we will have things like better renewable energy and nuclear fusion and so on, so that it will actually be increasing the carrying capacity of the planet far faster than the defeat of ageing could increase the number of people on the planet."


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