Fight Aging! Newsletter, August 11th 2014

August 11th 2014

The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and 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 medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.

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  • A Gameplan to End Age-Related Disease
  • Video: Aubrey de Grey Presenting at Google London
  • Until, a Short Film from the Wellcome Trust
  • Preventing Damage from Mitochondrial Mutations
  • Recent News in Stem Cell Research
  • Latest Headlines from Fight Aging!
    • A Press Article on the Cryonics Institute
    • An Example of Continuing Legal Opposition to Cryonics
    • A Mainstream Press Article on Longevity Science
    • Towards Cell Therapy to Treat Neurodegeneration
    • Most Gains in Life Expectancy are Now Realized Late in Life
    • Testing PTB as an AGE-Breaker in Bone
    • Claiming a Cure for Rheumatoid Arthritis in Mice
    • AGEs Contribute to the Development of Osteoporosis
    • Considering Cerebrospinal Fluid Flow Disruption as a Contributing Cause of Alzheimer's Disease
    • Compensating for Cognitive Decline in Alzheimer's Disease


SENS, the Strategies for Engineered Negligible Senescence, is the only presently plausible road to the prevention and cure of all age-related disease that could be accomplished in a short enough period of time to save most of those reading this today. It is a repair-based approach to treating the causes of aging, taking the present scientific consensus on the fundamental cellular and molecular differences between old and young tissue, and providing detailed plans to produce treatments capable of reverting or working around all of them. Given funding of a hundred million dollars a year, functional rejuvenation treatments following the SENS proposals could be demonstrated in mice a mere decade from now. The chief problem at this time is that we stand a long way away from that level of funding.

This is not to point out a lack of success: far from it. The existence of the SENS Research Foundation and its present $5 million yearly budget is just one of the visible signs of fifteen years of hard work and advocacy to bring a vision into reality. Fifteen years ago there was no SENS research and the scientific community was largely unwilling to talk about treating aging in public, for fear of endangering their ability to obtain grants. Yet today this is a line of research now widely supported within the scientific community, and researchers are far more willing now to talk about treating aging. Progress towards meaningful rejuvenation treatments is progressing more rapidly today than it ever has. These are still the early years in a longer process of decades, however, and we have barely started to climb the funding mountain, and barely started to build the aging research community of tomorrow.

Large-scale funding for rejuvenation research in the SENS model will happen eventually. No other faction in the research community is proposing or working on anything that can possibly be as effective as repair of damage in aging tissue. So over the course of time SENS will inevitably take over the research community mainstream simply by virtue of the fact that it will produce meaningful results in early stage work while other approaches to treating aging will continue to fail miserably on that count. The pressing question is how long it will take, give that the clock is ticking for all of us. In helping SENS move faster we are quite literally running for our lives.

Here is a recent article on the work of the SENS Research Foundation, and while all publicity is good publicity, I'm forced to note that is somewhat annoying to see the 2005 SENS challenge given so much of a focus, while only passing mention is given to the fact that the SENS Research Foundation is now an organization with scientific programs running in numerous noted laboratories in the US and Europe, as well as a scientific advisory board that includes well-known luminaries in the fields of genetics, tissue engineering, and other fields relevant to aging research. The decade old debate as to whether or not SENS is serious science was had and done and the skeptics lost because they were wrong. End of story, and way past time to move on.

Against the Biological Clock - A Gameplan to End Age-Related Diseases

To Aubrey de Grey, the body is a machine. Just as a restored classic car can celebrate its hundredth birthday in peak condition, in the future, we'll maintain our bodies' cellular components to stave off the diseases of old age and live longer, healthier lives.

Dr. de Grey is cofounder and Chief Science Officer of the SENS Research Foundation and faculty at Singularity University's November Exponential Medicine conference - an event exploring the healthcare impact of technologies like low-cost genomic sequencing, artificial intelligence, synthetic biology, gene therapy, and more. Recently speaking to participants in Singularity University's graduate studies program, de Grey said the greatest challenge in aging research today is less of a technical nature, more a misguided focus in the mainstream.

Most approaches to age-related disease aim to manage symptoms. They have contributed to longer life expectancy and eased complications, but because treatments interfere with the body's finely tuned systems, they can have nasty side effects and are ultimately powerless (even with advances) to reverse age-related illness. Why? "Aging is a side effect of being alive in the first place," says de Grey.

Metabolic processes drive the day-to-day business of living, but they also inevitably cause cellular damage. The body's range of self-repair mechanisms don't take care of everything. Eventually, a lifetime of accumulated damage causes the familiar signs of aging like "thinning skin, cloudy eyes, muscles sapped of strength, heart disease, and cognitive decline." Negligible senescence is a term used to describe certain animals that don't display symptoms of aging. De Grey believes we can use biotechnology to engineer negligible senescence in humans, and he cofounded the SENS Research Foundation to lead the way.


In any given year Aubrey de Grey, cofounder of the SENS Research Foundation, gives a great many presentations on his vision for the successful treatment and reversal of aging: at scientific conferences, for life insurance companies, in front of advocacy group meetups, and more. A sizable fraction of his work and the work of many of the staff at the Foundation is in essence persuasion. After all, the only reason we are not well on our way towards the robust demonstration of rejuvenation in old mice is that most people don't care about building new medical technologies to treat aging, and don't give much thought to the prospects for defeating age-related disease. There is consequently very little funding for the relevant research programs; you can compare and contrast the present state of aging research and its lack of support with the way society at large thinks about cancer and the size of the cancer research establishment. Two very different mindsets and very different research communities as a result.

Here is video of a presentation given last week to Google employees in London. It includes some implementation progress reports from the past few years that may or may not be news to you, depending on how closely you've been keeping track of the field. When you spend your time following along with your nose to the news feed, sometimes it is pleasant to step back and note that SENS has moved a fair way down the path from "here is a plan, and this is what we should do," and well into the realm of "this is what we're doing, and here is where we are now." A lot of people worked hard and donated generously to make that progress happen, and beyond that it is a testament to just how much you can do with a few million dollars in early stage biotechnology research these days: prices are falling even as capabilities improve dramatically.

Google brings in a lot of noted people to present to company employees, so don't read anything into this. I believe de Grey has presented there in the past, long before the California Life Company, Google's new venture into longevity science, came into being. He will probably present again in the future, regardless of whether Calico heads off into the wilderness of the genetics of human longevity or the leadership there choose to fund something more likely to produce meaningful results and treatments for aging, such as SENS-like repair biotechnologies.


The Wellcome Trust is a biomedical research foundation of some size and influence. A fellow from their publicity group recently pointed me to a short film published by their house magazine, Mosaic. To my eyes the noteworthy item here is not the film in and of itself, nor the fact that the Trust has aging and longevity on its agenda, but rather that this organization, which is far and away large enough to be very sober and conservative, is comfortable publishing serious discussions of radical life extension and the prospects for unlimited life spans achieved through future advances in medical science.

If you're interested in reading the tea leaves, you might take a look at the Wellcome Trust's strategic plan for 2010-2020. About a quarter of their grants, around $250 million each year, go towards research into aging and the diseases of aging:

This challenge encompasses a broad spectrum of research to understand the cellular and physiological processes underlying normal development and ageing, and the mechanisms that underpin the onset of non-communicable diseases. Looking ahead, we will continue to work with the research community to stimulate research applications in this challenge area. We will hold a Frontiers Meeting to examine the topic of healthy ageing, and we will also examine the topic of disease prevention as a potential future area of focus. We will take forward discussions to examine the potential to use human induced pluripotent stem cells for large-scale studies on how genomic variation affects cellular phenotype and disease mechanisms.

Funded work is all very mainstream, and the Trust appears to follow the safe philanthropic playbook of reinforcing successful, established fields that already have a great deal of attention and support. Here that includes regenerative medicine and investigations into the genetics of aging. That makes the film below somewhat more interesting in the context of this organization's recent history and stated goals. One might hope that it is a sign that the veneer of conservatism in large funding institutions is cracking a little in the face of what might be achieved in the near future if only the right research programs are funded.

Until: Who wants to live for ever?

Do you want to live to 100? 1,000? What about for ever? Meet a man seeking immortality, leading age-research scientists, the very young and the very old as they grapple with deciding what is the right age to die in Until, a journey of the lifetime.

The human lifespan is increasing by five hours a day - every day. But how much life is enough? What if society reached a point where individuals could essentially choose how long they lived? At what age would people decide to call it a day, meet their maker and embrace death? And, for those reaching towards immortality, what would they do with their infinite time?

These are the profound questions explored in Until. Part science, part philosophy, this film invites us all to ask just one question: would I want to live for ever?


SENS, the Strategies for Engineered Negligible Senescence, is an ongoing research and advocacy program that aims to bring aging under medical control. One day aging will be in exactly the same bucket as tuberculosis: it exists, it is a threat if you somehow lose access to modern medicine, but most people are never troubled by it. After watching the research community for more than a decade, I firmly believe SENS is the best path towards this goal, offering a shot at real working rejuvenation within our lifetimes if funded sufficiently. Aging is a matter of cellular and molecular damage, and SENS is in essence a repair program, outlining the shortest likely paths towards therapies that can revert the full list of known fundamental forms of damage that distinguish old tissue from young tissue.

SENS has been running as a research program for some years, albeit with far less funding that we'd like to see. A lesser known aspect of modern medical research is that near all early stage, proof of concept, high-risk work is funded by philanthropy. The better known institutional and for-profit sources of funding are risk averse and don't become involved until researchers already have demonstrations and prototypes. It's a wonder anything is ever accomplished, frankly. Thus SENS is funded near entirely by philanthropic donations. It has been since the days when research started under the auspices of the Methuselah Foundation, and this is still the case as it continues at the SENS Research Foundation.

One of the longer running SENS research programs is focused on mitochondrial DNA damage in aging, and an innovative way of dealing with this problem that was first pioneered by researchers working on inherited mitochondrial diseases. These conditions are very different from aging: in a genetic disease such as Leber's hereditary optic neuropathy a large fraction of a patient's mitochondria are dysfunctional from birth due to one or more damaged genes, whereas in a normal individual damage to mitochondrial genes accumulates over time as a side-effect of the operation of ordinary metabolic processes. Nonetheless, in both cases the damage is essentially similar and the same types of treatment will work. Genes encode protein machinery, and it is the proteins that are important. If the missing proteins can be supplied somehow, then it no longer matters that the genes are damaged. Thus the SENS plan, and the plan of researchers aiming to cure inherited mitochondrial diseases, is to place a copy of the crucial mitochondrial genes into the cellular nucleus.

Here is the latest in a series of articles from philanthropist Jason Hope on the nuts and bolts of the SENS research programs. This discusses work on mitochondrial damage in aging and how to make it no longer matter:

MitoSENS: Preventing Damage from Mitochondrial Mutations

Various structures inside the cell read DNA like a set of instructions on how to do their jobs. A body cell keeps most of its DNA safely tucked away in its nucleus. Mitochondria are different in that they have their own DNA, known as mtDNA, that they use as an instruction booklet to make the proteins that make up the machinery they use to harvest energy from our food and convert it to ATP. Mitochondria are also different from other cell structures because they keep this mtDNA nearby instead of storing the set of instructions in remote location inside the nucleus.

Just like municipal power plants, mitochondria create toxic waste as a byproduct. This toxic waste can pollute the surrounding cellular community and cause damage to structures within the cell. Mitochondria power plants spew out free radicals that impart particular damage to cellular structures. Because of proximity to the power plant, mtDNA is at special risk for exposure to toxic waste. Free radicals can assault vulnerable mtDNA and delete large chunks of genetic code. This can render the mitochondria incapable of reading the instructions for making the critical components these little power stations need to create energy.

To make matters worse, cells tend to hang on to mutant mitochondria while destroying healthy ones. As a result, once even one mitochondrion with these large deletions appears, its progeny quickly take over a healthy cell. In a perfect world, scientists would simply prevent deletions in mitochondrial DNA or repair deletions before they cause harm. Unfortunately, science is nowhere near ready to prevent or repair mtDNA deletions. For now, the most reasonable approach is to engineer a system that protects cells from damage caused by mutant mitochondria. One way of doing this is to create backup copies of mtDNA and safely tuck them away in the cell's nucleus, where free radicals cannot harm the information contained within the mitochondrial genes.

This approach of making backup copies is not new - evolution has already moved thousands of genes that were originally part of the mtDNA into the protective confines of the nucleus. Today, the mtDNA that mitochondria keep near the power plant contains instructions to build only the 13 different proteins it needs on a day-to-day basis, even though it originally contained over a thousand. The others are now safely ensconced in the nucleus. When accessed, these genes create proteins in the main body of the cell, outside the mitochondria. The cell then imports the newly created proteins into the mitochondria through specialized transport docks in the mitochondria membranes.

The greatest challenge to importing the 13 remaining proteins is that they tend to fold up on themselves while in the main body of the cell, creating folded structures too large to fit through the transport docks. Scientists at the SENS Research Foundation Research Center are working [on] ways to allow decoding the "working copies" of backup copies of genes whose proteins are destined for the mitochondria to occur near mitochondria rather than far away in the cell body. Because they do not have so far to travel, proteins may pass through transport docks before they fold up.

This new approach was pioneered by Professor Marisol Corral-Debrinski at the Institut de la Vision at Pierre and Marie Curie University, Paris. SENS Research Foundation funding helped Dr. Corral-Debrinski's team introduce into the eyes of a rat a mutated mitochondrial gene associated with an inherited form of blindness to cause vision loss in the lab animal. Using the same technique, the team then restored the rat's vision.


The rejuvenation toolkit of the near future must include ways to replace some populations of cells. The ones you might be familiar with are immune cells and some populations of long-lived cells that tend to diminish over time such as the dopamine generating neurons whose loss leads to Parkinson's disease and certain cells in the retina essential to vision. The situation for stem cell research is somewhat different to that of much of the rest of the scientific effort needed to bring degenerative aging under medical control and prevent all age-related disease. There is no real lack of funding for one: it is a very energetic, well-supported field that is making good progress towards the goal of fine control over cell operation and fate. The challenge here is more one of steering at least some of this research in the right direction, which is aided by the existing incentives: most of the conditions that will most benefit from stem cell therapies are age-related, and thus researchers must engage with stem cell aging in order to produce treatments that are effective.

Along the way the research community will probably wind up producing useful transitional technologies, ways to revert the decline in stem cell activity with aging that produce meaningful benefits without addressing the underlying damage of aging. It is most likely the case that stem cell populations become less active as a reaction to damage, but since this largely seems to key from circulating levels of specific proteins it is a reaction that can in principle be overridden. This is not a solution for the long term as it doesn't address the underlying causes. It is a patch, but a better class of patch: I think that it is fairly evident from the state of first generation stem cell therapies today that there are worthwhile gains to be obtained.

Here are a few recent snippets of news from the stem cell research community, illustrative of progress well underway. You'll notice there's a lot of focus on repair after the fact and less on the use of cell treatments in a preventative manner. This is one of the things that must change in today's research community, leading to a growing willingness to build therapies for people who are aging but classed as "healthy" so that they do not become damaged and stricken. Prevention trumps cure.

Dramatic Growth of Grafted Stem Cells in Rat Spinal Cord Injuries

Neurons derived from human induced pluripotent stem cells (iPSC) and grafted into rats after a spinal cord injury produced cells with tens of thousands of axons extending virtually the entire length of the animals' central nervous system. The iPSCs used were developed from a healthy 86-year-old human male. "These findings indicate that intrinsic neuronal mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons reprogrammed from very aged human cells."

While numerous connections were formed between the implanted human cells and rat cells, functional recovery was not found. [The researchers] are attempting to identify the most promising neural stem cell type for repairing spinal cord injuries. They are testing iPSCs, embryonic stem cell-derived cells and other stem cell types. "Ninety-five percent of human clinical trials fail. We are trying to do as much as we possibly can to identify the best way of translating neural stem cell therapies for spinal cord injury to patients. It's easy to forge ahead with incomplete information, but the risk of doing so is greater likelihood of another failed clinical trial. We want to determine as best we can the optimal cell type and best method for human translation so that we can move ahead rationally and, with some luck, successfully."

Stem cells show promise for stroke in pilot study

A stroke therapy using stem cells extracted from patients' bone marrow has shown promising results in the first trial of its kind in humans. Five patients received the treatment in a pilot study. The therapy was found to be safe, and all the patients showed improvements in clinical measures of disability. The therapy uses a type of cell called CD34+ cells, a set of stem cells in the bone marrow that give rise to blood cells and blood vessel lining cells. Previous research has shown that treatment using these cells can significantly improve recovery from stroke in animals. Rather than developing into brain cells themselves, the cells are thought to release chemicals that trigger the growth of new brain tissue and new blood vessels in the area damaged by stroke.

Stem Cell Advance May Increase Efficiency of Tissue Regeneration

A new stem-cell discovery might one day lead to a more streamlined process for obtaining stem cells, which in turn could be used in the development of replacement tissue for failing body parts. The work builds on a strategy that involves reprogramming adult cells back to an embryonic state in which they again have the potential to become any type of cell. The efficiency of this process may soon increase thanks to the scientists' identification of biochemical pathways that can inhibit the necessary reprogramming of gene activity in adult human cells. Removing these barriers increased the efficiency of stem-cell production, the researchers found.

Teeth Sprout from Glia-Derived Stem Cells

The researchers discovered that young cells, which at first are part of the neural support cells, or the glial cells, leave the nerves at an early stage of the fetal development. The cells change their identity and become both connective tissues in the tooth pulp and odontoblasts - that is, the cells that produce the hard dentin underneath the enamel. "The fact that stem cells are available inside the nerves is highly significant, and this is in no way unique for the tooth. Our results indicate that peripheral nerves, which are found basically everywhere, may function as important stem cell reserves. From such reserves, multipotent stem cells can depart from the nerves and contribute to the healing and reformation of tissues in different parts of the body."


Monday, August 4, 2014

This press article on the history of cryonics and the work of the Cryonics Institute skips over a lot of the important technical details, such as the fact that patients are vitrified these days rather than frozen, a technique that minimizes ice crystal formation in tissues, but is still worth reading:

Inside the brick-fronted warehouse in Clinton Township, the body count has topped 100. Nestled inside Wal-Mart sleeping bags, the bodies stand upside-down within 10-foot-high tanks resembling immense white thermos bottles. This is the Cryonics Institute, and the people in those tanks - "cryostats," they're called - after being declared dead, have had their bodies frozen in perpetuity in the belief that future science may be able to thaw them, cure their ills, and, just maybe, return them to youthful vigor. They've made a bet: that in a time yet to come, they'll rise again, with "death" only a temporary and reversible embarrassment easily remedied by medical know-how.

Death is a gray line and it's always moving. What might have been terminal 150, 15, even five years ago is treatable today. Something as simple as CPR has saved countless lives; cardiac defibrillation - the "shock paddles" used to jump-start a stopped heart - has revived patients previously considered dead. What's "dead" mean to medicine, other than a challenge? From that perspective a storehouse of frozen bodies is no more macabre than a heart transplant, a now-common medical procedure once considered grotesque.

Right now, though, cryonics is more like an in-progress medical trial. Advances in stem-cell research, nanotechnology, and therapeutic cloning give cryonicists hope, but there are no guarantees. Today's frozen people are already dead, or "deanimated," as some prefer; tomorrow's helpful scientists will not only have to successfully thaw their "patients," but return them to life. That's assuming, fingers crossed, that they've been frozen in a recoverable way, without too much tissue damage, and that they've been carefully maintained. Once thawed, they'll have to be treated for being "dead," by whatever methods would make that possible. And who wants to wake up alone in the future in a body already ravaged by time? Better to hope that a new, youthful body is waiting for you.

Monday, August 4, 2014

The small four decades old cryonics industry provides low-temperature storage at the end of life, an attempt to preserve the fine structure of the brain until future technologies can restore a preserved individual to life. This is not beyond the realm of the possible: it will require at the very least mature molecular nanotechnology and near complete control over cells, but both of these are expected to come to pass over the next century.

Cryonics has long faced legal opposition, and it remains illegal in many regions for reasons that have less to do with actual directed opposition and more to do with a state of bureaucracy surrounding death and funerary arrangements in which everything not explicitly permitted is forbidden. The tiny size of the cryonics community makes effective lobbying a challenge at this level; its membership can oppose local government and win, as happened in the US some years back, but that is about it at this time. This post outlines another similar situation in Canada, but here the legislative opposition to cryonics is more deliberate:

The Cryonics Society of Canada was created by Douglas Quinn in 1987. ​In 1990, British Columbia, our westernmost province passed a law prohibiting the marketing of cryonics, and the early 1990's were spent by the CSC unsuccessfully attempting to overturn it. Similar legislation was considered in Alberta, but it was not passed into law. Even though it is fortunate that no other state or province has passed such a law, it still remains in force to this date. Technically, a resident of British Columbia can have cryonics arrangements made, but as one can imagine, a law written in such a manner makes it difficult to find funeral directors and medical professionals that are comfortable assisting these efforts.

Cryonicists in BC have been trying to have that prejudicial law overturned for many years now. This is a very important issue, not only for the people of BC, but also for cryonicists in other regions. Having an anti-cryonics law on the books creates the potential for others to be influenced by that established precedent. It is in everyone's best interest to overturn it, lest another zealous lawmaker sees that as an opportunity to create similar rules. In consultation with a civil rights attorney, BC cryonicists have proposed that the best way to challenge the law is to create a business that would be directly affected by it and appeal on the grounds that it is discriminatory. This creates an opportunity to formally start an organization with a similar purpose that Suspended Animation Inc has in the USA, and it falls beautifully in line with the above mentioned goals of the CSC.

Tuesday, August 5, 2014

These days the mainstream press is giving a larger sliver of attention to various ongoing efforts to treat aging as a medical condition and thereby extend healthy life. We should expect to see an increasing number of articles similar to this one as funding for proactive aging research grows and more large institutions with publicity teams become involved:

There are a number of biological components involved in the process of ageing. These cause the body to slowly degrade at the cellular level. Old age is also a leading risk factor for many common illnesses, such as cancer and heart disease. Tackling ageing, therefore, is seen as a way to combat many diseases at once. This is the motivation behind Google's anti-ageing startup called Calico, which was founded last year and is led by Art Levinson, the former head of Genentech, a pioneer of the biotechnology industry. Craig Venter, a geneticist who was instrumental in the sequencing of the human genome, created a similar company earlier this year. The primary goal of these and other efforts is not necessarily to extend humans' lifespan, but rather their healthspan, or the number of years lived in good health. Many scientists, though, believe that any effort to slow or stop the progression of age-related diseases must deal with the cellular damage involved in ageing - so longer life is an inevitable and welcome byproduct.

These newer outfits and much anti-ageing research over the past decade have focused on genes. The chances of a person living to 80 are based mostly on behaviour - don't smoke, eat well and exercise - but the chances of living beyond that are based largely on genetics. So scientists are looking for the "protective genes" that slow cellular decline and ward off diseases in [long lived individuals]. If researchers can find them it is hoped that pharmaceutical firms might create drugs that mimic their effects in people otherwise likely to achieve normal lifespans. Others think that to go further the body must be treated like a machine in need of regular repair and replacement parts. Regenerative medicine offers some hope in this regard. Scientists are using stem cells to grow human replacement parts, like tissues and organs. In theory, a person could keep going back to the shop for new parts, so long as his brain remained intact. Scientists even talk about treating diseases that ravage the brain, like Alzheimer's and Parkinson's, with replacement nerve cells.

Optimists, like Aubrey de Grey, a provocative anti-ageing researcher in England, believe that technology will allow people alive today to live well beyond [the present limits of old age]. Most others believe that such progress is some way off. A more realistic hope is that anti-ageing research will lead to lower health-care costs. One of the characteristics of the very old is that they tend to be healthy right up until their deaths. They therefore cost health-care systems less than most old people, especially those suffering from chronic diseases. Scientists talk of a "longevity dividend" that might be achieved by compressing the period of ill health at the end of life for everyone. This would at least address the paradox of the quest for eternal life: people want to live for ever, but they don't want to grow old.

Tuesday, August 5, 2014

A range of neurodegenerative conditions that primarily involve cell loss, such as Parkinson's disease, might be treated with transplants of neural stem cells or more specialized differentiated cells. Replacing the cells doesn't address the underlying causes that led to their loss, the rising toll of molecular damage that accompanies aging, but it may be a far more effective patch treatment than those presently available. Perhaps more importantly, it is expected that any more general rejuvenation toolkit that does address underlying causes will still need some way of making up the numbers in various small populations of long-lived nerve cells of the brain and central nervous system that have diminished over time. Progress towards this goal is to be welcomed:

[Researchers] have grafted neurons reprogrammed from skin cells into the brains of mice for the first time with long-term stability. Six months after implantation, the neurons had become fully functionally integrated into the brain. This successful, because lastingly stable, implantation of neurons raises hope for future therapies that will replace sick neurons with healthy ones in the brains of Parkinson's disease patients, for example. "Successes in human therapy are still a long way off, but I am sure successful cell replacement therapies will exist in future. Our research results have taken us a step further in this direction."

The stem cell researchers' technique of producing neurons, or more specifically induced neuronal stem cells (iNSC), in a petri dish from the host's own skin cells considerably improves the compatibility of the implanted cells. The treated mice showed no adverse side effects even six months after implantation into the hippocampus and cortex regions of the brain. In fact it was quite the opposite - the implanted neurons were fully integrated into the complex network of the brain. The neurons exhibited normal activity and were connected to the original brain cells via newly formed synapses, the contact points between nerve cells. "Building upon the current insights, we will now be looking specifically at the type of neurons that die off in the brain of Parkinson's patients - namely the dopamine-producing neurons." In future, implanted neurons could produce the lacking dopamine directly in the patient's brain and transport it to the appropriate sites.

Wednesday, August 6, 2014

Much of the gain in life expectancy at birth over the past two centuries was realized through reductions in early mortality. This was achieved through sanitation, increased wealth, and control of infectious disease. As this paper notes, that trend is largely done with now, and the gains in life expectancy overwhelmingly arrive in later life due to advances in medical technologies aimed at treating the diseases of aging. The authors, economists rather than biogerontologists, see this as a potential problem because of increased length of retirement. In reality retirement is just a tradition, however, already unjust where it is enforced by law, and removed from the reality that individuals who remain healthy for longer thanks to modern medicine can just carry on being productive and working for a living. Do people serve laws or do laws serve people?

As life spans lengthen, retirement as an institution will change, as the reason for its existence - the ill health and incapacity that accompanies aging - will ultimately vanish. Similarly the culture of government-enforced entitlement in which resources are transferred from comparatively poor and disempowered young people to comparatively wealthy and empowered old people must also be dismantled in the years ahead: it is unsustainable and morally bankrupt besides. All of the financial problems that the political chattering classes fret about with respect to increasing longevity are created by the present system of governance and its entitlements and rules, which together threaten to make a grand and damaging economic ruin out of what would otherwise be a great benefit.

The original "demographic transition" describes a process that began in Europe by the early 1800s with decreases in mortality followed, usually after a lag, by decreases in fertility. This historical process ranks as one of the most important changes affecting human society in the past half millennium. The increase in life expectancy associated with this demographic transition has been accompanied by rising levels of per capita output, which have in turn spurred further improvements in population health.

Now, the United States and many other countries are experiencing a new kind of demographic transition. Instead of additional years of life being realized early in the lifecycle, they are now being realized late in life. At the beginning of the twentieth century, in the United States and other countries at comparable stages of development, most of the additional years of life were realized in youth and working ages; and less than 20 percent was realized after age 65. Now, more than 75 percent of the gains in life expectancy are realized after 65 - and that share is approaching 100 percent asymptotically. The choice of age 65 to illustrate this new demographic transition is somewhat arbitrary, but if we used 60 or 70 instead, the results would be qualitatively similar.

The new demographic transition is a longevity transition: how will individuals and societies respond to mortality decline when almost all of the decline will occur late in life? This issue is broader and more far-reaching than the issue of cohort size in each age group, with its focus on the prospective retirement of the unusually large "baby boomer" cohort, and has important socio-economic implications independent of patterns of fertility.

When the gains in life expectancy occur mainly towards the end of life, they contribute more to the age bracket that is traditionally mostly retired rather than to the age bracket in prime working years. Retirees are highly dependent on transfers from the working population for living expenses, including large consumption of medical care. Thus, gains in life expectancy concentrated at the end of life can unsettle an economy's balance between production and consumption in ways that pose a long-run challenge for public policy. The obvious changes that are needed (at least "obvious" to many economists") would be to raise productivity, to raise the savings rate, and to raise the age of retirement, but how to accomplish such goals is controversial and uncertain.

Wednesday, August 6, 2014

Advanced glycation endproducts, AGES, are a class of undesirable sugary metabolic waste that accumulate in tissues over time. They gum together important protein structures and cause cells to react to their presence in ways that are damaging and raise levels of chronic inflammation. There are many different types of AGE, but most are not all that relevant to the aging process in healthy people, being short-lived and well controlled by our biochemistry. More hardy types of AGE that cannot be effectively cleared are a fundamental difference between old and young tissues, and a contribution to degenerative aging. Of these glucosepane is the most important in human tissues.

Much of the limited work of past decades that aimed to produce AGE-breaker drugs capable of clearing out AGEs went nowhere, as drug candidates established in animal studies performed very poorly in people. It turned out that the types of AGE important in mice and rats are quite different from those that are important in humans. So researchers now realize that they have to work with human tissues to draw any reasonable conclusions, such as in this study. Note that the drug candidate PTB has been known as a potential AGE-breaker on the basis of animal studies for some years now, but it remains unclear as to its utility as a treatment for people:

Nonenzymatic glycation (NEG) describes a series of post-translational modifications in the collagenous matrices of human tissues. These modifications, known as advanced glycation end-products (AGEs), result in an altered collagen crosslink profile which impacts the mechanical behavior of their constituent tissues. Bone, which has an organic phase consisting primarily of type I collagen, is significantly affected by NEG. Through constant remodeling by chemical resorption, deposition and mineralization, healthy bone naturally eliminates these impurities. Because bone remodeling slows with age, AGEs accumulate at a greater rate. An inverse correlation between AGE content and material-level properties, particularly in the post-yield region of deformation, has been observed and verified.

Interested in reversing the negative effects of NEG, here we evaluate the ability of n-phenacylthiazolium bromide (PTB) to cleave AGE crosslinks in human cancellous bone. Cancellous bone cylinders were obtained from nine male donors, ages nineteen to eighty, and subjected to one of six PTB treatments. Following treatment, each specimen was mechanically tested under physiological conditions to failure and AGEs were quantified by fluorescence. Treatment with PTB showed a significant decrease in AGE content versus control NEG groups as well as a significant rebound in the post-yield material level properties. The data suggest that treatment with PTB could be an effective means to reduce AGE content and decrease bone fragility caused by NEG in human bone.

Thursday, August 7, 2014

Autoimmunity is one of the remaining dark frontiers of human disease, and the collection of medical conditions in which the immune system starts to attack a patient's own tissues are largely poorly understood. In the case of rheumatoid arthritis, for example, there is no real consensus on root cause or how the disease mechanisms work in detail, and it even may be a collection of several distinct issues lumped under one heading because the outcome looks the same. The effectiveness of treatments has been improving, but some patients just don't respond to the standard approach of trying to suppress the unwanted immune responses via TNF inhibitors.

Here researchers are making the bold claim of an effective cure for rheumatoid arthritis in mice, with a method that sounds like a more targeted way of suppressing unwanted immune activity rather an advance towards addressing root causes, and are heading for clinical trials:

Researchers have developed a therapy that takes the treatment of rheumatoid arthritis in mice to a new level: after receiving the medication, researchers consider the animals to be fully cured. The drug is a biotechnologically produced active substance consisting of two fused components. One component is the body's own immune messenger interleukin 4 (IL-4); previous studies have shown that this messenger protects mice with rheumatoid arthritis against cartilage and bone damage. [The] scientists have coupled an antibody to IL-4 that, based on the key-lock principle, binds to a form of a protein that is found only in inflamed tissue in certain diseases (and in tumour tissue).

"As a result of combination with the antibody, IL-4 reaches the site of the disease when the fusion molecule is injected into the body.It allows us to concentrate the active substance at the site of the disease. The concentration in the rest of the body is minimal, which reduces side-effects." The researchers tested the new fusion molecule [in] a mouse model in which the animals developed swollen, inflamed toes and paws within a few days. Among other things, the researchers studied the fusion molecule in combination with dexamethasone, a cortisone-like anti-inflammatory drug that is already used to treat rheumatoid arthritis in humans.

When used separately, the new fusion molecule and dexamethasone managed only to slow the progression of the disease in the affected animals. In contrast, the typical signs of arthritis, such as swollen toes and paws, disappeared completely within a few days when both medications were administered at the same time. Concentrations of a whole range of immune messengers in blood and inflamed tissue, which are changed in rheumatoid arthritis, returned to their normal levels. "In our mouse model, this combined treatment creates a long-term cure."

Thursday, August 7, 2014

Osteoporosis is the characteristic loss of bone mass and strength that occurs with aging, with proximate causes that include an imbalance in the distinct populations of cells responsible for bone creation and destruction, as well as the general decline in stem cell maintenance activities that occurs for every tissue in the body. For root causes you have to look to cellular and molecular damage of the sort listed in the SENS research programs, which include an accumulation of sugar-based metabolic waste molecules called advanced glycation endproducts (AGEs). These gum together important proteins in the extracellular matrix between cells and degrade tissue elasticity, but they also trigger increased levels of chronic inflammation through reacting with RAGE, the receptor for AGEs. Chronic inflammation is an unpleasant thing, a source of damage and dysfunction in and of itself, and it contributes meaningfully to many age-related conditions - such as osteoporosis.

Among the wide spectrum of bone disorders, osteoporosis has emerged as a medical and socioeconomic threat. Although it is accepted that more than 8.9 million fractures annually worldwide are caused by osteoporosis, they are often diagnosed only after the first clinical fracture has occurred because bone loss arises insidiously and is initially asymptomatic. The lifetime fracture risk of a patient with osteoporosis has been estimated to be in the order of 30-40%, which is very close to the risk for coronary heart disease. Moreover, in addition to pathologic fractures, osteoporosis carries a considerable risk of disability due to serious medical complications. With the aging of the population, the prevalence of osteoporosis is expected to further increase.

In the last twenty years, advanced glycation end products (AGEs) have been shown to be critical mediators both in the pathogenesis and development of osteoporosis and other chronic degenerative diseases related to aging. The accumulation of AGEs within the bone induces the formation of covalent cross-links with collagen and other bone proteins which affects the mechanical properties of tissue and disturbs bone remodelling and deterioration, underlying osteoporosis. On the other hand, the gradual deterioration of the immune system during aging (defined as immunosenescence) is also characterized by the generation of a high level of oxidants and AGEs. The synthesis and accumulation of AGEs (both localized within the bone or in the systemic circulation) might trigger a vicious circle (in which inflammation and aging merged in the word "Inflammaging") which can establish and sustain the development of osteoporosis.

Friday, August 8, 2014

Alzheimer's disease is associated with buildup of amyloid-β in the brain, aggregates formed of misfolded proteins. The amount of amyloid present at any given time is dynamic, however, which has long suggested that Alzheimer's is in part caused by a slow decline in the mechanisms responsible for clearing amyloid from the cerebrospinal fluid. You might look at investigations of the choroid plexus, for example, which acts as a filtration mechanism for cerebrospinal fluid. Here a researcher theorizes on the possible role of disruptions in the flow of cerebrospinal fluid in Alzheimer's disease, another way in which clearance of amyloid might be impacted with the progression of aging:

Plaques and tangles may be manifestations of a more substantial underlying cause of Alzheimer's disease (AD). Disease-related changes in the clearance of amyloid-β (Aβ) and other metabolites suggest this cause may involve cerebrospinal fluid (CSF) flow through the interstitial spaces of the brain, including an archaic route through the olfactory system that predates neocortical expansion by three hundred million years. This olfactory CSF conduit (OCC) runs from the medial temporal lobe (MTL) along the lateral olfactory stria, through the olfactory trigone, and down the olfactory tract to the olfactory bulb, where CSF seeps through the cribriform plate to the nasal submucosa.

Olfactory dysfunction is common in AD and could be related to alterations in CSF flow along the OCC. Further, reductions in OCC flow may impact CSF hydrodynamics upstream in the MTL and basal forebrain, resulting in less efficient Aβ removal from those areas - among the first affected by neuritic plaques in AD. Factors that reduce CSF drainage across the cribriform plate and slow the clearance of metabolite-laden CSF could include aging-related bone changes, head trauma, inflammation of the nasal epithelium, and toxins that affect olfactory neuron survival and renewal, as well as vascular effects related to diabetes, obesity, and atherosclerosis - all of which have been linked to AD risk. Problems with CSF-mediated clearance could also provide a link between these seemingly disparate factors and familial AD mutations that induce plaque and tangle formation. I hypothesize that disruptions of CSF flow across the cribriform plate are important early events in AD, and I propose that restoring this flow will enhance the drainage of Aβ oligomers and other metabolites from the MTL.

Friday, August 8, 2014

In this open access paper researchers report on a way to somewhat compensate for the measurable cognitive dsyfunction resulting from Alzheimer's disease by boosting synaptic activity. This is characteristic of much of what emerges from the medical research community in that it makes no attempt to engage with the causes of the condition, but rather adjusts biological processes so as to better force continued operation despite the underlying disease pathology:

A series of recent studies have found that the levels of the enzyme striatal-enriched protein tyrosine phosphatase (STEP) are raised in several different neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease, fragile X syndrome, and schizophrenia. STEP normally opposes the development of synaptic strengthening, and these abnormally high levels of active STEP disrupt synaptic function by removing phosphate groups from a number of proteins, including several glutamate receptors and kinases. Dephosphorylation results in internalization of the glutamate receptors and inactivation of the kinases - events that disrupt the consolidation of memories.

The increase in STEP activity [likely] contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we identify the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopenta​thiepin-6-aminehydrochloride (known as TC-2153) as a novel inhibitor of STEP, and we demonstrate the activity of TC-2153 both in vitro and in vivo. TC-2153 shows specificity towards STEP compared to several other tyrosine phosphatases and shows no toxicity to cultured neurons. Importantly, the compound reversed cognitive deficits in a mouse model of Alzheimer's disease in a way that did not involve changes in the usual pathological signs (p-tau and beta-amyloid).


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