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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- Help to Ensure that Aging is No Longer Inevitable by Becoming a SENS Patron
- Without an End to Aging, Every New Technological Advance is Just Another, Greater Monument to the Dead
- Antagonistic Pleiotropy and the Puzzle of Aging
- Engineers, Particularly Software Engineers, Have Long Supported SENS Rejuvenation Research
- Growth Signaling and Aging in Mammals
- Irisin Links Exercise and Bone Strength
- An Interview with Aubrey de Grey at the Longevity World Forum
- Upregulation of Slit Improves Functional Recovery After Stroke in Mice
- The Envirome in Aging
- APOE4 Points to NHE6 Inhibition as a Potential Means to Slow the Early Onset of Alzheimer’s Disease
- Body Mass Index Correlates Strongly with Hypertension Incidence
- PRRX1 as a Possible Point of Control for Remyelination
- Reviewing GDF11 as a Basis for Regenerative Therapy
- Beginning Exercise in Late Life Can Regain a Portion of Lost Cognitive Function
- EnClear Therapies: Working to Filter Cerebrospinal Fluid
Help to Ensure that Aging is No Longer Inevitable by Becoming a SENS Patron
As the year draws to a close, more than half of the SENS Patron 2018 challenge fund remains to be claimed. Fight Aging! and the other fund donors challenge you to make a commitment to the SENS Research Foundation and progress towards rejuvenation therapies that can bring an end to the suffering and debility that accompanies aging. Become a SENS Patron by setting up a monthly donation to the SENS Research Foundation, and we will match the next year of your gifts in support of the research programs ongoing in the network of labs and scientists dedicated to aging research.
It has never been as easy as it is today to help ensure that the decline and death of late life ceases to be inevitable. Competent, proven organizations such as the SENS Research Foundation and Methuselah Foundation offer reliable ways to direct funds to this goal, and making a charitable donation takes just a few moments online. Become a SENS Patron to support the SENS Research Foundation with regular donations, or join the Methuselah 300 to do the same for the Methuselah Foundation programs. Thanks to the efforts of the past twenty years, the first rejuvenation therapies are accepted and on their way to the clinic. No longer must we argue over the plausibility of turning back aging; now we only argue over how best to go about it.
As it happens, the best way forward in the matter of treating aging as a medical condition, a condition that can be controlled and minimized, is outlined by the SENS rejuvenation research programs. It involves building new therapies that can repair the well-known and well-cataloged forms of cell and tissue damage that lie at the root of aging. Yet even as easy as it is to make charitable donations to support this work, most of the SENS agenda is still poorly funded and little worked on when compared with the mainstream of medicine, in which tens of thousands of scientists and physicians engage in heroic, futile efforts to stave off aging, failing because they are not focused on repairing its causes. The consistent failures of the past have led to a culture in which failure is expected – but this is only the result of a bad choice of strategy. It can be changed.
The first rejuvenation therapies, involving senolytic drugs to selectively destroy senescent cells, are a going concern, but we are far from where we should be when it comes to the rest of the rejuvenation biotechnology toolkit. The philanthropic research programs that aim to unblock and open up important lines of research into repairing the causes of aging are still very important and very necessary. They still lack sufficient funding and support for meaningful progress. Our bodies are packed with scores of forms of metabolic waste, and few of the approaches needed to clear that waste are close to the point at which clinical development can begin. We have a lot of work to do!
This is how I can, on alternate days, first celebrate our progress (and we should celebrate, as we have achieved a great deal since the days in which rejuvenation therapies based on repair of damage were only a tenuous vision) and then the very next day bemoan the state of funding and limited focus. Collectively, our community has launched the senolytic revolution in medicine, but another dozen revolutions in the treatment of aging must still be brought to the point of readiness. All of the damage must be repaired, not just one thin fraction of it. So please, help us to move faster towards this goal.
Without an End to Aging, Every New Technological Advance is Just Another, Greater Monument to the Dead
A golden future is ahead of us. Humanity will build wonders upon the Earth, cities on the moon and Mars. There will be arcologies to touch the skies, artificial general intelligences that surpass the minds of humanity, molecular assemblers constructing the necessities of life from soil, resurrected dinosaurs grazing alongside de novo unicorns, and probes departing for the nearest stars. There will be wealth beyond measure, in an age of plenty for all. Hunger and disease will be banished, even as we engineer all of the greatest dreams of past visionaries into reality.
But what does any of this matter without longevity, without radical life extension, without an end to aging? The present, seen from the perspective of futurists two or three centuries past, already appears a golden age of staggering, near-magical machineries. An era of grand wealth and comfort, in which even the poorest of the wealthy nations live the lives of nobility, immune to famine and pestilence. But our cities and our achievements, the towering spires and the internet, the freeways and clinics, are little more than monuments to their originators. The engineers and the creators and the visionaries of this modern world of ours are long dead or even now dying of old age.
It is a noble thing to build a greater technology, to generate the wealth of choice and capability that will aid billions in years to come. To contribute to the construction of the golden future, one step at a time, is right and proper. Yet without biotechnologies to control aging, whatever you or I choose to build will be nothing more than a bigger and better monument to our passing, one increment greater than the monuments of our predecessors, and what difference that to the dead? It will become one of the countless tombstones of our age, of the all too short span of years in which we and our fellow travelers lived. Then we will be gone, and only the tombstones remain, and then even those will crumble.
We put fences around graveyards. That is a foolish thing, a wished-for separation of concerns that does not and cannot exist. Every city, every building, every road is a marker of the dead. Every last cultivated part of our environment was touched by someone who is now no more, gone to oblivion. When we walk into the doors, or drive over the asphalt, it becomes a marker for us as well. For our generation. This will be the way of it. Whatever we strive to build, no matter how noble, no matter how useful, it will be nothing more than a tombstone, a monument, a marker destined to be worn down to nothing while we no longer exist. What is the point to this?
The true value of building a better future can only exist when we are all assured of living to participate in that future, in health and vigor, of sound mind and body. A house can only be a house and not a tomb if its architect and resident is alive. Yes, we should build wonders, because we can, because we can dream into existence a far better world. But of greater importance than any other technology, we must build the means to end aging, to enable life to continue for as long as desired. Until we do, we are merely marking time amidst grave sites that will all too soon be our own, and therefter the grave sites of the next generation, and ever on until we break this cycle. Until we do, all that we achieve is ultimately meaningless. There is no continued story, there is no progression, there is simply death, oblivion, and an end, too soon, over and over again.
Antagonistic Pleiotropy and the Puzzle of Aging
The puzzle of aging is less how it happens, given that the scientific community has a good catalog of the forms of cell and tissue damage that cause aging, and can work to prove relevance by repairing that damage, but rather why it happens. Serious attempts to intervene in the aging process have long been a minority concern when compared to the funding and careers devoted to explaining the existence of aging. Understanding why evolution has led to a world dominated by species that age, alongside a tiny number of species that do not, is a thorny problem.
This is in part the case because arguments over the evolution of aging proceed by thought experiment and modeling rather than by examination of data. There is the world as it exists today, a few slim hints about the past, and researchers must deduce how this fantastically complex array of systems came into being over hundreds of millions of years from the minuscule sliver of information provided. There is a great deal of room in which to be wrong. Indeed, everyone involved in any given debate on the evolution of aging may be dramatically incorrect in the details of their models, and there is little that can be done in the short term to prove or disprove their positions.
Insofar as there is any consensus in the field on why we age, it might be found somewhere in the vicinity of the antagonistic pleiotropy hypothesis. Evolution selects for reproductive success in an environment in which mortality from disease and predation is an ugly reality – so the sooner that reproductive success occurs, the better. Selection pressure is much stronger in early life than in later life, and thus mechanisms that achieve early life resilience and success at the cost of later decay are selected for, while the additional expense of long-term resilience and success is selected against, outcompeted. The result is age-related decline. This, needless to say, is an overly simplistic and very high-level description of an area of theory within which are found many variants and dissenting opinions.
The adaptive immune system is a good example of antagonistic pleiotropy. It remembers past threats, making it highly effective in earlier life. But that act of memory consumes resources, requiring cells to be devoted to memory rather than action against new threats. Eventually there is no room left; the system runs out of space and its function declines. We can envisage an adaptive immune system that could work more effectively over longer spans of time, given just a few comparatively simple alterations to the way in which it manages its resources. That didn’t evolve, as there is insufficient selection pressure in later life for mechanisms that would make old adaptive immune systems more functional, and no gain in having those mechanisms in younger life where selection pressure is strong.
Is antagonistic pleiotropy ubiquitous in aging biology?
The logic of evolution by natural selection is straightforward. Within any population, the alleles of individuals that produce the most breeding descendants will increase in frequency in successive generations at the expense of the alleles of individuals less successful at reproduction. To be successful at leaving descendants requires that organisms also be successful at surviving – so that they live long enough to reach reproductive age and afterward continue reproducing. By this logic and process, natural selection ultimately produces individuals superbly designed to survive and reproduce in their environment.
From this perspective, aging presents an evolutionary puzzle. If continued survival and reproduction should always be favored by natural selection, why is aging – which in evolutionary terms can be defined as the age-related decline in survival rate and reproduction – nearly ubiquitous in the natural world? Or as George Williams put it, “it is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed.” Why doesn’t evolution, in other words, mold the biology of organisms such that aging never occurs?
One possible solution to this conundrum is that evolution does in fact mold the biology of organisms such that they never age in their natural environment, that is, the environment in which they evolved. Aging might seldom occur in nature and only become evident when animals live much longer than they ever would in the wild, such as when we protect them from natural hazards by making them pets or livestock, keeping them in zoos or, as in the case of ourselves, organizing them into climate controlled, predator-free civilizations. Some biomedical gerontologists believe this hypothesis to be the case. But it is not and, in fact, dozens of field studies to date have identified that aging in wild animals is rampant if not close to ubiquitous.
Thus, there is a real puzzle to be solved as to how aging develops in natural populations. Fortunately, evolutionary biologists have cracked this mystery. An evolutionary mechanism of aging was hypothesized 60 years ago to be the genetic trade-off between early life fitness and late life mortality. Genetic evidence supporting this hypothesis was unavailable then, but has accumulated recently. These tradeoffs, known as antagonistic pleiotropy, are common, perhaps ubiquitous. George Williams’ 1957 paper developed the antagonistic pleiotropy hypothesis of aging, which had previously been hinted at by Peter Medawar. Antagonistic pleiotropy, as it applies to aging, hypothesizes that animals possess genes that enhance fitness early in life but diminish it in later life and that such genes can be favored by natural selection because selection is stronger early in life even as they cause the aging phenotype to emerge.
No genes of the sort hypothesized by Williams were known 60 years ago, but modern molecular biology has now discovered hundreds of genes that, when their activity is enhanced, suppressed, or turned off, lengthen life and enhance health under laboratory conditions. Does this provide strong support for Williams’ hypothesis? What are the implications of Williams’ hypothesis for the modern goal of medically intervening to enhance and prolong human health? Overall, whenever antagonistic pleiotropy effects have been seriously investigated, they have been found. However, not all trade-offs are directly between reproduction and longevity as is often assumed. The discovery that antagonistic pleiotropy is common if not ubiquitous implies that a number of molecular mechanisms of aging may be widely shared among organisms and that these mechanisms of aging can be potentially alleviated by targeted interventions.
Engineers, Particularly Software Engineers, Have Long Supported SENS Rejuvenation Research
The SENS approach to the treatment of aging is explicitly engineering, in the sense that engineering is the application of science to produce useful technology in absence of full knowledge of the systems influenced. It is right there in the name: Strategies for Engineered Negligible Senescence. In fact all medicine is engineering, as no-one yet has access to the full map of cellular biology that would allow for complete knowledge of how any particular therapy actually functions. SENS is merely a particularly obvious example, perhaps because of the great divide that exists in the aging research community.
Firstly, there are those who think that far greater understanding of the progression of aging at the detail level is needed, and that any intervention should be a matter of slowing aging by changing the operation of metabolism. They believe that meaningful progress towards greater human life spans is still remote, and only small gains are possible in our lifetimes, if then. Secondly, on the other side of the divide, there are those who wish to use the known catalog of forms of cell and tissue damage that lie at the root of aging in order to bypass the need for full understand of how aging progresses, and to produce rejuvenation rather than merely a slowing of aging. If damage has no other contributing source than the normal operation of healthy metabolism, then let us just repair it and observe the results – that is how we find out what is relevant and what is not. This is a much more cost-effective approach, but despite tremendous and demonstrable success in the form of senolytic therapies that destroy senescent cells, it remains unpopular as a strategy within the research community.
Damage repair to produce rejuvenation is popular with engineers, however, and for the obvious reasons. People with a technical background can look at the summary above (or more detailed summaries, or the scientific literature on SENS-based approaches to rejuvenation therapies) and find it obviously true that the cheaper, faster path with larger and more reliable gains should be the one receiving the greatest attention. Engineering is all about producing that sort of gain in effectiveness, applying what is known to produce benefits, and understanding where the details matter and where the details do not matter when it comes to development, safety, and efficiency. If researchers can repair a form of damage, such as the accumulation of senescent cells, and show it to be safe, and to produce rejuvenation, then the scientific community can thereafter spend as much time as they like in finding out how exactly it works. Meanwhile, there is a working treatment in existence that can benefit the world.
The software engineering community has long been supportive of the SENS program of advocacy and research. Software engineers make up an outsized proportion of the donors to the SENS Research Foundation and Methuselah Foundation. They appear everywhere in the broader community of supporters; there is a lot of history here if you look back along the timeline of the transhumanist communities of the thirty years past and what has become of those involved since then – also a lot of software engineers. Where the software engineering community overlaps with the venture capital community, particularly in California, there too is a sizable level of support for rejuvenation research after the SENS model. It is no accident that the SENS Research Foundation is based in the Bay Area, California; that is as much connections to capital and support as for the aging research laboratories that are nearby.
An interesting side-effect of this core constituency of support has arisen with the development of blockchain implementations and the cryptocurrency goldrush; suddenly a lot of younger, more idealistic and optimistic software engineers have a lot of wealth, even following the recent bursting of the bubble. When you have wealth you can start to make the world better in the ways that matter to you – if you have the vision and the will, which is something that seems to go with youth more than age, sad to say. it is perhaps a measure of this that the lion’s share of donations to the SENS Research Foundation and Methuselah Foundation in the last 18 months have arrived in the form of cryptocurrencies. Indeed, Ethereum founder Vitalik Buterin donated 2.4 million last year, and has now donated another 350,000 to the present SENS year end fundraiser. Such fellow travelers are greatly appreciated as we strive to make human rejuvenation a reality.
Vitalik Buterin donates 350,000 to the SENS Research Foundation
SENS Research Foundation would like to send a huge thank you to Vitalik Buterin for donating 350,000 worth of ethereum to our end of year campaign!
The Bitcoiners Who Want To Defeat Death
The office of Aubrey de Grey, chief science officer of SENS (short for the very catchy Strategies for Engineered Negligible Senescence), is my first stop in my journey into the strange and surprisingly overlapping worlds of cryptocurrency and life-extension. But de Grey is not like most tech entrepreneurs, nor is he like most longevity researchers. He doesn’t buy into the health fads popular amongst his peers, like calorie restriction. He’s not hoarding the blood of spritely teenagers (though tech billionaire Peter Thiel, who may or may not be interested in youthful blood infusions, is a SENS donor). And, while he says that cryonics – in which bodies are preserved at low temperatures – is “an extremely valuable and neglected area of medicine,” the whole freezing-and-thawing process is not where his still-beating heart lies.
De Grey’s plan is more ambitious than resurrection: He wants to reverse aging all together. As he outlines in his 2007 book Ending Aging, his strategy is to discover therapies that address the “diseases and disabilities of aging.” Whereas most biogerontologists focus on the complex metabolic processes that cause aging damage, de Grey argues that the focus should be on the forms of damage themselves – like nuclear mutations, or the intracellular “junk” that forms as we get older. In short: Focus on treating the underlying causes, not the symptoms of aging.
Though he has plenty of critics, de Grey’s bold approach has also garnered him scores of devoted fans. As he sits stroking his Rip Van Winkle-worthy beard, it’s easy to see how de Grey’s achieved this “kind of a spiritual leader status,” as he calls it. He dives easily into intricate explanations of two research projects unfolding in the lab down the hall, eagerly describing how one studies mitochondrial mutations, which are thought to cause an increase in oxidative stress. The other looks at atherosclerosis, the narrowing and hardening of artery walls. If we understood more about this buildup, the logic goes, we could better clean it up before too much damage is done.
Though he attends lab meetings and oversees the SENS Research Foundation’s research, his primary task is convincing the general public that death is, in fact, bad and that we should be doing everything we can to stop it. This focus on messaging suits him just fine. Back in April, at a San Francisco blockchain conference called Block 2 the Future, de Grey began his talk with a disclaimer: “I probably ought to start by emphasizing that I don’t know fuck-all about cryptocurrencies. I am really only here because I have apparently quite a significant fan base in this community, and I am delighted that I do.” He was referring to the intertwining relationship between blockchain enthusiasts and life-extension advocates, which can feel less like a Venn diagram and more like overlapping circles. There’s a history of members of the blockchain community donating to life-extension efforts. Billionaire and cryptocurrency investor Michael Novogratz donated to the organization that predated SENS in the early 2000s, and the number of cryptocurrency donors has increased exponentially since. In the past year or so, SENS has received more than 6.5 million in cryptocurrency donations, including 2.4 million from Ethereum cofounder Vitalik Buterin last December.
Pine, the anonymous individual behind the Pineapple Fund who donated 55 million worth of bitcoin to various charities last year, gave 2 million of that to SENS. A few other anonymous crypto donors gave around 1 million each, says de Grey. And other cryptocurrency heavy-hitters have long-term involvements with SENS, too. De Grey believes that crypto’s philanthropic donors skew younger, like with Buterin, just 24, who became a fan after reading Ending Aging as a teenager. De Grey likes to call this new generation of donors “Children of the Revolution” – and he’s called out older people for not doing their part. “It’s a huge embarrassment to the kind of wealthy individuals of my age, like Peter Thiel or Jeff Bezos or the Google Twins or whatever, who are ostensibly really supportive of all of this, but who have put very small, if any, proportions of their net worth into supporting it. Peter is a shining example of someone who has put some money in – but let’s face it, he could have put more in.”
For now, the business of life extension is still a business – even nonprofits like the SENS Research Foundation need to fund their research. Despite the techno-spiritual affinity, the main reason life-extension proponents are regulars on the blockchain circuit is economic: They’re chasing crypto’s money.
Growth Signaling and Aging in Mammals
While the causes of aging are comparatively well mapped, supported by a great deal of solid evidence, the field more than ready for the development of rejuvenation therapies to begin in earnest, the biochemical details of the progression of aging remains a vast and poorly explored forest. This is also true of cellular metabolism as a whole: to fully understand aging, one must fully understand the inner workings of the cell to the finest level of detail. The research community is a lifetime removed from that goal, even taking into account a rapid pace of future progress in the capabilities of biotechnology.
Still, some parts of the overlap between aging and the operation of metabolism are mapped, at least at the high level. One of the most explored areas relates to the control of growth, the relationships between insulin, insulin-like growth factor 1, growth hormone, growth hormone receptor, and a broad collection of related proteins. Many of the earliest approaches to slowing aging via genetic engineering used these mechanisms. It remains the case that lineages of dwarf mice, engineered to exhibit disabled growth signaling, still hold the record for longevity in that species, living 70% or so longer than their unmodified peers.
Despite this record, modification of growth signaling is a false grail. Alongside research into the mechanisms of calorie restriction, it has led the research community to expend enormous effort on approaches that are technically challenging, make slow progress, and cannot greatly extend the healthy human life span. If billions in funding and entire scientific careers are to be spent on attempts to treat aging as a medical condition, why work on approaches that are incapable of producing more than a few extra healthy years? We know what disabled growth hormone signaling can achieve in humans: the small Laron syndrome population don’t live appreciably longer than any of the rest of us, and suffer a range of undesirable side-effects. Perhaps they exhibit a lower incidence of cancer and diabetes, but not so much lower that it leaps out of the data. Or consider the size of life span differences between short people and tall people; it isn’t large.
This is the great roadblock for all of the more established ways to alter metabolism in order to reach states in which aging is slowed, whether by disabling growth signaling or via calorie restriction mimetics. The effects are sizable in mice, and tiny in humans. The longer-lived the species, the less plastic its lifespan in response to metabolic changes induced by the environment, or through engineered genetic alterations that touch on the same regulatory mechanisms. This is a dead end, and is not where the research community should focus if the goals are rejuvenation and sizable extension of life span.
Impact of Growth Hormone-Related Mutations on Mammalian Aging
Much of the work in our laboratory during the last 30 years was directed at identifying mechanisms of extended longevity of mice with growth hormone (GH)-related mutations and answering the question how major reduction or absence of normal endocrine signals can have major beneficial impact on healthspan and lifespan. Both GH-deficient and GH-resistant mice have many phenotypic characteristics that presumably account for, or contribute to, healthy aging and extended longevity and, thus, represent likely mechanisms of these effects.
These characteristics include increased resistance to multiple stressors such as free radicals and toxins, reduced chronic low grade inflammation, senescent cell burden, and expression of pro-inflammatory cytokines in the central nervous system, reduced mTORC1 and increased mTORC2 signaling, as well multiple adaptations of carbohydrate, lipid, and energy metabolism. Many of the physiological characteristics of GH-related mutants interact, forming a complex network of mechanisms.
For example, reductions in the levels of pro-inflammatory cytokines, the number of senescent cells, the secretory capacity of pancreatic beta cells, and mTORC1 signaling, interact with increased levels of adiponectin and reduced GH signaling to improve insulin sensitivity, while each of these factors also influences aging by other mechanisms. We believe that the remarkable extension of longevity in mice with genetic GH deficiency or resistance results from alterations in multiple mechanisms of aging and interactions among these alterations.
Growth Signaling and Longevity in Mouse Models
Reduction of insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) extends the lifespan of various species. So far, several longevity mouse models have been developed containing mutations related to growth signaling deficiency by targeting growth hormone (GH), IGF1, IGF1 receptor, insulin receptor, and insulin receptor substrate. The gene expression profiles of these mice models have been measured to identify their longevity mechanisms.
GH signal-deficient mice, including Snell, Ames, Little, GHR-/- , and Fgf21 Tg dwarf mice, showed increased lifespans and smaller body masses than wild type (WT) mice. Therefore, body size was strongly dependent on GH action. This consistent trend suggests an inverse correlation between size and lifespan. However, small size can not be used as a general indicator of longevity, because Kl Tg, Irs2 +/-, p66 Shc-/-, and mtor +/-; mlst8 +/- mice had normal body masses like WT mice, but showed longer lifespans than WT. In addition, GHA Tg mice had normal lifespans like WT mice, and Kl -/- and Irs2 -/- mice showing dramatically shorter lifespans also had a dwarfism phenotype. Therefore more work is needed to elucidate factors contributing to the lifespan of these mice.
Irisin Links Exercise and Bone Strength
Researchers here find that the beneficial effects of regular exercise on bone density and strength are mediated in part by irisin, which acts on a receptor found on the surface of osteocytes. Osteocytes are a class of cell responsible for the constant remodeling of bone tissue that takes place throughout life, alongside osteoclasts and osteoblasts. The loss of density and strength in bone that occurs in later life, known as osteoporosis, is an imbalance between creation and destruction of bone. It might be reduced by means of modifying the behavior of the cells responsible for these activities, though to my eyes it would be preferable to identify the forms of underlying damage in aging that lead to this imbalance and then work to repair them.
Researchers have proposed that the irisin hormone serves as a link between exercise and its beneficial effects on health, including burning fat, strengthening bones, and protecting against neurodegenerative diseases. Until now, however, researchers hadn’t identified a specific molecular receptor for irisin – in effect, a docking structure allowing irisin to bind to cells and tissues. They are now reporting that the irisin receptor is a group of proteins called integrins situated on the surface of osteocytes.
Osteocytes are cells that act as the “command and control unit” for bone remodeling – that is, the loss and replenishment of bone that occurs both normally and in pathological states. Some research previously found that intermittent injections of irisin increased bone density and strength in mice. Now that it has shown that irisin targets the osteocyte through a specific receptor, the irisin-bone connection can be explored more mechanistically.
Osteocytes gradually die off with age, and their loss is believed to be a cause of age-related osteoporosis, the thinning and weakening of bones. In cell culture, the scientists observed that treating osteocytes with irisin protected them from being killed by hydrogen peroxide – a simulation of age-related death. The experiments also showed that treating osteocytes with irisin increased their production of sclerostin, a protein that triggers bone remodeling, and injecting irisin into mice raised their sclerostin levels. Sclerostin actually triggers the breakdown of bone, which might seem harmful rather than helpful. However, the intermittent breakdown of bone seems to be interpreted as a signal to remodel and build bones. So how could manipulating irisin be used therapeutically? Some form of intermittent irisin treatment might work.
An Interview with Aubrey de Grey at the Longevity World Forum
The Life Extension Advocacy Foundation recently published an interview with Aubrey de Grey of the SENS Research Foundation, on the occasion of the Longevity World Forum in Valencia, Spain. This interview ties in nicely with recent questions regarding whether we should be optimistic or pessimistic about progress toward human rejuvenation over the next ten to twenty years. It is not easy to predict the future, and it is true that even people closely connected to specific ares of work tend to overestimate the progress of a decade and underestimate the progress of two decades. For my part, I am of the opinion that, given the accelerating pace of the underlying science, when moving out to longer time frames the enormous, unnecessary costs and slowdown imposed by regulation of medicine becomes the largest determining factor governing clinical availability of new classes of medical biotechnology.
It was published recently that a therapy to reverse aging will be a reality within five years. What will be its mechanism of action, roughly?
There will not be just one medicine; there will be a lot of different medicines, and they will all have different mechanisms of action. For example, some of them will be stem cells, where we put cells back into the body in order to replace cells that the body is not replacing on its own. Sometimes, they will be drugs that kill cells that we don’t want. Sometimes, they will be gene therapy treatments that give cells new capabilities to break down waste products, for example. Sometimes, they will be vaccines or other immune therapies to stimulate the immune system to eliminate certain substances. Many different things. In five years from now, we will probably have most of that working. I do not think that we will really have it perfect by then; probably, we will still be at the early stages of clinical trials in some of these things. Then, we will need to combine them, one by one, to make sure that they do not affect each other negatively. So, there will still be some way to go. But, yes, I think it’s quite likely that in five years from now, we will have everything, or almost everything, in clinical trials.
Then clinical trials for seven years until it’s perfected. Don’t clinical trials usually take a long time?
It depends. For example, in aging, because there is this progressive accumulation of damage, you could have therapies that slow down the rate at which damage accumulates, or you could have therapies that repair the damage that has already happened. The second type of therapy is what we think is going to be most effective and is going to be easiest to do, and you can see results from that very quickly, like in one or two years. Now, of course, you still want to know what happens later on, but the first thing is to determine whether this is working at all, and as soon as it starts to work, then you can start to make it available. Clinical trials are changing in that way. Historically, clinical trials had to be completed before anybody could get these drugs, but now we are getting new policies; there is a thing called adaptive licensing, which is becoming popular in the US and elsewhere, where the therapy becomes approved at an earlier stage, and then it’s monitored after that.
Beyond the humanitarian perspective of avoiding the pain and suffering that comes with old age, if increasing the years of healthy life in people will significantly reduce health care spending by governments, why don’t they promote research in this area?
You’re absolutely right. It’s quite strange that governments are so short-sighted. But, of course, the real problem is psychological: it’s not just governments that are short-sighted. Almost everybody in the world is short-sighted about this. The reason I believe why that’s true is people still can’t quite convince themselves that it’s going to happen. Since the beginning of civilization, we have known that there is this terrible thing called aging, and we have been desperate to do something about it, to get rid of it. And people have been coming along, ever since the beginning of civilization, saying, “Yes, here’s the solution, here’s the fountain of youth!” And they’ve always been wrong. So, when the next person comes along and says they think they know how to do it, of course, there is going to be some skepticism until they have really shown that it’s true. Of course, if you don’t think it’s going to work, then you’re not going to support the effort financially. It’s very short-sighted, but it’s understandable.
Why do you think that the pharmaceutical industry does not devote its research and development efforts to this area, which causes the death of 100,000 people every day?
Today, the pharmaceutical industry is geared toward keeping old people alive when they are sick. It makes its money that way. It’s not just the pharmaceutical industry, it’s the whole of the medical industry. And so, most people say that they are worried that maybe the pharmaceutical industry will be against these therapies when they do come along. I don’t think that’s true at all. I think they will be in favor because people will be in favor, but people are not really in favor yet. People don’t really trust preventive medicine. They think “Okay if I am not yet sick…” They don’t trust medicine in general; they know that this is experimental. So, when they are not yet sick, they think “Well, I’ll wait until I am sick,” but we can change that. Eventually, people will understand that it’s going to be much more effective to treat yourself before you get sick, and then the whole medical industry will just respond to that; they will make the medicines that people want to pay for.
Upregulation of Slit Improves Functional Recovery After Stroke in Mice
Researchers here report on a mechanism that increase the regenerative capacity of brain cells following the damage of a stroke, at least in mice. There are now a few similar approaches demonstrated in the laboratory, but it remains to be seen whether any of them will lead to therapies in the near future. It is certainly the case that mammalian cells do not respond to structural damage and loss of blood supply in the most optimal way; many of their reactions make matters worse, not better. Perhaps that can be adjusted safely and soon, though it would be far preferable to focus on potential ways to prevent that sort of event from occurring at all, such as better maintenance of blood vessels, control of atherosclerosis, and the like.
Stroke is a leading cause of death and chronic disability in adults, causing a heavy social and economic burden worldwide. However, no treatments exist to restore the neuronal circuitry after a stroke. The mammalian brain has only a limited ability to regenerate neuronal circuits for functional recovery. While most neurons are generated during embryonic brain development, new neurons continue to be produced in the ventricular-subventricular zone (V-SVZ) of the adult brain.
In a rodent ischemic stroke model induced by transiently blocking the middle cerebral artery, the most commonly affected vessel in human patients, some V-SVZ-derived neuroblasts migrate toward the lesion, where they mature and become integrated into the neuronal circuitry. However, the number of these new neurons is insufficient to restore neuronal function. Within a few days after stroke, astrocytes, a major population of macroglia, in and around the injured area become activated, exhibiting larger cell bodies, thicker processes, and proliferative behavior. The migrating neuroblasts must navigate through this astrocyte meshwork to reach the lesion.
The research team demonstrated that neuroblast migration is restricted by the activated astrocytes in and around the lesion. In normal, olfaction-related migration, neuroblasts secrete a protein called Slit, which binds to a receptor called Robo expressed on astrocytes. Slit alters the morphology of activated astrocytes at the site of neuroblast contact, to move the astrocyte surface away and clear the neuroblast’s migratory path. However, in the case of brain injury, the migrating neuroblasts actually down-regulated their Slit production, crippling their ability to reach the lesion for functional regeneration. Notably, overproducing Slit in the neuroblasts enabled them to migrate closer to the lesion, where they matured and regenerated neuronal circuits, leading to functional recovery in the post-stroke mice.
The Envirome in Aging
We can divide aging into primary aging and secondary aging. Primary aging is inherent to the operation of our biochemistry, a relentless accumulation of damage that historically we could do little about, while secondary aging is driven by the environment, such as the pathogens we encounter, particulate air pollution, bad choices in diet, and a sedentary lifestyle. There is a very large gray area where primary aging meets secondary aging, and indeed it is far from settled where the line lies. The commentary here, proposing the concept of the envirome, falls into this area of inquiry.
To determine what is primary and what is secondary in aging, we would need a comprehensive model of the detailed progression of aging. I don’t expect that model to be produced any time soon. Firstly, it is a truly massive undertaking that will only be completed in this century given significant technological progress over the next few decades. Secondly, the progression of aging will become a moving target in the near future era of rejuvenation therapies. Who will care about the degree to which a specific mechanism of damage results from primary or secondary aging when it can be controlled near completely through periodic repair? The impetus to fund the deep, detailed investigation of aging will fade with the control of aging.
Although variations in the rate of aging across species suggests a strong role of genetics, the heritability of lifespan observed within each species is less than 35%, indicating that the environment plays an predominant role in aging. The reliability theory of aging portrays organisms as mechanical systems that contain components with varying probabilities of failure. Complex organisms have redundancy in vital systems (perhaps better understood as the capacity to self-repair) so that every occurrence of damage does not result in death, but rather, the organism accumulates defects (due to inefficient repair) that ultimately exhaust reparative capacity.
While, in the context of this theory, the frequency and severity of damage has been thought to be determined, at least in part, by the environment, there are few, if any, conceptual models with robust explanatory power and predictive capacity to account for the influence of the environment on the rate of aging. In this regard, the concept of the envirome, analogous to the genome, could provide a useful ontological model for studying the relationship between the environmental circumstance and genetic predisposition.
Broadly, the envirome could be thought of as an integrated set of natural, social, and personal environmental domains. The natural domain of the environment consists of ecological and geographic conditions, whereas the social environment, which lies within the natural environment, includes the built environment, social networks, and culture. Lastly, the personal environment lies within the social environment and includes the factors specific to an individual. In this model, interactions of the natural and social domains of the envirome with the genome could be viewed as the major determinants of aging. Aging, in turn, could be viewed as a progressive accrual of damage or unrepairable injury that results from a mismatch between the envirome and the genome and from exposure to adverse environmental conditions such as low socioeconomic status, smoking, or air pollution.
APOE4 Points to NHE6 Inhibition as a Potential Means to Slow the Early Onset of Alzheimer’s Disease
Why do people with the APOE4 variant of APOE have a much greater risk of Alzheimer’s disease? Past work has focused on its role in accelerating amyloid-β accumulation by disrupting recycling mechanisms in some way. Evidence is provided here for the relevant mechanisms to trace back to the acidity of the environment within parts of the cellular recycling system which APOE operates. APOE4 is more prone to dysfunction in that environment than is the case for other APOE variants. Manipulating the regulators of acidicity may thus enable Alzheimer’s disease to be slowed down at its very earliest stage – though the size of that effect in patients is a question mark. It seems plausible that it will have little effect on people with variants other than APOE4, for example.
ApoE is a lipid and cholesterol carrying protein that is primarily produced by the liver and is responsible for plasma lipid homeostasis. It occurs in three major isoforms in humans known as ApoE2, ApoE3 and ApoE4, with ApoE3 being the most frequent allele (~77% homozygosity) followed by ApoE4 (~15-20% allele frequency) which is present in more than 50% of late onset Alzheimer’s disease patients. The effect of ApoE4 on amyloid-β (Aβ) accumulation through impaired Aβ turnover, increased aggregation, and thus plaque formation is allele dosage-dependent and this can partly explain its effect on the earlier age of disease onset. However, ApoE4 can independently impair synapse function and Ca2+ homeostasis by disrupting the endocytic transport and recycling of synaptic ApoE receptors and the excitatory AMPA and NMDA type glutamate receptors that are regulated by those ApoE receptors and that are consequently trapped with them in the same vesicles.
The molecular basis by which ApoE4 causes the disruption of normal endosomal vesicle transport and recycling is most likely the result of its propensity to unfold and assume a ‘molten-globule’ conformation upon entering an acidic environment. ApoE4 differs from ApoE3 by a single amino acid, which alters its isoelectric point to coincide with the pH of ~6.5 that is present in the early endosome. We hypothesized that this isoelectric charge neutralization would make ApoE4 prone to aggregation, which could be the molecular basis for the ApoE4-induced and gene dosage-dependent recycling defect.
pH in the early endosome is maintained by the opposing functions of the proton pump, which decreases vesicular pH, and the Na+/H+ exchanger NHE6, which increases it. Here, we have investigated the role of NHE6 inhibition as a means of lowering endosomal pH, away from the isoelectric point of ApoE4. We found that this simple pharmacological intervention releases the endosomal ApoE4 block, restores the normal trafficking of ApoE receptors and glutamate receptors in neurons and corrects the functional defects in vitro and in vivo. Together these findings suggest that drugs that make vesicles in neurons more acidic may have the potential to help prevent individuals that carry the ApoE4 protein from developing Alzheimer’s disease. Current drugs that target NHE6 also affect other molecules, which can often lead to side effects. A next step will be to develop tailor-made, small molecule drugs that can enter the brain efficiently and selectively block NHE6.
Body Mass Index Correlates Strongly with Hypertension Incidence
After controlling for other factors, hypertension risk increases as excess fat tissue increases, according to the data from a recent epidemiological study. The more overweight you are, the greater your blood pressure, all other things being equal. Hypertension is no small thing: raised blood pressure damages delicate tissue throughout the body, such as via ruptures in tiny blood vessels in the brain, and it leads to the growth and weakening of heart muscle that ends in heart failure. Hypertension also accelerates the progression of atherosclerosis, and it raises the risk that blood vessels compromised by atherosclerotic plaque will rupture, causing a fatal stroke or heart attack.
It isn’t hard to suggest mechanisms that might link visceral fat tissue to hypertension. Visceral fat produces chronic inflammation through a range of mechanisms: inflammatory signaling by fat cells; greater numbers of inflammatory senescent cells; the creation of oxidized lipids; debris from dead fat cells; and more. Chronic inflammation in turn is thought to impair the operation of smooth muscle responsible for constriction and relaxation of blood vessels. When blood vessels cannot react to the environment as well as they should, when they stiffen, then hypertension follows. This seems the most plausible mechanistic link between weight, aging, and blood pressure.
The present study was undertaken to provide a better insight into the relationship between different levels of body mass index (BMI) and changing risk for hypertension, using an unselected sample of participants assessed during the Longevity Check-up 7+ (Lookup 7+) project. Lookup 7+ is an ongoing cross-sectional survey started in June 2015 and conducted in unconventional settings (i.e., exhibitions, malls, and health promotion campaigns) across Italy. Candidate participants are eligible for enrollment if they are at least 18 years of age and provide written informed consent. Specific health metrics are assessed through a brief questionnaire and direct measurement of standing height, body weight, blood glucose, total blood cholesterol, and blood pressure.
The present analyses were conducted in 7907 community-living adults. According to the BMI cutoffs recommended by the World Health Organization, overweight status was observed among 2896 (38%) participants; the obesity status was identified in 1135 participants (15%), with 893 (11.8%) participants in class I, 186 (2.5%) in class II, and 56 (0.7%) in class III. Among enrollees with a normal BMI, the prevalence of hypertension was 45% compared with 67% among overweight participants, 79% in obesity class I and II, and up to 87% among participants with obesity class III. After adjusting for age, significantly different distributions of systolic and diastolic blood pressure across BMI levels were consistent. Overall, the average systolic blood pressure and diastolic blood pressure increased significantly and linearly across BMI levels. In conclusion, we found a gradient of increasing blood pressure with higher levels of BMI. The fact that this gradient is present even in the fully adjusted analyses suggests that BMI may cause a direct effect on blood pressure, independent of other clinical risk factors.
PRRX1 as a Possible Point of Control for Remyelination
Researchers here outline what is possibly a new point of intervention in the processes that maintain the myelin sheath that wraps nerves. This sheath is vital to the correct operation of the nervous system, and as a consequence demyelinating conditions such as multiple sclerosis are unpleasant and fatal. Loss of myelin isn’t just restricted to named conditions, however: some degree of degradation occurs over the course of aging, and is thought to contribute to the progression of cognitive decline. Thus therapies that can boost myelin maintenance may be of greater interest than it might at first appear.
Myelin is maintained by oligodendrocyte cells, and the slow disruption of this cell population and its maintenance activities is the major cause of issues in aging. All cell populations exhibit loss of effectiveness or pathological behavior with the rising levels of inflammation and molecular damage present in older individuals. This research suggests a novel way to attempt to override the cellular reactions to the damage of aging in order to generate more oligodendrocytes and put them back to work. You might compare it with previous efforts that have focused on delivering greater numbers of oligodendrocytes in other ways.
Researchers have found that activation of a specific transcription factor induces in adult stem cells a phenomenon called pathological quiescence. This is when adult stem cells are rendered incapable of responding to injury by producing myelin-forming oligodendrocytes. The failure to remyelinate is the key feature of multiple sclerosis (MS). The work defines the role of the previously undescribed transcription factor known as PRRX1 in human oligodendrocyte progenitor cells, the cells that generate myelin-forming oligodendrocytes.
Current MS research focuses largely on drugs that induce the differentiation of human oligodendrocyte progenitors. In contrast, the UB research presents a novel concept for the development of new drugs based on blocking the pathological quiescence of progenitors. The research demonstrated that PRRX1 expression results in the cell cycle arrest and quiescence of oligodendrocyte progenitors, which disabled the production of myelin. In an animal model of leukodystrophy, the group of genetic disorders in which myelin fails to form or is destroyed, pathological quiescence induced by PRRX1 prevented cell colonization of white matter and effective myelin regeneration by transplanted human oligodendrocyte progenitors.
The researchers also found that blocking expression of this transcription factor prevented the negative effects of proinflammatory cytokines, such as interferon-γ, which regulates its expression. “Blockade of PRRX1 expression prevents the negative effects of interferon-γ, suggesting that PRRX1 expression might be a viable target in inflammatory diseases, such as multiple sclerosis, where interferon-γ may prevent successful myelin regeneration.”
Reviewing GDF11 as a Basis for Regenerative Therapy
I think it fair to say that GDF11 was the first concrete target to emerge from the modern reinvention of parabiosis research, in which the circulatory systems of an old mouse and a young mouse are joined. The old mouse rejuvenates a little, and the young mouse is aged a little, most of which seems to emerge from effects on inflammation and stem cell activity. Researchers thereafter started looking for specific signals carried in the bloodstream that might mediate this effect.
There has been no shortage of debate in this part of the field, such as over whether or not it is possible that beneficial factors from young blood can exist, given the evidence. Or whether the early work on GDF11 holds up at all. Work has continued, however, and matters have progressed to the point at which a well-funded biotech company, Elevian, has been launched. The Elevian researchers claim to have resolved the early conflicting evidence and confusion regarding GDF11, and are now well underway to building a regenerative therapy.
Cardiac hypertrophy is a prominent pathological feature of age-related heart failure. Using the parabiosis model, it has been demonstrated that age-related cardiac hypertrophy can be reversed via exposure to a young circulatory environment. These experiments revealed that age-related cardiac hypertrophy is at least in part mediated by circulating factors, such as GDF11, which is able to reverse the condition.
The reversal of cardiac hypertrophy in old mice exposed to a young circulation cannot be explained by a reduction in blood pressure in the older mice. An extensive proteomics analysis was performed on the serum and plasma of the animals. GDF11 was reduced in the circulation of aged mice and its levels were restored to those in young animals by parabiosis. A significant decrease was also found in both GDF11 gene expression and GDF11 protein levels in the spleens of old mice. These results suggest exciting therapeutic approaches for the management of age-related cardiac hypertrophy by restoring youthful levels of circulating GDF11.
Recently, the goal of a study in old mice was to reexamine the possibility to restore youthful levels of GDF11 by injecting recombinant GDF11 (rGDF11) and thus reversing cardiac hypertrophy and imparting a young phenotype to the old heart. The conclusions were that recombinant GDF11 (rGDF11) had no effect on cardiac structure and cardiac pump function; these results do not support the concept that GDF11 could be an anti-aging compound.
Muscle satellite cells are responsible for the postnatal growth and major regeneration capacity of adult skeletal muscle. Previous studies demonstrated that impaired regeneration in aged muscle can be reversed by parabiosis, which exposes aged tissues to a youthful systemic environment and restores injury-induced satellite cell activation by the up-regulation of Notch signaling. To determine whether supplementation of GDF11 from the young partner might underlie changes in skeletal muscle in the condition of heterochronic parabiosis, aged mice were treated with daily intraperitoneal injections of rGDF11 to increase systemic GDF11 levels.
After 4 weeks, satellite cell frequency, determined by flow cytometry, and function increased in the muscles of rGDF11-treated mice, whereas other myofiber-associated mononuclear cell populations were unaffected. Aged mice treated with rGDF11 also showed increased numbers of satellite cells with intact DNA. These results indicate that GDF11 is able to regulate muscle aging and may be therapeutically suitable for skeletal muscle dysfunction.
Beginning Exercise in Late Life Can Regain a Portion of Lost Cognitive Function
In this modern age of transport machinery, desk jobs, and idle leisure, few people exercise as much as they should. A perhaps surprisingly large fraction of the physical and mental decline characteristic of later life is the result of an increasingly sedentary lifestyle. One doesn’t have to look much further than a comparison with physically active hunter-gatherer populations to see as much. As a result, exercise looks like a therapy in the context of an older, sedentary population, an intervention that can reverse aspects of aging to some degree. Yet consider that a cessation of neglect always looks good in comparison to continued neglect. Better not to become sedentary in the first place, given the serious risks to long-term health that arise as a result.
The study involved 160 people with an average age of 65 and risk factors for heart disease, such as hypertension, who did not have dementia but reported problems with thinking skills. All participants were identified as having cognitive impairments without dementia and were sedentary at the start of the study. Researchers examined the effects of both exercise and diet, specifically the Dietary Approaches to Stop Hypertension (DASH) diet, which is a low sodium, high fiber diet rich in fruits and vegetables, beans, nuts, low fat dairy products, whole grains, and lean meats. The DASH diet was designed specifically for individuals with high blood pressure.
Participants were randomly assigned to one of four groups: aerobic exercise alone; DASH diet alone; both aerobic exercise and the DASH diet; or health education, which consisted of educational phone calls once every one or two weeks. People assigned to the exercise groups exercised three times a week for 45 minutes each session which included 10 minutes of warm-up exercises and 35 minutes of aerobic exercise, such as walking, jogging, or cycling on a stationary bicycle. At both the beginning and end of the six-month study, researchers evaluated participants’ thinking and memory abilities with standardized cognitive testing, cardiorespiratory fitness with treadmill stress testing, and heart disease risk factors with screenings for blood pressure, blood glucose and lipids. They also used questionnaires and food diaries to measure how closely the participants followed the DASH diet.
Researchers found that participants who exercised showed significant improvements in thinking skills when compared to those who did not exercise. Those who took part in both the exercise and diet had average scores of nearly 47 points on the overall tests of executive thinking skills, compared to an average score of about 42 points for those with exercise and diet alone and about 38 points for those who just received health education. There was no improvement in participants who only consumed the DASH diet, although those who exercised and consumed the DASH diet had greater improvements compared to health education controls.
At the start of the study, the participants had average scores for select subtests of executive function for people who were age 93, which was 28 years older than their actual chronological age. After six months, participants who exercised and followed the DASH diet saw their average executive function scores correspond with people who were age 84, a nine-year improvement. For those who received only health education, their performance on executive function tests worsened by a half year from their scores at the start of the study.
EnClear Therapies: Working to Filter Cerebrospinal Fluid
Older people have a lot of metabolic waste in their cerebrospinal fluid, of which the amyloid-β associated with Alzheimer’s disease is probably of greatest interest at the present time. It is an interesting question as to why this increase over time occurs, particularly considering the point that the presence of amyloid-β and other molecules is dynamic, a constant process of creation and destruction. A number of groups, such as Leucadia Therapeutics, make the case for failure of mechanical systems of drainage by which cerebrospinal fluid leaves the brain. Without that drainage to act as a sink for metabolic waste, the waste accumulates.
EnClear Therapies is a company pursuing a path analogous to that of Leucadia Therapeutics, but instead of restoring drainage they seek to filter cerebrospinal fluid. Increasingly sophisticated filtration of blood for various purposes is fairly common, albeit expensive. The challenge with cerebrospinal fluid is that it is locked away inside the spine and skull. If a suitable mechanical approach could be assembled to safely and reliably access and filter cerebrospinal fluid on a regular basis, which sounds like a tough job, then there are all sorts of things that might be built upon that foundation.
While the company is not initially focused on removal of amyloid-β, that is a possibility for the future, given success. Overall, I’d say that this is a most interesting approach: a worse strategy than restoration of drainage in the sense that each new target requires a development program to build a suitable filter to fit into the machinery, but on the other hand a better strategy for some conditions as it might be possible to clear more of a given target molecule.
EnClear Therapies was conceived with the purpose of developing novel device-based therapies to treat patients with neurodegenerative disease. Toxic proteins are generated in ALS and FTD patients with C9orf72 mutations. These proteins travel through the brain and spinal fluids and are taken up by neurons of the motor system that are very sensitive to their toxicity which leads to degeneration of these neurons leading to paralysis.
EnClear has developed a technology which clears these toxic proteins from the brain and spinal fluids of C9orf72 ALS and FTD patients. We are now developing this technology into a device that will recirculate the brain and spinal fluids while the toxic proteins are rendered harmless. With this technology Enclear aims to stop or significantly slow down the neuronal degeneration in ALS and FTD patients with C9orf72 mutations. This technology can potentially be used for other forms of ALS and FTD in which toxic prion like proteins propagate through the brain and spinal fluids.
Similar to ALS, Progressive Supranuclear Palsy (PSP) is hallmarked by the buildup of toxic proteins (in this case tau) in the brain. As with ALS, the toxic proteins travel through the brain and spinal fluids and are taken up by neurons that are very sensitive to their toxicity which leads to degeneration of these neurons leading to paralysis. EnClear Therapies aims to halt the progression of PSP by rendering the tau harmless through the same mechanism used for ALS.