Fight Aging! Newsletter, January 4th 2016

January 4th 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Existing Longevity Therapies that are Technically Feasible, but Difficult and Expensive to Obtain
  • Deletion of IGF-1R Attenuates Cardiac Aging in Mice
  • More Details on Bcl-2 Inhibitors as Senolytic Drugs
  • A Look Back at 2015 in Longevity Science
  • There is Widespread Desire for Extended Longevity, Provided it Brings More Healthy, Youthful Years
  • Latest Headlines from Fight Aging!
    • Wrapping Stem Cells for Hair Regeneration
    • A Large Study on Sedentary Behavior and Mortality Risk
    • Results from a Myostatin Antibody Trial to Boost Muscle Mass and Strength in the Old
    • The Unknown Interactions of Drugs that Slightly Slow Aging
    • A Look at KrioRus, Alcor, and Cryonics in General
    • Progress Towards Structurally Correct Engineered Cartilage
    • Protein Carbamylation is Associated with Aging
    • A Review of the State of Bone Tissue Engineering
    • Insight into the Role of SOD1 in the Proteopathy of ALS
    • An Example of CRISPR Gene Therapy in Adult Animals with Good Tissue Coverage


At the present time it is technically possible to benefit from a small range of therapies that we can reasonably expect to at least modestly slow or reverse specific narrow aspects of aging. I'm not talking about the pills and potions of the supplement sellers here, which are worthless, nor the efforts to repackage a few existing drugs as calorie restriction mimetics, as that is little better. If you want to do something about your long-term health and life expectancy that doesn't require any more effort than a trip to the store, then focus on exercise and calorie restriction - nothing else at that same level of easy availability is anywhere near as effective or as proven. What I have in mind here is instead the first gene therapies, stem cell transplants, and glimmerings of SENS-like repair therapies capable of removing some of the metabolic wastes associated with age-related diseases.

In order to actually undergo one of these new therapies, you would have to undertake some combination of the following: (a) spend money at early adopter levels, high in comparison to the cost a customer would pay for a final product years down the line, (b) network for connections to find access to the necessary services and other items, (c) persuade the small number of current developers to depart from their current practice of adhering to regulation and provide you access, (d) break (the unjust and largely horrible) laws related to provision of medical services, (e) travel to a less restrictive jurisdiction as a medical tourist, and (f) accept a fair degree of risk of failure - that even if everything else goes well, and all involved do their jobs, the present implementation of the treatment just doesn't work, or the present understanding of the science and data provides a false and inflated impression of what the treatment can achieve.

A good example of a combination of most of the above is the BioViva CEO's gene therapy from earlier this year: money and networking are the currency of a startup, and the existence of that startup was required to bring together all the necessary players to get the job done. That and medical tourism to a country where provision of the treatment is legal, as it would be everywhere in a just world. Sadly, in our world, there are entire branches of government in the wealthier nations staffed by those who, day in and day out, toil to block access to potential therapies for people who can make the educated decision to take the risk. This is one of many reasons why medical progress is inordinately slow and expensive. Early adoption plays an important part in the process of development for any technology, and medicine is no different.

Here are a few pointers based on the work of recent years, in no particular order, and with no attempt to be comprehensive. There are others I could list, many of which would fall under the heading of gene therapies in some implementations.

Gene therapies:

With the advent of CRISPR, the technical feasibility of gene therapy is now leaps and bounds ahead of where it was just a few years ago. The remaining challenge in delivery is obtaining reliable tissue coverage in adults; the results in terms of proportion of cells affected is very variable in animal studies, and understanding why these variations occur is an ongoing process. So you can undergo gene therapy and come out with too low a percentage of altered cells to make any meaningful difference.

That to one side, there are any number of gene therapies that are now technically feasible in humans. They span the spectrum of risk. In the most favorable camp are alterations already undertaken in animals for years, that researchers are practiced in, and which appear to be wholly beneficial, such as myostatin gene therapy to spur muscle growth and resist age-related muscle loss. In the least favorable camp there are alterations that could absolutely be set up quickly with CRISPR and a small lab, but have only been carried out in rodents a few times, and with limited long-term observation, such as adding extra lysosomal receptors to maintain youthful measures of liver function in old age via increased cellular garbage collection.

Stem cell therapies:

If you are 60 years old in the US, with a typical level of wealth for that age group, and a typical level of creakiness in the joints, then why wouldn't you spend 10-20,000 on first generation stem cell therapies that have a good expectation value in terms of delivering relief from pain, control of inflammation, improved function, and so forth? The only reason people aren't doing this in droves is that it is still something that you have to know about, to pester the right doctors, to do some legwork on clinics and hospitals. For these very simple treatments you don't even have to leave the country anymore, since the FDA finally relented a few years back, but if you want to save money then heading to Canada or Mexico is very feasible.

If you are younger and your joints are not at that point of constantly reminding you of their damage, the cost-benefit analysis is much less clear. Will a healthy person in their 30s or 40s gain any meaningful benefit - short term or long term - from today's simple stem cell therapies? "No" seems like a very plausible answer to that question, there will be no useful data to help pin down the bounds of the possible for decades yet, and by that time it'll probably be irrelevant.

Enhancing native stem cell activities:

Parabiosis research is uncovering signals in the blood that govern stem cell activities, such as GDF-11. Augmenting or reducing levels of these signals so as to spur greater stem cell repair and maintenance of tissues can be achieved via gene therapies of various sorts, as well as by targeted drugs. This is all still new enough that getting access to treatments would be a case of persuading one or more of a small circle of respected researchers to do this for you, and that just isn't going to happen outside of the context of licensing their intellectual property and funding their development process - things that look a lot like starting a company and building a technology. The risk here is also an unknown; will this spur cancer, or cause other interesting problems? There is too little work in rodents to even be certain of the present safety for laboratory animals.

Thymus restoration:

The loss of much of the thymus in early adulthood slows the supply of new immune cells to a trickle. Expanding that supply would be one way to reverse some of the age-related decline of the immune system. It is possible to grow thymic tissue from cells and transplant it, for example: both things have been done for humans, just not together in one patient. That is a very plausible near-term goal for a clinic outside the US that already has experience in cell therapies or tissue engineering. It is also possible to conduct gene therapy for FOXN1 to restore thymic activity - one of the many riskier options that CRISPR now makes possible should anyone be willing to do it for you.

Immune cell infusions:

Researchers and many clinics are perfectly capable of generating immune cells to order, and in large numbers. It just isn't present practice to make a therapy out of this by delivering those immune cells to patients. It would be a matter of money and organization rather than new science to put together such a treatment given a clinic with the ability to carry out existing stem cell therapies. Provided regularly, such a therapy may well augment the aging immune system with large numbers of new immune cells capable of defending against pathogens and eliminating unwanted cells.

Clearance of transthyretin amyloid:

Earlier this year, promising trial results were announced for clearance of transthyretin amyloid, a form of metabolic waste associated with mortality in the oldest of old people, as well as with heart disease in younger old people. The therapy is one of the first successful implementations of a SENS approach to aging, meaning repair of damage and clearance of wastes, but since it is being developed within the regulatory system it is being used to treat a specific age-related disease rather than as a therapy for a general form of damage that underpins many aspects of age-related degeneration.

This is another great example of a treatment that is technically feasible, has a reasonable expectation to produce some level of long-term benefits to everyone, but the only way to obtain access for the foreseeable future is to have the funds and connections to start a development collaboration with the small group of researchers involved: they are not going to step beyond the bounds of the system. The picture changes somewhat when this becomes a generally available clinical therapy, at which point things come back to medical tourism, but that is still years away for this particular approach to amyloid clearance given the slow pace of regulatory processes in medicine.


Bisphosophonates were shown to grant a sizable five year increase in life expectancy in a study population of a little more than a hundred osteoarthritis patients. Obtaining and using drugs of this nature without a prescription - which you won't get unless you have osteoarthritis or one of the other conditions that bisphosophonates are used to treat - is of course going to be illegal in highly regulated nations like the US. The primary risk is that the data is incorrect, however; an effect of this size should not just appear out of the blue for a class of medicine that has been used for a long time. While researchers are investigating potential mechanisms that might explain these results, this seems a case of data that needs replication and confirmation rather than unquestioning acceptance.


In the paper I'll point out today, researchers demonstrate one of the many ways in which insulin signaling and its surrounding mechanisms can be manipulated to slow specific measures of aging. In this case the focus is on the aging of heart tissue, and the methodology is genetic engineering to delete the gene encoding IGF-1R, the receptor for insulin-like growth factor 1 (IGF-1), a method already demonstrated to enhance longevity in mice.

A great deal of the aging research community restricts itself to cataloging the molecular biology of aging: firstly assessing which mechanisms are more or less important in the relationship between metabolism and aging, and secondly manipulating the operation of metabolism in order to produce new states with a modestly altered pace of aging. For most of these researchers therapies are not the goal, but rather only information. Where therapies do become the goal, the standard practice of developing drugs to alter metabolism so as to slow aging has so far demonstrated itself to be an expensive way to produce little but knowledge. Consider the hundreds of millions spent on sirtuin research, all the hype that accompanied that investment, and how little there is to show for it today. That is par of the course.

In the list of influential mechanisms linking cellular biochemistry with aging, insulin metabolism is perhaps the most studied and cataloged to date. It is of central importance in the behavior of cells, and as such this topic touches on numerous others: the role of growth hormone, diabetes, inflammation, regulation of cellular housekeeping activities, cellular senescence, and calorie restriction, as well as species life span and variations in aging, all areas of interest for diverse research groups in the life sciences. The researchers here deleted IGF-1R in heart tissue and observed the benefits in mice as they aged, looking for links to mechanisms known to be important in aging, such as inflammation and cellular senescence. The full text of this open access paper is only available in PDF format, I'm afraid, but here are some of the relevant portions:

Deletion of IGF-1 Receptors in Cardiomyocytes Attenuates Cardiac Aging in Male Mice

The prevalence of cardiovascular disease increases with advancing age. In addition to long-term exposure to risk factors for heart disease, the aged heart exhibits intrinsic structural remodeling which reduces cardiac functional reserve and predisposes the heart to hemodynamic stress. Senescent remodeling includes left ventricular (LV) hypertrophy, diastolic dysfunction, interstitial fibrosis, and reduction in maximal heart rate.

Prior studies report that reduction of insulin/insulinlike growth factor (IGF)-1 signaling leads to longevity in a number of species. Notably, IGF-1R heterozygous knockout mice live on average 33% longer than their wild type controls without differences in food intake, physical activity or metabolic rate. However, it is not known if decreasing IGF-1R signaling in the heart can retard cardiac aging. We sought to test the hypothesis that long-term inactivation of IGF-1R in cardiomyocytes delays the development of aging-associated myocardial pathologies using very old cardiomyocyte-specific IGF-1R knockout mice.

The present study demonstrates that deletion of IGF-1R in cardiomyocytes attenuated aging-related cardiac pathologies, including ventricular hypertrophy, interstitial fibrosis, and inflammation. Mechanistically, we showed that IGF-IGF-1R-Akt signaling may be an essential regulator of cardiomyocyte senescence. IGF-1 is primarily produced in the liver following stimulation by growth hormone (GH) and acts by binding to IGF-1Rs to promote organ growth. The mRNA expression of GH in the pituitary declines with age in mice, as they do in humans. In parallel, serum IGF-1 levels decline progressively in healthy people from early adulthood to older age.

Our data provide novel evidence that physiological IGF-1R signaling promotes cardiomyocyte senescence and that long-term deletion of IGF-1R in cardiomyocytes prevents structural deterioration in aged hearts. It seems paradoxical that IGF-1R expression increased in aged hearts given that local IGF-1 or IGF-1R levels may decline with aging in mice. For example, in cerebral vasculature, expression of IGF-1 significantly decreases with age. Although the underlying mechanism is not understood, we speculate that induction of IGF-1R but not IGF-1 in aging hearts could represent a compensatory mechanism that promotes aging-associated cardiac remodeling. Thus, it could be anticipated that the very old IGF-1R knockout mice would display blunted cardiac hypertrophy under natural aging circumstances. Furthermore, aging related fibrosis was diminished in IGF-1R knockout mice hearts. The decreased fibrosis could be associated with an increased ability to adapt to hemodynamic stress. The capacity for adaptation to hemodynamic stress and ischemia is diminished in aged myocardium.

The heart produces proinflammatory cytokines such as TNF, IL-1, IL-6, and RANKL in pathological states, and these cytokines may promote cardiac remodeling by facilitating hypertrophy and fibrosis. Moreover, chronic inflammation is a characteristic of aging and senescent cells secrete components of the SASP, the senescence-associated secretory phenotype, including proinflammatory cytokines, chemokines, and proteases. Although the role of SASP in aging phenotypes has been extensively investigated, the association of cardiac inflammation with aging is not clearly defined. One of the salient features of our findings is that aging induces proinflammatory cytokines in the heart mediated by, at least in part, the IGF-1R system.


A few weeks ago researchers announced the discovery of a potential new class of drug capable of some degree of clearance of senescent cells in old tissues. As an approach to treating aging and its associated medical conditions this has long been advocated by the SENS Research Foundation, and is now coming to be known as a senolytic therapy. The paper is published in Nature Medicine, but is unfortunately not open access. The researchers there referred to the most effective drug candidate by its development code name, ABT-263. Another collaborating research group, those involved in identifying dasatinib and quercetin as senolytic drugs in research announced earlier this year, published their own paper on the ABT-263 discovery yesterday in Aging Cell. There they use ABT-263's generic name navitoclax, and this latest paper is open access, so you'll find more of the details laid out and easily accessible.

Cells become senescent as a result of damage, toxins, and stress, ceasing to divide and secreting a range of signals. This is most likely an evolutionary adaptation of processes involved in embryonic development and wound healing that have also come to suppress cancer risk in early old age, shutting down the ability to replicate in those cells most at risk. Senescent cells are destroyed by their own programmed cell death mechanisms or by the immune system, but some evade these fates and linger. The immune system becomes damaged and ineffective itself in later life, and that no doubt doesn't help matters. As senescent cells accumulate in ever greater numbers over the years, the combined effects of their secreted signals become damaging to surrounding tissues, generating inflammation, remodeling important structures, and eventually encouraging the generation of cancer rather than suppressing it. The presence of senescent cells contributes to the progression of near all of the common age-related diseases.

Selective destruction of cells is a major theme in cancer research and other areas of medicine, and destruction of senescent cells looks to be the shortest path to removing this contribution to degenerative aging. A good means of clearing these cells means that we don't have to stop to fully understand how and why cellular senescence causes damage - we can just test removal in the laboratory and look for a beneficial outcome. So far, that is exactly the outcome seen in animal studies. Early this year the first senolytic drug combination of dasatinib and quercetin was tested in mice with mediocre results in terms of percentage of cells cleared and a level of removal that varied widely by tissue type. Nonetheless it produced measurable, significant benefits after just a single treatment. This is a form of narrow, selective rejuvenation, the restoration of some parameters of biology in a living individual to the state they were in earlier life.

The focus of the research and drug screening that identified navitoclax is the inhibition of Bcl-2 and related proteins. These proteins are involved in the regulation of apoptosis, a programmed cell death mechanism. In theory senescent cells should already be predisposed to that fate, so nudging more of them over the line to trigger apoptosis is a plausible approach.

Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl-2 Family of Anti-Apoptotic Factors

Senescent cells contribute to age-related diseases. Much like cancer cells, senescent cells are resistant to apoptosis, potentially protecting them from their own pro-inflammatory secretions, reactive metabolites, and activated DNA damage response. They are instead eliminated by the immune system. We therefore hypothesized that senescent cells depend upon anti-apoptotic defenses similarly to cancer cells. Indeed, our analysis of the transcriptome of senescent human preadipocytes identified pro-survival pathway up-regulation.

Here, we tested if the Bcl-2 family inhibitors, navitoclax and TW-37, are senolytic. Like the combination of dasatinib and quercetin, navitoclax is senolytic in some, but not all types of senescent cells: it reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl-xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, TW-37 had little senolytic activity. Navitoclax targets Bcl-2, Bcl-xl, and Bcl-w, while TW-37 targets Bcl-2, Bcl-xl, and Mcl-1. The combination of Bcl-2, Bcl-xl, and Bcl-w siRNA's was senolytic in HUVECs and IMR90 cells, while combining Bcl-2, Bcl-xl, and Mcl-1 siRNA's was not. Susceptibility to navitoclax correlated with patterns of Bcl-2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to navitoclax. Thus, navitoclax is senolytic and acts in a potentially predictable cell type-restricted manner.

Senolytics could be valuable in treating disorders related to senescent cell accumulation, e.g., atherosclerosis, chronic obstructive lung disease, idiopathic pulmonary fibrosis, osteoarthritis, diabetes, kidney dysfunction, dementias, and neurodegenerative diseases. It appears that the senolytics described so far are limited in the senescent cell types they can target, underscoring the value of testing each cell type involved in particular diseases of interest as part of the senolytic drug development process. We speculate that it may be possible to base selection of senolytic drugs for a particular disease indication on the molecular profiles of the types of senescent cells that underlie that disease. Furthermore, combination treatments for certain indications involving multiple senescent cell types may be optimal in some cases. Overall, our findings support the feasibility of using our hypothesis-driven, bioinformatics-based strategy to develop more, perhaps better senolytic agents. Furthermore, it appears feasible to develop senolytic agents that target senescent cells of a particular type, in a particular tissue, or for a particular indication.


I think that in years to come, we'll consider 2015 to be the point at which things really start to move for SENS rejuvenation research. It has to be said that medical research moves slowly at the best of times. It takes a good long run-up to show results, and it took a decade for SENS to grow from an idea and a few interested researchers to its present state of a foundation, the support of leaders in the research community, a loose network of research groups, and a few newly formed startup companies. It is perhaps an appropriate year for the unveiling of the Methuselah 300 monument, listing the donors who provided the initial funds and support to start this ball rolling.

Senescent cell clearance as a treatment for degenerative is having its breakout year. The Methuselah Foundation and SENS Research Foundation provided seed funding to Oisin Biotechnology for work in mice on a method of clearing senescent cells. Meanwhile another research group spent 2015 uncovering tissue specific drug candidates that tip senescent cells into the mode of programmed cell death called apoptosis, demonstrating this in mice with a couple of different drugs, producing results good enough to prove that meaningful health benefits result from a single treatment in older animals. This work should once and for all settle that SENS advocates have been right for the last decade, and the rest of the research community should have listened years ago.

It has also been a breakout year for gene therapy, but in a much bigger way. CRISPR has reached critical mass, and we are going to see an avalanche of gene therapies taking place in the years ahead both in trials and outside the regulatory system. A demonstration of this point was made by the BioViva CEO, who used medical tourism and the connections of a biotech startup company to undergo telomerase and follistatin gene therapies. Five years from now, it won't take any connections - just look up a reputable clinic outside the US and take a trip. If you look back at the progression of stem cell therapies since the turn of the century, that is exactly what is going to happen for the first gene therapies. Very few of the plausible candidates are what I'd call rejuvenation therapies at this point, more compensatory approaches that can spur additional stem cell activity or muscle growth or the like, but the growth in expertise in gene therapy in the field as a whole is a good thing for the future of SENS treatments that do require gene therapy.

Glucosepane cross-links are an important contribution to aging in humans - they are a part of the reason that skin and blood vessels lose their elasticity. The former is unfortunate, the latter ultimately fatal. For some years now the SENS Research Foundation has been funding efforts to develop the tools needed to work with glucosepane in cells and tissues, and this year a first success was published in a prestigious journal: a reliable method of synthesizing glucosepane as needed, a very important part of the toolkit.

Another lengthy SENS research program now blossoming is the use of allotopic expression of mitochondrial genes. The researchers originally funded by the Methuselah Foundation and SENS Research Foundation formed a company, Gensight, that is now well on its way to clinical application of this technology for inherited mitochondrial disease. That foundation of practice and experience will hopefully create a much better basis to finish up the work for all mitochondrial genes and the treatment of aging in the years ahead.

The long-running efforts by SENS researchers to find bacterial enzymes capable of breaking down some of the waste chemicals that form lipofuscin, a mix of metabolic wastes that clogs up lysosomes in old cells, have reached the point of commercial development. Candidate drugs have been licensed out to newly formed Human Rejuvenation Technologies, Inc.. Now we wait and see how that goes, but in general you should consider these sorts of deals a way to bring in more money for later stage research - it's just less visible until it reaches its goals.

Even the cancer programs based on preventing the lengthening of telomeres at the SENS Research Foundation are getting more attention from publications, and are no longer alone in the research community. Other groups are striking out in their own attempts to suppress cancer by preventing cells from lengthening their telomeres.

Speaking of commercial development: this year's Rejuvenation Biotechnology conference was a success. The hand off from academia to industry doesn't just magically happen in any field, and longevity science is no exception to this rule. This conference series exists to build the relationships and awareness needed for a smooth transition of rejuvenation therapies from the laboratory to biotech startups and Big Pharma in the years ahead.

Amyloid clearance inside the Alzheimer's research community continues to be a long, slow, painful progress of advancement by small degrees. This is not the only sort of amyloid, however, and this year efforts to clear transthyretin amyloid - associated with heart disease in the old and heart failure in the very oldest individuals - met with success in a human trial. This is perhaps the most advanced of SENS repair therapies at this point in time, an actual honest to goodness narrow scope rejuvenation therapy with a successful trial behind it. Next up should be an sober assessment on how to jailbreak this advance out of the regulatory regime and into more general availability via medical tourism.

2015 saw continued and louder debate within and around the scientific community on the topic of whether or not aging should be officially defined as a disease. I expect this discussion to continue to grow, given the financial and regulatory incentives involved:

  • From the 2014 International Conference on Aging and Disease
  • Why Seek to Classify Aging as a Disease?
  • Another Call to Classify Aging as a Disease
  • Insight into the Machinations of Classifying Aging as a Disease
  • Aging as the Greatest Disease of All
  • Arguing that Public Reluctance to Treat Aging as a Medical Condition is at Root a Categorization Problem

Crowdfunding by the longevity science community continues apace. We're still not as good at fundraising as our nearest cultural neighbors, the strong AI philosophy of development typified by the Machine Intelligence Research Institute, but a little friendly competition never hurt anyone. That branch of the strong AI community, like SENS and much of the radical life extension advocacy community, arose from the transhumanist communities of the past few decades, and many of the same people have interests on both sides of the fence. It seems reasonable to think that we can do just as well as MIRI and related organizations when it comes to pulling in funds for our goals in healthy longevity. This year the Fight Aging! matching fundraising held in collaboration with the SENS Research Foundation raised 250,000 for rejuvenation research, and an earlier crowdfunding project at raised 45,000. We're improving year over year, but there's much further to go yet.

What about the large investments in our space? Calico continues to make deals and be a mystery to anyone other than the insiders, but increasingly looks like something halfway between Big Pharma and the NIH, which is to say irrelevant to any meaningful progress towards human longevity in the near term. It will be sad if it ends up another Ellison Medical Foundation, but that may well be where things are heading. The principals at Human Longevity Inc. are much more vocal in talking up their position, but are definitely not doing anything that is of great relevance to life extension - it's more a personalized medicine company with great PR, nothing exceptional. You might look at a good interview with Aubrey de Grey and Brian Kennedy from earlier this year for more on these two initiatives. On a different and more positive note, philanthropist Peter Thiel has been talking more openly about his interest in longevity science this year: I think it is important the people who are backing the more important ventures speak out in this way.

Off in the research community interested in slowing aging, the population of people without large amounts of funding in other words, advocacy for change is continuing. A trial of metformin to treat aging is being used to change the way in which the FDA views aging and therapies - at least I hope that's the intended goal here, as I have no expectation that this will move the needle on human health and life span. The Longevity Dividend advocates have, meanwhile, set down their scientific evidence and vision for more NIA funding for therapies to gently slow the aging process in a new book.

Parabiosis research, linking together the circulatory systems of an old and a young individual to identify factors that may influence or be influenced by aging, is proceeding apace. It is being used to identify various potential drug targets, mostly with the expectation of increasing stem cell activity in old individuals. The debate over the validity of previous discoveries, such as GDF-11, also continues.

As usual there have been some novel or early and odd results here and there in the literature, things that stand out and make you wonder. We can never expect anything of relevance to emerge from any of these, but you never know. For one, researchers identified a marker for less fit cells, and by eliminating those cells made flies live longer - with a lot of subtlety in what exactly "less fit" and the presence of the marker actually means. In other news, a company is working on therapies using isotope replacement in water, based on evidence suggesting that this increases resistance to oxidative stress in proteins and slightly slows aging. Elsewhere, the quest to understand the suspiciously large gain in life expectancy resulting from bisphosphonate treatment for osteoarthritis in a study some years ago has progressed to a hunt for plausible mechanisms. I'd rather see an attempt to reproduce the initial results. Elsewhere again, researchers provided evidence to show that twins with different exercise levels do not have any longevity differences - which is hard to reconcile with what the data presently shows on exercise and its benefits.

On a completely different topic, a novel Alzheimer's theory is that accumulation of amyloid is due to a slow physical failure of drainage channels for cerebrospinal fluid near the nose. As a theory this has the attractive property that it is comparatively easy to prove or disproved, and the Methuselah Foundation funded a test this year - so we shall see. In other news, the types of age-related diabetes are multiplying again; the assignment of Alzheimer's disease as type 3 diabetes seems to be an ongoing unresolved debate, while researchers have recently produced a much more compelling set of data to believe that there is a type 4 diabetes caused by a novel form of age-related immune dysfunction.

The cryonics community provided a demonstration of memory retained in vitrified and restored nematode worms, a great piece of evidence to support the hypothesis that present cryonics practices are sufficient to preserve the fine structure of the human brain. Other evidence continues to be presented in the Brain Preservation Foundation technology prize contest, and in a milestone the year James Bedford became the longest surviving human being to evade the final end of information-theoretic death. This year also saw the launch of a new research-focused cryonics collaboration in the UK.

Researchers investigating proficient regeneration in salamanders have uncovered an unsuspected link between harmful senescent cells and this regeneration: salamanders suddenly become very good at clearing senescent cells while they are regrowing a limb. In zebrafish, another regenerative species of interest, researchers used a human gene to turn off limb regeneration, a result that perhaps points out why this desirable feature doesn't exist in our biology. In other news, researchers using decellularization of donor organs as a tissue engineering strategy have advanced to the point of being able to decellularize and repopulate an entire rat limb and all of its structures. Other researchers have restored the immune system in mice with transplants of engineered thymus organoids, grown from cells. In another area of regenerative medicine, a team showed that converting nerve cells into photoreceptors could restore sight to mice with degenerative blindness - a possible alternative to more conventional visions of cell therapy.

Lastly, here are links to a few short commentaries that might be worth reading again, you never know. Certainly I'd forgotten that half of them existed:

  • Is it Different this Time Around?
  • The Scientific Institution is Biased Against Shortcuts to the Production of Practical Technology
  • Disappointing Comments on Longevity Science From Bill Gates
  • The Arcane
  • The Immortals Among us
  • The Relevance of SEC Changes to Crowdfunding Rules
  • Existing Longevity Therapies that are Technically Feasible, but Difficult and Expensive to Obtain
  • Scores of Labs Should be Gearing Up to Work on Glucosepane Cross-Link Breakers, But Are They?


There is a prevailing public disinterest in medical research to extend healthy life. The open access survey linked here is an attempt to understand which of the present widespread beliefs on medicine, aging, and longevity is a more important determinant of this public disinterest. Note that the paper is only available in PDF format at the moment. Also note that this is a project of the Health Extension folk in the Bay Area - so good for them for stepping up, doing the work, and getting it published.

The longevity science community has long known that the public appears indifferent or even hostile to the prospect of treating aging and extending healthy life spans. I and others believe this goes a long way towards explaining why the funding situation for aging research is particularly bad, even for a world in which near all useful medical research is poorly funded and given little attention by people outside the scientific community. There are a number of schools of thought as to why people don't appear to want to live longer, which include the mistaken belief that only wealthy people would benefit from longevity assurance therapies, the mistaken belief that overpopulation and dystopia would result, and the mistaken belief that greater longevity would mean more years of being ill, frail, and decrepit. There is also the role of conformity to the norm to consider, where the norm is what happened to your parents and grandparents, and the open question of why all of these widespread erroneous beliefs persist though year after year of numerous scientists telling the public that they are incorrect.

I'm sure many long-time readers here will not be surprised to find that the survey linked below identified the primary problem as being the fear of frailty, the unfounded assumption that being older as a result of new medical treatments must mean being having more of the characteristics of people who are presently old. Perhaps it is that many people see all medicine as equal, and make no practical distinction between (a) the present patching over of age-related illness without addressing its causes, an approach that allows survivors to struggle on, to age and decline some more and die later rather than die sooner, and (b) a future treatment that reverses and repairs some of the causes of aging and thus postpones or reverses all age-related disease and decline. This is one of the challenges of standing at the point at which the approach to aging and medicine is fundamentally changing: the old common wisdom is not longer correct, and the expectations among researchers for the near future are not yet widely appreciated.

Great desire for extended life and health amongst the American public

Recent advances in aging research and regenerative medicine may soon translate into dramatically increased human lifespans. But does the American public want to live longer? Popular press argues the answer is no, e.g. a recent survey on desired lifespan reported in the New York Times found 60% of respondents voted for the shortest option, an 80 year lifespan, while fewer than 1% opted for an unlimited lifespan. Here, we show that negative attitudes to longer lives are a consequence of erroneously equating extended life with an extended period of frailty. When we stipulated continued health to the original survey question, responses dramatically favored longer life: only 20% wish to die at age 85, while 42% want an unlimited lifespan. Since funding for aging research depends on its perceived value, better science communication is needed to align public policy with public interests.

We surveyed 1000 individuals about how long they wished to live (to age 85, 120, 150, or indefinitely), under 3 scenarios: (1) sustained mental and physical youthfulness, (2) mental youthfulness only, (3) physical youthfulness only. While responses to the two partial youthfulness conditions recapitulated the results of previous surveys - i.e., most responders (65.3%) wished to live to age 85 only - under scenario (1) the pattern of responses was completely different. When guaranteed mental and physical health, 797 of 1000 people wanted to live to 120 or longer, and 53.1% of the 797 desired unlimited life spans. Furthermore, 70.1% of the people who responded 85 to scenario (2) or (3) changed their answer to 120 or longer in scenario (1). Full survey response data are publicly available. We also reproduced our primary finding - that most people wish to live far longer than the average human lifespan so long as they stay healthy - using Google Surveys. In this replication cohort of 1500 respondents, we found that 74.4% wished to live to 120 or longer if health was guaranteed, but only 57.4% wished to live that long if it wasn't. Full survey data and results are publicly available in an interactive browsable format.

The public wants to live long, and live healthy. Human supercentenarians give some of the best evidence for the possibility of increased healthspan and healthy aging, or compression of morbidity. Making healthy aging a reality for the rest of the population will be scientifically challenging. Nevertheless, it is becoming increasingly more necessary: chronic age-related diseases account for 75% of Medicare spending, and these numbers are projected to rise as baby boomers age. The National Institute on Aging currently receives less than 1% of the National Institutes of Health's overall annual budget, or less than 0.05% of annual Medicare spending; this is a misallocation of resources. There is a growing demand for more awareness and more funding for basic aging research, and new initiatives such as the Healthspan Campaign and the trans-NIH Geroscience Interest Group are helping lead the way forward. Investing in scientific research and development that targets aging, the process underlying multiple chronic diseases, can offer uniquely high potential returns.


Monday, December 28, 2015

A number of research groups in different areas of regenerative medicine are working on ways to wrap individual stem cells in supporting materials that enable the cells to both survive and behave as desired for long enough to produce results following transplantation. In this case, the focus is on hair regeneration:

The dermal papilla cell (DPC) is a type of highly specialized mesenchymal cells located in hair follicles (HF). Due to the primary role in the epithelial-mesenchymal interaction that enables hair-follicle morphogenesis and hair cycling, DPC has become an attractive cell source for hair regeneration to treat alopecia patients. However, DPCs tend to lose their function during in vitro culture. Hence, there exists a clear need to develop a microenvironment that can recapitulate the interactions within the native milieu of DPCs.

Layer-by-layer (LBL) nano-coating with biocompatible materials on the cell surface displays the versatility with tunable loading and release properties, which can provide a remodeled microenvironment for regulating cell function. Here, we developed a LBL self-assembly technique for single DPCs to create a nano-scale ultrathin extracellular matrix (ECM). We showed that the single cell-based LBL-encapsulation would not impact the viability, morphology, proliferation and intrinsic properties of DPCs. We then included fibroblast growth factor-2 (FGF-2) into the LBL nano-structure to regulate the DPC function. Finally, we performed in vivo hair reconstitution assays using LBL-encapsulated DPCs combined with freshly isolated epidermal cells (EPCs) and found this strategy can treat hair loss. Tests on nude mice showed that the implanted encapsulated cells caused abundant hair growth with the hair follicle organisation showing mature characteristics.

Monday, December 28, 2015

Television viewing time is available in some large epidemiological data sets, and is a useful proxy for time spent sedentary rather than active. Past studies have demonstrated an association between higher television viewing time and higher mortality rates, and this much larger study shows the same:

Television viewing is a highly prevalent sedentary behavior among older adults, yet the mortality risks associated with hours of daily viewing over many years and whether increasing or decreasing viewing time affects mortality is unclear. This study examined: 1) the long-term association between mortality and daily viewing time; 2) the influence of reducing and increasing in television viewing time on longevity and 3) combined effects of television viewing and moderate-to-vigorous physical activity (MVPA) on longevity. Participants included 165,087 adults in the NIH-AARP Diet and Health Study (aged 50-71 yrs) who completed questionnaires at two-time-points (Time 1: 1994-1996, and Time 2: 2004-2006) and were followed until death or December 31, 2011.

Over 6.6 years of follow-up, there were 20,104 deaths. Compared to adults who watched less than 3 h/day of television at both time points, mortality risk was 28% greater in those who watched 5+ h/day at both time-points. Decreasing television viewing from 5 + h/day to 3-4 h/d was associated with a 15% reduction in mortality risk and decreasing to lest than 3 h/day resulted in an 12% lower risk. Conversely, adults who increased their viewing time to 3-4 h/day had an 17% greater mortality risk and those who increased to 5+ h/day had a 45% greater risk, compared to those who consistently watched less than 3 h/day. The lowest mortality risk was observed in those who were consistently active and watched less than 3 h/day of television.

We confirm that prolonged television viewing time was associated with greater mortality in older adults and demonstrate for the first time that individuals who reduced the amount of time they spent watching television had lower mortality. Our findings provide new evidence to support behavioral interventions that seek to reduce sedentary television viewing in favor of more physically active pursuits, preferably MVPA. Given the high prevalence of physical inactivity and prolonged television viewing in older adults, favorable changes in these two modifiable behaviors could have substantial public health impact.

Tuesday, December 29, 2015

Myostatin is a part of the system of regulation that controls muscle growth. Linked here you'll find recent news of a clinical trial of myostatin inhibition as a treatment for age-related loss of muscle mass, though note that the atrophy of tissue is only one of the reasons for loss of strength. There are also issues within the biochemistry and structure of muscles caused by aging and which must be understood and repaired. Nonetheless, removing the myostatin gene entirely does dramatically increases muscle mass, as demonstrated in natural and engineered mutant lineages in a number of mammalian species. There are even a few rare natural myostatin loss of function human mutants, as muscled as you might expect even at very young ages, and at least one human recipient of gene therapy intended to enhance muscle growth through the same system of regulation. An alternative to one-time, permanent gene therapy is an ongoing treatment with antibodies tailored to block the action of myostatin, as is this case in this clinical trial. The degree of effect is likely to be lower, but from the point of view of the researchers involved the ability to stop the treatment is more important than optimizing performance at this stage:

A proof-of-concept, phase 2 trial by an international research team has found promising results for a myostatin antibody in treating the decline in muscle mass and power associated with aging. "Myostatin is a natural protein produced within the body that inhibits muscle growth. It has been hypothesized for some time that inhibition of myostatin may allow muscle to grow, resulting in improved muscle mass and physical performance. The current study confirms these beliefs."

In the study, injections of a myostatin antibody over a 24-week period resulted in an increase in lean (muscle) mass and improved performance on tasks requiring muscle power in patients older than 75 with low muscle strength, low muscle performance and a history of falling. "This is the first study to show that myostatin antibody treatment improves performance on activities requiring muscle power. 'Muscle power' refers to the ability to generate muscle force quickly. During aging, it is lost more rapidly than muscle strength, contributing to disability, falls, reduced quality of life and, in some instances, death. Myostatin antibody treatment improved muscle power in the elderly, as indicated by improvements in the ability to climb stairs, walk briskly and rise repetitively from a chair. Treatment particularly benefited those who were most frail at baseline, a population who may not be receptive to conventional intervention such as resistance exercise."

Tuesday, December 29, 2015

In this post, someone much more enthusiastic than I about the use of traditional drug development to slightly slow the progression of aging makes the point that next to nothing is known about how the present collection of candidates interact. This is of interest from a pure science perspective, but not - to my eyes - from a getting things done perspective. The expected outcome for this sort of drug development, largely meaning reuse of existing drugs, as measured in terms of how much additional healthy life we would expect to obtain, and how much that progress would cost, is just not worth it in comparison to focusing on the establishment of SENS-like rejuvenation therapies based on damage repair. That doesn't stop the science of drug interactions from being interesting, but it does mean we should be looking elsewhere for meaningful progress towards healthy life extension.

I take about a dozen different pills for longevity. There is some evidence behind each of them, but what we really don't know is how they interact. It would be nice to think that their benefits simply add, so that if one pill produces a 10% average increase in life span, then 10 pills increase life span 100%. Fat chance. Some of them are ineffectual, of course. But for the ones that offer a benefit, most of the benefits are probably redundant. (When different treatments work via the same pathway, we can't expect that two together work any better than either one of them separately). A few may mutually interfere. But there also may be a few magic combinations that synergize positively. If they work via pathways that are substantially independent, we might hope that the life extension from the two together might be equal or even greater than the sum of the benefits separately. Most of the life extension drugs that we have target a single pathway: they work through the insulin metabolism. The remainder work to suppress inflammation, or re-energize mitochondria, or lengthen telomeres, or reduce TOR signaling.

Almost no work has been done with combinations of longevity treatments. In 2013, Steve Spindler's lab published a study based on eight different commercial formulas of vitamins and supplements. Their data were beautiful - and the survival curves for each of the eight fell exactly along the survival curve of the control group. I have heard that the NIA's Interventions Testing Program (ITP) has tested rapamycin in combination with metformin, with successful results (to be published next year). In a rational world, some of the billions that go into "me too" drug development and chemotherapy trials by Big Pharma would be diverted to test all of the above compounds, alone and in combination. But in the branch of the multiverse where you and I live, this will not happen in 2016. Hence "quick and dirty" (meaning cheap) alternatives look attractive.

This is a research proposal, the germ of an academic publication that I have been working on in recent months: the plan is to screen for combinations of drugs that offer dramatic life extension in mice, using the minimum number of mice to test the maximum number of combinations. Standard practice is to use 30-80 mice for each test in order to get a clean survival curve. The innovation I am offering is to use just a few mice for each combination of treatments so that more combinations can be tested, albeit less precisely. How many mice do we really need to be reasonably sure of not missing an outstanding combination of treatments? I have been modeling the situation with computer-generated data, testing different statistical methods to see which works best, and how many mice are needed in order to be reasonably certain of not missing a great combination. My definition of a great combination is that it extends life span in excess of 50%. The test I propose will not be capable of distinguishing "which is better" among the rank-and-file of many treatments and combinations. However, there will be enough statistical power to identify the really hot performers, which are of most interest to us.

I believe that using about 1400 mice in an experiment lasting about 3 years, we should be able to evaluate all combinations of 15 separate life extension treatments, and narrow the field to 6 candidate triples that show offer life extension in excess of 50%, and thus show promise for further testing. The program I have outlined could be undertaken for less than the cost of testing the 15 separate treatments using traditional methodology, and I think what we would learn from the combinations protocol could be a great deal more useful. The total cost might be 1-3 million, depending mostly on where the work is done. The biggest risk is that the high-benefit "magical" synergistic combinations that this program is designed to look for simply don't exist. If they do exist and can be found, the public health impact is likely to be enormous.

I would wager on these synergies not existing, but of course you don't know for sure if you don't look - again pure science versus getting things done. Everything is a trade-off. However, even if such synergies do exist, note that growth hormone receptor knockout (GHRKO) mice, the current record holders for mouse longevity, live more than 60% longer than their unaltered peers. Yet the small human population with the hereditary condition of Laron-type dwarfism, caused by a dysfunctional growth hormone receptor, doesn't appear to enjoy any meaningful extension of healthy life span, though it is possible they are modestly more resistant to diabetes and cancer.

Wednesday, December 30, 2015

This popular press article takes a look at the Russian cryonics provider KrioRus and the long-standing US provider Alcor. As for many such articles it is perhaps too ready to selectively quote skeptical scientists while ignoring the vocal support of many other scientists. The small cryonics industry provides low-temperature storage of the body and brain on death, using vitrification for avoidance of ice formation and the best possible preservation of fine structure that stores the data of the mind. This is the only possibility at a longer life in the future for those who will age to death prior to the advent of rejuvenation biotechnology, and it is a tragedy that so few people are interested in cryopreservation as an alternative to oblivion and the grave. In a better world, near everyone would be preserved for a future of medical molecular nanotechnology capable of restoring vitrified tissue and regenerative medicine capable of rebuilding a body, and no-one would think it normal to embrace self-destruction rather than hope at the end of life.

In both countries, the cryopreservation process is largely the same. Once a patient is pronounced legally dead, the body must be cooled within the next few hours to start bringing down the body temperature. Most cryonics companies work with standby services whose main purpose is to get the body out of the hospital or morgue as soon as possible to begin the process. Over several hours, the patient's blood is replaced with a cryoprotectant, essentially a chemical anti-freeze that shields tissue from freezing damage. Then the patient is cooled to -196C over the course of several days using nitrogen gas.

Those who elect to sign up seem to fall into two categories. The first consists of people who consider themselves pioneers and would be quite content to come back in the future, knowing no one and nothing of the current culture. The second is of people scared both by the prospect of death and by the finality that comes with saying goodbye to a loved one for ever, a feeling most sceptics would find hard not to empathise with.

Of those two categories, Gary Abramson and Maria Entraigues-Abramson probably fall into the former. A photogenic couple who live in Los Angeles, the two met at a conference devoted to life extension and married not long after. "I had this curiosity since I was a little girl about ageing. I always felt it was something that was not right," Entraigues-Abramson told me. "If you're frozen, you're locked in time," Abramson chimed in. "If you wait 100 years or 1,000 years or however much time it takes for the technology to develop, it doesn't matter. I'm sure it's a split second for your experience. It may be a one in one thousand chance. But the alternative is a 100 per cent guarantee annihilation of your existence." "And if you don't like it in the future, you can always die again if you want to," Entraigues-Abramson said. "You can take a peek and say, 'I like it' or 'I don't. I'd rather be dead. People think cryonics is freaky but lying in the ground and decomposing isn't? What's the difference?"

Wednesday, December 30, 2015

The challenge in tissue engineering lies in recreating the precise structure of the extracellular matrix observed in natural cartilage. Without that correct structure all that results is a sloppy gel of cartilage cells rather than a useful load-bearing tissue, and that sloppy gel was the only outcome of early attempts to grow cartilage. In recent years progress has been made towards getting the structure right, either through better approaches to growing cartilage cells or through decellularization of existing donor cartilage. In recent news, researchers have claimed sufficient progress in growing cartilage from a patient's own cells to move forward into human trials:

Cartilage injuries and diseases are very common. About 40 percent of adults over 65 years old have osteoarthritis. Cartilage has no nerves and so does not cause pain until the cartilage is gone and the bone underneath starts to be affected. Cartilage also has no blood vessels and therefore cannot heal on its own once injured. In the worst case, the knee joint has to be replaced by an artificial joint. Currently, the clinical gold standard for repairing cartilage is a surgical procedure known as osteochondral autograft transplantation. It involves harvesting a graft from one part of the joint and transplanting it to replace the damaged cartilage. However, this procedure leaves the autograft donor sites injured and may lead to chronic pain and degeneration. An alternative is to use the patients' own cells such as stem cells and grow them into a three dimensional tissue-like structure until it becomes at least partially functional, before replacing the defective tissue.

Over the last eight years, researchers have developed several technologies enabling the growth of complex tissues consisting of multiple tissue components. The core technology is to grow cartilage tissues complete with underlying bone tissues in vitro using the patient's own stem cells isolated from clinically accessible sources such as bone marrow. This 'complex tissue plug' mimics the structural organization of native cartilage-bone tissues. Animal studies in rabbits have shown that replacing defects in knee joint cartilage with these tissue engineered cartilage-bone tissue plugs gives rapid and sustained regeneration of high quality cartilage with structure, composition and mechanical properties comparable to that of the clinical gold standard autografts. The use of these regenerative complex tissue plugs allows surgeons to use the same autograft surgical procedure to repair cartilage damage without the need to hurt the patients' own cartilage. Currently, by working with orthopaedic surgeons, the research team is preparing to translate this technology for human applications.

Thursday, December 31, 2015

Chemical reactions leading to modification of long-lived proteins in tissues, such as those making up the extracellular matrix or that occupy important positions in nerve cells, are a source of damage and dysfunction. Proteins can only perform correctly when they possess the right structure: modify that structure and problems arise. Degenerative aging is, at root, nothing more than an accumulation of damage, but there remains a lot of room to debate which specific types of damage might be more or less important than others over the present span of human life. One of the better known classes of damaging modification to proteins is produced by reactions with sugar compounds, particularly advanced glycation end-products (AGEs) such as glucosepane, but this is far from the only type of modification that occurs in the complex biology of a living individual. In the research noted here, for example, the authors add data to what is know about carbamylation of proteins.

Definitively establishing the relative degrees of significance of different forms of protein modification will probably require a means of clearing out and reversing each of these chemical reactions: given that technology, run the test and see what happens. This is somewhat complicated by the fact that species with different life spans tend to have radically different relationships with the various types of damaging protein modification. This has been amply demonstrated over the past twenty years of work on AGEs: those relevant to long-term health in mice and rats are not particular relevant in humans, and vice versa, a unfortunate circumstance that led to failure for the first efforts to produce treatments capable of clearing AGEs.

Chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as glycoxidation, are responsible for protein molecular aging. Carbamylation is a more recently described NEPTM that is caused by the nonenzymatic binding of isocyanate derived from urea dissociation or myeloperoxidase-mediated catabolism of thiocyanate to free amino groups of proteins. This modification is considered an adverse reaction, because it induces alterations of protein and cell properties. It has been shown that carbamylated proteins increase in plasma and tissues during chronic kidney disease and are associated with deleterious clinical outcomes, but nothing is known to date about tissue protein carbamylation during aging.

To address this issue, we evaluated homocitrulline rate, the most characteristic carbamylation-derived product (CDP), over time in skin of mammalian species with different life expectancies. Our results show that carbamylation occurs throughout the whole lifespan and leads to tissue accumulation of carbamylated proteins. Because of their remarkably long half-life, matrix proteins, like type I collagen and elastin, are preferential targets. Interestingly, the accumulation rate of CDPs is inversely correlated with longevity, suggesting the occurrence of still unidentified protective mechanisms. In addition, homocitrulline accumulates more intensely than carboxymethyl-lysine, one of the major advanced glycation end products, suggesting the prominent role of carbamylation over glycoxidation reactions in age-related tissue alterations. Thus, protein carbamylation may be considered a hallmark of aging in mammalian species that may significantly contribute in the structural and functional tissue damages encountered during aging.

Thursday, December 31, 2015

This open access review looks over present work on the engineering of new bone tissue, created from a patient's own cells, and the state of progress towards clinical availability. For most people the greatest problem with bones is the loss of strength and resilience that occurs in later life. One can hope that work presently largely focused on regrowing bone lost to physical damage or surgery will lead to a much greater understanding of the relevant cellular biology along the way, which in turn will uncover ways to restore strength to bone tissue in the old.

Medical advances have led to a welcome increase in life expectancy. However, accompanying longevity introduces new challenges: increases in age-related diseases and associated reductions in quality of life. The loss of skeletal tissue that can accompany trauma, injury, disease or advancing years can result in significant morbidity and significant socio-economic cost and emphasise the need for new, more reliable skeletal regeneration strategies. Current approaches to replace or restore significant quantities of lost skeletal tissue come with substantial limitations and inherent disadvantages that may be harmful. Tissue engineering and regenerative medicine have come to the fore in recent years with new approaches for de novo skeletal tissue formation in an attempt to address the unmet need for bone augmentation and skeletal repair. These approaches seek to harness stem cells, innovative scaffolds and biological factors to create, ideally, robust, reproducible and enhanced bone formation strategies to improve the quality of life for an ageing population.

A wealth of in vitro data over the last four decades has elucidated invaluable information on the molecular and cellular mechanisms involved in osteogenic repair, and the more recent development of complex, multicellular, three-dimensional models has significantly enhanced our understanding of osteogenesis and bone healing. However, these techniques remain unable to mimic the cellular, molecular, physiological and biomechanical intricacies present at the whole organism level. Critical aspects in bone repair such as the presence of a vascular network and biomechanical stimulation have proven difficult to reproduce outside of the living organism.

To date, stem cell therapy is hampered predominantly by our limited understanding of skeletal stem cells. There is a need for facile, safe and efficacious protocols of stem cell isolation and expansion together with enhanced bioinformatics knowledge on the phenotypic 'fingerprint' of the skeletal stem cell at a single-cell resolution and the generation of skeletal cells from pluripotent stem cell sources. It is likely new cell approaches and the development of 'smart' hydrogels, able to temporally and spatially control growth factor release to render safe and efficacious growth factor use in stimulation of fracture healing and arthrodesis, are areas that will see significant development. The next 5 to 10 years will see intense interest in the potential of additive manufacture to produce synthetic multiphasic scaffolds in which the internal architecture and topography are analysed for cartilage and bone regeneration requirements.

Friday, January 1, 2016

Researchers here uncover more details of the role of SOD1 in killing cells in amyotrophic lateral sclerosis (ALS). Many degenerative conditions are associated with proteopathy, cell damage and death caused by the abnormal clumping or misfolding of specific proteins. The caveat with this research, as for many similar lines of work, is that it results from investigations of individuals with a mutation that predisposes them to suffer the disease. The mechanisms outlined here may or may not also be central and important to the development of ALS in genetically normal individuals, but given what is known to date it seems promising.

Patients with ALS suffer gradual paralysis and early death as a result of the loss of motor neurons, which are crucial to moving, speaking, swallowing, and breathing. The study focuses on a subset of ALS cases - an estimated 1 to 2 percent - that are associated with variations in a protein known as SOD1. However, even in patients without mutations in their SOD1 gene, this protein has been shown to form potentially toxic clumps. The researchers discovered that the protein forms temporary clumps of three, known as a "trimer," and that these clumps are capable of killing motor neuron-like cells grown in the laboratory. "This is a major step because nobody has known exactly what toxic interactions are behind the death of motor neurons in patients with ALS. Knowing what these trimers look like, we can try to design drugs that would stop them from forming, or sequester them before they can do damage. We are very excited about the possibilities."

Researchers zeroed in on SOD1 after genetic mutations affecting the protein were linked with ALS in the early 1990s. But the exact form of aggregated protein that is responsible for killing neurons has been hard to identify, and many of the clumps that are thought to be toxic disintegrate almost as soon as they form, making them exceedingly difficult to study. "It is thought that part of what makes them so toxic is their instability. Their unstable nature makes them more reactive with parts of the cell that they should not be affecting." Until now, researchers did not know what these fleeting clumps looked like or how they might affect cells.

To crack the mystery, the research team used a combination of computational modeling and experiments in live cells. Researchers spent two years developing a custom algorithm to determine the trimers' structure, an aspect of the study akin to mapping the structure of a ball of yarn after taking snippets of just its outermost layer and then figuring out how they fit together. Once the trimers' structure was established, the team spent several more years developing methods to test the trimers' effects on motor neuron-like cells grown in the laboratory. The results were clear: SOD1 proteins that were tightly bound into trimers were lethal to the motor neuron-like cells, while non-clumped SOD1 proteins were not. The team plans to further investigate the "glue" that holds the trimers together in order to find drugs that could break them apart or keep them from forming.

Friday, January 1, 2016

Gene therapy is going to be very influential in medicine of all types in the next few years, and this is due to the advent of CRISPR, a cheap and reliable genetic editing technology. However, while it is reliable in embryos, since researchers only have to ensure coverage of a small number of cells to create a change that will later be present throughout the whole of the adult body, obtaining that same coverage in a therapy delivered to adults has been a challenge. If a gene therapy fails to change a large enough percentage of cells in an adult individual, then it will have no useful effect. Hence we should be watching for progress on this front.

The research results linked here focus on an inherited disorder with no relevance to aging, but the importance lies in the delivery mechanism and its demonstration, not the therapeutic goals. It is an example of a methodology for adult gene therapy with CRISPR that is (a) easy to carry out for existing labs and (b) generates good tissue coverage in adults. This is significant: it means that all of the gene therapies we might like to carry out as treatments to compensate for age-related damage and decline, such as myostatin deletion to boost muscle growth, adding extra lysosomal receptors to better clear out damage in old tissues, or moving mitochondrial genes to the cell nucleus, are now much more technically feasible. Progress is presently very rapid in this space.

Researchers had previously used CRISPR to correct genetic mutations in cultured cells from Duchenne muscular dystrophy patients, and other labs had corrected genes in single-cell embryos in a laboratory environment. But the latter approach is currently unethical to attempt in humans, and the former faces many obstacles in delivering treated cells back to muscle tissues. Another approach, which involves taking CRISPR directly to the affected tissues through gene therapy techniques, also faces challenges, particularly with delivery. In the new study, researchers overcame several of these obstacles by using a non-pathogenic carrier called adeno-associated virus, or AAV, to deliver the gene-editing system.

To use viruses as delivery vehicles for gene therapy, researchers take all the harmful and replicative genes out of the virus and put in the therapeutic genes they want to deliver. While early virus types didn't work well for various reasons, such as integrating into the genome and causing problems or triggering immune responses, AAV thus far has proven special. It's a virus that many people are exposed to anyway and is non-pathogenic, but still exceptionally effective at getting into cells. AAV is in use in many late-stage clinical trials in the United States, and has already been approved for use in one gene therapy drug in the European Union. There are also different versions of AAV that can preferentially go to different tissues, such as skeletal and cardiac muscle, so researchers can deliver them systemically.

But there's always a catch. "AAV is a really small virus and CRISPR is relatively large. It simply doesn't fit well, so we had a packaging problem." The solution came from a CRISPR system in a different bacterium than the one commonly used. In the natural bacterial immune system, CRISPR is the mug shot that helps identify the target DNA, and Cas9 is the blade that slices the strands. The large Cas9 protein typically used by researchers comes from the bacterial species Streptococcus pyogenes. After scouring the bacterial kingdom, researchers discovered the much smaller Cas9 protein of Staphylococcus aureus - small enough to fit comfortably inside of AAV.

In the study, researchers worked with a mouse model that has a debilitating mutation on one of the exons of the dystrophin gene. They programmed the new CRISPR/Cas9 system to snip out the dysfunctional exon, leaving the body's natural repair system to stitch the remaining gene back together to create a shortened - but functional - version of the gene. Researchers first delivered the therapy directly to a leg muscle in an adult mouse, resulting in the restoration of functional dystrophin and an increase in muscle strength. They then injected the CRISPR/AAV combination into a mouse's bloodstream to reach every muscle. The results showed some correction of muscles throughout the body, including in the heart - a major victory because heart failure is often the cause of death for Duchenne patients.


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