Fight Aging! Newsletter, September 29th 2014

September 29th 2014

Herein find a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress on the road to bringing aging under medical control, the prevention of age-related disease, and present understanding of what works and what doesn't when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Our SENS Fundraiser Starts this Week on Longevity Day, October 1st
  • Strive to Live or Strive to Die, But at Least Do Something, Show a Little Agency in the Matter
  • Further Altering GHRKO Mice to Determine the Necessary Mechanisms of their Longevity
  • Demonstrating Decellularized Heart Valves
  • A Summary View of Everything in Modern Longevity Science Except the Work that Really Matters
  • SENS Research Foundation Newsletter, September 2014
  • Latest Headlines from Fight Aging!
    • Insight into Peter Thiel's Support of Longevity Science
    • Telomerase has an Off Switch
    • A New Approach to Targeting Metastasis in Cancer
    • Testing a Bioartificial Liver
    • Proposing Combination Gene Therapy to Slow Aging
    • Using Songbird Brains to Investigate Regenerative Neurogenesis
    • The Glenn Research Consortium Continues to Grow
    • Nanogel Scaffolding and Cellular Heart Patches
    • Altered Myeloid Microglia Improve Alzheimer's Symptoms
    • How Does Tau Protein Accumulation Harm Brain Cells in Age-Related Neurodegenerative Conditions?


Wednesday October 1st is the International Day of Older Persons, and the International Longevity Alliance would like to make it Longevity Day as well. This is a time each year to draw attention and raise funds for research aimed at preventing and reversing the harms caused by aging. It is a good day to start our fundraiser in support of the SENS Research Foundation and its ongoing rejuvenation research programs. Christophe and Dominique Cornuejols, David Gobel of the Methuselah Foundation, Dennis Towne, Håkon Karlsen, philanthropist Jason Hope, Michael Achey, Michael Cooper, and Reason of Fight Aging! are all long-time supporters of SENS research to repair and reverse the known causes of aging. For every dollar donated to the SENS Research Foundation before the end of 2014, we will will donate an additional $2 from the matching fund we have assembled. Come Wednesday, please join us in making a difference and speeding progress towards the end of age-related frailty, pain, and suffering.


There will always be naysayers when it comes to the prospects for enhanced health and longevity: people who claim that they want to die younger than they might, that they don't want to do anything about the aging process, and that they'll be content with a lifespan that is the same as their parents and their peers. They tend to say all this while materially benefiting from medical technologies that didn't exist for their parents and grandparents, and the fact that a great many people presently say that they don't want to extend their lives through advances in medicine has a lot to do with the fact that the necessary technologies don't yet exist. They are just around the corner, a few decades away, something that needs work and advocacy and funding support to come in to existence.

If rejuvenation treatments after the SENS model existed in the clinic, providing accessible ways to turn back aging and live in good health for decades longer, then I think that the number of naysayers would be much smaller. Consider the modest population of people who today refuse a range of effective, proven forms of medical care for religious or other reasons and suffer as a consequence. They are very much in the minority. That is the future for people who decide not to undertake treatment of their aging process: there won't be many of them once rejuvenation treatments are a reality for all the same bland cultural reasons that exist today. It is done because most people do it, and that is the way of things whether it involves helping yourself with medicine or hurting yourself with cigarettes and too many calories.

All of this presents quite the obstacle when we are right on the verge of promising new medicine to address aging, standing at the point at which support is needed for rapid progress towards the creation of effective treatments capable of reversing the specific root causes of age-related disease. All too few people are willing to stand up in public to say "go for it!", and for every one of those someone else dolefully touts the path of resignation, relinquishment, and aging to death on a predetermined schedule. It is probably extremely charitable to believe that any of these people would hold the same views were they born fifty years later: they'd be using health assurance treatments that repair metabolic damage to hold back aging and maintain youthful health and vigor just like near everyone else.

Still, there will always be naysayers. Just not so many of them as there are today. The fellow quoted below seems to me to be touting a position that is the result of a profound failure of the imagination and ambition. He fails to see that the current state of medicine for the elderly is the outcome of failing to treat the causes of aging, but rather just trying to shore up the consequences. That never works well: you can't make a failing machine work well unless to address the cause of failure. He fails to mention that the field is changing to move in that direction: the future of treatments for age-related disease and trends in healthy life span will have little to do with the past. A discontinuity is coming as the result of a change in fundamental strategy coupled with a sudden leap in the capabilities of biotechnology over a few short decades. Further, I really have to complain about anyone who claims that refusing medical care in late life equates to "going quietly." That the unassisted end of life is a simple fade to black is a malicious lie propagated by those who, for often petty reasons, like to keep the suffering in this world behind curtains and out of sight. The end of old age is painful, bloody, drawn out, and horrible. Many of the options include some of the worst things that can happen to anyone, and that process as a whole happens to everyone.

Why I Hope to Die at 75

That's how long I want to live: 75 years. I am sure of my position. Doubtless, death is a loss. It deprives us of experiences and milestones, of time spent with our spouse and children. In short, it deprives us of all the things we value. But here is a simple truth that many of us seem to resist: living too long is also a loss. It renders many of us, if not disabled, then faltering and declining, a state that may not be worse than death but is nonetheless deprived. It robs us of our creativity and ability to contribute to work, society, the world.

I am talking about how long I want to live and the kind and amount of health care I will consent to after 75. Americans seem to be obsessed with exercising, doing mental puzzles, consuming various juice and protein concoctions, sticking to strict diets, and popping vitamins and supplements, all in a valiant effort to cheat death and prolong life as long as possible. This has become so pervasive that it now defines a cultural type: what I call the American immortal. I reject this aspiration. I think this manic desperation to endlessly extend life is misguided and potentially destructive. For many reasons, 75 is a pretty good age to aim to stop.

Once I have lived to 75, my approach to my health care will completely change. I won't actively end my life. But I won't try to prolong it, either. Today, when the doctor recommends a test or treatment, especially one that will extend our lives, it becomes incumbent upon us to give a good reason why we don't want it. The momentum of medicine and family means we will almost invariably get it.

Doctors wanted to extend life. Instead they extended death

There's this idea that as we grow older we'll be healthier. I call it the rectangularization of life. You go on as healthy as you've always been and then at the end you just fall off a cliff and die of a heart attack or stroke or something. But over the last 30 years the data has said the opposite. As we add years of life we're adding more years of life with disabilities. We are saving more people who have strokes. That's a triumph. But the consequence is people are living after strokes and they typically have disabilities - they have speech problems or cognitive problems. There's a tradeoff. We have extended the dying process.

This is a view of a future of stasis. If you think that it is going to be more of the same, forever and always, then one might ask what the point of it all is. Nihilism starts with "why live longer," and moves on to "why live at all," but people making arguments like those quoted above are to my eyes living in an incoherent half-way house somewhere distant from any point of actual conviction. Live if you want to live. Die if you want to die. But above all do something about it, don't just lie back in your chair and exist or fail to exist at the whim of fate and the machinations of your own cells. Show some agency.


Growth hormone receptor knockout (GHRKO) mice are one of the longest-lived genetically engineered mouse lineages produced to date, and this is one of the few interventions that can slow aging and extend life to a greater degree in mice than is possible via the practice of calorie restriction. It produces dwarf mice with low body temperatures and improved insulin metabolism, alongside a range of other improvements such as greater stress resistance, reduced inflammation, increased reservoirs of pluripotent stem cells, and improved genome maintenance. It is worth recalling, however, that it seems much easier to extend life in short-lived species such as mice. There is a human population with a growth hormone receptor mutation that has a similar impact, people who have inherited Laron-type dwarfism. These individuals do not appear to live any longer than the rest of us, however, though they may be more resistant to some age-related disease.

Pursuing ways to slow down aging through alteration of metabolism is a poor strategy for the future of our health and longevity, and one of the reasons why this is the case is that it is an immensely complex undertaking, and we stand more or less at the beginning of it. The intersection of metabolism and aging is still only just beginning to be cataloged, and even for noted and comparatively well-studied ways to slow aging in mammals in the laboratory - such as GHRKO - it is still an open question as to how it actually works. Just for this one method, one single alteration to a single gene, years of hard work and funding have passed just to get to the point at which I can say "this has barely started." There is enough here in the effects of this single gene to keep teams of researchers occupied for years to come, and at a great cost. We've seen this elsewhere too, in the billion dollars consumed by work on a few sirtuin genes and their possible role in calorie restriction. Yet at the end of the day, we shouldn't expect to see practical results emerge. Knowledge, yes, but not great lengthening of life or reversal of aging. We already know what happens in humans when you disable the function of the growth-hormone receptor, and it isn't anything to write home about.

The knowledge is interesting, however. Just bear in mind that this isn't rejuvenation research: it is exploring how and why the natural pace of aging is somewhat plastic, and detailing the important mechanisms involved. To use an analogy, it tells us how we can marginally affect engine failure rates in cars with choice of oil and driving routes. It says nothing about how to periodically repair wear and damage so as to extend prime operational life far beyond the natural outcome of leaving an engine alone to fail in its own time. If you want repair and reversal of aging, you need to look to the sorts of research approaches detailed in the SENS outline rather than investigations of the details of the progression of aging, most of which deal with operation while being somewhat irrelevant to repair.

Specific suppression of insulin sensitivity in growth hormone receptor gene-disrupted (GHR-KO) mice attenuates phenotypic features of slow aging

Insulin sensitivity, defined as the efficacy and kinetics of glucose clearance from the blood, is highly positively correlated to modifications of longevity, whether induced by genetic or dietary interventions, and many studies of long-lived mutants have investigated their insulin sensitivity and related it to their enhanced survivorship. Although there is a wealth of data showing a clear association between the two, the proffered mechanisms for how insulin sensitivity might engender longevity are few, and those that have been proposed remain untested. Endeavoring to address multiple aging-associated maladies by study of the basic biology of longevity, as outlined in the concept of the Longevity Dividend, we investigated the positive association between insulin sensitivity and retained healthspan.

Increased insulin sensitivity and efficient homeostatic control of blood glucose have been associated with extended survival and retention of good health and functionality in exceptionally long-lived mice and humans (centenarians and long-lived families). Over the past fifteen years, the concept of an endocrinological component to the regulation of longevity has been substantiated by a considerable number of studies integrating endocrinology and gerontology. We have conducted many associative studies of this type with long-lived, somatotrophic signaling-defective mutant mice; we now progress to the first steps in testing the necessity for enhanced insulin sensitivity for the delayed senescence of these mice or the sufficiency of improved blood glucose homeostatic control for delayed aging in their normal counterparts.

The GHR-KO mouse has multiple, gerontologically intriguing characteristics, including increased circulating GH concentration, conversely decreased GH hormonal signaling, decreased circulating IGF-1 concentration, decreased body size, obesity, and altered endocrine function. In order to exclusively test whether the insulin sensitivity due to decreased insulin production/secretion in the GHR-KO mouse is necessary for the delayed and decreased pace of senescence of this mouse, we have used a GHR-KO mouse that carries a transgene driving expression of rat Igf-1 under the potent, β-cell-expression-enriching rat insulin promoter 1 (RIP) (the GHR-KO;RIP::IGF-1 double mutant). This transgene partially corrects the reduction in pancreatic islet cell mass and size present in the GHR-KO mouse, potentially increasing blood insulin levels and thus decreasing insulin sensitivity. If decreased β-cell production and/or secretion of insulin is necessary for the full longevity of the GHR-KO mouse, then a GHR-KO mouse with partially normalized β-cell production of insulin should age sooner/faster than a standard GHR-KO mouse.

The insulin sensitivity-suppressed GHR-KO;RIP::IGF-1 double mutant differs from the GHR-KO mouse in slow-aging-related parameters but in few, if any other, characteristics. This supports the hypothesis that enhanced insulin sensitivity is necessary for the retardation of senescence in the GHR-KO mouse. Lifespan was not assessed as part of our study. Future analyses of whether GHR-KO;RIP::IGF-1 mice live shorter than their standard GHR-KO counterparts, as the data that we have presented would suggest, are clearly required.

The objective of this study was to test the hypothesis that the insulin sensitivity of the GHR-KO mouse is causal in the decreased rate of aging of this long-lived animal. Employing a twenty-fold range of insulin concentrations, we showed that the RIP::IGF-1 transgene normalizes the widely studied insulin sensitivity of slow-aging GHR-KO mice. Although there were other blood glucose regulation-related phenotypes engendered by the transgene, it is this normalization effect on insulin responsiveness that provided the basis for testing the potential effect of the transgene on other slow-aging-associated characteristics.

You'll find a lot of details in this open access paper, but I think the telling one is that the GHRKO mice with additional insulin ate more. The effects of calorie intake on life span in mice are large in comparison to most others, and probably make this work of little value beyond pointing the way to trying again but with calorie controlled diets this time. The hypothesis that insulin metabolism drives alterations in natural longevity is an interesting one, and has a lot of supporting evidence, but if more conclusively proven it just moves the point of investigation one step deeper into the operation of metabolism. One has to again ask "why?" and spend much money and time to make the next step.

Bearing in mind that investigations of insulin, IGF-1, and aging have been ongoing for a couple of decades in earnest, it becomes very clear that this is no way to work effectively on extending human life and addressing the causes of aging in the near term. A better path and more efficient forward is very much needed. Fortunately it exists in the form of SENS, only needing the research community and its extremely conservative funding institutions to buy in to a greater degree.


Decellularization of donor organs and tissue sections has been demonstrated in laboratory animals and trialed in humans for some years now. It is clearly an improvement over straight organ donation in that it greatly reduces transplant rejection, and may even put a dent in the issue of organ availability by allowing the xenotransplantation of pig organs repopulated with human cells.

Absent some bold, unexpected, and rapid advances in tissue engineering, I would expect that decellularization will become the mainstay technology for organ and tissue transplantation for the next two decades or so. The process of removing cells from tissue while leaving behind the extracellular matrix and its chemical guides is comparatively simple and it dovetails well with present progress in control over stem cells and cell growth, enabling emptied organs to be reliably repopulated with a patient's own cells and made to work once again. Further, it circumvents a very hard problem, which is to say the challenge of creating an artificial scaffold that works as well as a biological extracellular matrix for these purposes. That has only been effectively achieved for small amounts of comparatively simple tissues such as muscle, and even there the real thing is generally better. There is a way to go yet in tissue engineering before decellularization will cease to be an extremely useful technology.

These publicity materials note recent work on engineering replacement heart valves for children using decellularized tissues, something that was being done in Europe far back as six years ago. Research proceeds on an uneven front, and some groups are always years out in front of others. This is but one among many applications of decellularization that will follow in the years ahead, and the expertise and inclination to follow this path is spreading, albeit more slowly than we'd all like.

Skin Cells Can Be Engineered Into Pulmonary Valves for Pediatric Patients

Researchers have found a way to take a pediatric patient's skin cells, reprogram the skin cells to function as heart valvular cells, and then use the cells as part of a tissue-engineered pulmonary valve. "Current valve replacements cannot grow with patients as they age, but the use of a patient-specific pulmonary valve would introduce a 'living' valvular construct that should grow with the patient. Our study is particularly important for pediatric patients who often require repeated operations for pulmonary valve replacements." While the study was conducted in vitro (outside of the body), the next step will be implanting the new valves into patients to test their durability and longevity.

Engineering Patient-Specific Valves Using Stem Cells Generated From Skin Biopsy Specimens

We generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblast cells. We then differentiated iPSCs to mesenchymal stem cells (iPCSs-MSCs) using culture conditions that favored an epithelial-to-mesenchymal transition. Next, decellularized human pulmonary heart valves were seeded with iPCS-MSCs using a combination of static and dynamic culture conditions and cultured up to 30 days. Our results demonstrate the feasibility of constructing a biologically active human pulmonary valve using a sustainable and proliferative cell source. The bioactive pulmonary valve is expected to have advantages over existing valvular replacements, which will require further validation.

Ultimately even very sophisticated transplants are a stepping stone technology: no-one really wants to be opened up for surgery if there are better alternatives. The better alternative will probably emerge naturally as control over cells continues to evolve. Don't build the ship outside the bottle if you can build it inside the bottle. Find ways to control the necessary regrowth and regeneration of damaged organs in situ by making the cells already present in the body perform the needed actions in concert. That lies a way beyond decellularization as a practical and going concern, widespread in hospitals and clinics, but not a very long way beyond.


There are three classes of aging research, in order of decreasing size and funding: firstly the work that only investigates and catalogs aging, with no attempt to intervene; secondly work on ways to slow aging through metabolic and genetic alteration, which is doomed to very expensive and very slow progress to a marginal end result; and lastly work on repairing the cellular and molecular damage that causes aging. The latter is the only practical path forward to greatly extending healthy life and defeating age-related disease soon enough to matter for those of use reading this today. After a decade of advocacy to get to the present point of the existence of multiple labs and organizations such as the SENS Research Foundation explicitly funding work on rejuvenation biotechnology, if it has 1% of the funding of work on slowing aging, I'd be surprised. Work on slowing aging might in turn have 1% of the funding directed to merely studying aging. It is a frustrating situation, and must change.

The mainstream of modern research is steered by regulation into the inefficient process of examining late-stage mechanisms in disease and then working backwards. Since commercial development is only permitted to treat named diseases, and since putting potential treatments through the regulatory process generally requires demonstration of a comprehensive understanding of the relevant underlying biological mechanisms, the whole pipeline all the way back to funding for fundamental research is geared towards producing marginal impact on late stage disease in the most difficult way possible. Researchers struggle to understand the very complicated final stages of the disease process, with all its attendant confusion and interacting mechanisms of degeneration, and pull out some way to try to make our biological machinery work better while horribly damaged.

This is of course far from the best way to proceed for any machine, biological or not. The best way is to start with the much simpler roots of dysfunction, the damage that accumulates initially as a consequence of the ordinary operations of biological machinery, and block it before it spirals out into all sorts of different forms of dysfunction. Researchers know what that damage is - a list exists, well supported by evidence - and most of the arguments over how important it is and how exactly it connects to age-related disease could be settled by simply repairing that damage and observing the consequences. Working forwards in this way is a much, much cheaper prospect than trying to work backwards in the way forced by present regulation. Yet of course it is not the mainstream.

In fact, the approach of repairing the damage that causes aging is so very much not the mainstream that summary reviews of the state of the field such as the one quoted below can omit it entirely, focusing only on ways to alter metabolism to maybe slow down aging just a little bit. This is the real fight in the field of aging research now and for the next decade or two, the only important battle to my eyes: whether the research community (a) keeps on spending vast sums to better understand the fine details of how aging progresses while at the same time failing to do much of anything to actually help people, or whether (b) more than the present small minority of researchers wake up and turn to the better course of repairing damage, the course that offers a real chance of defeating degenerative aging and preventing the suffering and illness of old age.

Thus this review is not really a review of aging research; it is a review of work on slowing aging only, which is not all but rather only near all of the work presently aimed at intervening in the aging process. It is my believe that slowing aging is ultimately destined to be a dead end, producing only knowledge and no treatments of real value: it is most likely so very much harder and less productive than the repair approach that it will be displaced, but the repair approach is so much earlier in its development and funded to a fraction of the same level that it is taking time for this to become self-evident. So this is a review written from the position that repair of the causes of aging is not an option and that all we can really do is alter metabolism to slow the onset of damage. This is simply not the case, but those who hold to that position are right to assume that, by their metric and on their road, progress in the future will be hard, slow, and produce only marginal benefits.

Aging Research - Where Do We Stand and Where Are We Going?

The magnitude of the challenge is illustrated by considering known causes of aging. The good news is that many mechanisms causing aging, as well as pathways that can mitigate effects of aging, have been identified. This is also the bad news - aging processes and pathways offering an ability to modify their effects are extremely complex. It is widely assumed that aging is a major risk factor for most late-onset diseases (cancer, cardiovascular disease, diabetes, neurodegenerative diseases, etc.), and therefore interventions directed at aging offer an opportunity to ameliorate all these diseases at once. Although this idea has attracted much attention, we must also consider that the complexities of aging processes likely exceed those of specific diseases, and the challenge of reigning in the global decline of cellular processes across many tissues will be large.

We may have but scratched the surface of what bioinformatics can provide in identifying new genes and pathways important in human aging, as well as allowing for the knowledge we have already gained to be applied in a more effective, personalized way. Analysis of the transcriptome, epigenome, and proteome of individuals spanning a wide age range will provide the most detailed phenotyping of human aging so far.

If the genes and pathways that seem to correlate with slow or fast aging can be thus identified by big data analysis, resulting hypotheses about brain aging may be tested by conducting field studies. Possible treasure troves are the various long-term human longitudinal studies, which provide a cornucopia of health information spanning decades and, in some cases, provide access to genotyping. This may potentiate testing whether genetic haplotypes that correlate with slow or rapid aging identified bioinformatically exert predictable effects in a human population over the course of a lifetime. For example, one might test whether haplotypes correlating with slow molecular brain aging protect against cognitive decline or neurodegenerative diseases in these longitudinal studies.

The past two centuries have witnessed advances at many levels that allow people to live longer and more productive lives. I have attempted to place current research on the biology of aging into this context and have arrived at a few predictions. First, it will be more achievable and desirable to extend human health span rather than life span per se. Changes in maximum human life span will, in my opinion, be quite difficult to achieve and will take many years to even assess. From the point of view of economic and societal benefits, striving to make people healthier longer without necessarily extending their maximum life span may be the wisest course. Put another way, the nightmare scenario would be to extend maximum human life span without extending health span.

Second, bioinformatics will play a substantial role in the progress of aging research, especially as it applies to humans. There may already be buried in the sea of ever-increasing human genomic data novel clues about genes and pathways that govern aging in different tissues. In this regard, it remains to be seen how much of aging will prove to be systemic and affect all tissues simultaneously emanating from brain signals, for example, and how much will be tissue autonomous.

Third, aging and the genes and pathways that govern its effects are complex. It is not likely that there will be a silver bullet for aging any more than there will be a silver bullet for cancer. However, there will likely be novel pharmaceutical interventions for the effects of aging emerging directly from aging research. These interventions may need to be tissue specific, taking into account the personalized way aging impacts an individual tissue-by-tissue. Overall, it is an exciting, albeit uncertain, time to speculate how human health will be impacted in the decades to come by research on the biology of aging.


The latest news from the SENS Research Foundation turned up in my inbox today. The Foundation is perhaps the only organization in the world today that is organizing and funding serious scientific work on prevention and reversal of aging. Near every other funding organization and research group aiming to intervene in the aging process, and there are far too few of those by the way, are working on the foundation of ways to slow aging, not halt it or reverse it. Unfortunately this is the wrong path to produce results in the near term. Think in terms of metal machinery failing due to rust: the slow aging crowd wants to build an machine that rusts more slowly by altering the properties of its component parts and the metals it is made of. The prevention and reversal approach, by comparison aims at removing rust and rust-proofing - which is a much easier path, focusing on a much less complex and far better understood problem space.

To return to our biology, the rust in this analogy corresponds to the small number of types of fundamental damage to cells and molecular machinery that accumulate as a result of the ordinary operation of metabolism. The slow aging crowd are looking into the very expensive process of learning enough about altering the way in which our metabolism works in order to slow down the pace of damage. The research community has barely started on establishing the knowledge needed to do this, and even getting to the present point has required years and billions of dollars. There will be decades and tens of billions ahead before any sort of meaningful result will emerge, and even when it does it will be of no use to old people. What help is slowing down damage when you are already so damaged that you are close to death?

In comparison to metabolism, the rust - the cellular and molecular damage that causes aging - is simple. The results are only complicated because we are complicated. Further, these forms of damage are comparatively well understood and enumerated. The research community knows enough to be able to propose detailed research plans leading to repair therapies. That is far more than can be done for ways to slow aging. Repair is the better path, more cost-effective, and the end goal far more effective for patients, and yet so very few groups are working on it. This is why our support for the SENS Research Foundation is very important. Their work must receive enough funding to demonstrate its worth beyond any doubt and thus be adopted by all those other groups presently working on the slow road to nowhere.

On to the newsletter, which notes that the Foundation will be a sponsor for the forthcoming World Stem Cell Summit. You might recall that last year's meeting was where the Methuselah Foundation announced the New Organ Liver Prize.

SENS Research Foundation is proud to be a Bronze Level Sponsor of this year's World Stem Cell Summit. The World Stem Cell Summit is the largest global meeting of stem cell science and regenerative medicine stakeholders. Attendees enjoy unequaled opportunities for networking, collaboration, new partnerships, and shaping the future of this rapidly advancing field. The WSCS will be held December 3-5, 2014, at the Marriott RiverCenter, San Antonio, TX, USA. SRF CSO Dr. Aubrey de Grey will be moderating a panel at the conference.

As always the question of the month section is well worth reading. One of the present themes of the Foundation's work, illustrated by the recent Rejuvenation Biotechnology 2014 conference, is establishing the necessary relationships between research and industry that will enable a smooth transition from lab to clinic of the first prototype treatments for the causes of aging. It takes years to lay groundwork, so best to start now.

Question of the Month #6: Meeting The Challenges of the Regulatory Maze and Getting Rejuvenation Biotech Into the Clinic

Q: In response to a previous question of the month, you explained why the fact that "aging" is not recognized as a "disease" for which the FDA and other regulatory bodies license therapies should not actually pose a significant hurdle to getting rejuvenation biotechnologies licensed and into widespread use. But there was a lot of discussion at the recent Rejuvenation Biotechnology 2014 Conference about the challenges to rejuvenation biotechnology posed by current regulatory structures and some gestures toward what might be needed to advance the science into the clinic. Would you spell those out?

A: Rejuvenation biotechnologies are a new approach to preventing and treating the diseases and disabilities of aging, based on the repair and maintenance of the cellular and molecular structures that become damaged over time. Degenerative aging processes occur all across our bodies as this damage accumulates in particular tissues; the "diseases" that emerge in our bodies late in life are simply the recognizable impairment of organ-specific function resulting from the gradual build-up of this damage.

This approach is so new that it is not very well-served by current regulatory structures, which mostly assume the presence of an existing disease, and that drugs will either alleviate current symptoms, or will intervene in metabolic pathways that perpetuate aspects of abnormal function without having any effect on the underlying damage that causes it.

Several regulatory changes would help to bring rejuvenation biotechnologies into clinical trials and then into widespread use. One is to reverse the sequence in which rejuvenation biotechnologies are tested.

First, there are several states of ill health driven by the degenerative aging process that are clearly extremely disabling and deadly, but that are not yet recognized as "diseases" by the FDA. The most glaring of these is sarcopenia (or, some have argued, "dynapenia"): the age-related loss of muscular strength that results from the combination of loss of muscle mass, and the degradation of the cellular and molecular integrity of what muscle remains. Sarcopenia is highly disabling, restricts people's ability to take care of themselves, increases the risk of accidents and fractures, and is strongly linked to increased risk of death - but it is not yet a licensed "disease" indication.

Fortunately, the FDA seems to be open to the idea of developing a new indication for therapies that combat sarcopenia, and several pharmaceutical companies are working in the field. There have now been several scientific conferences and high-level summit meetings in which senior FDA officials, sarcopenia researchers, and major pharmaceutical companies have worked toward defining diagnostic criteria and suitable outcomes for licensing anti-sarcopenia drugs. The sooner they succeed, the better.

Second: today, new drugs are usually first tested in patients with existing disease. Regulatory approval depends on the drug showing a clear impact on clearly-defined, hard clinical outcomes such as heart attacks or progression to dialysis. Over time, many therapies initially approved on this basis later come to be used in a more preventive approach in high-risk patients without overt disease, through a mixture of informal practice and clinical trials. This occurred, for example, with statins, antihypertensives, and antidiabetics.

Unfortunately, this progression begins to yield useful data too late in the pathological process to optimally test rejuvenation biotechnologies. Our goal is to develop therapies that will keep people's tissues sufficiently healthy and functional that such late-stage pathologies do not occur. Thus, we will want to test these therapies in patients not yet exhibiting overt disease, with minimal or no symptoms and no near-term risk of death or disability from the disease.

Instead, it would be preferable for regulators to accept the removal, repair, or replacement of cellular and molecular damage itself as an initial goal of clinical trials. The prevention of particular diseases' emergence would then be incorporated in a kind of "conditional licensing" a longer-term goal, perhaps to be monitored in a robust system of postmarket surveillance. This, again, reverses the usual practice in today's regulatory system, where the endpoint is initially a catastrophic patient outcome such as heart attack or stroke, and only later are surrogate outcomes on mediating metabolic factors (such as lowering LDL cholesterol or blood glucose) accepted.

Finally, it would be of tremendous benefit to test rejuvenation biotechnologies in combination with each other from the outset. The normal approval path for a candidate drug entails that it first be tested for effectiveness and safety on its own, or as an add-on to drugs that are already the standard of care. But many specific, diagnosed diseases of aging are actually the clustering together of several forms of aging damage in one or more tissues. Additionally, it is often the case (as with the beta-amyloid protein and aberrant tau species in Alzheimer's disease) that the contributing kinds of aging damage are intertwined with one another in complex causal chains.

In such cases, the removal of only one form of aging damage may not be enough to demonstrate a positive effect on tissue function or disease-related outcomes. If researchers are forced to test individual rejuvenation therapies that each remove only one of these contributing forms of damage in isolation, they may well fail to show any meaningful effect, and be kept out of the hands of doctors and patients - even though they would have indefinitely postponed the disease if tested together.

This potential dilemma could be resolved if complementary rejuvenation biotechnologies - each targeting one of the key lesions driving such a disease state - could be tested in combination from the outset, following the collection of basic safety data, without first having to prove their individual effectiveness in averting catastrophic outcomes.

All of these moves are dramatic departures from the ways that medical therapies are currently tested, approved, and regulated for use. Fortunately, substantial moves in these directions are already afoot in the testing of rejuvenation biotechnologies for Alzheimer's disease and other neurological disorders. We believe that these moves can be supported and normalized, and then used as a template for the testing of rejuvenation biotechnologies generally.


Monday, September 22, 2014

Philanthropist Peter Thiel is one of the patrons of the SENS Research Foundation, perhaps the only organization in the world at this point that is coordinating and funding serious efforts to build rejuvenation treatments. Thiel recently published a book, and by the alchemy involved in these matters we are thus seeing more press of late on his views and the causes he supports:

An hour into my conversation with Peter Thiel the conversation turns, as it seems conversations with Thiel often do, to the question of death. 'Basically,' Thiel says earnestly, 'I'm against it.' What he calls 'the problem of death' is a topic that he returns to often. 'I think there are probably three main modes of approaching it,' he says. 'You can accept it, you can deny it or you can fight it. I think our society is dominated by people who are into denial or acceptance, and I prefer to fight it.'

Thiel is an amiable, softly spoken man who gives the impression of thinking out loud. Questions are frequently greeted with a series of 'ums... aahs... I think... let me put it this way...', beginning a thought, stopping, trying another, and then another, as if he is testing the best way to be as precise as he can possibly be. 'Hobbes said that in the state of nature life is nasty, brutish and short,' he says. 'And, um, I do think we want to overcome the state of nature. It is true that you can say that death is natural, but it is also natural to fight death. But if you stand up and say this is a big problem, we should do something about this, that makes people very uncomfortable, because they've made their peace with death. In some ways it's a microcosm of the whole complacency of the Western world. I do think there is this danger that our society has made its peace with decline. I'd like to jolt them out of their complacency a little bit.'

He has poured millions of dollars into what he calls 'the immortality project'. 'I would like to live longer, and I would like other people to live longer.' His belief is such that he has signed up with Alcor, the leading company in the field of cryonics, to be deep-frozen at the time of his death - as much as an 'ideological statement', he says, as in any expectation of being thawed out any time in the near future. 'In telling you that I've signed up for it cryonics, there's always this reaction that it's really crazy, it's disturbing. But my take on it is it's only disturbing because it challenges our complacency.'

He is, as you might expect, a definite optimist. Thiel believes there will be a cure for cancer in the next 20 years, and that a cure for Alzheimer's is within reach. Immortality, he allows, may take a little longer. He has given more than $6 million to support the work of Aubrey de Grey, the English gerontologist who co-founded the Methuselah Foundation, and is now the chief research scientist of SENS Research Foundation (Strategies for Engineered Negligible Senescence). De Grey has famously pronounced that he believes the first person to live to 1,000 is already alive today.

The 'life extension project', Thiel says, is as old as science itself. 'It was probably even more important than alchemy. Finding élan vital, the water of life, was of greater interest than finding something that could transmute everything into gold. And I do think people would prefer immortality to lots of gold. On a fundamental level, the question is whether ageing can be reversed or not. Many biological processes appear to be irreversible, but computational processes are reversible. If it is possible to understand biological systems in informational terms, could we then reverse these biological processes, including the process of ageing? I do think that the genomics revolution promises a much greater understanding of biological systems and opens the possibility of modifying these seemingly inevitable trajectories in far more ways than we can currently imagine.' So immortality may be possible? 'Well, "immortal" is a long time.

'There are many arguments against life extension, and they all strike me as extraordinarily bad: it's not natural; there will be too many people; you will be bored. But I don't think it would be boring at all.' He pauses. 'People always say you should live your life as if it were your last day. I think you should live your life as though it will go on for ever; that every day is so good that you don't want it to end.'

Monday, September 22, 2014

Telomerase is the enzyme responsible for lengthening telomeres, caps of repeating DNA sequences at the end of chromosomes. Telomere length acts as a clock of sorts, as telomeres shorten with each cell division. This is one part of a complicated mechanism that limits the replicative life span of ordinary somatic cells that make up the bulk of tissues, producing the well-known Hayflick limit. Telomerase is active in differerent cell populations to different degrees: in stem cells, for example, it operates to consistently maintain lengthy telomeres, such that the stem cells can renew their own population throughout life, while still periodically creating fresh new batches of somatic cells to replace lost cells in the tissue they support.

Average telomere length is fairly dynamic, depending on the details of tissue maintenance and delivery of fresh cells, and tends to shorten with age and illness. It is most commonly measured in white blood cells, which may have more of a correlation with illness than if measured in other tissues. Telomere length is largely thought of as a marker of age-related damage, not a primary cause of aging, but nonetheless delivery of additional telomerase to mice via genetic engineering has been shown to extend life. It is still an open question as to how exactly this works: slowing the onset of tissue frailty through cell loss is one possibility, but it has been suggested that telomerase may interact with mitochondria in ways that reduce their impact on aging. Mice have quite different telomere dynamics from humans, and delivery of telomerase comes with an associated concern of raised cancer risk: all cancers incorporate mechanisms to keep telomeres long in their cells despite frequent cell divisions.

Here researchers present an interesting new finding about the mechanisms of telomerase, which will no doubt be incorporated into existing initiatives aiming to use telomerase as a way to intervene in the aging process:

In our bodies, newly divided cells constantly replenish lungs, skin, liver and other organs. However, most human cells cannot divide indefinitely - with each division, a cellular timekeeper at the ends of chromosomes shortens. When this timekeeper, called a telomere, becomes too short, cells can no longer divide, causing organs and tissues to degenerate, as often happens in old age. But there is a way around this countdown: some cells produce an enzyme called telomerase, which rebuilds telomeres and allows cells to divide indefinitely.

In a new study [scientists] have discovered that telomerase, even when present, can be turned off. "Previous studies had suggested that once assembled, telomerase is available whenever it is needed. We were surprised to discover instead that telomerase has what is in essence an 'off' switch, whereby it disassembles." Understanding how this "off" switch can be manipulated - thereby slowing down the telomere shortening process - could lead to treatments for diseases of aging (for example, regenerating vital organs later in life).

Every time a cell divides, its entire genome must be duplicated. While this duplication is going on, [researchers] discovered that telomerase sits poised as a "preassembly" complex, missing a critical molecular subunit. But when the genome has been fully duplicated, the missing subunit joins its companions to form a complete, fully active telomerase complex, at which point telomerase can replenish the ends of eroding chromosomes and ensure robust cell division.

Surprisingly, however, [researchers] showed that immediately after the full telomerase complex has been assembled, it rapidly disassembles to form an inactive "disassembly" complex - essentially flipping the switch into the "off" position. They speculate that this disassembly pathway may provide a means of keeping telomerase at exceptionally low levels inside the cell. Although eroding telomeres in normal cells can contribute to the aging process, cancer cells, in contrast, rely on elevated telomerase levels to ensure unregulated cell growth. The "off" switch [may] help keep telomerase activity below this threshold.

Tuesday, September 23, 2014

Most cancers kill through metastasis, the spread of cancerous cells throughout the body to seed numerous secondary tumors. Without this process cancer would be much less threatening and more amenable to treatment. Thus numerous research groups are investigating ways to shut down or otherwise interfere with metastasis, and here is a recent example:

[Researchers have] developed a protein therapy that disrupts the process that causes cancer cells to break away from original tumor sites, travel through the blood stream and start aggressive new growths elsewhere in the body. Today doctors try to slow or stop metastasis with chemotherapy, but these treatments are unfortunately not very effective and have severe side effects. [This] team seeks to stop metastasis, without side effects, by preventing two proteins - Axl and Gas6 - from interacting to initiate the spread of cancer.

Axl proteins stand like bristles on the surface of cancer cells, poised to receive biochemical signals from Gas6 proteins. When two Gas6 proteins link with two Axls, the signals that are generated enable cancer cells to leave the original tumor site, migrate to other parts of the body and form new cancer nodules. To stop this process [researchers] used protein engineering to create a harmless version of Axl that acts like a decoy. This decoy Axl latches on to Gas6 proteins in the blood stream and prevents them from linking with and activating the Axls present on cancer cells.

The researchers gave intravenous treatments of this bioengineered decoy protein to mice with aggressive breast and ovarian cancers. Mice in the breast cancer treatment group had 78 percent fewer metastatic nodules than untreated mice. Mice with ovarian cancer had a 90 percent reduction in metastatic nodules when treated with the engineered decoy protein. "This is a very promising therapy that appears to be effective and non-toxic in pre-clinical experiments. It could open up a new approach to cancer treatment."

Tuesday, September 23, 2014

Artificial organs capable of performing some of the functions of the real thing don't have to look or be structured in the same way as our evolved organs. They just have to work. Efforts to develop artificial organs have benefited from progress in the ability to control and manage cell populations, giving rise to a first generation of hybrid devices that use both cells and machinery. A number of bulky prototypes to augment various kidney, pancreatic, lung, and liver functions with engineered tissue have been developed in recent years. In these cases the necessary cells can be grown and maintained outside the body and a patient's blood circulated through them on a regular basis. Miniaturization isn't necessary in order to obtain these benefits, which makes the research and development process much easier. In the future one might imagine that smaller and more efficient versions could be implanted, putting this technology in competition with regenerative medicine and tissue engineering of replacement organs.

Physicians and scientists are testing a novel, human cell based, bioartificial liver support system for patients with acute liver failure, often a fatal diagnosis. "Liver failure patients and their doctors have long been frustrated by the critical need to provide the kind of life-saving care kidney patients are afforded by dialysis. The quest for a device that can fill in for the function of the liver, at least temporarily, has been underway for decades. A bioartificial liver, also known as a BAL, could potentially sustain patients with acute liver failure until their own livers self-repair."

In the bioartificial liver under investigation, blood is drawn from the patient via a central venous line, and then is filtered through a component system featuring four tubes, each about 1 foot long, which are embedded with liver cells. The external organ support system is designed to perform critical functions of a normal liver, including protein synthesis and the processing and cleaning of a patient's blood. The filtered and treated blood is then returned to the patient through the central line. "If successful, a bioartificial liver could not only allow time for a patient's own damaged organ to regenerate, but also promote that regeneration. In the case of chronic liver failure, it also potentially could support some patients through the long wait for a liver transplant."

Wednesday, September 24, 2014

There are all sorts of longevity-associated genetic manipulations either demonstrated or postulated to produce benefits in mice. Why not try them all at once to see what happens? If you think that slowing aging through alteration of metabolism to reduce the impact of the cellular and molecular damage that causes aging is a useful strategy, or you believe that aging is programmed and not actually caused by damage, then this is an ambitious (though possibly overoptimistic) plan of exploration that wouldn't require more than a few million dollars to carry out.

To my eyes, however, this is merely a way to spend more money avoiding the better approach of repairing that damage. Slowing aging - slowing down damage - won't benefit the old who are already heavily damaged, and it won't produce as large an effect as repairing that damage. Yet it will be much more expensive and complicated: researchers have made only small inroads into sufficient understanding of metabolism and aging in detail to know how to make safe alterations, and can't even yet fully explain how natural age-slowing processes such as calorie restriction work, but we already have a comprehensive research program for repair planned out and know more than enough to steer it to near completion. Time is ticking and we don't have the luxury of being able to spend more to produce less when it comes to treatments for degenerative aging.

This research proposal comes from scientists associated with the Russian language advocacy community and the Science for Life Extension Foundation. They have had some success in the last few years raising funds from the community for smaller projects with mice, and may manage to get this funded the same way:

We propose developing a gene therapy that will radically extend lifespan. Genes that promote longevity of model animals will be used as therapeutic agents. We will manipulate not a single gene, but several aging mechanisms simultaneously. A combination of different approaches may lead to an additive or even a synergistic effect, resulting in a very long life expectancy.

11 genes that are most promising in terms of life extension will be used as targets for gene therapy. We will affect both the biological aging mechanisms, common to all the cells of the organism, as well as the primary neuroendocrine center, that regulates the whole organism's longevity - the hypothalamus. The expression increase or decrease of these genes in animal models was shown to result in boosted longevity. If the increase in expression of a particular gene is necessary for longevity, we will deliver this gene into the body. If, on the other hand, longevity depends on the inhibition of a certain gene's expression, we will introduce a genetic construct that encodes small RNAs that inhibit the expression of the target gene.

In addition, we will deliver 8 genes that prevent the individual tissue function disruption in old age. Each of these genes separately has previously been successfully used for gene therapy of one of the age-related diseases in rodent models.

All groups of mice will be regularly tested for aging markers, and also the blood and adipose tissue transcriptome, proteome and metabolome will be analyzed. All age-related histological and physiological changes will be studied. Behavioral test will be performed to analyze cognitive ability and locomotor activity in mice. The average and maximum lifespan of mice will be determined. In addition, a detailed study of side effects will be performed. Mice will be compared with old mice of the control group as well as with young mice.

Wednesday, September 24, 2014

An unusual characteristic of some songbirds is that parts of their brain vary greatly in size between seasons. Researchers believe that finding the exact mechanisms that trigger this atrophy and regrowth of neurons will lead to ways to spur the latter part of this process in humans, forming the basis for treatments that can increase the slow pace of natural regeneration in the mammalian brain:

Neuroscientists have long known that new neurons are generated in the adult brains of many animals, but the birth of new neurons - or neurogenesis - appears to be limited in mammals and humans, especially where new neurons are generated after there's been a blow to the head, stroke or some other physical loss of brain cells. That process, referred to as "regenerative" neurogenesis, has been studied in mammals since the 1990s.

The researchers worked with Gambel's white-crowned sparrows, a medium-sized species 7 inches (18 centimeters) long that breeds in Alaska, then winters in California and Mexico. Like most songbirds, Gambel's white-crowned sparrows experience growth in the area of the brain that controls song output during the breeding season when a superior song helps them attract mates and define their territories. At the end of the season, probably because having extra cells exacts a toll in terms of energy and steroids they require, the cells begin dying naturally and the bird's song degrades.

As the [steroid] hormone levels decrease, the cells in the part of the brain controlling song no longer have the signal to 'stay alive.' Those cells undergo programmed cell death - or cell suicide as some call it. As those cells die it is likely they are releasing some kind of signal that somehow gets transmitted to the stem cells that reside in the brain. Whatever that signal is then triggers those cells to divide and replace the loss of the cell that sent the signal to begin with.

"This paper doesn't describe the exact nature of the signals that stimulate proliferation. We're just describing the phenomenon that there is this connection between cells dying and this stem cell proliferation. Finding the signal is the next step. [The researchers] nailed this down by going in and blocking cell death at the end of the breeding season. There are chemicals you can use to turn off the cell suicide pathway. When this was done, far fewer stem cells divided. You don't get that big uptick in new neurons being born. That's important because it shows there's something about the cells dying that turns on the replacement process. There's no reason to think what goes on in a bird brain doesn't also go on in mammal brains, in human brains. As far as we know, the molecules are the same, the pathways are the same, the hormones are the same. That's the ultimate purpose of all this, to identify these molecular mechanisms that will be of use in repairing human brains."

Thursday, September 25, 2014

For some years now the Glenn Foundation for Medical Research has been establishing a network of labs to work on aging and longevity, seeding them with grants of a few million dollars apiece. The research they carry out is fairly mainstream, such as investigation of calorie restriction mimetics as a way to slightly slow aging, and thus I don't expect to see meaningful results in terms of added years of life in the current form of these laboratory groups. Their primary output will be knowledge and data relating to the fine details of the intersection of metabolism and aging, leading to a better understanding of the causes of natural variations in longevity.

However this is a good example of the growing focus on aging as a treatable condition in the research community, and the Glenn Consortium is exactly the sort of research network we'd like to see pick up work on the rejuvenation biotechnology of SENS in the future. With more results, support, and tools generated by existing SENS research, it will become ever more attractive for scientists working on the go-nowhere path of slowing aging through metabolic manipulation to switch to reversing aging through repair of cellular and molecular damage. That is the only way forward likely to produce meaningful extension of healthy life within our lifetimes. For that switch to happen, it isn't just necessary for SENS to make progress, but there also must be more of a mainstream community whose members are interested in intervention in the aging process in the first place.

A $3 million grant from The Glenn Foundation for Medical Research will allow the University of Michigan to establish a national center of excellence in biogerontology research. The Glenn Center for Aging Research at U-M will focus on exploiting and expanding the growing evidence that drugs can slow the effects of aging and postpone diseases in animal models. Researchers aim to unlock mechanisms of aging that can help develop medications that may help people live longer, healthier lives. The award recognizes U-M as among a select group of elite members of The Glenn Consortium for Research in Aging in the country.

The Glenn Foundation for Medical Research sponsors outstanding laboratories and scientists conducting research to understand the biology that governs normal human aging and its related physiological decline, with the objective of developing interventions that will extend the human health span. The grant recognizes the quality and productivity of the U-M Geriatrics Center's biogerontology program by the Foundation, which does not solicit proposals but funds highly-promising research in gerontology.

The Glenn Center at U-M will have two components: The Model Systems Unit will analyze pharmaceutical agents using worms, flies and cultured cell lines, [while] the Slow-Aging Mouse facility [will] use these animals to discover the pathways by which the drugs slow the effects of aging and postpone disease.

Thursday, September 25, 2014

One approach to scaffolding for tissue engineering is to deliver a dissolving material along with transplanted cells that provides just enough support for those cells to get them past the point of generating their own extracellular matrix scaffold to replace the artificial material. Here researchers test that approach in tissue patches that can restore function to damaged heart tissue:

Researchers have coaxed stem cells to develop into heart cells called cardiomyocytes and then transplanted them into animals. However, these cells can't make it alone. Half of them die right after injection, and the survival rate is as low as 10% after one week. A second ingredient is necessary - some kind of biological mortar to hold them in place and support their development and integration into the body.

[Researchers] developed a self-assembling nanogel made up of two peptides. The peptides each have a hydrophobic and a hydrophilic part; this drives them to form a nanostructured gel when mixed in water. The gel mimics the structure and mechanical properties of the natural extracellular matrix. One peptide acts like a natural protein that adheres to cells and promotes cell survival. The second peptide is readily broken down by a protease. The team designed the gel so that when it is implanted, it begins to degrade a bit, allowing cells from the body to migrate in. Eventually the gel should disintegrate completely as the heart tissue builds its own extracellular matrix. This particular gel has already performed well as a support for other kinds of cells grown from stem cells, including pancreatic and muscle cells.

[Researchers] mixed the gel with cardiomyocytes derived from embryonic stem cells and injected this mixture into the hearts of mice with injuries simulating the damage caused by a heart attack. They compared the health and survival of the cells transplanted naked with the health of cells transplanted in the nanogel. As a further control, they also monitored mice that had been injected with a salt solution. After two weeks, mice treated with cells, whether in the gel or not, had better heart function on an echocardiogram than untreated mice. Animals injected with the cells in the nanogel continued to have strong cardiac function through the end of the 12-week experiment. But the health of mice treated with cells alone began to deteriorate after three weeks. Examining the mice's hearts under the microscope after 14 weeks, the researchers found new cells integrating into the heart tissue in animals treated with the nanogel. In mice treated with naked cardiomyocytes, all the therapeutic cells were gone.

Friday, September 26, 2014

Growing amounts of amyloid-β (Aβ) between cells forms one part of the pathology of Alzheimer's disease. This is a dynamic process, as much a matter of reduced clearance rates as increased production or simple accumulation: there are systems in the body capable of clearing out this amyloid and which can in theory be altered to increase clearance rates. One part of the puzzle of what makes Alzheimer's disease an age-related condition is why exactly these clearance mechanisms fail with advancing aging: which of the known forms of cellular and molecular damage associated with aging cause this to happen? These researchers are working with microglia, supporting cells of the innate immune system present in the brain, with an eye to producing therapies to enhance amyloid clearance:

Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) deposits and microglia-dominated inflammatory activation. Innate immune signaling controls microglial inflammatory activities and Aβ clearance. However, studies examining innate immunity in Aβ pathology and neuronal degeneration have produced conflicting results.

In this study, we investigated the pathogenic role of innate immunity in AD by ablating a key signaling molecule, IKKβ, specifically in the myeloid cells of [a mouse model of Alzheimer's disease]. Deficiency of IKKβ in myeloid cells, especially microglia, simultaneously reduced inflammatory activation and Aβ load in the brain and these effects were associated with reduction of cognitive deficits and preservation of synaptic structure proteins. IKKβ deficiency enhanced microglial recruitment to Aβ deposits and facilitated Aβ internalization, perhaps by inhibiting TGF-β-SMAD2/3 signaling, but did not affect Aβ production and efflux.

Therefore, inhibition of IKKβ signaling in myeloid cells improves cognitive functions in AD mice by reducing inflammatory activation and enhancing Aβ clearance. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying AD progression.

Friday, September 26, 2014

One of the discoveries of past years in Alzheimer's disease research is that the β-amyloid accumulating between cells is less harmful to neurons than other associated proteins involved in the creation of that amyloid. Here is a paper that suggests much the same sort of thing for neurofibillary tangles, the other characteristic form of protein deposit associated with Alzheimer's:

Pathological aggregation of the microtubule-associated protein tau and subsequent accumulation of neurofibrillary tangles (NFTs) or other tau-containing inclusions are defining histopathological features of many neurodegenerative diseases, which are collectively known as tauopathies. Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood.

An emerging view is that NFTs are not the toxic entity in tauopathies; rather, tau intermediates between monomers and NFTs are pathogenic. Several proteins associated with neurodegenerative diseases, such as β-amyloid (Aβ) and α-synuclein, have the tendency to form pore-like amyloid structures (annular protofibrils, APFs) that mimic the membrane-disrupting properties of pore-forming protein toxins.

The present study examined the similarities of tau APFs with other tau amyloid species and showed for the first time the presence of tau APFs in brain tissue from patients with progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB), as well as in the P301L mouse model, which overexpresses mutated tau. Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate. Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type. These findings establish the pathological significance of tau APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative tauopathies.


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