Fight Aging! Newsletter, November 10th 2014

November 10th 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: A Third of the Way
  • A Look at Age-Related Changes in Protein Abundance Throughout the Fibroblast Proteome
  • Further Investigations into FGF21 in Calorie Restriction
  • A First Look at the Bowhead Whale Transcriptome
  • The Goal is This: Suffering and Death Should Be Optional
  • Latest Headlines from Fight Aging!
    • Proposing a Trial of Rapamycin in Dogs
    • Smooth Muscle Cells in Blood Vessel Stiffening
    • Molecular Chaperones Decline with Age
    • A Programmed Aging Point of View on Objectives in Treating Age-Related Degeneration
    • A Potential Way to Target Ras in Cancers
    • Suggesting that SCNT is Better than Induced Pluripotency for Producing Cells for Therapy
    • A Look at the State of Neuroprosthetics Development
    • Suggesting Impaired Quality Control as the Cause of Greater Mitochondrial DNA Damage in Aging
    • Testing Dopamine Neuron Transplants in Rats
    • The Funding Issues of Longevity Science


The Fight Aging! 2014 fundraiser to benefit the work of the SENS Research Foundation launched a month ago and will run for another two months - until the end of the year. Until the end of December a sizable matching fund waits to be drawn down by your donations: for every $1 given to the Foundation to help expand their rejuvenation research programs, $2 is drawn from the fund. So donate!

Why give to support the Foundation? The SENS Research Foundation funds research programs to produce the basic technologies required to build rejuvenation therapies, treatments that will be capable of repairing the various forms of cellular and molecular damage that cause age-related frailty, disease, and death. Some of this research already takes place in the mainstream, such as in the cancer and stem cell research communities, but these are only a few of the many lines of work needed to produce a working rejuvenation toolkit and the clinical community to support it. Despite great progress in biotechnology over the past decade, and despite a good understanding of the goals and the damage that must be repaired, that other research is still largely languishing. The SENS Research Foundation is perhaps the only organization in the world that is wholly focused on speeding all of these necessary threads by funding research groups and laboratories.

Stem cell based regenerative therapies and even a partial cure for most cancers alone will not greatly extend our lives, even though they provide significant improvements over the present state of affairs for people suffering age-related disease. Aging is caused by other processes as well, and if one doesn't get you then one of the others will. To help the old and to help prevent ourselves from suffering in same way as today's old people the research community must also tackle other important issues in the aging body and brain: metabolic waste products building up inside and around cells; growing levels of mitochondrial DNA damage; immune system dysfunction; and senescent cell accumulation. All of these produce eventually fatal medical conditions on roughly the same timescales, and thus removing frailty and disease from aging will require progress on all of these fronts.

As noted, however, far too little work takes place on most of these projects. That is why our assistance is so important; that is why we must have fundraisers and philanthropy and advocacy. The work funded and encouraged by the SENS Research Foundation represents the future, and the SENS vision of repair of the causes of aging is to my eyes the only viable replacement for the present day collection of poor strategies for tackling aging in medicine. There can and should be more than just palliative care, or attempts to slightly slow down aging, or the same old-style drug discovery programs attempting to do more good than harm for people in the very end stages of aging. The near future can and should be one of targeted, designed treatments that zero in on the known forms of cellular and molecular damage that cause aging. The more support we can provide to organizations like the SENS Research Foundation, the faster this future will arrive, and the better all of our lives will be as a result.

We're now a third of the way through our 2014 fundraiser and over the last month more than 300 people from the community have generously stepped up to provide a third of the donations needed to reach the target. If you're on the fence, consider this: you'll probably spend more than most of these folk gave on coffee and cake this coming month, and what is that going to do for your future prospects? So invest a little in the rest of your life, in making the future a place you'd like to live in, I'd say. Small actions taken now will snowball, and make large differences down the line.


The proteome is the entire set of proteins generated by an organism under discussion. Here we'll use it in the more restricted sense of the entire set of proteins generated by a specific type of cell, the common fibroblast. Fibroblasts are connective tissue cells responsible in part for building the extracellular matrix that supports cell populations in a three-dimensional structure. We live in an age of rapidly advancing biotechnology, and the areas in which progress is most rapid are those related to genetics and proteomics: measuring, cataloging, and altering the thousands of different types of complex molecule present in and around cells. As the costs fall and the tools become ever more capable, researchers can now easily amass a great deal of data on the abundance of all proteins in specific tissues and under specific circumstances.

So to aging: it is now possible to compare cells from young tissue and old tissue in great detail - at least insofar as relative protein levels are concerned. From the perspective of aging considered as a process of damage accumulation, a snapshot of an old cell and a young cell created in this way is a comparison that shows the high level outcome of low level underlying processes. It tells us something about how the cell has altered its behavior, the pace at which it synthesizes different proteins, but not in great detail. That detail must be painstakingly inferred, a process that involves taking the catalog of changes in protein abundance and working backwards through what is presently known of what these proteins actually do.

Interestingly, we know already where researchers will end up at the end of this process should they follow it through to the very end, tracing back every change through nested layers of cause and effect. There is already a good, well-established list of the forms of damage to cells and tissues that are fundamental, not caused by some other change, but rather occurring as a natural result of the normal operation of cellular metabolism. There is a starting point and an ending, and a vast and very, very complicated blank space on the map in between.

Fortunately that blank space doesn't matter from the practical perspective of producing treatments: what researchers should do is to find ways to fix the fundamental damage and work forward to see what happens when it is fixed. That strategy should along the way generate effective treatments for aging. Unfortunately, this is not what 99% of the research community is actually doing. Rather, they are working backwards from the end, a process that will in the end come to the same filling in of the map, but has very little chance of generating effective treatments for aging along the way. Why little chance? Because their discoveries relate to proximate causes, changes in protein levels that are happening for very complicated reasons and are consequently hard to safely alter to try to make the situation less bad. Even if they are altered safely, that fails to address the underlying causes, which march on, and no doubt lead to all sorts of other forms of harm.

Here is a paper that demonstrates just how far the tools have come in the past two decades. Consider that the Human Genome Project kicked off in 1990 with a very long timeline, and then the whole thing was basically completed in a couple of years by Celera between 1998 and 2001 using newer technologies. The costs were staggering. Yet less than fifteen years later it is entirely unremarkable for genomes to be sequenced and the costs are small and falling rapidly. Proteome analysis is a much more complex affair, but the advance in capabilities has been similarly relentless. Today's machinery allows thousands of different proteins to be efficiently assessed and analysed per sample, and at costs that are tiny in comparison to event just a few years past. This paper isn't unusual at all in terms of what is taking place in the laboratory these days; be sure to read in far enough to find the diagrams:

Proteome-wide analysis reveals an age-associated cellular phenotype of in situ aged human fibroblasts

We analyzed an ex vivo model of in situ aged human dermal fibroblasts, obtained from 15 adult healthy donors from three different age groups using an unbiased quantitative proteome-wide approach applying label-free mass spectrometry. Thereby, we identified 2409 proteins, including 43 proteins with an age-associated abundance change. Most of the differentially abundant proteins have not been described in the context of fibroblasts' aging before, but the deduced biological processes confirmed known hallmarks of aging and led to a consistent picture of eight biological categories involved in fibroblast aging, namely proteostasis, cell cycle and proliferation, development and differentiation, cell death, cell organization and cytoskeleton, response to stress, cell communication and signal transduction, as well as RNA metabolism and translation.

Our present analyses showed 43 proteins with altered expression in these cells according to the different donor age groups. Remarkably, we found no overlap between the mRNA and protein expression data for these 43 proteins. This could be due to the fact that individual proteins or transcripts may not meet the threshold for statistical significance as the used technologies have different noise levels. On the other hand, it has been shown and confirmed by our data that in mammalian cells approximately only one third of the mRNA abundance is reflected in the proteome. However, the fact that 77% of the age-associated proteins were not linked to expression changes of the corresponding transcripts suggested that most of the age-associated alterations detected at the proteome level are likely caused by other processes, such as post-transcriptional regulation, translation efficiency, protein stability or modifications, rather than by differential regulation of gene expression.

There is a lot more theorizing in that vein in the paper; this is characteristic of this approach of working down from the top. It generates as many questions and new leads to follow as it does answers. As you might note the generation of proteins from genetic blueprints is a process with a lot of distinct stages, all of which are quite capable of reacting to circumstances independently from the others, producing a net change in abundance. Personally I think the "protein stability or modifications" segment is worth looking at in more detail given the apparently falling levels of chaperone proteins and decline in other parts of the cellular housekeeping processes with age.


In most species examined to date reducing caloric intake while maintaining optimal levels of required dietary micronutrients extends healthy life spans and maximum life spans. In laboratory mice the effect can extend maximum life spans by up to 40% or more, but the consensus is that in humans lifelong calorie restriction would perhaps add just a few years to life spans even through the effects on health are quite similar. Even regular exercise is not quite as impressive in its benefits to long term health, however, which raises the question as to why it is that calorie restriction doesn't have the same effect on life span in humans as it does in mice.

The evolutionary argument for this conclusion is pretty straightforward: the calorie restriction response evolved in the deep past as a way to better survive periods of seasonal famine. A season is long for a mouse, short for a human, and therefore only the mouse evolves a very plastic life span. There are other considerations that pertain only to primates, as well. We humans are long lived in comparison to our neighboring species such as chimpanzees and gorillas, and that is a fairly recent development in the grand sweep of evolutionary time. It is thought that our growing intelligence and culture led to new selection effects that extended life because the old could contribute to the success of their grandchildren. Out of the set of switches and dials available to evolution on a shorter time frame, it is possible that many that would be affected by calorie restriction are already turned on all the time in our species, as it were.

I can speculate wildly in this way without great fear of contradiction because the metabolic response to calorie restriction is fantastically complex and still only understood in broad outline. The short summary is that near everything that can be measured in the operation of cell metabolism changes when there are fewer calories coming in. This makes it a real challenge to pull apart exactly what is going on in detail: what is important, what is secondary, which systems are driving which changes. A cell is a big mess of feedback loops based on changing abundances of various proteins, and everything interacts with everything else in a constant, dynamic dance of change. The research community has put serious time and money into the attempt to understand how calorie restriction works over the past fifteen years, and there isn't much to show for it yet - one can argue that most of that money and time has been spend on what turned out to be interesting dead ends. A vast amount of data has been generated, and yet just a few sentences can now be added to the summary of what was known at the turn of the century. A lot more work lies ahead.

One of the proteins implicated in the calorie restriction response is fibroblast growth factor 21 (FGF21). More of it extends life in mice, and more of it is generated during methionine restriction. Some researchers are looking on it as a possible calorie restriction mimetic due to these results. In general its ability to produce life extension on its own makes it seem worthy of further investigation, and here is a typical result of such investigation, which is to say that the situation is rendered more complicated than prior work suggested, and more questions are raised than answers are provided:

Fibroblast Growth Factor 21 Is Not Required for the Reductions in Circulating Insulin-Like Growth Factor-1 or Global Cell Proliferation Rates in Response to Moderate Calorie Restriction in Adult Mice

Calorie restriction (CR), reduced caloric intake without malnutrition, increases maximum lifespan and delays the onset of many age-related diseases in organisms ranging from worms to rodents, and possibly non-human primates. Decreased signaling through the somatotropic axis is one mechanism that has been suggested to mediate these effects of CR, perhaps through a reduction in cell proliferation, which is predicted to contribute to lifespan extension by delaying cellular replicative senescence and inhibiting the promotional phase of carcinogenesis. Several lines of evidence contribute to a strong case for this hypothesis. First, CR in mice leads to a reduction in circulating levels of insulin-like growth factor-1 (IGF-1) in association with reduced rates of proliferation in a number of cell types. Second, repletion of circulating IGF-1 levels in CR rodents attenuates the CR-induced reduction in cell proliferation. Last, disruption of IGF-1 signaling in several mouse models mimics many of the effects of CR including, increased maximum lifespan, reduced tumor progression, delayed cellular replicative senescence and reduced rates of cell proliferation. Thus, identifying mechanisms that regulate IGF-1 signaling and cell proliferation in response to CR in mice could provide insight into the biology of aging and offer therapeutic targets for treating age-related diseases.

Using FGF21-knockout mice, we asked directly whether FGF21 was necessary for the IGF-1 and cell proliferation responses to moderate CR in adult mice. In order to capture possible circadian fluctuations in mRNA and circulating levels of factors of interest, mice were euthanized at two different time points. We found that the relative levels of circulating FGF21 and hepatic FGF21 mRNA in ad libitum (AL) vs. CR mice exhibited characteristic circadian fluctuations. The pattern of FGF21 expression in response to CR was unexpected in light of previous observations that FGF21 expression is robustly up-regulated in fasted mice. In contrast to these studies, we found that at 1500 h, CR mice, which had essentially been without food for more than 20 h, had lower hepatic FGF21 mRNA levels and a trend towards lower circulating levels of FGF21 compared to AL mice. Furthermore, at 1900 h, CR mice, which were in a postprandial state, had higher circulating FGF21 and hepatic FGF21 mRNA levels compared to AL mice. These data underscore the fact that CR is not simply repeated fasting and that CR and fasting are two distinct dietary paradigms.

Interestingly in humans, long-term (1-6y) CR does not reduce circulating IGF-1 levels and a very low calorie diet in obese diabetics actually reduces circulating FGF21 levels, with the caveat that baseline circulating FGF21 levels are elevated in this population. More studies are needed to confirm and clarify the effect of varying degrees of CR on circulating IGF-1 and FGF21 levels and the potential interplay between these two hormones in healthy humans.


Numerous research groups are involved in comparative genetic analysis of aging and longevity: investigating the biology of unusually long-lived species in search of the reasons why these animals are unusually long-lived in comparison to their peer. We humans actually fall into this category, having a greater longevity than our nearest primate cousins. Nonetheless, there are much more exceptional species out there, even if we restrict ourselves to the study of mammals. Some whales can live for centuries, and naked mole rats live for nine times as long as other similarly sized rodents.

There is the hope that beyond new knowledge the investigation of long-lived species might point the way towards means of slowing aging or treating age-related disease in humans. That really depends on the details, however: it is entirely possible for a mechanism of longevity (or regeneration as in salamanders, or cancer resistance as in naked mole rats, and so forth) to in the end turn out to be clear, well-understood, and nonetheless in no way useful to human medicine. The more likely outcome is that it takes a very long time and a lot of money to come to even a preliminary understanding, and at the end of the day those resources might have better been spent on directly advancing human medicine. If you've been following research into salamander regeneration over the past decade, for example, you'll see what I mean. Perhaps there is a grail there, perhaps not, and we won't know without a great deal more research - and this at a time when purely human regenerative medicine is advancing by leaps and bounds.

Nonetheless, comparative studies of aging and longevity are underway, and like all such research these days the scientists involved are producing mountainous vaults of data. The Methuselah Foundation, for example, presently provides a modest grant to a UK research group to sequence the genome of bowhead whale. On the basis of various direct and indirect evidence individuals of this species are thought to live for more than two centuries, and it seems only reasonable to ask how the whales manage this feat. The UK group are not the only researchers to work on answering this question. Another group that has studied bowhead whales for some years has recently published their first pass at the bowhead whale genome:

The transcriptome of the bowhead whale Balaena mysticetus reveals adaptations of the longest-lived mammal

Mammals vary dramatically in lifespan, by at least two-orders of magnitude, but the molecular basis for this difference remains largely unknown. The bowhead whale Balaena mysticetus is the longest-lived mammal known, with an estimated maximal lifespan in excess of two hundred years. It is also one of the two largest animals and the most cold-adapted baleen whale species. Here, we report the first genome-wide gene expression analyses of the bowhead whale, based on the de novo assembly of its transcriptome.

The bowhead's lifespan far exceeds that of other renowned long-lived species of mammals studied for molecular insights into aging. However, limited access to tissues of these animals has precluded detailed analyses of biological functions based on gene expression. As a first step in identifying such patterns, we present the liver, kidney and heart transcriptomes of the bowhead whale. Comparison of the bowhead whale transcriptome with that of the related minke whale and other mammals enabled us to identify candidate genes for the exceptional longevity of the bowhead whale.

It has been proposed that the difference in longevity between humans and other primates stems from differential expression of a small number of genes. A recent study comparing humans to eight other mammals, including primates, revealed that 93 liver and 253 kidney genes showed evidence of human lineage-specific expression changes. The number of genes differentially expressed in the bowhead whale liver (45 genes) and kidney (53 genes) compared to other mammals is similar, albeit using a different computational method. We speculate that the genes differentially expressed, with unique coding sequence changes and rapidly evolving in the bowhead whale, represent candidate longevity-promoting genes. We particularly stress the findings suggestive of altered insulin signaling and adaptation to a lipid-rich diet. The availability of a single heart tissue sample from the bowhead whale precluded identification of distinct gene expression patterns in the long-lived bowhead whale, but revealed that argininosuccinate lyase (Asl) may protect the heart of cetaceans during hypoxic events such as diving.

This is just a starting point, and other research groups will add to it in the years ahead. It is interesting to speculate on the role of hypoxia in the evolution of longevity, for example, as both whales and naked mole rats experience frequent long exposure to oxygen-poor environments: diving for the whales, and life underground in poorly ventilated tunnels for the naked mole rats. In fact these are not the only species in which hypoxia is theorized to spur the evolution of longevity, not directly, but as a side-effect of the class of cellular mechanisms needed for a complex animal to thrive in oxygen-poor environments.


The accelerating advance of technology and consequent growth in individual wealth created over the past few centuries can also be seen as an expansion of individual freedom and choice. Wealth is greater available choice, enabled by technology. All of the coins, numbers, and possessions, all of the details of our society and its capabilities are really just a way to enumerate that expanded opportunity for the individual: the choice to fly, the choice to communicate with people on the opposite side of the world, the choice to be warm rather than cold or cold rather than warm, and most importantly the choice to be alive and free of pain and disability rather than suffering or dead due to any number of medical conditions.

Taken as a whole, medicine is the march towards immortality as an ideal, never expecting to get there, but stolidly knocking down as many walls as it takes to move forward one step at a time, each new advance bringing us all just that little bit closer to a world without pain and death. This is a fine and noble thing, and the work of our ancestors has brought us a long, long way from the state of medicine just a few hundred years ago. Helping to continue and expand this progress in technology is the best of what we can do as individuals and as a species, and it is but one slice of what we might call paradise engineering: building the technologies needed to create a rich world of enormous choice and experience that nonetheless entirely lacks involuntary suffering and death.

Here is an eminently sensible article from a professional philosopher that I somehow missed when it was published earlier this year. It makes for a refreshing change in comparison to much of what emerges from philosophy and ethics on the subject of radical life extension and efforts to bring an end to suffering:

Death Should Be Optional

As a non-scientist I am not qualified to evaluate scientific claims about what science can and cannot do. What I can say is that plausible scenarios for overcoming death have now appeared. This leads to the following questions: If individuals could choose immortality, should they? Should societies fund and promote research to defeat death? The question regarding individuals has a straightforward answer - we should respect the right of autonomous individuals to choose for themselves. If an effective pill that stops or reverses aging becomes available at your local pharmacy, then you should be free to use it. My guess is that such a pill would be wildly popular! (Consider what people spend on vitamins and other elixirs on the basis of little or no evidence of their efficacy.) Or if, as you approach death, you are offered the opportunity to have your consciousness transferred to your younger cloned body, a genetically engineered body, a robotic body, or into a virtual reality, you should be free to do so. I believe that nearly everyone will use such technologies once they are demonstrated effective. But if individuals prefer to die in the hope that the gods will revive them in a paradise, thereby granting them reprieve from everlasting torment, then we should respect that too. Individuals should be free to end their lives even after death has become optional for them.

The argument about whether a society should fund and promote the research relevant to eliminating death is more complex. Societies currently invest vast sums on entertainment rather than scientific research; although the latter is a clearly a better societal investment. Ultimately the arguments for and against immortality must speak for themselves, but we reiterate that once science and technology have extended life significantly, or defeated death altogether, the point will be moot. By then almost everyone will choose to live as long as possible. In fact many people do that now, at great cost, and often gaining only a few additional months of bad health. Imagine then how quickly they will choose life over death when the techniques are proven to lead to longer, healthier lives. As for the naysayers, they will get used to new technologies just like they did to previous ones.

[Nonetheless], the defeat of death completely obliterates most world-views that have supported humans for millennia; no wonder it undermines psychological stability and arouses fierce opposition. Thus monetary and psychological reasons help to explain much opposition to life-extending therapies. Still people do change their minds. We now no longer accept dying at age thirty and think it a great tragedy when it happens; I argue that our descendants will feel similarly about our dying at eighty. Eighty years may be a relatively long lifespan compared with those of our ancestors, but it may be exceedingly brief when compared to those of our descendants. Our mind children may shed the robotic equivalent of tears at our short and painful lifespans, as we do for the short, difficult lives of our forebearers. In the end death eradicates the possibility of complete meaning for individuals; surely that is reason enough to desire immortality for all conscious beings. Still, for those who do not want immortality, they should be free to die. But for those of us that long to live forever, we should free to do so. I want more freedom. I want death to be optional.


Monday, November 3, 2014

Rapamycin has been shown to modestly extend life in mice, though there is some ongoing debate as to whether this is an effect caused by cancer risk reduction rather than a slowing of aging. Some researchers are now intending to embark on a small study using dogs:

Yeast, worms and mice: all have lived longer when treated with various chemical compounds in laboratory tests. But many promising leads have failed when tried in humans. This week, researchers are proposing a different approach to animal testing of life-extending drugs: trials in pet dogs. Their target is rapamycin, which is used clinically as part of an anti-rejection drug cocktail after kidney transplants and which has also been shown to extend the lives of mice by 13% in females and 9% in males.

The compound's effect on lifespan has not yet been tested in people - human trials are expensive and it takes a long time to learn whether a drug can extend a human life. Furthermore, rapamycin is no longer patentable, so pharmaceutical companies are unwilling to invest effort in it. The drug can also cause some serious side effects that might rule it out as a pharmaceutical fountain of youth. It has, for example, been linked to an increased risk of diabetes in people who have had kidney transplants. But at low doses, researchers suspect that the drug will not be a problem for healthy dogs.

[Molecular biologists] propose to give low doses of rapamycin to dogs in a study that would also test whether the drug can extend the animals' lives. The researchers hope to test rapamycin in large dogs that typically live for eight to ten years; they would start giving the drug to animals aged six to nine. A pilot trial would involve about 30 dogs, half of which would receive the drug, and would allow the researchers to dose the dogs for a short time and observe effects on heart function and some other health measures. The trial could be completed in as little as three years, but researchers will know long before that - perhaps in months - whether rapamycin improves cardiac function or other aspects of health.

Monday, November 3, 2014

Blood vessels lose their flexibility and structural integrity with age, which contributes to a range of ultimately fatal cardiovascular conditions, as well as loss of cognitive function caused by disruption of blood flow in the brain. This process of stiffening in blood vessels is thought to be at least partially due to cross-linking in the extracellular matrix, in which the mechanical properties of tissue degrade due to rising levels of advanced glycation endproducts, sugary metabolic wastes that can glue together proteins to disrupt their function.

Here, however, researchers look at another potential causative process for vascular stiffness, in this case connected to focal adhesion structures. These are built by cells in order to anchor to the extracellular matrix and hold steady in its tissue, but can be quite dynamic in some circumstances, destroyed and recreated as a cell shifts its position:

The aorta is the main artery of the body. It is connected to the heart and carries oxygen-rich blood pumped from the left ventricle to the rest of the circulatory system. Pumping blood from the heart causes pulsing waves that reverberate into the aorta. As it branches off into smaller blood vessels, the aorta acts as a shock absorber, blunting the impact of these waves. But with age, changes in the blood vessel wall can cause the aorta to lose some of its flexibility and its ability to buffer high-pressure waves as they travel to the smaller vessels. The reduced shock-absorbing capacity can lead to changes in microcirculations and negative effects on organ function.

The underlying cause of aortic stiffening is unclear. While much of the previous research pointed to the extracellular matrix (ECM) - a group of molecules secreted by the cells that support cell attachment and communication - as the culprit, a few studies suggest that vascular smooth muscle may play a role. [Researchers] directly measured the mechanical properties of the aortas of young and old mice to observe how smooth muscle cells factor into aortic wall stiffness. They also observed how focal adhesion signaling - which helps promote arterial flexibility in young mice - is impaired with aging. They used a novel biomechanical method to distend the aorta, mimicking circumferential strain, to measure how the smooth muscle affected arterial stiffness.

"A major finding of the present study is that the smooth muscle cell is a major source and regulator of vascular stiffness, in contrast with the often-assumed dominance of ECM in effecting changes in wall stiffness with aging. The decrease in the focal adhesion signaling mechanism led to higher stiffness in old vessels. We conclude from our results that the smooth muscle focal adhesions represent a potential therapeutic target in the context of preventing or reversing increases in aortic stiffness. An understanding of this mechanism may lead to an approach to reverse this aging-induced deficiency."

Tuesday, November 4, 2014

Chaperone proteins work to ensure correct protein folding and function in cells. The more chaperone activity taking place, the less damage in the form of dysfunctional protein machinery at any given time. Artificially boosting forms of chaperone activity is a potential form of treatment for some of the causes and consequences of age-related degeneration, as it could turn back the clock on rising levels of misfolded and otherwise damaged proteins.

Aging is the most significant and universal risk factor for developing neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's, Parkinson's and Huntington's diseases. This risk increases disproportionately with age, but no one really knows why. Now a team of [scientists] has uncovered some clues. The researchers are the first to find that the quality of protective genes called molecular chaperones declines dramatically in the brains of older humans, both healthy and not, and that the decline is accelerated even more in humans with neurodegenerative disease.

Molecular chaperones are a special set of highly conserved genes that watch over cells, keeping them and the entire organism healthy by preventing protein damage. The researchers specifically found the decline in 100 genes, approximately one-third of all human molecular chaperone genes. Then, with additional studies, they winnowed that number down to 28 human genes specifically involved in age-associated neurodegeneration. These critical genes provide a basis for a biomarker, an early indicator of disease and a target for new therapeutics.

"Imagine if we had biomarkers that tell doctors how you are doing in terms of aging, warning of any problems long before neurological deficits appear. This would be a remarkable tool, especially considering the increases in life expectancy in many parts of the world. Let's say a person is age 50, but we see his molecular chaperones have declined and aren't repairing proteins and cellular damage. The chaperones are acting more like age 85 or 90. That's a sign that medical intervention could help. Molecular chaperones really are the barrier we have between disease and no disease. If this critical system declines, it leads to misfolded and damaged proteins, and eventually tissues become dysfunctional and die. If we can keep the chaperones healthy, we should be able to keep the person healthy. The next step is to understand the basis for the decline of these specific chaperones and to develop treatments that prevent their decline. The goal is not to make people live forever but rather to match health span more closely with life span - to improve the quality of life being lived."

Tuesday, November 4, 2014

The majority of the research community sees aging as a consequence of damage, which leads to reactions in the form of changes in the operation of metabolism. Cells react with altered levels of gene expression, leading to different amounts of various proteins in circulation, and other more complex changes also take place. Not all of these reactions are a good thing, and many cause further harm. In the programmed aging viewpoint, the changes in protein levels are the fundamental cause of aging, an evolved system that causes aging and exists because it provided selection benefits in early life. Thus to one school of thought repair of damage is absolutely the best approach while to the other it is pointless, and vice versa for efforts to change protein levels directly in old tissues without repairing damage.

The strange thing about modern aging research, or the tragic thing depending on your viewpoint, is that despite the majority considering aging to be caused by damage, the research they undertake is actually far more suited to the programmed aging school of thought. The most common approach to research is to examine the end stage of a particular aspect of aging, and pick out proximate causes, or changes in protein levels and gene expression, and try to alter them. This is the path forced upon researchers by the regulatory structure they work within: commercialization of treatments is only permitted for named diseases, the late stages of age-related damage. So they must work from the end backwards, and thus the first things they find are always going to be proximate causes and reactions.

This must all change if we are to see effective treatments based on damage repair. Meanwhile the programmed aging theorists should be pretty pleased with the current state of affairs, since it is going in the direction they would recommend even though they are ostensibly having a tough time in winning over their colleagues to their hypotheses on aging. This is a slow moving debate that is only ever going to be settled by the establishment of rejuvenation treatments that actually work, and thereby demonstrate one view to be wrong. That goal is muddied by the fact that there are many layers of damage and reaction, and thus one can in fact achieve modest benefits in some cases by altering proximate causes.

It is my belief that the timing of development and aging is determined by chromatin state. The body knows how to be young, and it knows how to be old. The difference is coded in chromosomes, especially in telomere length of stem cells and epigenetic markers in endocrine cells. I am proposing that aging is, in large part, a matter of epigenetics. A different set of genes is turned on when we are young compared to when we are old, and that makes all the difference.

I believe that aging is controlled by several biological clocks. This is a strong claim, but I think it has good support, outlined in the references above. Biological clocks certainly control development, puberty and related schedules early in life. How the body knows its own age is yet incompletely understood. It's a good bet that the same clocks that control development have been re-purposed to control aging. There are three clocks we know something about. These are the epigenetic clock, cellular senescence (telomere loss), and life-long shrinkage of the thymus, master gland of the immune system. A common way to construct a clock is with a feedback loop. A clock looks at itself to determine its next move. The body has a feedback loop between epigenetic state (at a cell level) and circulating hormones and RNAs (at a systemic level).

There is intriguing data from parabiosis that circulating factors may be able to reprogram the body's age state. (This is the "back end" of the feedback loop described above.) If we're looking for quick progress against aging, the circulating hormones are more accessible and make a more convenient target than trying to get inside the cell nucleus to reprogram epigenetic state directly. If we're lucky, then adding some factors to the blood while blocking others will have a long-lasting effect of re-programming epigenetics, and the body will take over by continuing to secrete a "young mix" into the blood stream. If we're not so lucky, it may be necessary to perform some epigenetic re-programming more invasively.

Wednesday, November 5, 2014

The future of effective cancer treatment will involve finding ways to selectively target and sabotage common mechanisms used by sizable fractions of the many different forms of cancer. The goal is to produce treatments that work well with few side effects, and can be applied to many cancers, so that the next generation of the commercial cancer therapy industry can be established on the back of, say, a dozen different broadly applicable therapies rather than hundreds of different treatments each specific to a subtype of cancer. Here is an example of incremental progress towards one such potential treatment:

[Researchers have] uncovered a new strategy and new potential drug to target an important signalling protein in cells called Ras, which is faulty in a third of cancers. When the Ras protein travels from the centre of a cell to the cell membrane, it becomes 'switched on' and sends signals which tell cells to grow and divide. Faulty versions of this protein cause too many of these signals to be produced - leading to cancer. Scientists have been attempting for decades to target Ras, but with little success. The reason the protein is so difficult to target is because it lacks an obvious spot on its surface that potential drug molecules can fit into in order to switch it off, like a key closing a lock.

But now the researchers have shown that instead of directly targeting the faulty protein itself they can stop it moving to the surface of the cell by blocking another protein which transports Ras - preventing it from triggering cancer in the first place. By targeting a link in the chain reaction that switches on the Ras protein, the scientists have opened opportunities to develop new treatments in the future. "We've been scratching our heads for decades to find a solution to one of the oldest conundrums in cancer research. And we're excited to discover that it's actually possible to completely bypass this cancer-causing protein rather than attack it directly. We're making new improvements on compounds for potential drugs, although the challenge still lies in developing a treatment that exploits this discovery without ruining the workings of healthy cells."

Wednesday, November 5, 2014

There are now several methods of producing pluripotent cells from a patient's tissue. These are cells that are similar to embryonic stem cells in that they can be used to produce any type of cell in the body. A supply of patient-matched cells enables a broader range of more effective regenerative therapies to be developed. The earliest methodology for the production of pluripotent cells is known as somatic cell nuclear transfer (SCNT), and over the years has proven to be technically challenging. Few groups even now can reliably use these techniques. A much easier method called induced pluripotency was developed more recently and has captured most of the effort in this field in recent years. However, there are some indications that SCNT produces better cells, free from some classes of abnormality that can be introduced by the induced pluripotency reprogramming process:

Human pluripotent stem cells hold potential for regenerative medicine, but available cell types have significant limitations. Although embryonic stem cells (ES cells) from in vitro fertilized embryos (IVF ES cells) represent the 'gold standard', they are allogeneic to patients. Autologous induced pluripotent stem cells (iPS cells) are prone to epigenetic and transcriptional aberrations.

To determine whether such abnormalities are intrinsic to somatic cell reprogramming or secondary to the reprogramming method, genetically matched sets of human IVF ES cells, iPS cells and nuclear transfer ES cells (NT ES cells) derived by somatic cell nuclear transfer (SCNT) were subjected to genome-wide analyses. Both NT ES cells and iPS cells derived from the same somatic cells contained comparable numbers of de novo copy number variations. In contrast, DNA methylation and transcriptome profiles of NT ES cells corresponded closely to those of IVF ES cells, whereas iPS cells differed and retained residual DNA methylation patterns typical of parental somatic cells. Thus, human somatic cells can be faithfully reprogrammed to pluripotency by SCNT and are therefore ideal for cell replacement therapies.

Thursday, November 6, 2014

Interfacing with the central nervous system is an important part of replacing many structures in the body, whether with new tissues or artificial structures that accomplish at least some of the same functions. Much of the work in this direction is concerned with the development of more functional artificial limbs and powered exoskeletons, but there is a lot more than just that going on in the research community:

Neural control of a prosthetic device for medical applications is now becoming commonplace in labs around the world. In its simplest form, a neuroprosthetic is a device that supplants or supplements the input and/or output of the nervous system. For decades, researchers have eyed neuroprosthetics as ways to bypass neural deficits caused by disease, or even to augment existing function for improved performance. Today, several different types of surgical brain implants are being tested for their ability to restore some level of function in patients with severe sensory or motor disabilities. [Perhaps] the most visible recent demonstration of the power of neuroprosthetics was a spinal cord-injured patient using a brain-controlled exoskeleton to kick off the 2014 World Cup in Brazil. In short, tinkering with the brain has begun in earnest.

When connecting an external device to the human nervous system, researchers have traditionally used a setup that records brain signals from the user, computationally analyzes those signals to infer the user's intentions, and then relays the information to an external effector that acts on those intentions. Inputs can be the firing of individual neurons in the brain, the cumulative voltages across areas of cortex encompassing millions of neurons, or the action potentials conducted by peripheral nerves anywhere in the body. In terms of output effectors, researchers have demonstrated that brain or nerve signals can be used to control computer cursor movements and robotic arms, or enable the reanimation of paralyzed limbs.

But information transfer via neuroprostheses is not a one-way street; some systems are able to convert environmental stimuli into perceptions by capturing an external input and translating it into an appropriate stimulus delivered directly to the nervous system. In this light, researchers have developed cochlear implants and functional retinal prostheses. Such reversal of information transfer can also be beneficial for limb prostheses. Under normal circumstances, meaningful movements of the body can only be accomplished in conjunction with appropriate sensation of the limb or body part. While this area of research is still young, researchers are beginning to create "bidirectional" brain-computer interfaces.

Thursday, November 6, 2014

Thousands of mitochondria swarm within each of our cells, working to produce energy store molecules that power cellular processes. Mitochondria multiply by division, contain remnant DNA from their origin as symbiotic bacteria, and are culled when dysfunctional by cellular quality control mechanisms. Despite the destruction of faulty mitochondria, damage to their DNA nonetheless accumulates. More serious forms of this mutational damage can block the production of proteins necessary for mitochondrial function, leading to dysfunctional cells and contributing to a range of ultimately fatal age-related conditions.

There is a fair degree of debate over just how this damage originates, spreads, and increases with age, however. Whatever the process by which a single damaged mitochondrion can replicate its damage throughout all of the mitochondria in a cell in some circumstances, this transformation happens rapidly: researchers don't have intermediate states to study. The causes of increasing damage might include mitochondrial division, or the reactive oxygen species produced by the normal operation of mitochondrial processes, or some other process, such as a progressive failure of quality control as suggested here:

We review the impact of mitochondrial DNA (mtDNA) maintenance and mitochondrial function on the aging process. Mitochondrial function and mtDNA integrity are closely related. In order to create a protective barrier against reactive oxygen and nitrogen species (RONS) attacks and ensure mtDNA integrity, multiple cellular mtDNA copies are packaged together with various proteins in nucleoids. Regulation of antioxidant and RONS balance, DNA base excision repair, and selective degradation of damaged mtDNA copies preserves normal mtDNA quantities.

Oxidative damage to mtDNA molecules does not substantially contribute to increased mtDNA mutation frequency; rather, mtDNA replication errors of DNA PolG are the main source of mtDNA mutations. Mitochondrial turnover is the major contributor to maintenance of mtDNA and functionally active mitochondria. Mitochondrial turnover involves mitochondrial biogenesis, mitochondrial dynamics, and selective autophagic removal of dysfunctional mitochondria (i.e., mitophagy). All of these processes exhibit decreased activity during aging and fall under greater nuclear genome control, possibly coincident with the emergence of nuclear genome instability. We suggest that the age-dependent accumulation of mutated mtDNA copies and dysfunctional mitochondria is associated primarily with decreased cellular autophagic and mitophagic activity.

Friday, November 7, 2014

Parkinson's disease involves loss of a small population of dopamine generating neurons in the brain. The underlying processes causing this loss happen in all aging brains, but to a greater extent in those who ultimately manifest this condition. One approach to treatment under development is direct replacement of the lost cells, but like many types of cell therapy a lot of work and testing is involved to find the most useful strategies given the cell sources and technologies presently available:

Parkinson's disease is caused, in part, by the death of neurons that release a brain chemical called dopamine, leading to the progressive loss of control over dexterity and the speed of movement. [Researchers have shown] that transplantation of neurons derived from human embryonic stem cells (hESCs) can restore motor function in a rat model of Parkinson's disease, paving the way for the use of cell replacement therapy in human clinical trials.

Another approach involving the transplantation of human fetal cells has produced long-lasting clinical benefits; however, the positive effects were only seen in some individuals and can also cause involuntary movements driven by the graft itself. To rigorously assess an alternative hESC-based treatment approach, [scientists] transplanted hESC-derived dopamine neurons into brain regions that control movement in a rat model of Parkinson's disease. The transplanted cells survived the procedure, restored dopamine levels back to normal within five months, and established the correct pattern of long-distance connections in the brain. As a result, this therapy restored normal motor function in the animals. Importantly, the hESC-derived neurons show efficacy and potency similar to fetal neurons when transplanted in the rat model of Parkinson's disease, suggesting that the hESC-based approach may be a viable alternative to the approaches that have already been established with fetal cells in Parkinson's patients.

Friday, November 7, 2014

Aging research receives very little funding in comparison to other lines of medical research, which makes little sense given that it is the cause of the overwhelming majority of deaths in wealthier regions of the world with large research communities. Within aging research, very little funding is devoted towards intervening in the aging process, the work of producing treatments for aging. Within that set of funding, very little indeed is going towards research programs like SENS that have a shot at producing real results in the decades ahead.

Indeed, if one were to be cynical, one might view the past ten to fifteen years of research in sirtuins and longevity genes, work that ostensibly has the aim of slowing aging, as a successful attempt by metabolic researchers to find a flag to wave that will let them obtain much more funding for their work on cataloging the exceedingly complex operation of cells. Certainly the output from most so-called longevity research has been more data on cellular metabolism, and nothing of material use beyond that - and if you spend time watching the field, that is exactly what we should expect from this work.

Only comparatively new, disruptive approaches like SENS, based on repair of the cellular and molecular damage that causes aging rather than manipulating metabolism to slightly slow the onset of damage, have the plausible outcome of producing rejuvenation treatments at the end of the day. Even in the best of outcomes for work on sirtuins or calorie restriction mimetic drugs, the end result will be of little use for old people, and will have only marginal benefits for everyone else. That is not a path to add decades to healthy life spans, and such a result simply isn't within the bounds of the possible for current efforts aimed at slowing aging only. For more than that we need to focus on damage repair. Yet damage repair receives only a tiny sliver of funding within the field.

Today, in an increasingly ageing world, anyone who found a formula to prevent or just slow down the process would no doubt make a killing. But the controversial scientists working to engineer a fountain of youth claim that, despite an increased interest from Silicon Valley types over the past few years, they're still low on funds. Research on life extension doesn't have to be particularly expensive. Aubrey de Grey told me that to run his brainchild, SENS, "The procedures and machinery that are needed are very much the same as for any biology research," with high-precision equipment such as microscopes accounting for the biggest expenses. The often hostile response to life-extension work surely plays a role in the equation, with many suggesting the idea of curing ageing is simply snake oil or outright dangerous.

But even if you buy into the idea, there's a lack of foreseeable payoff. Investing in such ventures could potentially yield big returns - but only in the long term. While de Grey is convinced that the first person to live 1,000 years has already been born, the prospect that one of the laboratories working to beat ageing will hit the jackpot any time soon sounds farfetched to most. "People want to invest today to make money tomorrow, that's the thing. With life extension, things take a little longer."

Right now, life-extension research is still research, pure and simple. Scientists exploring the uncharted territories of longevity mainly tinker with cells and telomeres, or strive to spawn long-lived mice; so far the opportunities for life-extension institutes to churn out marketable products are virtually non-existent. If some breakthroughs along these lines were achieved, the life-extension sector has the potential to be a hugely profitable industry. In 2013 [people] worldwide spent $195.9 billion to keep the signs of ageing at bay with products aimed at countering such nuisances as wrinkles, hair loss, or faltering memory. Just imagine if feasible treatments emerged to tackle those problems at their root, eradicating ageing altogether. That's why the current dearth of funds doesn't make any sense. "My argument is the following: Health is a huge business, and illness is a huge business too. If we can offer products to live longer it'll be a huge business. What will the value of future gains be? It'll be huge. What is worth investing in it? Let's say 100 billion dollars a year, but actually any amount is worth spending."


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