AC5 Knockout in Mice Increases Exercise Performance as Well as Extending Life
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Here I'll point out some of the latest work on adenylate cyclase 5 (AC5), a longevity gene in mammals, which is now shown to boost exercise performance as well as longevity in mice. It is an open question as to the degree to which the longevity effects are secondary to the exercise effects. The authors of this paper note that there has been little study of exercise effects for most of the other methods of enhancing longevity in laboratory mice, which is an interesting oversight. Perhaps this will change with a growing interest in the development of exercise mimetic drugs.

Disruption of AC5, such as through gene knockout, is one of the many methods shown to modestly slow aging and extend healthy life in mice. As for all of these approaches, much work is yet needed to understand exactly how it works under the hood. The present high level understanding of single gene longevity enhancements in laboratory animals varies from sketchy theory to fairly robust outline, and getting any further than that is proving to be a slow, expensive, and time-consuming business. Every mechanism influences every other mechanism inside a cell, nothing happens in isolation, and so understanding any one life-extending genetic alteration blurs at the edges into the much, much larger project of understanding the enormous complexity of cellular biochemistry as a whole.

The major finding of this investigation is that disruption of AC5, which actually decreases sympathetic tone, increases exercise performance. This is novel, as the most common mechanism mediating enhanced exercise is via increased sympathetic stimulation and catecholamines, resulting in increased AC activity and augmented cardiac output. This was not the mechanism in AC5 knockout mice, where AC activity is actually reduced, and there was no greater increase in cardiac output during exercise compared with WT mice, based on direct measurements of ascending aortic blood flow with implanted ultrasonic flow probes and heart rate in chronically instrumented mice. Further confirming the lack of a cardiac mechanism, the cardiac-specific AC5 knockout did not exhibit enhanced exercise. Accordingly, the mechanism resided at the level of the exercising skeletal muscles, which was confirmed, when we found that exercise performance was also elevated in the skeletal muscle-specific AC5 knockout.

Another key finding of the current investigation was demonstrating that protection against oxidative stress, by increased MnSOD levels and activity in AC5-deficient skeletal muscles, is also involved in the mechanism of enhanced exercise capacity in AC5 knockout mice, as exercise capacity of AC5 knockout mice was significantly attenuated in AC5 knockout / MnSOD heterozygous knockout bigenic mice. One question that arose is whether these effects of enhanced exercise in AC5 KO mice are simply due to a decrease in AC, which might be evoked in a knockout from any of the 9 AC isoforms, or are they due to unique signaling in AC5. To address this question, we examined exercise in 10 AC6 KO mice and 7 wild type controls. The AC6 KO mice did not show increased distance or speed with exercise compared to their wild type. Therefore, the enhanced exercise was not simply due to a reduction in AC, but was rather unique to the AC5 KO and its signaling pathway noted above.

Exercise plays an essential role in longevity, in general, and healthful aging, in particular, as it protects not only against obesity, diabetes, and cardiovascular disease, but also reduces the risk of cancer and improves bone health and even mental diseases that impair aging. Therefore, the demonstration of improved exercise performance in the AC5 knockout model is particularly germane, as this is also a model for longevity, and protects against cardiovascular stress, diabetes, and obesity. In view of the important link between exercise and longevity, it is surprising that of 20 mouse models we reviewed, only two studied exercise and found it to be increased.


Lab-Grown Intestinal Tissue Regenerates Gut Lining in Dogs
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Over the last five years considerable progress has been made in the tissue engineering of intestines. Researchers have created sections of intestine, grown intestine organoids, and regenerated damage to intestines in laboratory animals. Here is the latest example:

Working with gut stem cells from humans and mice, scientists have successfully grown healthy intestine atop a 3-D scaffold made of a substance used in surgical sutures. The tube-shaped scaffold was a big first step on the quest to develop an implantable replacement intestine. But the new work pushes that effort further because it shows how stem cells, when mixed with immune and connective tissue cells, can grow into normal gut tissue around the scaffold and function inside a living mammal. Researchers caution that a fully functioning replacement intestine for humans is far off, but they say their results have laid the critical groundwork to do so. "Our experiments show that the architecture and function of our lab-made intestine strikingly resemble those of the healthy human gut, giving us real hope that our model could be used as the backbone for replacement intestine."

In an initial set of experiments researchers took stem cells from the colons of babies undergoing intestinal surgeries and from mice, then added immune cells called macrophages, the body's scavengers that seek out and engulf debris along with foreign and diseased cells. To this mix, they added cells called fibroblasts, whose function is to form collagen and other connective substances that bind tissues and organs together. The idea, the scientists say, was to create a mixture that closely mimics the natural composition of the gut. In another set of experiments, researchers added probiotic bacteria to the newly created intestinal tissue. Doing so further amplified the growth and differentiation of new gut cells, specifically the growth of Paneth cells responsible for production of infection-fighting proteins that guard against intestinal infections.

Next, researchers implanted the newly created intestine into the bellies of mice. In a matter of days, the implanted intestine began producing new intestinal stem cells and stimulated the growth of new blood vessels around the implant. That observation, researchers say, affirmed the ability of the 3-D intestine to spur the growth of new tissue not only in lab dishes, but also in living organisms. In a final step, the investigators implanted pieces of the newly created intestine - about 1.6 inches in length - into the lower portion of dog colons lacking parts of their intestinal lining. For two months, the dogs underwent periodic colonoscopies and intestinal biopsies. Strikingly, the guts of dogs with implanted intestines healed completely within eight weeks. By contrast, dogs that didn't get intestinal implants experienced continued inflammation and scarring of their guts.


A View of the Importance of Neurogenesis
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Neurogenesis is name given to the creation of new neurons in the central nervous system, and particularly the brain. Only within the last thirty years, quite recently in the grand scheme of things, have researchers proved that neurogenesis occurs at a low level in adults, that the brain is not a fixed set of long-lived and non-dividing cells, but is augmented with new arrivals on an ongoing basis. Once verified, this became a topic of considerable interest for the growing fields of regenerative medicine and stem cell research. Can the rate of neurogenesis be safely increased, and will this produce benefits for patients suffering neurodegenerative conditions, or postpone the onset of such conditions? Can investigation of neurogenesis be used to guide improvements in first generation stem cell therapies based on transplanted cells?

With more research into the biology of the brain, aided by the rapid improvement in the tools of biotechnology since the 1990s, there is an increased realization of the importance of adult neurogenesis. Few evolved processes exist without serving multiple ends, and this one is no exception in that regard. More than a mere repair and replacement mechanism, neurogenesis in adults is necessary to the correct functioning of the brain. Couple that to the discovery that rates of neurogenesis decline with age, and the processes of slow growth and change in the brain become ever more attractive as an area of medical research. It is worth noting that some of the recent work emerging from parabiosis studies, in which alterations are made to levels of some of the molecular signals in the circulatory system, have shown preliminary signs of being able to reduce the age-related decline in neurogenesis.

The article linked below is a good read, and goes some way to providing the high-level context and background to explain why research into neurogenesis is so important to those parts of the life science community focused on aging, age-related diseases of the brain, neurobiology, and regenerative medicine. Clearly there is a lot more to be done before an initial set of therapies emerge via the traditional drug development approach, and those therapies will likely be pretty marginal at the outset if history is any guide, but it is an interesting field to watch.

Brain Gain: Young Neurons in the Adult Human Brain are Likely Critical to its Function

At a lab meeting in the mid-1990s a neuroscientist told his team that he wanted to determine whether new neurons are produced in the brains of adult humans. At the time, adult neurogenesis was well established in rodents, and there had been hints that primate brains also spawned new neurons later in life. But reports of neurogenesis in the adult human brain were sparse and had not been replicated. Soon enough, a clear picture emerged: the human hippocampus, a brain area critical to learning and memory and often the first region damaged in Alzheimer's patients, showed evidence of adult neurogenesis. In November 1998, the group published its findings. "When it came out, it caught the fancy of the public as well as the scientific community. It had a big impact, because it really confirmed neurogenesis occurs in humans."

Fifteen years later, in 2013, the field got its second (and only other) documentation of new neurons being born in the adult human hippocampus - and this time learned that neurogenesis may continue for most of one's life. Neuroscientistists took advantage of nuclear bomb tests carried out during the Cold War. Atmospheric levels of carbon-14 have been declining at a known rate since such testing was banned in 1963, and researchers were able to date the birth of neurons in the brains of deceased patients by measuring the amount of carbon-14 in the cells' DNA.

In the late 1990s and early 2000s, researchers delved into the cell biology of neurogenesis, characterizing the populations of stem cells that give rise to the new neurons and the factors that dictate the differentiation of the cells. They also documented significant differences in the behavior of young and old neurons in the rodent brain. Most notably, young neurons are a lot more active than the cells of established hippocampal networks, which are largely inhibited. "For a period of about four or five weeks, while the newborn neurons are maturing, they're hyperexcitable. They'll fire at anything, because they're young, they're uninhibited, and they're integrating into the circuit."

To determine the functional role of the new, hyperactive neurons, researchers began inhibiting or promoting adult neurogenesis in rodents by various means, then testing the animals' performance in various cognitive tasks. What they found was fairly consistent: the young neurons seemed to play a role in processing new stimuli and in distinguishing them from prior experiences. This type of assessment is called pattern separation. While some researchers quibble over the term, which is borrowed from computational neuroscience, most who study hippocampal neurogenesis agree that this is a primary role of new neurons in the adult brain. The basic idea is that, because young neurons are hyperexcitable and are still establishing their connectivity, they are amenable to incorporating information about the environment. If a mouse is placed in a new cage when young neurons are still growing and making connections, they may link up with the networks that encode a memory of the environment.

While studying the function of hippocampal neurogenesis in adult humans is logistically much more difficult than studying young neurons in mice, there is reason to believe that much of the rodent work may also apply to people - namely, that adult neurogenesis plays some role in learning and memory. "Given that the dentate gyrus is so highly conserved and that the mechanisms of its function are so similar between the species - and given that neurogenesis is there in humans - I would predict that the general principle is the same." And if it's true that hippocampal neurogenesis does contribute to aspects of learning involved in the contextualization of new information - an ability that is often impaired among people with neurodegenerative diseases - it's natural to wonder whether promoting neurogenesis could affect the course of Alzheimer's disease or other human brain disorders. Epidemiological studies have shown that people who lead an active life - known from animal models to increase neurogenesis - are at a reduced risk of developing dementia, and several studies have found reduced hippocampal neurogenesis in mouse models of Alzheimer's. But researchers have yet to definitively prove whether neurogenesis, or lack thereof, plays a direct role in neurodegenerative disease progression.

Of course, the big question is whether researchers might one day be able to harness neurogenesis in a therapeutic capacity. Some scientists say yes. "I think the field is moving toward that. Neurogenesis is not something de novo that we don't have at all - that would be much harder. Here, we know it happens; we just need to enhance it."

Study Suggests More Moderate Exercise is Better
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Researchers here crunch the numbers to suggest that people who exercise for longer are better off in terms of risk of suffering age-related cardiovascular disease. One of the emerging themes in epidemiology in recent years is an attempt to pin down the dose-response curve for exercise. How is long term health and life expectancy affected for different levels of exercise, and do these differences reflect correlation or causation? Is it a matter of people obtaining health benefits through exercise or a matter of more healthy people tending to exercise more? These are hard questions to answer for human populations, but as technology lowers the cost of obtaining and using large data sets, ever more research groups are taking a stab at it. As with all such statistical studies, it is wise to wait for more data and the work of different teams before taking anything published by one group at face value, however:

Doubling or quadrupling the minimum federally recommended levels of physical activity lowered the risk of developing heart failure by 20 percent and 35 percent, respectively, according to researchers. "Walking 30 minutes a day as recommended in the U.S. physical activity guidelines, may not be good enough - significantly more physical activity may be necessary to reduce the risk of heart failure." The researchers found that the current U.S. physical activity guidelines recommendation of a minimum of at least 150 minutes of moderate intensity physical activity a week was associated with only a modest reduction in heart failure risk, and suggest that higher levels of physical activity, up to twice the minimum recommended dose, is needed to reduce the risk of heart failure.

They also found a "dose-dependent" inverse association between physical activity and heart failure, that is, higher levels of physical activity were associated with a lower risk of heart failure. This relationship was consistent across all age, sex, race, and geographic location based subgroups studied. Although the role of physical activity in coronary heart disease - the narrowing of the arteries that causes heart attacks - has been comprehensively studied, this study focused exclusively on the quantitative relationship between the amount, or specific "dose" of regular physical activity and the risk of heart failure.

The researchers pooled data from 12 studies from United States and Europe that collectively included 370,460 individuals with varying levels of physical activity at baseline and 20,203 heart failure events over a mean follow-up of 15 years. Physical activity was measured by self-reported levels of activity by study participants using standard questionnaires. "Future physical activity guidelines should take these findings into consideration, and potentially provide stronger recommendations regarding the value of higher amounts of physical activity for the prevention of heart failure."


CRISPR Gene Editing and Xenotransplantation
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The present best approach to enabling xenotransplantation of pig organs into human patients is decellularization: strip all the cells and repopulate the extracellular matrix scaffold of the organ with human cells. However, with the existence of cheap and efficient genetic alteration based on CRISPR it may be possible to edit all of the genes in pig cells that produce problem proteins instead of replacing these cells. My first thought on this is that decellularization is still a better option; after any reasonable number of genetic edits on pig cells the result remains an organ built out of edited pig cells, not human cells, and not matched to the patient. Still, this is an interesting demonstration of the cost-effectiveness of CRISPR, making genetic alterations in much larger batches than have been achieved to date:

For decades, scientists and doctors have dreamed of creating a steady supply of human organs for transplantation by growing them in pigs. But concerns about rejection by the human immune system and infection by viruses embedded in the pig genome have stymied research. By modifying more than 60 genes from pig embryos - ten times more than have been edited in any other animal - researchers believe they may have produced a suitable non-human organ donor.

The researchers used CRISPR gene-editing technology to inactivate 62 porcine endogenous retroviruses (PERVs) in pig embryos. These viruses are embedded in all pigs' genomes and cannot be treated or neutralized. It is feared that they could cause disease in human transplant recipients. They also modified more than 20 genes in a separate set of embryos, including genes encoding proteins that sit on the surface of pig cells and are known to trigger the human immune system or cause blood clotting. Eventually, pigs intended for organ transplants will have both these modifications and the PERV deletions.

A biotech company founded to produce pigs for organ transplantation, eGenesis in Boston, is now trying to make the process as inexpensive as possible. The team released few details about how they managed to remove so many pig genes. But both sets of edited pig embryos are almost ready to implant into mother pigs. eGenesis has procured a facility at Harvard Medical School where the pigs will be implanted and raised in isolation from pathogens.


The Long Road Ahead to Exercise Mimetics
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Today I'll point out a couple of recent research publications on the topic of the molecular mechanisms of exercise: how it might work to improve health, how it extends healthy life span but not maximum life span in animal studies, and how the response to exercise might be safely improved or otherwise manipulated. Researchers nowadays tend to comment on future directions for drug discovery based on their investigations of exercise, and in that this slice of the field is becoming much like calorie restriction research ten to fifteen years ago.

Take a moment to think about how much work and funding has gone into investigations of calorie restriction and the search for drug candidates that can mimic even just a fraction of the beneficial metabolic alterations and extension of healthy life spans that occur in response to calorie restriction: probably a few billion dollars and year after year of dedicated investigations by hundreds of scientists in the past decade alone. Yet at the end of all that, and after the collection of enormous amounts of data, there is only a small number of drug candidates, few of which are anything other than marginal in animal studies, none of which can reproduce all of the beneficial changes observed in calorie restriction, and there is still no comprehensive accounting of how calorie restriction works under the hood, just an outline of ever-growing complexity.

It has taken fifteen years to get that far. Processes like the reaction to restricted calorie intake and exercise are enormously complex. They impact near every aspect of metabolism and cellular biology, and the quest to understand them well enough to manipulate them is more or less the same thing as the quest to understand cellular biology completely. This and the past history of calorie restriction mimetic drug research is why I'm not holding my breath waiting on exercise mimetic drugs. Researchers will talk about this as a goal, just as they have talked about calorie restriction mimetic drugs, but the reality is that the inherent complexity involved makes this is a very long-term project, one that tends to produce marginal outcomes at great expense. Exercise mimetics and calorie restriction mimetics that are safe and reliable would be a pleasant thing to have around, to be sure, but it seems to me that at the present time there are better and more cost-effective approaches to the treatment of aging as a medical condition.

Exercise Pills: At the Starting Line

Excessive caloric intake and limited physical activity contribute to the current explosion of 'modern' chronic diseases such as obesity, type 2 diabetes, muscle atrophy, and cardiovascular diseases. By contrast, regular physical exercise maintains glucose homeostasis and induces physiological adaptations that effectively prevent, and often reverse, these diseases. Recognizing the human and economic burdens these diseases cause, and taking into account the health benefits of exercise, have led many exercise scientists to suggest that physical exercise may be the preferred method in the treatment and prevention of these 'modern' chronic diseases.

Unfortunately, exercise compliance levels are almost universally low, especially for people using home-based exercise programs. A variety of factors including poor physical condition, weakness, sickness, lack of time, and poor motivation contribute to low exercise compliance. The much publicized poor compliance begs the question: is there an alternative approach that both induces the health benefits of physical exercise and overcomes the problem of low compliance rate? Regular physical exercise activates a number of molecular pathways in whole organ systems and reduces the risk of developing numerous chronic diseases. Although nothing can fully substitute for physical exercise, candidate exercise pills that have emerged in recent years may be an attractive alternative.

Exercise in a bottle could become a reality

Researchers exposed a thousand molecular changes that occur in our muscles when we exercise, providing the world's first comprehensive exercise blueprint. "Exercise is the most powerful therapy for many human diseases, including type 2 diabetes, cardiovascular disease and neurological disorders. However, for many people, exercise isn't a viable treatment option. This means it is essential we find ways of developing drugs that mimic the benefits of exercise." The researchers analysed human skeletal muscle biopsies from four untrained, healthy males following 10 minutes of high intensity exercise. Using a technique known as mass spectrometry to study a process called protein phosphorylation, they discovered that short, intensive exercise triggers more than 1000 changes.

"Exercise produces an extremely complex, cascading set of responses within human muscle. It plays an essential role in controlling energy metabolism and insulin sensitivity. While scientists have long suspected that exercise causes a complicated series of changes to human muscle, this is the first time we have been able to map exactly what happens. This is a major breakthrough, as it allows scientists to use this information to design a drug that mimics the true beneficial changes caused by exercise. Most traditional drugs target individual molecules. With this exercise blueprint we have proven that any drug that mimics exercise will need to target multiple molecules and possibly even pathways, which are a combination of molecules working together. We believe this is the key to unlocking the riddle of drug treatments to mimic exercise."

Is Alzheimer's Disease Effectively a Type 3 Diabetes?
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For some years a faction of researchers have argued that Alzheimer's disease really should be considered a type 3 diabetes, based on the shared risk factors and what is known of the way that it ties into the mechanisms associated with insulin resistance. It is certainly the case that based on epidemiological data Alzheimer's, like type 2 diabetes, is enough of a lifestyle disease that you should add it to the list of very good reasons not let yourself become fat and sedentary. But is the connection with insulin metabolism relevant enough to class Alzheimer's as a form of diabetes, or is this just a good example of the way in which everything connects to everything else in the operation of our cellular biology?

Aging is known to be one of the top risk factors for both Alzheimer's disease (AD) and Type 2 Diabetes (T2D). The pathologies of these disorders are somewhat understood, with AD being associated with the accumulations of amyloid-β plaques and/or phosphorylated tau tangles (two proteins involved in neuron structure and development) and T2D being associated with resistance to insulin (the growth factor that controls glucose uptake by cells). For many years these two diseases have been treated separately, with few overlaps. In more recent years, however, the overlap between them has become more prominently recognized. The rate of AD in diabetic individuals is elevated, and it may be worth considering these two "separate" disorders as a related problem.

The first suggestion of AD being a previously unrecognized type of diabetes was in 2005, where it was noted that insulin signaling and insulin-like growth factor (IGF) expression were greatly affected in the instance of AD. It has since been shown that in the instance of AD, IGF, insulin receptor, and insulin expression are all reduced in the temporal cortex and hippocampus of the brain. Further, as AD progresses the levels of these gene transcripts continue to decrease. These inhibited insulin-related signals result in a deficiency and similar symptoms to those shown in other cases of diabetes. This deficiency also contributes to a vicious cycle, as impaired insulin receptor expression can contribute to further AD-like pathology such as hyperphosphorylation of tau and increased amyloid-β deposits as well as decreased clearance of these deposits from the brain.

Although seldom considered a metabolic disorder, it is clear that AD is metabolically affected in a similar fashion to diabetes. Although frequently treated separately, the same basic principles which are used for diagnosing an individual as diabetic may also be applied to understand some of the mechanisms affected in AD. As such, it may be appropriate to consider AD as a type of diabetes of the brain.


An Efficient Method of Creating Photoreceptor Cells for Transplantation to Treat Degenerative Blindness
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An important factor in the speed of development, cost, and availability of future stem cell therapies is the existence of an efficient, reliable way to create large numbers of the specific cell types needed. This is one of the main limiting factors for many areas of medical development in cell-based regenerative medicine. Here, researchers establish a methodology for generation of photoreceptor cells that could be used to rebuild retinal tissue, which is good news for progress towards regenerative therapies for conditions such as macular degeneration:

Age-related macular degeneration (ARMD) is due to the degeneration of the macula, which is the central part of the retina that enables the majority of eyesight. This degeneration is caused by the destruction of the cones and cells in the retinal pigment epithelium (RPE), a tissue that is responsible for the reparation of the visual cells in the retina and for the elimination of cells that are too worn out. However, there is only so much reparation that can be done as we are born with a fixed number of cones. They therefore cannot naturally be replaced. Moreover, as we age, the RPE's maintenance is less and less effective - waste accumulates, forming deposits.

A research team has developed a highly effective in vitro technique for producing light sensitive retina cells from human embryonic stem cells. "Our method has the capacity to differentiate 80% of the stem cells into pure cones. Within 45 days, the cones that we allowed to grow towards confluence spontaneously formed organised retinal tissue that was 150 microns thick. This has never been achieved before."

In order to verify the technique, researchers injected clusters of retinal cells into the eyes of healthy mice. The transplanted photoreceptors migrated naturally within the retina of their host. "Cone transplant represents a therapeutic solution for retinal pathologies caused by the degeneration of photoreceptor cells. To date, it has been difficult to obtain great quantities of human cones." The discovery offers a way to overcome this problem, offering hope that treatments may be developed for currently non-curable degenerative diseases, like Stargardt disease and ARMD. "Researchers have been trying to achieve this kind of trial for years. Thanks to our simple and effective approach, any laboratory in the world will now be able to create masses of photoreceptors. Even if there's a long way to go before launching clinical trials, this means, in theory, that will be eventually be able to treat countless patients."


Fundraising Posters: Spread the Word that We're Matching SENS Donations Dollar for Dollar
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Last week we launched the Fight Aging! fundraiser for SENS rejuvenation research programs, work on the biotechnologies needed to repair the cellular and molecular damage that causes aging and all age-related disease. Do we want to see meaningful progress towards the defeat of degenerative aging in our lifetime? Yes, yes we do. We will be matching dollar for dollar all donations to the SENS Research Foundation until either the end of the year or our $125,000 matching fund runs out - whichever happens first. Obviously we'd love to see the community hit this target, as that would mean an extra quarter of a million dollars for the best lines of early stage research into ending frailty and disease in aging. As of today, 94 donors have given $22,542 since the fundraiser launched on the 1st. A good start!

The SENS Research Foundation has a track record of producing results, as I outlined recently. The philanthropy of past years has blossomed into a first round of startups, clinical development, and greater ongoing funding: Gensight is commercializing an approach to mitochondrial repair, Oisin Biotech is working on senescent cell clearance, and Human Rejuvenation Technologies was formed to further develop the use of bacterial enzymes to remove of some of the metabolic waste compounds that contribute to atherosclerosis. The wheel is turning and now is the time for greater efforts, to remove the hurdles and fund the groundwork needed for the next round of biotechnologies for human rejuvenation.

I ran up a pair of new fundraising posters over the weekend, sticking to this year's simple motif of text and color, suitable for signs and more visible from a distance. This year's fundraiser is a stretch goal for our community, based on how we've been doing over the past couple of years. We need to get out there and wave the flag, track down new supporters and expand our corner of the world, the small community interested in actually getting something done about aging.

2015 Fundraiser #1: 4200 x 2800px

2015 Fundraiser #2: 4200 x 2800px

On the Road to Measuring the Mutational Damage of Aging
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Researchers are now able to compare the mutational damage to nuclear DNA in individual long-lived cells such as neurons, which is a step towards measuring how much of this damage there is and how it varies over time and from cell to cell. That in turn is a step towards getting a handle on whether or not this damage has any meaningful effect over the course of a human life span beyond raising the risk of cancer. For example is the presence of stochastic mutational damage causing large enough alterations in the day to day operation of metabolism across enough cells to matter? There is some debate on this issue, and certainly a lack of good enough data to nail down a proof one way or another.

A single neuron in a normal adult brain likely has more than a thousand genetic mutations that are not present in the cells that surround it, according to new research. The majority of these mutations appear to arise while genes are in active use, after brain development is complete. "We found that the genes that the brain uses most of all are the genes that are most fragile and most likely to be mutated." It's not yet clear how these naturally occurring mutations impact the function of a normal brain, or to what extent they contribute to disease.

Cells of many shapes, sizes, and function are intimately intertwined inside the brain, and scientists have wondered for centuries how that diversity is generated. Scientists are further interested in genome variability between neurons due to evidence that mutations that affect only a small fraction of cells in the brain can cause serious neurological disease. Until recently, however, scientists who wanted to explore that diversity were stymied by the scant amount of DNA inside neurons: Although researchers could isolate the genetic material from an individual neuron, there was simply not enough DNA to sequence, so cell-to-cell comparisons were impossible. However, technology has become available in the last few years for amplifying the full genomes of individual cells. With plenty of DNA now available, the scientists could fully sequence an individual neuron's genome and scour it for places where that cell's genetic code differed from that of other cells.

The scientists isolated and sequenced the genomes of 36 neurons from healthy brains donated by three adults after their deaths. For comparison, the scientists also sequenced DNA that they isolated from cells in each individual's heart. What they found was that every neuron's genome was unique. Each had more than 1,000 point mutations (mutations that alter a single letter of the genetic code), and only a few mutations appeared in more than one cell. What's more, the nature of the variation was not quite what the scientists had expected. "We expected these mutations to look like cancer mutations, in that cancer mutations tend to arise when DNA is imperfectly copied in preparation for cell division, but in fact they have a unique signature all their own. The mutations that occur in the brain mostly seem to occur when the cells are expressing their genes. To what extent do these mutations normally shape the development of the brain, in a negative way or a positive way? To what extent do we have a patch of brain that doesn't work quite right, but not so much that we would call it a disease? That's a big open question."


A Look at the Work of David Sinclair
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This article paints a picture of David Sinclair as one of the important researchers in the move towards treating aging as a medical condition. I'd say that he's certainly good at publicity and fundraising, and has more than done his part to make drug development for the treatment of aging plausible in the eyes of the public, but it is a pity that all of this is coupled to lines of research (such as the investigation and manipulation of sirtuins) that to my eyes have no hope of producing meaningful therapies. Even if sirtuin-based therapies could do all that the original hype promised, the end result would be a marginal, slight slowing of the aging process. As an end goal for the investment of billions and years of time, that simply isn't worth it when there are far better approaches to the problem such as SENS that can in principle lead to actual rejuvenation and the addition of decades of healthy life.

Today, Sinclair's work on slowing the ageing process, and even reversing some aspects of it, could lead to the most significant set of medical breakthroughs since the discovery of antibiotics nearly a century ago. At the heart of what motivates him is a deceptively simple notion: if the greatest driver of disease in old age is old age itself, then why not find a cure for ageing, which he describes as being "the greatest problem of our time". Sinclair's statement is borne out by the World Health Organisation's Global Burden of Disease Project, which estimates that the number of years lost to premature death or compromised by disability in 2010 was 2.5 billion, meaning that about a third of potential human life goes to waste. The toll from crime, wars and genocides does not come close to matching this. Yet, as Sinclair points out, just one per cent of medical research funding is spent on understanding why we age and even less on doing something about it. His goal is to find the "master control switch" that can regulate the pathways that contribute to ageing itself. "It could be one pill for 20 diseases at once. It would be the most profitable drug ever made."

Extending the generally accepted limits of human life is now being taken seriously by some of the world's top scientists. Backed by wealthy philanthropists and tech giants such as Google, billions of dollars are being poured into longevity research. Press releases and PowerPoint presentations come laced with terms such as health-span, not lifespan. The elderly, we are told, will become the wellderly. There will be fewer bedridden geriatrics taxing our overstretched medical systems. The ever-growing list of billionaires funding research into longevity includes PayPal co-founder Peter Thiel, who has set up Breakout Labs, a non-profit organisation that supports early-stage companies, and Oracle founder Larry Ellison, who has donated more than $US430 million ($600 million) to anti-ageing research.

Sinclair is decidedly reticent when it comes to passing judgment on the work of other scientists such as Craig Venter at Human Longevity Inc. and Cynthia Kenyon at Calico: "I think it's going to take a lot of resources to find the needle in the haystack, but it's helpful that more people are getting involved in ageing research. If Craig and his associates tackle it from the sequencing side and we tackle it from the fundamental biology side and Google's Calico attacks it from bioinformatics side, then there's more chance of finding the right medicines." Circumspection is embedded in Sinclair's DNA. He speaks slowly and deliberately, giving his audiences time to absorb both the complex science behind his discoveries and to underline what motivates him. "How sad would it be if we, after 10,000 generations, we were the last ones to live a normal lifespan? Imagine if we were born one generation too early to reap the benefits of this technology."


Panel Discussion: How Can Life Extension Become as Popular as the War on Cancer?
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Given the BioViva press release I pointed out earlier today, you may be interested in listening to a Longevity Day roundtable held yesterday, since Elizabeth Parrish of BioViva was participating, as well as Keith Comito of the Life Extension Advocacy Foundation, and a few other names you might recognize. From my perspective it is great to see so much going on that I only find out about after the fact: one of the signs of a healthy and growing community is that people are off doing things and I have no idea, since there is too much to keep track of in any reasonable amount of time.

What can be done to raise public support for the pursuit of indefinite life extension through medicine and biotechnology to the same level as currently exists for disease-specific research efforts aimed at cancers, heart disease, ALS, and similar large-scale nemeses? In this panel discussion, held on October 1, 2015 - International Longevity Day - Mr. Stolyarov asks notable life-extension supporters to provide input on this vital question and related areas relevant to accelerating the pursuit of indefinite longevity. This panel is coordinated in conjunction with MILE, the Movement for Indefinite Life Extension.

Panelists: Adam Alonzi, Sven Bulterjis, Keith Comito, Roen Horn, B. J. Murphy, and Elizabeth Parrish

A set of presentation slides was put together by Butlerjis, and is worth a few minutes of your time. In particular, one of the lessons to take away here is that big budget cancer research didn't just magically happen overnight. Rather it was the culmination of many failed attempts to create such a state of affairs over the course of half a century. Prior to the 1970s cancer research in fact looked quite similar to the situation for aging research today: little interest, little funding, large gaps in the scientific understanding of the fine details of the disease, but the clear potential to make a big difference to patients and therapies with what was known at the time.

Aging Research Needs Marketing: What Can We Learn from Cancer Research?

1910: The American Association for Cancer Research convinces president Taft to ask congress to build a national lab for cancer research: failure.

1927: Senator Matthew Neely asks congress to give 5 million USD for information that could lead to a cure for cancer: he got 50,000 USD.

1937: Neely, Senator Homer Bone and Representative Warren Magnuson : National Cancer Institute Act, success signed by president Roosevelt: NCI founded, but the war in Europe soon ended funds for the NCI.

1946-47: Neely and Senator Claude Pepper: 3rd proposal for nation wide cancer research: rejected.

Solomon Garb said in 1969: "A big obstacle in the fight against cancer is the severe an chronic lack of money, something that is not known to most people. We won't get there by repeating this. It is also necessary to explain how it will be used, what kind of projects will be financed with it, why these projects deserve our support, and where the scientists and technicians that have to execute them will come from."

Why do some diseases have a big impact only in a given era? Theory: the society couples diseases to psychological crises. For Cancer: in the '70s when the focus changed from external (USSR) to internal (cancer). For AIDS: in the '80s when the generation was obsessed with sexuality and freedom. For SARS: in the 21st century alongside the fears of globalization. But what about aging?

To conclude: cancer has a similar history to aging, we also need marketing, business people, and celebrities on our side, and aging has to be recognized as a disease.

Mitochondrial Catalase Suppresses Cancer Incidence in Mice
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Gene therapy to raise levels of the natural antioxidant catalase in mitochondria is one of many methods shown to modestly extend life in mice. Cancer is so very prevalent in mice that it is frequently worth asking whether or not life extension is a matter of slowing aging or a matter of suppressing cancer - though there is certainly a lot of room for argument as to whether or not these are just two ways of stating the same thing, based on the details of the mechanisms involved. See the debate over whether rapamycin slows aging or suppresses cancer, for example. Given all this, the paper linked here is interesting:

The antioxidant enzyme catalase targeted to mitochondria (mCAT) has been shown to delay aging and cancer in mice, and the progression of transgenic oncogene and syngeneic tumors was suppressed, helping support the notion that attenuation of mitochondria-generated hydrogen peroxide signaling is associated with an antitumor effect.

In order to determine if mCAT has any effect on naturally occurring lung cancer of the adenocarcinoma type in old mice, the tumor incidence and progression were examined in the lungs of old mCAT transgenic and wild-type (WT) mice with a CB6F1 background. CB6F1 mice with a WT genotype were found to have a high incidence of adenomas at 24 months of age, which progressed to adenocarcinomas at 32 months of age. CB6F1 mice with the mCAT genotype had significantly reduced incidence and severity of lung tumors at both ages.

Fibroblasts isolated from the lungs of old mCAT mice, but not WT mice, were shown to secrete soluble factors that inhibited lung tumor cell growth suggesting that stromal fibroblasts play a role in mediating the antitumor effects of mCAT. The aged CB6F1 mouse, with its high incidence of K-ras mutant lung cancer, is an excellent model to further study the anticancer potential of mitochondria-targeted therapy.


BioViva Moving Ahead With Human Gene Therapy for Telomerase Activation
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BioViva is one of the small groups interested in bringing telomerase therapies to humans sooner rather than later. It seems they have started in on their small long-term trial of human gene therapy for telomerase activation, and have treated the first volunteer.

I should say that at any given time there is a fairly large gap between what can be done in human medicine, the technology that actually exists and works, and what is being done in trials. Most of this gap is due to regulation, and the rest of it because development groups want to have a reasonable certain that what they are doing actually works, does more good than harm, and so forth. The regulatory process might last a decade, while the actually useful part of that testing (does it basically work, and is the risk profile sufficiently defined and acceptable to patients) is only a few years. As the cost of research and development in the life sciences falls, it will become increasingly untenable that a huge ball and chain slows progress thanks to regulatory risk aversion, and a growing number of initiatives will forge ahead and build anyway. Some years ago I proposed the Vegas Group fable, something that I think will happen in the fullness of time: alternative roads that bypass official regulation in favor of faster progress, an inevitability in an environment of low-cost research. Also, I think, a necessity.

What about the science here? I've never been a big fan of telomere lengthening approaches, as average telomere length as it is measured today in immune cells looks very much like a marker of the progress of aging, an end stage consequence far removed from root causes. Telomeres shorten with cell division and new long-telomere cells are delivered into tissues by stem cell populations. Thus average telomere length in immune cells reflects some combination of immune health and stem cell activity, both of which are known to decline with age. You can't argue with the fact that telomerase gene therapy has been shown to extend life in mice, however, though you can certainly note that the size of the effect has been getting smaller as the research groups have refined their data and approaches.

How does this work to slow aging in mice? At this point I lump enhanced telomerase activity into the general category of approaches that either probably work or intend to work by boosting the activation of old stem cell populations, resulting in increased repair and tissue maintenance and thus a slower decline into frailty and organ failure. More telomerase doesn't seem to raise cancer risk in mice, but mice have very different telomere dynamics and cancer risk profiles than we humans. The fastest way to figure out what is going to happen in humans is of course to try it, and kudos to anyone volunteering at this stage, but I'd be waiting for a few more years of testing first in animal or tissue models closer to human telomere dynamics. In part that decision would be driven by the fact that I don't think that this is the best approach to move ahead with practical applications, to push ahead and get things done. I absolutely agree that pushing ahead to get things done needs to happen, but I'd rather see this sort of boldness for SENS treatments like senescent cell clearance.

BioViva USA, Inc. has become the first company to treat a person with gene therapy to reverse biological aging, using a combination of two therapies developed and applied outside the United States of America. Testing and research on these therapies is continuing in BioViva's affiliated labs worldwide. BioViva CEO Elizabeth Parrish announced that the subject is doing well and has resumed regular activities. Preliminary results will be evaluated at 5 and 8 months with full outcome expected at 12 months. The patient will then be monitored every year for 8 years.

Gene therapy allows doctors to treat disease at the cellular level by inserting a gene into a patient's cells instead of using the regular modalities of oral drugs or surgery. BioViva is testing several approaches to age reversal, including using gene therapy to introduce genes into the body. Although not generally considered a disease, cellular aging is the leading cause of death in the developed world. Side effects like muscle wasting (sarcopenia), grey hair and memory loss are the well-known hallmarks. And the aging cell is also responsible for the diseases of aging, including Alzheimer's disease, heart disease and cancer. BioViva is leading the charge to treat the aging cell and reverse aging. "The aging cell is a key factor that has been overlooked for too long. Companies have put millions of dollars into treating the diseases of aging, such as dementia, frailty, kidney failure and Parkinson's disease, and we still do not have a cure. Aging involves multiple pathways. We wanted to target more than one for a better outcome."


Launching the Fight Aging! 2015 $125,000 Matching Fundraiser for SENS Rejuvenation Research
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Today I'm pleased to announce the launch of this year's Fight Aging! matching fundraiser in support of the work of the SENS Research Foundation, funding scientific programs to speed progress towards working rejuvenation therapies and an end to frailty and disease in aging. In 2013 we raised $60,000, in 2014 $150,000, and this year we're shooting at a cool quarter of a million dollars. You never know where the limits really are unless you forge ahead, and support for the treatment of aging as a medical condition is growing more rapidly today than at any time since the creation of Fight Aging!

We have kicked things off with a Reddit /r/futurology post this year, as we did last year. Please do take a look and share the link and this fundraiser with those who might appreciate it. The /r/futurology community has been a great help in the past, and a source of many new supporters of longevity science.

Front and center, I'd like to thank Josh Triplett, Christophe and Dominique Cornuejols, Michael Greve of, and Stefan Richter for joining Fight Aging! in putting money on the table to set up a $125,000 matching fund for this event. From today until December 31st 2015, we will match every donation to the SENS Research Foundation dollar for dollar. I'd also like to thank David Gobel at the Methuselah Foundation for leaping in to be the first donor, providing an additional $15,000 for SENS research this year. Only another $110,000 to go, and three months to do it in!

How do we create a real, actual medical rejuvenation industry? By building technologies capable of repairing the known forms of cellular and molecular damage that cause aging. These types of damage are well-cataloged, and there is broad consensus on their relevance to age-related disease, but surprisingly little work takes place in the research community when it comes to making use of this knowledge to create treatments. This is even more surprising given that where progress has been made, such in amyloid clearance, senescent cell clearance, and mitochondrial repair, even early stage outcomes are of great quality, and clearly well worth further attention.

Funding for SENS technologies has been underway at a modest level for a decade now, and I can point to concrete progress occurring as a result. The wheel is starting to turn, and prospective SENS and SENS-like damage repair treatments targeting the causes of aging are beginning to leave the labs for clinical translation. Our community created this achievement, through advocacy and a comparatively small amount of funding directed to speed and enable to most promising scientific programs. One of the great secrets of our age is that early stage research is very cheap, but next to no-one other than philanthropists is willing to fund it. Just as soon as a prototype can be built, however, other institutions flock to fund the next stages. When looking at this is seems pretty clear that creating new and far more effective medical technologies really does fall upon the shoulders of the average person with a little vision, and the willingness to stand up and make a difference.

For example, all of these growing lines of development were originally seeded by small amounts of funding at critical times over the past decade, all of it provided by philanthropic donations. You can find further details in the latest SENS Research Foundation annual report.

Firstly: from 2008, donors to the Methuselah Foundation and then SENS Research Foundation collectively helped fund the work of the Marisol Corral-Debrinski lab on mitochondrial DNA damage. That was successful and in the years since then these researchers founded, grew, and found venture funding for Gensight, a company that is now devoting tens of millions of dollars to establishing the first clinical trials of this technology for inherited mitochondrial disease. Yet without the funding at the earliest stage, provided by forward-thinking SENS supporters, that early stage work struggled to find a patron. This is the sort of difference that we can make.

Secondly: The SENS Research Foundation has for years been using donor funds to support efforts to clear senescent cells from tissues, to remove their insidious contribution to the aging process. In 2015 the Methuselah Foundation and SENS Research Foundation have provided seed funding for the startup company Oisin Biotech that will be further developing one of these methodologies: these clearance technologies are leaving the lab and starting on their own journey to the clinic, one that will see them attract far greater funding. But again, without the years of low-level philanthropy, these are projects that languished unfunded by the institutional research establishment in their early stages.

Thirdly: One of the first and longest-running SENS programs was aimed at clearing age-related chemical junk from the cellular recycling organelles called lysosomes. With age, these organelles become clogged and faulty, and cells drown in garbage and broken components. The SENS Research Foundation has produced drug candidate molecules from studies of bacteria known to consume these compounds, and the long-time supporter Jason Hope has founded Human Rejuvenation Technologies to develop the first round of treatments based on this technology, aimed initially at removing the characteristic blood vessel plaques of atherosclerosis.

This is how the world is changed, a weight of small decisions to help, snowballing into significant projects. This is how, step by step, we can build a near future in which being old isn't accompanied by pain, suffering, disease, and death.