An Update on DNA Methylation Patterns as a Biomarker of Aging
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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.

A Canine Longitudinal Aging Study Proposed
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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.


A Decellularized Oesophagus Demonstrated in Rats
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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.


What is Robust Mouse Rejuvenation, and Why Should We Care?
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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.

More Evidence of the Inverse Relationship Between Dementia and Cancer Mortality
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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.


The Fragile Elderly Hip
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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.


Commercial Blood Factories Lie Ahead
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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.

Learning to Reverse Aspects of Cell Aging By Observing the Embryo
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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.


TRF2 as a Potential Biomarker of Cellular Senescence
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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.


SENS Research Foundation Newsletter, April 2014
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The SENS Research Foundation is one of the few scientific organizations energetically working on realistic approaches to human rejuvenation treatments, based on repair of the known cellular and molecular damage that causes aging. This is very much a departure from the current mainstream of medicine where researchers largely ignore aging as a cause of disease in favor of trying to patch over age-related conditions in their late stages. As a strategy this is doomed to be an expensive and poor path forward, which is precisely why we need disruptive initiatives like the SENS Research Foundation to shake things up and illustrate the better path ahead. The Foundation funds research where there are roadblocks or a lack of progress, but is as much involved in advocacy, both within the scientific community to convince more researchers to work in this important field, and outside the community in order to sway funding sources and the public at large.

The latest SENS Research Foundation newsletter arrived in my in-box today, along with an announcement that registration is open for a new rejuvenation biotechnology conference that will be held in California later this year.

Registration Now Open For Rejuvenation Biotechnology 2014

Where: Hyatt Regency Santa Clara, Santa Clara, CA
When: August 21 - 23, 2014
To Register:

SENS Research Foundation is pleased to announce that registration is now open for the Rejuvenation Biotechnology 2014 Conference. The conference theme is Emerging Regenerative Medicine Solutions for the Diseases of Aging. The Rejuvenation Biotechnology Conference builds upon novel strategies being pioneered by the Alzheimer's and cancer communities. By convening the foremost leaders from academia, industry, investment, policy, and disease advocacy, SRF seeks to inspire consideration of the wider potential of these strategies and evaluate the feasibility of preventative and combinatorial medicine applications to treat all aging-related diseases.

Confirmed speakers include:

* Richard Barker, CASMI
* Maria Blasco, Spanish National Cancer Research Centre
* George Church, Harvard Medical School
* Aubrey de Grey, SENS Research Foundation
* Caleb Finch, USC Davis School of Gerontology
* Jeanne Loring, Scripps Research Institute
* Stephen Minger, GE Healthcare Life Sciences, UK
* Brock Reeve, Harvard Stem Cell Institute
* Matthias Steger, Hoffmann-La Roche
* Michael West, Biotime, Inc.

Students and researchers are invited to submit poster abstracts for the Rejuvenation Biotechnology Conference Poster Session. Poster submissions will be evaluated by members of the SENS Research Foundation Team. The deadline for poster submissions is July 15, 2014.

We invite everyone in our community to register and participate in this new conference, our first in the US in over 6 years.

As is usually the case, the scientific section of the newsletter is also well worth reading. This time it is an examination of mitochondria and their role in aging:

Question Of The Month #2: Aging and the Limits of Mitochondrial Restoration

Q: Why can't fixing mitochondrial mutations and restoring peak ATP levels in the majority of cells in older people fix everything? I understand there are several classes of accumulated age-related damage like plaque build-up and glycation, which is why it seems like we'd need more than one approach to reverse aging, but if we give cells enough energy, could it be possible that all of it will just take care of itself? In other words, if cells once again have enough energy to perform their jobs to full capacity, couldn't they then carry out functions/mechanisms crucial to getting rid of all the age-related damage? I mean it sounds odd if you think of it using the car analogy: if you give an old car a new battery it's not going to fix other things like rust accumulation or leaky pipes... but because cells all work as a system, I think it's more likely that they'd be able to help control age-related accumulations.

A: While mitochondrial DNA mutations are indeed important to address in the context of a comprehensive rejuvenation strategy like SENS, there are several reasons to think this alone would not be enough to deal with most other forms of aging damage.

First, it's actually not all that clear that the mitochondria in the great majority of an aging person's cells actually suffer much decline in capacity to produce ATP. Certainly many older cells do suffer energy deficits, related to insulin resistance and/or secondary to other age-related metabolic (mal)adaptations - but those are causes unrelated to mitochondrial mutations.

True, the cells whose mitochondria we're most concerned about suffer a pretty drastic reduction in energy production: those are cells that have been taken over by mitochondria harboring large deletions. But remember that such cells constitute a tiny percentage of the cells in the body. If the goal is simply to restore the capacity of the mitochondria in the majority of aging people's cells to produce ATP to levels similar to young people, we're already there.

Also, while individual cells overtaken by mutant mitochondria certainly lack energy, such energy deficits don't do anything to hold back the great majority of the body's cells (since individual cells have their own mitochondrial power supply). Yet they still suffer aging damage. Furthermore, much aging damage accumulates because we lack the means to deal with it, meaning no amount of energy alone can prevent its accumulation.

Third, a lot of aging damage is extracellular, and such damage can't really be addressed in most cases by cells. This is especially true in the case of damage to extracellular matrix (glycation crosslinks and mechanical fatigue of arterial and other elastin lamellae, for instance), where typically there isn't even any ATP available, irrespective of a person's age.

Fourth: remember, we were all young once. At that point, few or none of our cells had been taken over by mutant mitochondrial DNA, and yet even at that point in our lives we were aging. Indeed, this is true of the two examples you cite in your question: we are all born with at least some aging damage, such as fraying of arterial elastin and early atherosclerotic lesions. If youthful mitochondrial energetics were enough to abrogate the accumulation of aging damage, the degenerative process wouldn't get going until a substantial number of our cells were occupied by mutant mitochondria (which, again, arguably doesn't even happen when people reach what are today rather advanced ages).

Most importantly: while it may one day be possible to begin administering rejuvenation therapies to people who are still in their youthful prime, at present we do not have the luxury to do this. Early recipients of rejuvenation biotechnologies will, by and large, be people whose bodies are already riddled with multiple kinds of cellular and molecular aging damage. Even if mitochondria capable of churning out ATP with the alacrity of Usain Bolt in his prime were enough to prevent other forms of aging damage from getting started (and again, the normal course of aging argues strongly otherwise), it seems far less plausible that it would be able to reverse the accumulation of aging lesions in people who have already been suffering such damage for six decades or more of life.

In short: if we are to save the greatest possible number of people from the age-related slide into disease, disability, dependence, dementia, and eventual death, we are going to have to tackle the full spectrum of aging damage that has already riddled their bodies, and obviating mitochondrial mutations seems highly unlikely to achieve this key goal on its own.

Nose Reconstruction With Tissue Engineered Cartilage
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Cartilage is a surprisingly complex tissue. While researchers are making progress in growing cartilage from a patient's own cells, they have yet to reliably and fully reproduce all of the mechanical properties of the real thing. Fortunately this is less of an issue in the nose than, say, in the knee, as you aren't resting the weight of your body on your nose:

A research team [has] reported that nasal reconstruction using engineered cartilage is possible. They used a method called tissue engineering where cartilage is grown from patients' own cells. This new technique was applied on five patients, aged 76 to 88 years, with severe defects on their nose after skin cancer surgery. One year after the reconstruction, all five patients were satisfied with their ability to breathe as well as with the cosmetic appearance of their nose. None of them reported any side effects.

The type of non-melanoma skin cancer investigated in this study is most common on the nose [because] of its cumulative exposure to sunlight. To remove the tumor completely, surgeons often have to cut away parts of cartilage as well. Usually, grafts for reconstruction are taken from the nasal septum, the ear or the ribs and used to functionally reconstruct the nose. However, this procedure is very invasive, painful and can, due to the additional surgery, lead to complications at the site of the excision.

[Researchers have] now developed an alternative approach using engineered cartilage tissue grown from cells of the patients' nasal septum. They extracted a small biopsy, isolated the cartilage cells (chondrocytes) and multiplied them. The expanded cells were seeded onto a collagen membrane and cultured for two additional weeks, generating cartilage 40 times the size of the original biopsy. The engineered grafts were then shaped according to the defect on the nostril and implanted.


Creation of Functional Tissue Engineered Vaginas
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In terms of complexity, this seems on a par with generating a new trachea or esophagus, both goals that were achieved in recent years:

Four young women born with abnormal or missing vaginas were implanted with lab-grown versions made from their own cells, the latest success in creating replacement organs that have so far included tracheas, bladders and urethras. Follow-up tests show the new vaginas are indistinguishable from the women's own tissue and have grown in size as the young women, who got the implants as teens, matured. All four of the women are now sexually active and report normal vaginal function. Two of the four, who were born with a working uterus but no vagina, now menstruate normally.

The pilot study is the first to show that vaginal organs custom-built in the lab using patients' own cells can be successfully used in humans, offering a new option for women who need reconstructive surgeries. All four of the women in the study were born with Mayer-Rokitansky-K├╝ster-Hauser (MRKH) syndrome, a rare genetic condition in which the vagina and uterus are underdeveloped or absent. Conventional treatment generally involves the use of grafts made from intestinal tissue or from skin, but both tissues have drawbacks.

The researchers started off by collecting a small amount of cells from genital tissue and grew two types of cells in the lab: muscle cells and epithelial cells, a type of cell that lines body cavities. About four weeks later, the team started applying layers of the cells onto a scaffold made of collagen, a material that can be absorbed by the body. They then shaped the organ to fit each patient's anatomy, and placed it in an incubator. A week later, the team created a cavity in the body and surgically attached the vaginal implants to existing reproductive organs. Once implanted, nerves and blood vessels formed to feed the new organ, and new cells eventually replaced the scaffolding as it was absorbed by the body.


No One Cares About Research Funding
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To a first approximation no-one cares about research funding. No-one cares until it is too late, until their life depends upon a cure or at least a treatment that doesn't yet exist. The vast majority of people are focused on circuses and distractions among the possibilities that presently exist, not on the creation of new possibilities. Just look at the ocean of funding for sports, politics, and war in comparison to the small drops of funding for medical research.

Among the comparatively small class of people who do care about research funding, most of these individuals care because they are in business and the existence of competitors forces them onto the rat wheel of progress. They don't care because they want to produce specific end results, they care because they have to organize research in order to keep up and defend their business. That feels like a rat wheel when you are on the inside, since all of your competitors have wheels of their own and are rarely far behind, tomorrow's board meeting will be much the same as today's regardless of how fast you run, and success on the wheel just means the chance to run again later. From the outside these are the true engines of progress, however, racing ahead to give us ever better products and services - including ever-better medicine.

But this is why we have patient advocacy, in which the small number of people with greater foresight, those who do care about medical research funding because they have looked ahead and understand enough of a field to know what is plausible, try to convince those with lesser foresight of the need for action.

At present research into aging and longevity receives a pittance in funding, private or public, in comparison to any sensible yardstick. People simply don't care to do anything about degenerative aging, and this prevalent attitude is reflected at the large scale in funding levels for various activities. Where there is a will to act and work on ways to treat aging, it is driven by iconoclasts, heretics, and visionaries: the sensible few, not the comfortably conformist many.

Yet it isn't just longevity research in which researchers can bemoan the fact that their field is unjustly the poor cousin in the broader field of medicine, receiving next to nothing in comparison to its great importance. While more than 90% of the Western world suffers and dies due to aging, only a fraction of existing medical research funding goes towards doing anything about this, and even then all existing medical research funding is but a fraction of the funds spent on either (a) idle pastimes, or (b) cleaning up after the consequences of aging. This is the common condition for anyone involved in medical research of any sort, and even the most mainstream of institutions working on diseases of aging can point out that they too are neglected in comparison to their importance:

Alzheimer's Is Expensive, Deadly and Growing. So Where's the Research Money?

"The epidemic is upon us," says Dr. John Trojanowski, co-director of the Center for Neurodegenerative Disease Research and director of the Institute on Aging, both at the University of Pennsylvania School of Medicine. "It's a very difficult thing to say to a patient that there's nothing we have for you, but that is the honest response. There are no disease-modifying therapies for Alzheimer's."

Alzheimer's is one of the costliest chronic diseases to the country. Total costs of caring for Americans with Alzheimer's and other dementias is expected to reach $214 billion this year, with Medicare and Medicaid covering $150 billion and out-of-pocket expenses reaching $36 billion.

Historically, Alzheimer's research has been grossly underfunded. The National Institutes of Health (NIH) dedicated $5.3 billion to cancer research in 2013, nearly $3 billion to HIV/AIDS, $1.2 billion to heart disease and $1 billion to diabetes. Alzheimer's research received just over $500 million.

"I believe that this disease will be the defining medical condition of our generation--hopefully not the next generation," says Dr. Ronald Petersen, director of the Mayo Clinic Alzheimer's Disease Research Center and chair of the Advisory Council for NAPA. "If we don't get on top of it, it will bankrupt the health-care system."

As is the style of the press these days the article above focuses on public funding and its grandstanding political theater rather than the larger and arguably more important body of private research funding. The public funding numbers might seem large, but they are only a fraction of the valuation of the bubblegum industry or any single large sports franchise, of which there are many. But as I said above, to a first approximation no-one cares about research funding. If they did a great many problems would perhaps already be solved.

Sensory Neuron Function and Calorie Restriction Induced Longevity Linked in Nematodes
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Researchers here theorize that alterations to neurons are an important part of the metabolic improvements and enhanced longevity produced by calorie restriction, at least in nematode worms:

Progressive neuronal deterioration accompanied by sensory functions decline is typically observed during aging. On the other hand, structural or functional alterations of specific sensory neurons extend lifespan in the nematode C. elegans. Hormesis is a phenomenon by which the body benefits from moderate stress of various kinds which at high doses are harmful. Several studies indicate that different stressors can hormetically extend lifespan in C. elegans and suggest that hormetic effects could be exploited as a strategy to slow down aging and the development of age-associated (neuronal) diseases in humans. Mitochondria play a central role in the aging process and hormetic-like bimodal dose-response effects on C. elegans lifespan have been observed following different levels of mitochondrial stress.

Here we tested the hypothesis that mitochondrial stress may hormetically extend C. elegans lifespan through subtle neuronal alterations. In support of our hypothesis we find that life-lengthening dose of mitochondrial stress reduces the functionality of a subset of ciliated sensory neurons in young animals. Notably, the same pro-longevity mitochondrial treatments rescue the sensory deficits in old animals. We also show that mitochondrial stress extends C. elegans lifespan acting in part through genes required for the functionality of those neurons. To our knowledge this is the first study describing a direct causal connection between sensory neuron dysfunction and extended longevity following mitochondrial stress. Our work supports the potential anti-aging effect of neuronal hormesis and open interesting possibility for the development of therapeutic strategy for age-associated neurodegenerative disorders.


Stem Cells Show Promise in Stroke Treatment
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The research community continues to validate the benefits resulting from comparatively simple first generation stem cell transplants, of the sort that have been available via medical tourism for a decade:

In an analysis of published research, [researchers] identified 46 studies that examined the use of mesenchymal stromal cells - a type of multipotent adult stem cells mostly processed from bone marrow - in animal models of stroke. They found MSCs to be significantly better than control therapy in 44 of the studies. Importantly, the effects of these cells on functional recovery were robust regardless of the dosage, the time the MSCs were administered relative to stroke onset or the method of administration. (The cells helped even if given a month after the event and whether introduced directly into the brain or injected via a blood vessel.)

MSCs do not differentiate into neural cells. Normally, they transform into a variety of cell types, such as bone, cartilage and fat cells. The cells are attracted to injury sites and, in response to signals released by these damaged areas, begin releasing a wide range of molecules. In this way, MSCs orchestrate numerous activities: blood vessel creation to enhance circulation, protection of cells starting to die, growth of brain cells, etc. At the same time, when MSCs are able to reach the bloodstream, they settle in parts of the body that control the immune system and foster an environment more conducive to brain repair.

"Stroke remains a major cause of disability, and we are encouraged that the preclinical evidence shows [MSCs'] efficacy with ischemic stroke. MSCs are of particular interest because they come from bone marrow, which is readily available, and are relatively easy to culture. In addition, they already have demonstrated value when used to treat other human diseases."


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