Fight Aging! Newsletter, April 21st 2014

April 21st 2014

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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  • Commercial Blood Factories Lie Ahead
  • What is Robust Mouse Rejuvenation, and Why Should We Care?
  • An Update on DNA Methylation Patterns as a Biomarker of Aging
  • The Crossroads for Human Longevity
  • Somatic Cell Nuclear Transfer Achieved in Adult Human Cells
  • Latest Headlines from Fight Aging!
    • TRF2 as a Potential Biomarker of Cellular Senescence
    • Learning to Reverse Aspects of Cell Aging By Observing the Embryo
    • The Fragile Elderly Hip
    • More Evidence of the Inverse Relationship Between Dementia and Cancer Mortality
    • A Decellularized Oesophagus Demonstrated in Rats
    • A Canine Longitudinal Aging Study Proposed
    • Public Views on the Future of Technology
    • A Midlife Crisis for the Mitochondrial Free Radical Theory of Aging
    • Turning Cells into Programmable Medical Devices
    • Is Parkinson's an Autoimmune Disease?


A number of competing lines of research aim at producing large volumes of blood to order, with an eye to eventually eliminating the need for blood donors and all of the shortcomings inherent in donated blood - the need for screening and other expenses in the donation process, the short shelf-life of blood outside the body, and so forth. Firstly there is the approach of creating synthetic blood substitutes, which will be most likely restricted to short-term use in trauma cases for the near future as the intent is to provide the critical function of oxygen transport and little else. Then there are the varied efforts to grow blood from stem cells, some of which are coming closer to clinical trials, an initial step on the way to commercialization. A decade from now blood factories will be established in much the same way as skin factories are a going concern at present: there will likely be some mix of generic blood types produced in bulk from known lineages alongside the ability to create blood to order from a specific patient's cells.

A few years back the researchers involved in the work quoted below estimated that blood derived from stem cells would be in trials by now. They are presently looking at starting small trials in 2016 at the earliest, which perhaps illustrates why scientists are usually cautious about putting timelines on the table, especially in an environment of heavy government regulation, where new delays and new expenses are ever on the menu.

First volunteers to receive blood cultured from stem cells in 2016

The consortium will be using pluripotent stem cells, which are able to form any other cell in the body. The team will guide these cells in the lab to multiply and become fresh red blood cells for use in humans, with the hope of making the process scalable for manufacture on a commercial scale. The team hopes to start the first-in-man trial by late 2016.

Blood transfusions play a critical role in current clinical practice, with over 90m red blood cell transfusions taking place each year worldwide. Transfusions are currently made possible by blood donation programmes, but supplies are insufficient in many countries globally. Blood donations also bring a range of challenges with them, including the risk of transmitting infections, the potential for incompatibility with the recipient's immune system and the possibility of iron overload. The use of cultured red blood cells in transfusions could avoid these risks and provide fresh, younger cells that may have a clinical advantage by surviving longer and performing better.

Professor Marc Turner, Principal Investigator, said: "Producing a cellular therapy which is of the scale, quality and safety required for human clinical trials is a very significant challenge, but if we can achieve success with this first-in-man clinical study it will be an important step forward to enable populations all over the world to benefit from blood transfusions. These developments will also provide information of value to other researchers working on the development of cellular therapies."

Artificial blood 'will be manufactured in factories'

Prof Turner has devised a technique to culture red blood cells from induced pluripotent stem (iPS) cells - cells that have been taken from humans and 'rewound' into stem cells. Biochemical conditions similar to those in the human body are then recreated to induce the iPS cells to mature into red blood cells - of the rare universal blood type O.

There are plans in place for the trial to be concluded by late 2016 or early 2017, he said. It will most likely involve the treatment of three patients with Thalassaemia, a blood disorder requiring regular transfusions. The behaviour of the manufactured blood cells will then be monitored.

This sort of pace of development will likely be beaten to the end goal of commercial blood manufacture by less constrained and more ambitious commercial development in East Asia, I'd imagine. That has been the pattern so far in the development of applied stem cell technologies, at least.


SENS, the Strategies for Engineered Negligible Senescence is a detailed research plan for developing the means to prevent and reverse degenerative aging by repairing its causes. SENS assembles the list of causes from the present scientific consensus on fundamental differences between old and young tissues, differences that are not known to be caused by any lower-level process. The potential repair therapies are also assembled from the best and latest of research strategies in a range of fields: stem cell therapies, targeted cell destruction, engineered enzymes to break down unwanted biomolecules, immune therapies, and so forth. SENS as a program is shepherded by the SENS Research Foundation but has growing support in the broader scientific community, and far from every last relevant research program is actually initiated by, funded by, or even known to the Foundation.

Robust mouse rejuvenation (RMR) has been the first long term milestone for SENS since its proposal and initial development by Aubrey de Grey. No new technology arrives fully formed, and it is understood that the first versions will be flaky, expensive, and generally much less effective than the later refinements. But in the case of rejuvenation treatments, this may not matter all that much, as even a somewhat effective form of rejuvenation provides the patient more time in which to wait on those refinements - or perhaps even assist in their development. So robust mouse rejuvenation as originally outlined means a full enough implementation of SENS to be capable of doubling the remaining life expectancy of an elderly mouse, demonstrated and then replicated in rigorous laboratory studies. It doesn't mean an absolutely complete implementation, and it doesn't mean full and absolute rejuvenation: it is a first pass to demonstrate greater benefits than any other approach to date.

It is important to note that when I talk about implementation of SENS in the laboratory, I am almost always talking about robust mouse rejuvenation. I do not mean clinical translation of this result, and neither do I mean a complete and fully effective suite of rejuvenation treatments. The path from robust mouse rejuvenation to the clinic might be decades long in the highly regulated US and Europe, but first generation SENS treatments will hopefully jump into clinics in other parts of the world just as rapidly as did first generation stem cell therapies. Medical tourism is a wonderful thing, and will probably one day save your life.

SENS is presently divided into seven general categories of damage that cause aging, each of which seems largely independent from one another and requires a very different approach to repair: a whole different line of research, no doubt running in different labs and organized by different research groups. We may see the seven categories split further in the years ahead if any of the subcategories prove to be either much harder or more important to aging than is presently assumed. For example, if I were writing SENS from scratch I might put immune system aging in its own bucket rather than lumping it under the general category of death-resistant cells. But that's just my view.

It is presently thought that each category of age-related damage in SENS is enough to kill you in roughly a human life span or a little longer even if all of the others are defeated. This may or many not turn out to be the case, but the evidence for this viewpoint is compelling, as each of the SENS categories of damage has at least one fatal age-related condition associated with it, and for which it is the primary known driver. This is in fact how these forms of damage were first categorized and investigated by the research community, as researchers work backwards from the visible and deadly consequences of aging in search of the mechanisms by which they unfold. The assumption that all aspects of SENS must be at least partially addressed in order to prevent aging and extend healthy life is why robust mouse rejuvenation is marked as a goal: get every category of repair treatment in the SENS portfolio working to at least the level of a proof of concept.

How long remains between now and the implementation of robust mouse rejuvenation? Ah well, there's the rub. How long is a piece of string? It is very hard to predict timelines for research when funding is at a low ebb, even research like SENS wherein it is fairly clear as to what the researchers should be working on, which lines of work are most promising, and where the end goals lie. If there was a good level of funding for SENS, say at the level of $100 million a year, then we could fall back to planning estimates of a decade or so to get to robust mouse regeneration. We could do that because with that much money there can be many irons in the fire, and the law of averages begins to smooth out random chance: some projects fail, some do very well and come in early, surprise advances sometimes happen, and some projects take far longer than they were expected to. When there is comparatively little funding then progress in research is uncertain, and I would be surprised to learn that there was more than about $10 million devoted to directly SENS-related work outside the stem cell and cancer research communities this year given that the SENS Research Foundation's yearly budget is around $5 million at the moment.

The glass half full way of looking at this is to see that people like you and I can make a large difference to the level of funding just through ordinary fundraisers, like those that raised $20,000 and $60,000 for SENS research projects last year.

But I think it is worth bearing in mind that robust mouse rejuvenation is not a coordinated single point in time at which all parts of SENS will suddenly become available at once. Different areas of SENS research stand at very different stages of readiness and progress, and some will clearly be done first, and perhaps considerably in advance of the others. The best candidates at this point for early success are, I think, breaking of glucosepane cross-links and mitochondrial repair of some form. If a method of breaking down the predominant form of cross-links in human tissues is demonstrated to produce benefits, will the world sit around waiting for robust mouse rejuvenation in order to develop it? Of course not. In fact, I'd wager that robust mouse rejuvenation will probably be contemporary with medical tourism for first generation treatments based on the more easily developed parts of the SENS rejuvenation toolkit.

You may still get nailed by one of the other forms of age-related damage on roughly the same time scale as a normal human life span, but it is hard to argue that you will not find improvements to health and function through repair of only one or two forms of age-related damage. If you can undergo a treatment to remove glucosepane cross-links to improve function of skin and blood vessels, then I'd argue that your life is better as a result even though all of the other forms of damage are gnawing away at your health in their own ways. Robust mouse rejuvenation is an aspirational goal, but it isn't a dividing line. Results will be more piecemeal and staggered, and any result with significant merit will probably be rapidly developed as a treatment in less regulated parts of the world. Until research funding for SENS and SENS-like research grows greatly, the pace of progress towards rejuvenation will remain variable and uncertain.


The research community is very interested in a reliable method of measuring biological age: not how old you are in years, but how far along you are in the aging process, how much damage has accumulated in cells and macromolecules and how well or poorly your organs and other systems are reacting to that damage. Such a measurement of age is known as a biomarker of aging, and while there are all sorts of measures that correlate fairly well with biological age - good enough for large statistical studies to use in order to mine data for meaning - there is not yet a good, accurate, standardized way to run some numbers and use them as a measure of how aged you are.

Why is this important? Principally because it costs an enormous amount of money to assess the ability of any treatment to slow or reverse aspects of aging and thereby extend healthy life. The only way to know at present is to wait and see, and even in mice that means years and millions of dollars. But what if we could be fairly sure that by taking some measurements after a single treatment, researchers could predict with a high degree of accuracy whether or not aging is reversed or slowed and future life span thus extended? If achieved, that would mean ten times as much work on assessment of possible therapies in mice could take place for a given amount of funding. That's a big deal, even without considering that the only practical way to determine whether a putative life-extending treatment actually works or not in humans is to establish an accurate biomarker of aging based on short term, immediate measures. It simply isn't practical to take the wait and see approach for decades.

Personally I rather hope that the arrival of an accepted biomarker of aging will do much to damp down the level of fraud and misinformation that spills forth from the "anti-aging" marketplace. There's always someone trying to sell a lie to the masses, and it is unfortunate that their voices are so very much louder than those of the scientific community. Given that pretty much nothing sold on the market today will move the needle at all on human life span, and nothing is yet shown to even match the benefits of calorie restriction or exercise, I look forward to a way to demonstrate this unequivocally.

In any case, in recent years the measurement of patterns of DNA methylation has shown promise as a potential biomarker of aging. DNA methylation is a part of the process of epigenetic changes that take place in response to circumstances, altering levels of proteins produced by cells. Our biology is essentially an assembly of fluid machines in which the controlling switches and levers are the levels of various proteins in circulation. Everything reacts to everything else, in a complex never resting dance of overlapping feedback loops at every level. From this, however, patterns emerge. Aging takes a broadly similar path for all of us, and thus there are some broadly similar reactions to its damage in our cells. The trick is having enough computational power and the right tools of biotechnology to be able to pull out those patterns from the thousands of unrelated variations in DNA methylation that exist in all our tissues.

This is a popular science piece, but still has some interesting information on how things are going with the DNA methylation approach to generating a biomarker of aging that might prove useful as a measure of the effectiveness of future treatments for aging:

Biomarkers and ageing: The clock-watcher

Horvath's clock emerges from epigenetics, the study of chemical and structural modifications made to the genome that do not alter the DNA sequence but that are passed along as cells divide and can influence how genes are expressed. As cells age, the pattern of epigenetic alterations shifts, and some of the changes seem to mark time. To determine a person's age, Horvath explores data for hundreds of far-flung positions on DNA from a sample of cells and notes how often those positions are methylated - that is, have a methyl group attached.

He has discovered an algorithm, based on the methylation status of a set of these genomic positions, that provides a remarkably accurate age estimate - not of the cells, but of the person the cells inhabit. White blood cells, for example, which may be just a few days or weeks old, will carry the signature of the 50-year-old donor they came from, plus or minus a few years. The same is true for DNA extracted from a cheek swab, the brain, the colon and numerous other organs. This sets the method apart from tests that rely on biomarkers of age that work in only one or two tissues, including the gold-standard dating procedure, aspartic acid racemization, which analyses proteins that are locked away for a lifetime in tooth or bone.

Others began downloading the epigenetic-clock program from Horvath's website to test it on their own data. Marco Boks at the University Medical Centre Utrecht in the Netherlands applied it to blood samples collected from 96 Dutch veterans of the war in Afghanistan aged between 18 and 53. The correlation between predicted and actual ages was 99.7%, with a median error measured in months. At Zymo Research, a biotechnology company in Irvine, California, Wei Guo and Kevin Bryant wondered whether the program would work on a set of urine samples Zymo had collected from 11 men and women aged between 28 and 72. The correlation was 98%, with a standard error of just 2.7 years.

[Researchers] expect that the most interesting use of the clock will be to detect 'age acceleration': discrepancies between a person's epigenetic and chronological ages, either overall or in one particular part of their body. Horvath says that recent work has found that people with HIV who have detectable viral loads appear older, epigenetically, than healthy people or those with HIV who have suppressed the virus. Another study, not yet published, observes that some tissues show significant age acceleration in morbidly obese people.


In these years we stand at the crossroads for human longevity. A long, slow, and largely unintentional upward trend in health and life expectancy has been running for near two hundred years now, caused by increases in wealth and technological progress, each driving the other. Increased longevity in turn helps to increase wealth and speed progress: all of these benefits are individually but facets of the whole gem.

The medical science of the past has blossomed into full-bored biotechnology, and change and growth in this field has become exceptionally rapid over the past twenty years, mirroring progress in computing hardware and software development. Scientists can now individually carry out tasks in a few months that would have required an entire laboratory staff and years of labor in the early 1990s, if it even possible at all back then. Many researchers advocate that now is the time to approach aging as the medical condition it is, to stop treating it with religious awe, as though it were some mystical thing that stands outside of the rest of medicine, and use the tools we have to make it go away.

Some of these researchers are engaged in a form of networked disruptive innovation within aging research that they hope will eventually displace the present mainstream. This is how progress happens in human organizations: the heretics agitate and prove themselves correct via research and development until such time as the old mainstream gives in and agrees that they were right all along.

That is the high road ahead from the crossroads. Upon this road the research community abandons its reluctance to treat aging, the public comes to think of aging in the same way as they presently think of cancer, research funding flows, and great progress is made towards means of halting and reversing the underlying causes of aging. Age-related diseases start to become things of the past, like widespread cholera and tuberculosis, just a few decades past this turning point.

But there are other roads ahead. Disruptive movements don't always win in their first spin around the block. The old guard can last for decades past their time, poisoning the well and ensuring that progress remains slow. Regulation can also suppress new paradigms, and indeed entire fields of human endeavor, for decades at a time - and medical development certain does not lack for obstructive bureaucracy. The treatment of aging is actually forbidden in the US by regulatory fiat, and there is no effective path towards gaining approval for the commercial application of potential therapy to intervene in the causes of aging. This is well known and the chilling effect percolates all the way back up the chain of research and development to create difficulties in fundraising for such goals.

So there are low roads to either side away from the crossroads. These are largely the ruts of status quo and slow progress in which billions of dollars continue to go towards research that increases our knowledge of the details of the molecular dance that is aging, but which can offer no plausible hope or promise of significantly extending life soon enough to matter to us. Life spans continue to edge upward, but we all die just a little older than our parents, and suffer all of the same age-related conditions, just a little less painfully. It is the road on which the study of aging for the sake of knowledge rather than action continues to dominate, and in which the public continues to be largely disinterested in extended healthy life or avoidance of the diseases of aging: marching towards death in their tens of millions, but never raising a hand to do anything about it.

This possibility is why advocacy for the better options in longevity science and human rejuvenation must exist. Without disruptive change in the public perception of aging and medicine for aging, without disruptive change in the attitudes of the scientific community, then the status quo is what we will get - and it will let us die by failing to take full advantage of all that can be done in this age of biotechnology.

The paper quoted below is a joint effort by Jan Vijg and Aubrey de Grey, both scientists who see the potential for big changes to the field in the years ahead and would like to see those changes come about. It isn't open access, unfortunately, but the abstract is a good encapsulation of the crossroads we presently find ourselves at.

Innovating Aging: Promises and Pitfalls on the Road to Life Extension

One of the main benefits of the dramatic technological progress over the last two centuries is the enormous increase in human life expectancy, which has now reached record highs. After conquering most childhood diseases and a fair fraction of the diseases that plague adulthood, medical technology is now mainly preoccupied by age-related disorders. Further progress is dependent on circumventing the traditional medical focus on individual diseases and instead targeting aging as a whole as the ultimate cause of the health problems that affect humankind at old age.

In principle, a major effort to control the gradual accumulation of molecular and cellular damage - considered by many as the ultimate cause of intrinsic aging - may rapidly lead to interventions for regenerating aged and worn-out tissues and organs. While considered impossible by many, there really is no reason to reject this as scientifically implausible. However, as we posit, it is not only scientific progress that is currently a limiting factor, but societal factors that hinder and may ultimately prevent further progress in testing and adopting the many possible interventions to cure aging.


The future of cell therapies includes regenerative treatments and tissue engineering, as well as many other possibilities, but it all depends on the development of highly efficient, low-cost ways to generate a ready supply of cells of any given type from a patient's own cells, such as a skin sample. The lower the cost the faster that research progresses today, and the establishment of low-cost methods of generating patient-specific cells is very much required to enable widespread use of affordable therapies tomorrow.

A little more than a decade ago it looked like the best way to create these cell supplies was to work on a technique called somatic cell nuclear transfer (SCNT), in which the nucleus from a patient's cell is introduced into an egg cell that has had its nucleus removed. The result recapitulates some of the early development of a blastocyst from which pluripotent cells can be harvested and developed into any type of human cell. Unfortunately this turned out to be more challenging than expected from a technical point of view, and as you may recall there was in addition a great deal of foolish political intervention that made it even harder to move forward. Then not so long afterwards the techniques for generating induced pluripotent stem (IPs) cells by direct reprogramming were discovered and the majority of the research community jumped ship for that much easier methodology.

Some researchers kept working on the roadblocks preventing implementation of SCNT in human cells, however, and have now finally achieved an initial success with adult human cells. This is the sort of result that can lead to the infrastructure necessary to generate patient-specific cells, but in this case it has more of the feel of the closing of a chapter. The leading edge of the research community now works with induced pluripotency and related forms of direct cell reprogramming, and is making rapid progress with those techniques. Success with SCNT is to be praised, but I think unlikely that it will gather much support in the present environment.

First Embryonic Stem Cells Cloned From A Man's Skin

Last year, scientists in Oregon said they'd finally done it, using DNA taken from infants. Robert Lanza, chief scientific officer at Advanced Cell Technology, says that was an important step, but not ideal for medical purposes. "There are many diseases, whether it's diabetes, Alzheimer's or Parkinson's disease, that usually increase with age," Lanza says. So ideally scientists would like to be able to extract DNA from the cells of older people - not just cells from infants - to create therapies for adult diseases.

"What we show for the first time is that you can actually take skin cells, from a middle-aged 35-year-old male, but also from an elderly, 75-year-old male" and use the DNA from those cells in this cloning process, Lanza says. They injected it into 77 human egg cells, and from all those attempts, managed to create two viable cells that contained DNA from one or the other man. Each of those two cells is able to divide indefinitely, "so from a small vial of those cells we could grow up as many cells as we would ever want."

Scientists use cloning to make stem cells matched to two adults

Lanza and his colleagues said their experiments revealed that some eggs were better at it than others. Researchers used 49 eggs from three women, though eggs from only two of them produced results. "The magic is in the egg," Lanza said.

Lanza said that most stem cell scientists have "jumped on the iPS bandwagon," but he argued that stem cells created by SCNT could still play a vital role in regenerative medicine. He envisions a day when multiple lines of stem cells are kept in banks and made available to patients based on their biological similarity, much the way blood and donor organs are now handled. "If we had these banks, we would have the raw material to do tissue engineering and grow up organs, or to grow up vessels, tendons or whatever you want."

Human Somatic Cell Nuclear Transfer Using Adult Cells

Derivation of patient-specific human pluripotent stem cells via somatic cell nuclear transfer (SCNT) has the potential for applications in a range of therapeutic contexts. However, successful SCNT with human cells has proved challenging to achieve, and thus far has only been reported with fetal or infant somatic cells. In this study, we describe the application of a recently developed methodology for the generation of human embryonic stem cells via SCNT using dermal fibroblasts from 35- and 75-year-old males. Our study therefore demonstrates the applicability of SCNT for adult human cells and supports further investigation of SCNT as a strategy for regenerative medicine.


Monday, April 14, 2014

The accumulation of senescent cells with age is one of the causes of degenerative aging, as senescent cells behave badly, emitting proteins that harm surrounding tissues. Finding a way to clearly identify senescent cells is a necessary step on the path to a targeted treatment that can destroy them, using engineered immune cells, nanoparticles, viruses, or any of the other approaches to selective cell destruction that are presently under development. Much of the work towards this end is focused on p16, which seems promising but may or may not in the end prove to be discriminating enough. Here researchers are exploring a different marker of senescence:

While TRF2 is found at telomeres, where it plays an essential role in maintaining telomere integrity, little is known about the cellular localization of methylated TRF2. In this report, we have shown that methylated TRF2 is associated with the nuclear matrix and that this localization is largely free of human telomeres. We show that methylated TRF2 drastically alters its nuclear staining as normal human primary fibroblast cells approach and enter replicative senescence. This altered nuclear staining, which is found to be overwhelmingly associated with misshapen nuclei and abnormal nuclear matrix folds, can be suppressed by hTERT and it is barely detectable in transformed and cancer cell lines.

We find that dysfunctional telomeres and DNA damage, both of which are potent inducers of cellular senescence, promote the altered nuclear staining of methylated TRF2, which is dependent upon the ATM-mediated DNA damage response. Collectively, these results suggest that the altered nuclear staining of methylated TRF2 may represent ATM-mediated nuclear structural alteration associated with cellular senescence. Our data further imply that methylated TRF2 can serve as a potential biomarker for cellular senescence.

Monday, April 14, 2014

Adults are old, but children are young: at some point in the early development of an embryo, a collection of presently poorly cataloged processes erase the changes of aging present in the adult cells that created it. It is probably the case that there is little in this that can be applied directly to making us live longer, as the sort of radical restructuring of cells that takes place in the developing embryo would be fatal to the much more complex adult organism. We couldn't apply this to ourselves for all the same reasons that we can't constantly renew ourselves like the tiny creatures called hydra. Our nervous system, mind, and other complex and finely balanced processes depend on the present detailed structure of our long-lived cells, and that structure would be erased.

However, as the authors of this paper point out, there is potentially much to be learned from the embryo that could be of benefit for stem cell treatments. In this case the research community absolutely wants to be able to reverse the damage of aging in induced pluripotent stem cells (IPSCs) generated from an old patient. To a certain extent this already happens, but greater control and effectiveness is desired:

Stem cells are defined not only by their differentiation potential but also by their capacity for unlimited self-replication. The need for prolonged self-replication requires adequate telomere length and telomere maintenance, which can limit the powerful new methods available for generating induced pluripotent cells. IPSCs lacking sufficient telomere length fail to [pass] the most stringent tests of pluripotency, and cannot be maintained in culture over long periods. This might have contributed, in part, to the variable quality of iPSCs during early efforts [and] may ultimately limit the future application of iPSCs in regenerative medicine. To correct this, present efforts in the field of iPSCs have strived to improve the quality of iPSC generated by focusing on telomere dynamics during the process of reprogramming.

Telomeres protect and cap linear chromosome ends, yet these genomic buffers erode over an organism's lifespan. Short telomeres have been associated with many age-related conditions in humans, and genetic mutations resulting in short telomeres in humans manifest as syndromes of precocious aging. In women, telomere length limits a fertilized egg's capacity to develop into a healthy embryo. Thus, telomere length must be reset with each subsequent generation. Although telomerase is purportedly responsible for restoring telomere DNA, recent studies have elucidated the role of alternative telomeres lengthening (ALT) mechanisms in the reprogramming of early embryos and stem cells.

Telomere length in the oocyte is markedly shorter than somatic cells. In contrast, sperm are of the few cell types documented to elongate telomeres over the human lifespan, presumably due to the effects of telomerase activity in spermatogonia throughout the life of the male. Following fertilization and activation of the egg, embryonic cells undergo dramatic telomere lengthening. Notably, telomerase activity remains undetectable in these cells. This effect remains robust in telomerase knock-out mice, suggesting an ALT-dependent mechanism at play in preimplantation mammalian development. Moreover, the lengthening takes place in parthenogenetically activated eggs, which lack sperm input during activation, suggesting that the capacity for telomere length reprogramming resides in the oocyte.

Tuesday, April 15, 2014

Here is an open access review that looks at what is known of the proximate mechanisms that cause increasing fragility of bone with advancing age. These are not the root causes, but it remains to be determined how exactly the laundry list of primary differences between old tissues and young tissues produces the results discussed below. Arguably it is faster and more efficient to investigate by doing; work to reverse these primary changes in tissue samples and animals and see what happens. That is a lot easier than trying to understand the full scope of the complexity of aging, and has a much greater chance of producing meaningful therapies to halt the advance of aging in the near term:

Every hip fracture begins with a microscopic crack, which enlarges explosively over microseconds. Most hip fractures in the elderly occur on falling from standing height, usually sideways or backwards. The typically moderate level of trauma very rarely causes fracture in younger people. Here, this paradox is traced to the decline of multiple protective mechanisms at many length scales from nanometres to that of the whole femur.

With normal ageing, the femoral neck asymmetrically and progressively loses bone tissue precisely where the cortex is already thinnest and is also compressed in a sideways fall. At the microscopic scale of the basic remodelling unit (BMU) that renews bone tissue, increased numbers of actively remodelling BMUs associated with the reduced mechanical loading in a typically inactive old age augments the numbers of mechanical flaws in the structure potentially capable of initiating cracking.

Menopause and over-deep osteoclastic resorption are associated with incomplete BMU refilling leading to excessive porosity, cortical thinning and disconnection of trabeculae. In the femoral cortex, replacement of damaged bone or bone containing dead osteocytes is inefficient, impeding the homeostatic mechanisms that match strength to habitual mechanical usage. In consequence the participation of healthy osteocytes in crack-impeding mechanisms is impaired.

Observational studies demonstrate that protective crack deflection in the elderly is reduced. At the most microscopic levels attention now centres on the role of tissue ageing, which may alter the relationship between mineral and matrix that optimises the inhibition of crack progression and on the role of osteocyte ageing and death that impedes tissue maintenance and repair.

Tuesday, April 15, 2014

It is perhaps unexpected that incidence of dementia and incidence of cancer seem to have a robust inverse relationship, one that has shown up in multiple different study populations. In general we think of aging as a global phenomenon in the body keyed to rising levels of damage in all tissues: if you are farther down the road than your peers for whatever reason then you would expect a higher risk of all of the potential failure modes in the complex systems of your body.

In one sense, yes, this is true. But in some people risk of cancer rises significantly more rapidly than risk of dementia, and in others vice versa. As this study shows the differentiation in risk starts early in the progression of age-related cognitive decline:

Older people who are starting to have memory and thinking problems, but do not yet have dementia may have a lower risk of dying from cancer than people who have no memory and thinking problems. "Studies have shown that people with Alzheimer's disease are less likely to develop cancer, but we don't know the reason for that link. One possibility is that cancer is underdiagnosed in people with dementia, possibly because they are less likely to mention their symptoms or caregivers and doctors are focused on the problems caused by dementia. The current study helps us discount that theory."

The study involved 2,627 people age 65 and older in Spain who did not have dementia at the start of the study. They took tests of memory and thinking skills at the start of the study and again three years later, and were followed for an average of almost 13 years. The participants were divided into three groups: those whose scores on the thinking tests were declining the fastest, those whose scores improved on the tests, and those in the middle.

During the study, 1,003 of the participants died, including 339 deaths, or 34 percent, among those with the fastest decline in thinking skills and 664 deaths, or 66 percent, among those in the other two groups. A total of 21 percent of those in the group with the fastest decline died of cancer, according to their death certificates, compared to 29 percent of those in the other two groups. People in the fastest declining group were still 30 percent less likely to die of cancer when the results were adjusted to control for factors such as smoking, diabetes and heart disease, among others.

Wednesday, April 16, 2014

Researchers here make use of the process of decellularization to match a donor organ to the recipient. In the ideal procedure, donor cells are removed and the remaining extracellular matrix of the organ is repopulated with the recipient's cells, thereby eliminating most issues of transplant rejection. The use of a donor matrix bypasses the present inability to construct a sufficiently complex scaffold for most tissues, complete with cues and guides for blood vessel formation and other structures within tissue:

A tissue-engineered oesophageal scaffold could be very useful for the treatment of pediatric and adult patients with benign or malignant diseases such as carcinomas, trauma or congenital malformations. Here we decellularize rat oesophagi inside a perfusion bioreactor to create biocompatible biological rat scaffolds that mimic native architecture, resist mechanical stress and induce angiogenesis.

Seeded allogeneic mesenchymal stromal cells spontaneously differentiate (proven by gene-, protein and functional evaluations) into epithelial- and muscle-like cells. The reseeded scaffolds are used to orthotopically replace the entire cervical oesophagus in immunocompetent rats.

All animals survive the 14-day study period, with patent and functional grafts, and gain significantly more weight than sham-operated animals. Explanted grafts show regeneration of all the major cell and tissue components of the oesophagus including functional epithelium, muscle fibres, nerves and vasculature. We consider the presented tissue-engineered oesophageal scaffolds a significant step towards the clinical application of bioengineered oesophagi.

Wednesday, April 16, 2014

As noted below researchers are making an effort to establish the basis for a comprehensive study of aging in longer-lived species. Most present work on aging in mammals takes place in mice and rats, and while there are many similarities between mice and humans there are also sometimes unexpected differences in the biochemistry of aging between short-lived and long-lived species. For example that the important types of advanced glycation end-product (AGE), which produce cross-links that accumulate in tissues over a life span to cause damage and dysfunction, turned out to be very different in rodents and humans sabotaged some of the first serious efforts to produce AGE-breaker drugs to slow or reverse this contribution to the aging process.

Scientists aim to bridge the gap between lab research and aging's complexities in real life using the power of dogs. [They] are joining interdisciplinary collaborators from across the country to form the Canine Longevity Consortium - the first research network to study canine aging. It will lay the groundwork for a nationwide Canine Longitudinal Aging Study (CLAS), using dogs as a powerful new model system that researchers can study to find how genetic and environmental factors influence aging and what interventions might mitigate age-related diseases.

"Dogs offer tremendous potential as a model system for human aging. They share many genetic characteristics with humans that let us combine traditional demographic and epidemiological approaches with new techniques like comparative genomics. Unlike any other model system for aging, dogs share our environment and, increasingly, our health care options. Once developed, a canine model holds enormous promise, and we expect it to have a significant impact on aging research."

[Researchers] aim to craft the CLAS to see how an individual dog's aging trajectory is shaped by genes and the environment, gain detailed understanding of when and why dogs die, and find treatments to combat age-related illness. The researchers will start with pilot projects to choose the best breeds for the study and to determine how best to collect, analyze and share the large-scale data it will produce. The team will conduct an epidemiological analysis of genetic and environmental factors influencing canine lifespan, high-resolution mapping of canine longevity, and a yearlong epidemiological analysis of age and cause of death in all dogs seen within a select group of three private veterinary clinics.

Thursday, April 17, 2014

A few things are of interest in this survey, with one being that a majority of people don't like specific instances of societal change resulting from technological advances if asked about them, which isn't much of a surprise given human nature. Another is that extended human longevity shows up as a desired goal for a larger minority than has been the case in the past - I would expect to see growth in this number when measured, given the events of the past few years. This being a survey there is little distinction made between the fantastical drawn from science fiction and the plausible drawn from science, which is unfortunate, but it is still worth a look.

The American public anticipates that the coming half-century will be a period of profound scientific change, as inventions that were once confined to the realm of science fiction come into common usage. This is among the main findings of a new national survey by The Pew Research Center, which asked Americans about a wide range of potential scientific developments - from near-term advances like robotics and bioengineering, to more "futuristic" possibilities like teleportation or space colonization.

Asked to describe in their own words the futuristic inventions they themselves would like to own, the public offered three common themes: 1) travel improvements like flying cars and bikes, or even personal space crafts; 2) time travel; and 3) health improvements that extend human longevity or cure major diseases. One in ten Americans (9%) list the ability to travel through time as the futuristic invention they would like to have, and an identical 9% would want something that improved their health, increased their lifespan, or cured major diseases.

At the same time, many Americans seem to feel happy with the technological inventions available to them in the here and now - 11% answered this question by saying that there are no futuristic inventions that they would like to own, or that they are "not interested in futuristic inventions." And 28% weren't sure what sort of futuristic invention they might like to own.

A substantial majority of Americans (81%) believe that within the next 50 years people needing an organ transplant will have new organs custom made for them in a lab. Belief that this development will occur is especially high among men, those under age 50, those who have attended college, and those with relatively high household incomes. But although expectations for this development are especially high within these groups, three-quarters or more of every major demographic group feels that custom organs are likely to become a reality in the next half-century.

Thursday, April 17, 2014

Here is an open access paper that covers some of the challenges that have faced the interpretation of just how and why it is that mitochondria have an important role in the aging process. The mitochondrial free radical theory of aging has been broadly considered, in several forms, but as for just about every theory of aging early models turned out to be too simple and straightforward. The reality on the ground is more complex, which is why you'll find a mass of data that supports this theory and another mass of data that contradicts it:

Since its inception more than four decades ago, the Mitochondrial Free Radical Theory of Aging (MFRTA) has served as a touchstone for research into the biology of aging. The MFRTA suggests that oxidative damage to cellular macromolecules caused by reactive oxygen species (ROS) originating from mitochondria accumulates in cells over an animal's lifespan and eventually leads to the dysfunction and failure that characterizes aging.

A central prediction of the theory is that the ability to ameliorate or slow this process should be associated with a slowed rate of aging and thus increased lifespan. A vast pool of data bearing on this idea has now been published. ROS production, ROS neutralization and macromolecule repair have all been extensively studied in the context of longevity. We review experimental evidence from comparisons between naturally long- or short-lived animal species, from calorie restricted animals, and from genetically modified animals and weigh the strength of results supporting the MFRTA.

Viewed as a whole, the data accumulated from these studies have too often failed to support the theory. Excellent, well controlled studies from the past decade in particular have isolated ROS as an experimental variable and have shown no relationship between its production or neutralization and aging or longevity. Instead, a role for mitochondrial ROS as intracellular messengers involved in the regulation of some basic cellular processes, such as proliferation, differentiation and death, has emerged. If mitochondrial ROS are involved in the aging process, it seems very likely it will be via highly specific and regulated cellular processes and not through indiscriminate oxidative damage to macromolecules.

Friday, April 18, 2014

Targeted delivery of drugs and proteins to modify metabolism and cell behavior may in the future be accomplished by engineered cells. Cells already do a great many useful things, so why reinvent the wheel when there is existing machinery that can be adapted to new purposes? This is a line of research with the potential to radically change the face of medicine and our own biology, leading to a future in which most of us have large numbers of enhanced and altered cells in every organ, monitoring and reacting to local conditions in order to help maintain the body against the processes of aging and disease far more effectively than our present evolved mechanisms can manage.

A synthetic biology team has created a new technology for modifying human cells to create programmable therapeutics that could travel the body and selectively target cancer and other sites of disease. "The project addressed a key gap in the synthetic biology toolbox. There was no way to engineer cells in a manner that allowed them to sense key pieces of information about their environment, which could indicate whether the engineered cell is in healthy tissue or sitting next to a tumor."

The end result is a protein biosensor that sits on the surface of a cell and can be programmed to sense specific external factors. For example, the engineered cell could detect big, soluble protein molecules that indicate that it's next to a tumor. When the biosensor detects such a factor, it sends a signal into the engineered cell's nucleus to activate a gene expression program, such as the production of tumor-killing proteins or chemicals. Since this toxic program would be activated only near tumor cells, such an approach could minimize side effects as well as improve therapeutic benefits.

Called a Modular Extracellular Sensor Architecture (MESA), the biosensor platform is completely self-contained so that several different biosensors can be present in a single cell without interfering with one another, allowing bioengineers to build increasingly sophisticated functional programs. The platform is also highly modular, enabling the biosensors to be customized to recognize factors of relevance to various patients' needs. "By linking the output of these biosensors to genetic programs, one can build in a certain logical command, such as 'turn the output gene on when you sense this factor but not that factor.' In that way, you could program a cell-based therapy to specify which cells it should kill."

Friday, April 18, 2014

This is an interesting view on the later stages Parkinson's disease that seems fairly orthogonal to the present mainstream focus on α-synuclein and its removal:

The cause of neuronal death in Parkinson's disease is still unknown, but a new study proposes that neurons may be mistaken for foreign invaders and killed by the person's own immune system. "This is a new, and likely controversial, idea in Parkinson's disease; but if true, it could lead to new ways to prevent neuronal death in Parkinson's that resemble treatments for autoimmune diseases."

For decades, neurobiologists have thought that neurons are protected from attacks from the immune system, in part, because they do not display antigens on their cell surfaces. "That idea made sense because, except in rare circumstances, our brains cannot make new neurons to replenish ones killed by the immune system. But, unexpectedly, we found that some types of neurons can display antigens."

Cells display antigens with special proteins called MHCs. Using postmortem brain tissue donated to the Columbia Brain Bank by healthy donors [researchers] first noticed - to their surprise - that MHC-1 proteins were present in two types of neurons. These two types of neurons - one of which is dopamine neurons in a brain region called the substantia nigra - degenerate during Parkinson's disease.

[The researchers] conducted in vitro experiments with mouse neurons and human neurons created from embryonic stem cells. The studies showed that under certain circumstances - including conditions known to occur in Parkinson's - the neurons use MHC-1 to display antigens. Among the different types of neurons tested, the two types affected in Parkinson's were far more responsive than other neurons to signals that triggered antigen display. The researchers then confirmed that T cells recognized and attacked neurons displaying specific antigens.

"Right now, we've showed that certain neurons display antigens and that T cells can recognize these antigens and kill neurons, but we still need to determine whether this is actually happening in people. We need to show that there are certain T cells in Parkinson's patients that can attack their neurons. This idea may explain the final step. We don't know if preventing the death of neurons at this point will leave people with sick cells and no change in their symptoms, or not."


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