Fight Aging! Newsletter, October 26th 2015

October 26th 2015

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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  • Rejuvenation Biotechnology 2015 Keynote Videos
  • Myostatin Knockout Achieved in Dogs via CRISPR
  • Methuselah Foundation Podcast: An Interview with David Gobel
  • A Couple More Minority Theories on Alzheimer's Disease
  • Evidence for the Importance of Inflammation and Neurogenesis in Age-Related Cognitive Decline
  • Latest Headlines from Fight Aging!
    • End the Virus: Crowdfunding Campaign for DRACO
    • Stem Cell Therapy as a Treatment for Lewy Body Dementia
    • On Cryonics and Preserving the Mind
    • SENS Research Foundation Benefit Party, November 3rd
    • Reporting from a Comparative Biology of Aging Conference
    • Is Nutrition Really Worth Spending Time On in the Context of Neurodegeneration?
    • People Should Plan for Very Long Lives Indeed, But Do Not
    • The Latest on the Debate Over GDF-11 Findings
    • Correlating Fitness to Specific Cognitive Functions in Aging
    • Another Step Towards Immune Cell Infusions as Therapy


The SENS Research Foundation has released videos of the keynote addresses given at the Rejuvenation Biotechnology 2015 conference held earlier this year. The SENS Research Foundation is one of the very few organizations focused on speeding up progress towards medical technologies capable of repairing the cell and tissue damage that causes aging. This has been a neglected area of research and development, scattered across many fields in medicine, and with little coordination between research groups working on aspects of the same form of damage and degeneration. As a consequence the basic science is far ahead of its application; for more than twenty years now more than enough has been known to make real inroads into repairing the causes of aging and age-related disease. Yet all too little of that has happened, despite tremendous progress in biotechnology and its tools. What is needed today is much more work on turning what is known about cell and tissue damage - and how to fix it - into therapies, and this rather than the generation of ever more data on the detailed interactions between metabolism and aging, which is the present focus for the majority of the aging research community.

Fortunately significant progress on the basis for rejuvenation therapies has been made in the labs in recent years, even given the struggles for funding and attention. Senescent cell clearance has been demonstrated, as have methods of working around the consequences of mitochondrial DNA damage, and more besides. For organizations like the SENS Research Foundation this means that it is time to devote more energy to making connections with the for-profit medical development industry. More technologies will be arriving at the point of readiness for development in the years ahead, but the hand-off from research group to company to clinic is not something that just magically happens. It all requires organization, raising awareness, making connections, giving clear signals as to what is coming down the line. This is the purpose of the Rejuvenation Biotechnology conference series, to help smooth the path and build the network of relationships that will needed for what is to come. The next step is to bring large-scale funding to bear on creating the first generation of effective therapies to treat aging out of technology demonstrations of rejuvenation carried out in the laboratory.

Chas Bountra RB2015 Keynote

Chas Bountra is Chief Scientist at the Structural Genomics Consortium (SGC). Bountra's keynote provides an overview of how new medicines are commonly discovered and researched today, citing organizational and scientific challenges as the causes behind a process that is slow, costly and risky. In light of these factors, Bountra is developing - and succeeding with - a new approach to drug discovery at the University of Oxford's Nuffield Department of Clinical Medicine. The group works with a consortium of labs in Canada, US, Brazil, Sweden and Germany, collectively called the SGC. He outlines key initiatives that are accelerating the development of new medicines:

Pooling resources: Because there is high risk associated with this business, it is unrealistic to think that any one organization, group or individual can succeed alone. The SGC is working with a consortium of 10 large pharmaceutical companies, benefitting from their financial resources as well as their expertise in medicinal chemistry, screening, and drug discovery.

Crowdsourcing and transparency: the group freely shares its outputs (data, knowledge, reagents) with the academic, pharmaceutical and biotech world because such transparency creates trust, facilitates collaboration, and catalyzes science and drug discovery. This form of crowdsourcing science is opening up new areas of biology and disease understanding.

Immediate disclosure: Everything that the SGC does is immediately released to the world, disclosing its data, knowledge and new reagents (high quality tools for early target discovery). Making these assets publicly available helps to reduce unnecessary replication and wastage.

Frances Colón RB2015 Keynote

Frances Colón is the Acting Science and Technology Advisor to the Secretary of State, United States Department of State. Colón outlined the importance of advising political leaders in the areas of science and technology so they can make better, more informed decisions that lead to greater peace, stability and prosperity. Colón explained that science diplomacy is the interaction between science policy and foreign policy, or the translation of technology and scientific trends to political leaders who aren't particularly well versed in these areas. Bridging this gap allows for change in business and the way in which foreign affairs are handled. She noted that scientists working within the White House, are engaging with non political tools. While policy may dictate the nature of relationships between the U.S. and other countries, scientists cooperate across borders and political divides. As such, science diplomacy has been an excellent asset in many situations.


In mammals, reduced levels of myostatin or increased levels of follistatin, which acts to inhibit myostatin production, can be achieved by a variety of methods ranging from gene therapy to RNA interference, the standard panoply of technologies used to adjust the amounts of a particular protein in animal studies. Suitably altered levels of myostatin or follistatin result in greatly increased muscle growth, lower amounts of body fat, and in mice at least a possible but disputed modest life extension to go along with it. The most direct methodology is knockout of the myostatin gene, and this is the path chosen of late by Chinese researchers in their work on dogs, using CRISPR, one of the latest advances in genetic editing technology.

The creation of genetically altered, heavily muscled dogs is not an isolated line of research. There is at least one dog breed in which a myostatin mutation has occurred naturally, and the same goes for cows, another species heavily influenced by centuries of quite sophisticated human breeding strategies. There are even a few human natural myostatin mutants presently alive, as well-muscled as their animal peers. Gene therapies have been used for nearly a decade to create "mighty mouse" myostatin and follistatin mutants. Early this year scientists demonstrated myostatin knockout pigs using TALENs, another modern improvement on older methods of gene therapy.

Obviously this is a road that at some point branches away from the production of improved animal lineages towards the production of enhancements and therapies for humans. The conventional view is that enhanced muscle production is a viable therapy for the collection of wasting diseases known as myopathies and sarcopenia, the characteristic progressive loss of muscle mass and strength that occurs with aging. This would be a compensatory approach, a way to improve quality of life by overriding some of the results of damage or disease on the natural balance of muscle tissue repair and regeneration, but without actually fixing the damage itself.

I have in the past argued that myostatin or follistatin gene therapies look very much like an all upside treatment, something that everyone should undergo in an ideal world, not just older or sicker people, after it has been developed for use in humans. On the other hand SENS Research Foundation staffer Michael Rae has suggested more caution; if you look back at some of the archived posts on animal studies of myostatin knockout you'll see some of the data to back up that point of view. A decade of animal studies, naturally occurring mutant lineages, numerous mammalian examples of successful gene therapy, and early human trials of the same for myopathies is enough for some people, however. It is interesting to note that BioViva CEO Liz Parrish recently became the first publicly acknowledged healthy recipient of follistatin gene therapy, carried out as a first step towards spurring greater progress towards human clinical trials and treatments aimed at slowing or reversing the effects of aging.

All in all, if you were going to pick one gene therapy to move on with today, myostatin or follistatin would be near the top of the list given the present state of the art and the level of experience present in the scientific community. This is no doubt why the researchers here chose it as a first step in their program of producing genetically altered dog lineages. Their ultimate goal is the production of new models for disease research, not enhancement or treatments per se, but work on myostatin is sufficiently well advanced that it makes a good test case for the newer technologies and methodologies used along the way.

First Gene-Edited Dogs Reported in China

Scientists in China say they are the first to use gene editing to produce customized dogs. They created a beagle with double the amount of muscle mass by deleting a gene called myostatin. The dogs have "more muscles and are expected to have stronger running ability, which is good for hunting, police (military) applications. The goal of the research is to explore an approach to the generation of new disease dog models for biomedical research. Dogs are very close to humans in terms of metabolic, physiological, and anatomical characteristics."

Genome editing refers to newly developed techniques that let scientists easily disable genes or rearrange their DNA letters. The method used to change the beagles, known as CRISPR-Cas9, is particularly inexpensive and precise. Last month, the work was highlighted as part of a large Chinese effort to modify animals using CRISPR. The list of animals already engineered using gene editing in China includes goats, rabbits, rats, and monkeys. The efforts were described as a national scientific priority and part of China's effort to establish world-class research.

The dog researchers took much the same approach, directly introducing the gene-editing chemicals - a DNA snipping enzyme, Cas9, and a guide molecule that zeroes in to a particular stretch of DNA - into more than 60 dog embryos. Their objective was to damage, or knock out, both copies of the myostatin gene so that the beagles' bodies would not produce any of the muscle-inhibiting protein that the gene manufactures. In the end, of 65 embryos they edited, 27 puppies were born, but only two, a female and a male, had disruptions in both copies of the myostatin gene. They named the female Tiangou, after the "heaven dog" in Chinese myth. They named the male Hercules. In Hercules the gene editing was incomplete, and that a percentage of the dog's muscle cells were still producing myostatin. But in Tiangou, the disruption of myostatin was complete and the beagle "displayed obvious muscular phenotype," or characteristics.


The Methuselah Foundation volunteers are setting up a new podcast series, to be published at the Bristlecone and available on mobile devices via the standard channels such as iTunes; you'll find links to the first few editions below.

The Methuselah Foundation continues to be very influential in that part of the research community interesting in making significant progress towards rejuvenation therapies and related technologies, and among the supporters of this work. Since spinning off the SENS Research Foundation into its own organization back in 2009, the Methuselah Foundation has focused as much on tissue engineering as on other needed advances in longevity-related medicine, such as through initiatives like the New Organ prizes and providing seed funding to bioprinting startup Organovo in its early stages. An eclectic range of other projects have also been funded, such as bowhead whale sequencing, funding for Oisin Biotechnology's work on senescent cell clearance, and of course the original Methuselah Mouse Prize to encourage the creation of greater healthy longevity in animal studies is still running.

Perhaps of greater importance is what you don't see. The networking and influence applied behind the scenes by Methuselah Foundation co-founders David Gobel and Aubrey de Grey, and by numerous allies inside and outside the scientific community, has played a large role in the transformation of the aging research community and the public perception of its work over the past decade, most importantly in the acceptance of treating aging as a medical condition, and the willingness of researchers to speak out in public on this topic. Fifteen years ago was a very different time, in which to talk seriously about extending human longevity was to risk your professional future in the research community. Forcing that to change was a necessary first step on the road to ending aging as a threat to health.

And now here we are, on the verge of prototype versions of several rejuvenation biotechnologies, with stem cell and genetic medicine advancing rapidly alongside, equipped with the ability to get out there and raise funds, to convince people that the golden future is just around the corner, if only the support is found. It's a whole new age in comparison to just a few short years ago, and a lot of people should be waking up to ask how they can help, and what will happen next. In the second and third podcast linked here you'll find an interview with David Gobel; I think you'll find it an interesting look at what the Methuselah Foundation is doing to help advance the cause of human longevity, accelerating progress towards numerous facets of the treatment of aging as a medical condition.

Episode 001 of the Methuselah 300 Podcast

An introduction to a new way of staying in touch with the the Foundation's work. In this episode, you'll learn what the podcast will be about and what you can expect to see in the future.

Episode 002 of the Methuselah 300 Podcast

In this episode of the Methuselah 300 Podcast, we'll interview founder Dave Gobel and learn what planted the seed for the idea that would grow into the Methuselah Foundation. You'll also learn the specifics of some of the innovations the foundation is working hard to create.

Episode 003 of the Methuselah 300 Podcast

In this episode of the Methuselah 300 Podcast, we'll continue our interview with founder Dave Gobel as he explains more of the areas of regenerative medicine that the foundation is working toward, some new partnerships and backers -including NASA - and how he believes future life will be impacted in the near and mid term by exciting progress currently being made in medical research.


Alzheimer's research is comparatively well funded, but the production of therapies based on the presently dominant amyloid hypothesis is proving to be a hard, slow grind. The most promising involve directing the immune system to break down amyloid-β or related proteins, but even this line of work is a litany of failed early stage trials at this point. Since theorizing and preliminary investigation of new theories is a lot cheaper than contributing to the messy and very complicated late stage development of potential amyloid clearance treatments, a lot of theorizing is taking place. This is human nature at work; any faltering steps for the majority position in a field will lead to more work on alternative theories, even if it is just a matter of it being harder than expected to turn science into medicine in this case.

The failures haven't dented the primacy of amyloid and tau as targets: the consensus is that this is a hard problem, and the Alzheimer's research community is essentially having to build all of the technology and infrastructure to make immune therapies for clearance of misfolded proteins work at all, never mind work for amyloid. Still, Alzheimer's research is indistinguishable at the edges from general research into understanding the biochemistry of the brain. The pathology of Alzheimer's is entangled with the way in which the brain works in quite fundamental ways, and this is one of the reasons why this research is so well funded: it is driving much of the progress towards a greater understanding of neural biochemistry at all levels.

That is the background. Here I'll point out a couple of minority hypotheses on the causes and pathology of Alzheimer's disease. These are often quite interesting in and of themselves, such as the painkiller hypothesis, but you should probably take both of these papers with a grain of salt. All research has to be critically considered, and not just for the details of a specific paper - small sample size, possible errors, other interpretations that would also explain the data, and so forth - but also in the context of the bigger picture. Does it connect to other well-supported research? Does it stand alone, with no other groups looking into it? Being both alone and associated with a large and active field is usually not a good sign; it's a quiet rejection on the part of other researchers, who would otherwise comment, experiment, and write their own variant theories based on it.

Different Brain Regions are Infected with Fungi in Alzheimer's Disease

The possibility that Alzheimer's disease (AD) has a microbial aetiology has been proposed by several researchers. Here, we provide evidence that tissue from the central nervous system (CNS) of AD patients contain fungal cells and hyphae. Fungal material can be detected both intra- and extracellularly using specific antibodies against several fungi. Different brain regions contain fungal material, which is absent in brain tissue from control individuals. Analysis of brain sections from ten additional AD patients reveals that all are infected with fungi. Fungal infection is also observed in blood vessels, which may explain the vascular pathology frequently detected in AD patients. Sequencing of fungal DNA extracted from frozen CNS samples identifies several fungal species. Collectively, our findings provide compelling evidence for the existence of fungal infection in the CNS from AD patients, but not in control individuals.

Divalent Copper as a Major Triggering Agent in Alzheimer's Disease

Alzheimer's disease (AD) is at epidemic proportions in developed countries, with a steady increase in the early 1900 s, and then exploding over the last 50 years. This epidemiology points to something causative in the environment of developed countries. This paper will review the considerable evidence that that something could be inorganic copper ingestion. The epidemic parallels closely the spread of copper plumbing, with copper leached from the plumbing into drinking water being a main causal feature, aided by the increasingly common use of supplement pills containing copper.

Inorganic copper is divalent copper, or copper-2, while we now know that organic copper, or copper in foods, is primarily monovalent copper, or copper-1. The intestinal transport system, Ctr1, absorbs copper-1 and the copper moves to the liver, where it is put into safe channels. Copper-2 is not absorbed by Ctr1, and some of it bypasses the liver and goes directly into the blood, where it appears to be exquisitely toxic to brain cognition. Thus, while aggregation of amyloid-β has been postulated to be the cause of AD under current dogma, the great increase in prevalence over the last century appears to be due to ingestion of copper-2, which may be causing the aggregation, and/or increasing the oxidant toxicity of the aggregates.

An alternative hypothesis proposes that oxidant stress is the primary injuring agent, and under this hypothesis, copper-2 accumulation in the brain may be a causal factor of the oxidant injury. Thus, irrespective of which hypothesis is correct, AD can be classified, at least in part, as a copper-2 toxicity disease. It is relatively easy to avoid copper-2 ingestion, as discussed in this review. If most people begin avoiding copper-2 ingestion, perhaps the epidemic of this serious disease can be aborted.

Of course a great many things parallel the past century of economic development, not just copper plumbing. This is one of the problems with the painkiller hypothesis as well: near everything associated with wealth, technology, and progress has an upward curve that happens to correlate with Alzheimer's incidence.


Here I'll point out news of a recent study carried out in old rats, wherein the scientists involved claim a partial reversal of cognitive decline resulting from, probably, a reduction in chronic inflammation and increase in neurogenesis in the brain. The researchers pulled an existing drug from the rack for this experiment because it is known to affect the particular molecular targets they had in mind, but the results should be taken as a demonstration of the importance of inflammation and neurogenesis to brain aging, not as a sign that everyone should jump in and take that drug. It is only the particular tool of convenience for this study, and it is always wise to wait on replication of results and studies with larger numbers of animals in any case.

Neurogenesis is the term given to the production and integration of new neurons into the brain. It was only comparatively recently in the history of neuroscience, twenty to thirty years ago, that this process was proven to occur in adults. The consensus now is that a supply of new neurons is vital to learning and other forms of mental flexibility, and they have an effect on the overall behavior of neural networks that is large in comparison to their numbers. Unfortunately the pace of neurogenesis, like the pace of generation of new cells by stem cell populations throughout the body, declines with aging. This may be part of an evolved balance between death by cancer on the one hand and death by increasing frailty on the other. As molecular damage accrues to cells and tissues, created as a byproduct of the normal operation of cellular metabolism, too much cellular replication would speed the slow rise in the risk of fatal cancer. Conversely too little cellular replication will accelerate the slow decline into various forms of organ failure, nowhere more complex and subtle than in the brain.

Chronic inflammation contributes to a wide range of issues in aging, including most neurodegenerative conditions. The immune system runs awry and malfunctions with age, becoming ever more overactive and yet failing to accomplish its job at the same time. This excessive activity has consequences, including signals sent and received that change the behavior of cells and tissues. In short bursts this is necessary for regeneration and defense against pathogens, but when always on it causes harm. Higher levels of chronic inflammation resulting from metabolic dysregulation are probably one of the more important ways in which excess visceral fat tissue raises the risk of early death and of suffering all of the common age-related medical conditions along the way to that fate.

Will medical science produce the means to rescue people from the consequences of poor health and lifestyle choices? Yes, in the fullness of time. But that level of control - and reliability - remains a couple of decades away at least, I suspect. Metabolism is ferociously complex and still far from understood to the degree needed in order to create such science fiction staples such as safe obesity with perfect health. For the foreseeable future it is better not to get into that position in the first place, since at least some means of rejuvenation through repair of cell and tissue damage will probably arrive more rapidly. These are the important technologies to keep an eye on, as rising inflammation and lost neurogenesis are indirect consequences of this damage.

Old rat brains rejuvenated and new neurons grown by asthma drug

As we get older, most of us will experience some kind of brain degeneration. Typically, we lose the ability to make new neurons. Another problem is chronic, low-grade inflammation in the brain, which is implicated in many age-related brain disorders. To tackle both problems in one go, researchers targeted a set of receptors in the brain that, when activated, trigger inflammation. High numbers of these receptors are found in areas of the brain where neurons are born, suggesting they might also be involved in this process, too.

A drug called montelukast, regularly prescribed for asthma, blocks these receptors, so the researchers tried it on young and old rats. The team used oral doses equivalent to those taken by people with asthma. The older animals were 20 months old - roughly equivalent to between 65 and 75 in human years. The younger rats were 4 months old - about 17 in human years. The animals were fed the drug daily for six weeks, while another set of young and old rats were left untreated. There were 20 young and 14 old rats in total.

The rats took part in a range of learning and memory tests. By the end of their six-week drug regime, old animals performed as well as their younger companions. "We've restored learning and memory 100 per cent, to a level comparable with youth." When the team studied the brains of the animals, they found that old rats that had been given montelukast had 80 per cent less inflammation. They also had an enhanced level of new neuron growth compared with untreated old rats - about 50 per cent of that seen in young rats. The team also found that the blood-brain barrier - which stops infectious agents reaching the brain and which weakens in old age - was stronger in treated old rats. "Structurally, the brain had rejuvenated." The drug had no effect on young animals, probably because it targets inflammation associated with age and disease.

The researchers say the results from the rat study are significant enough to warrant a clinical trial, and will start by testing the drug in people with Parkinson's disease.


Monday, October 19, 2015

Supporters of the DRACO (double-stranded RNA activated caspase oligomerizer) approach to antiviral medicine have launched a crowdfunding campaign, seeking enough philanthropic funding to move forward from the excellent results in cell and animal studies. DRACO represents an entirely novel approach to the problem of viral infection, potentially applicable to near all viruses, including those that currently cannot be effectively treated. The SENS Research Foundation is acting as a sponsoring organization, allowing donations to be tax deductible. The legal side of setting up a non-profit takes a couple of years these days, so this sort of assistance is pretty common for new initiatives. DRACO has been featured at SENS conferences in past years, so it seems like a good match.

Viruses must infect human or animal cells in order to replicate, and virtually all virus-infected cells contain long double-stranded RNA, whereas healthy cells do not. DRACOs detect double-stranded RNA inside the infected cells and then cause those cells to commit suicide before the viruses can replicate and spread to other cells. DRACOs do not harm uninfected cells because DRACOs are only looking for the general structure of double-stranded RNA that is made by a wide variety of viruses. By the process of efficiently eliminating only virus-infected cells, DRACOs may be able to permanently cure viral infections that can currently only be controlled. When tested in human and animal cells, DRACOs have been nontoxic and effective against 15 different viruses, including rhinovirus (the common cold) and dengue hemorrhagic fever.

Currently, DRACOs are in the well-known Valley of Death - the financial and experimental gap between the previously funded National Institutes of Health (NIH) proof of concept experiments and the threshold for convincing major pharmaceutical companies to advance DRACOs toward human trials. This campaign has been set up to raise the funding necessary to bridge that gap. With your assistance, we hope to raise enough funding to test and optimize DRACOs against clinically relevant viruses in human cells. If successful, the results of those experiments should persuade pharmaceutical companies and other major sponsors to commit their own resources to advance DRACOs through large-scale animal trials and hopefully human trials. Without your assistance, DRACOs may never progress further, and their potential to revolutionize the treatment of viral infections may remain unfulfilled.

Monday, October 19, 2015

Researchers here demonstrate a stem cell therapy that produces improvements in a mouse model for dementia with Lewy bodies, a common form of neurodegenerative condition in which the mechanisms and progression overlap with those of Parkinson's disease to some degree. This looks like a compensatory therapy, partially restoring some of the lapse in necessary function in the brain that occurs due to damage without actually addressing the damage itself. In that it is an incremental improvement in the present mainstream approach to therapies for age-related disease, but still cannot possibly be as effective as approaches that succeed in repairing the damage. In synucleinopathies like dementia with Lewy bodies, that most likely means the development of methods to safely clear alpha-synuclein aggregates from brain tissues:

Neural stem cells transplanted into damaged brain sites in mice dramatically improved both motor and cognitive impairments associated with dementia with Lewy bodies. DLB is the second-most common type of age-related dementia after Alzheimer's disease and is characterized by the accumulation of a protein called alpha-synuclein that collects into spherical masses called Lewy bodies - which also accumulate in related disorders, including Parkinson's disease. This pathology, in turn, impairs the normal function of neurons, leading to alterations in critical brain chemicals and neuronal communication and, eventually, to cell death.

The researchers transplanted mouse neural stem cells into genetically modified mice exhibiting many of the key features of DLB. One month later, the mice were retested on a variety of behavioral tasks, and significant gains in both motor and cognitive function were observed. The researchers examined the effects of the stem cells on brain pathology and circuitry connecting neurons. They found that functional improvements required the production of a specific growth factor - called brain-derived neurotrophic factor - by neural stem cells. The team examined two of the key brain structures that become dysfunctional in DLB - dopamine- and glutamate-making neurons - to determine how BDNF might drive recovery. "Our experiments revealed that neural stem cells can enhance the function of both dopamine-and glutamate-producing neurons, coaxing the brain cells to connect and communicate more appropriately. This, in turn, facilitates the recovery of both motor and cognitive function."

To further confirm the importance of BDNF in these effects, the researchers modified the stem cells so that they could no longer produce the growth factor. When these modified cells were transplanted, they failed to improve behavioral function and no longer enhanced dopamine and glutamate signaling. Testing the possibility that BDNF alone might be an effective treatment, the researchers used a virus to deliver the growth factor to the brains of DLB mice. They found that this treatment resulted in good recovery of motor skills in the test rodents but only limited recovery of cognitive function. This suggests that while BDNF is critical to stem cell-mediated motor and cognitive recovery, it does not achieve this outcome alone.

Tuesday, October 20, 2015

As this article points out, despite the fact that much is left to be determined in neurobiology, based on the current evidence and understanding it is reasonable to expect that cryopreservation of the brain via vitrification preserves the data of the mind. When considering cryonics as an end of life option this is the critical question: the whole point of the exercise is to prevent the pattern that is you from decaying away to nothing. While that pattern continues to exist, most likely encoded in the molecular structure of synapses, a preserved individual can wait for as long as it takes for technology to advance to the point at which restoration is a possibility.

Can any technology, even in principle, preserve the unique features of an individual's mind? We agree there is more to the mind than the synaptic connections between neurons. The exact molecular and electrochemical features of the brain that underlie the conscious mind remain far from completely explored. However, available evidence lends support to the possibility that brain features that encode memories and determine behavior can be preserved during and after cryopreservation. Cryopreservation is already used in laboratories all over the world to maintain animal cells, human embryos, and some organized tissues for periods as long as three decades. When a biological sample is cryopreserved, cryoprotective chemicals are added and the temperature of the tissue is lowered to below the glass transition temperature (typically about -120 C). At these temperatures, molecular activities are slowed by more than 13 orders of magnitude, effectively stopping biological time.

Although no one understands every detail of the physiology of any cell, cells of virtually every conceivable kind are successfully cryopreserved. Similarly, while the neurological basis for memory, behavior, and other features of a person's identity may be staggeringly complex, understanding this complexity is a problem largely independent of being able to preserve it. Direct evidence that memories can survive cryopreservation comes from the roundworm Caenorhabditis elegans. For decades C. elegans have commonly been cryopreserved at liquid nitrogen temperatures and later revived. This year, using an assay for memories of long-term odorant imprinting associations, one of us published findings that C. elegans retain learned behaviors acquired before cryopreservation. Similarly, it has been shown that long-term potentiation of neurons, a mechanism of memory, remains intact in rabbit brain tissue following cryopreservation.

It is easy to dismiss controversial practices such as cryonics and gloss over the research surrounding them, but we should remember and even respect that prevailing views are often shown to be incorrect, and that what is impossible now may be possible in the future. For example, Ignaz Semmelweis, the father of germ theory, was widely ignored when he proposed in the 19th century that nurses and doctors should wash their hands before treating patients. Even today, physicians are frequently incorrect when predicting outcomes in end-of-life situations. Cryonics deserves open-minded discussion, as do mainstream efforts to understand the nature of consciousness, preserve human tissue and organs for life-saving transplants, and rescue critically injured patients by understanding the boundaries between biological life and death.

Tuesday, October 20, 2015

Some of the SENS Research Foundation supporters in the Bay Area have organized a charity benefit party in Brisbane, just down the road a little from San Francisco, to be held on November 3rd. If you're in the area, give some thought to attending: your donations to SENS rejuvenation research programs will be matched by this year's Fight Aging! matching fund. All these funds go towards advancing the state of the art in repairing the cell and tissue damage that causes aging.

This event is a great idea, and I'd love to see more of this sort of thing taking place. Charitable fundraising for medical research is hard work, but also largely a solved problem at the detail level. A wide array of time-proven strategies exist when it comes to raising modest amounts of money through your own personal network. You just have to get out there and persistently put in the time and effort, be willing to be known as someone who raises funds for a good cause.

SENS Research Foundation volunteer Walter Crompton and Johnny Adams will be hosting a Benefit Party for SENS Research Foundation on November 3rd at the 7 Mile House in Brisbane, CA. The party will include dinner, a live band, and a silent auction. Aubrey de Grey will be there to meet and greet all the attendees. Space is limited to 30 people, so book your tickets now.

When: November 3, 2015, 6:30 - 9:00 pm
Where: 7 Mile House
2800 Bayshore Blvd
Brisbane, CA

"You are invited to the first of a series of events dedicated to slowing and ultimately reversing aging (specifically the diseases of aging) in humans! Each event will benefit a different organization. Our premiere event will be held in the San Francisco Bay Area benefiting SENS Research Foundation. You can enjoy a luscious dinner and drinks, live jazz, a silent auction, and meet & greet celebrities - Aubrey de Grey, Irina Conboy and Michael Conboy - and get a tax deduction."

Wednesday, October 21, 2015

Josh Mitteldorf here reports on the presentations given at a recent conference on the comparative biology of aging. He has a programmed aging point of view, considering aging to be an evolved genetic program that produces damage and dysfunction. On the other hand I as a long-time observer of the field, along with the majority the research community, consider the evidence to point to aging to be the result of accumulated cell and tissue damage, and where epigenetic and other changes are observed in old individuals, these are reactions to that damage. To the degree that this division steers research and development priorities, it is the most important debate in aging research.

Comparative biology is a field that has grown with advances in genetic biotechnology, and the plummeting cost of good genetic data is producing a wealth of information on long-lived species for those researchers who want to better understand how exactly age-related degeneration progresses from first cause to final outcome at the most detailed level of genetic and cellular mechanisms. The purpose of science is to generate knowledge, so all this is good and according to plan, but it seems to me to be largely unlikely to lead to great breakthroughs in methods to build rejuvenation therapies. We already know how to do that, which specific forms of cell and tissue damage to repair, and the problem there is directing more funding and attention to that work, not a need for more data. The comparative biology community may be well placed to answer questions about which forms of damage are more important than others, aiding prioritization in repair approaches, but even there it would be faster just to spend more efforts on repair and then see what happens as a result.

The conference was opened by a theoretical lecture by Tom Kirkwood, father of one of the more popular theories of aging. He admonished us that evolution is a mathematical science that yields specific and quantitative information about what aging can and cannot be. These provide a powerful mathematical underpinning for the understanding of aging.

The next morning, Annette Baudisch told us that in reality, nature has produced every combination of aging strategy that you can imagine, and some that you probably never imagined. The kind of aging that humans know is gradual and accelerating, leading to death on a timetable that is predictable within about 10-15%. But this brand of aging is a small minority in nature. There are salmon and octopuses and annual plants that reproduce in a burst and then die suddenly. There are beetles and jellyfish that are able to "age backward", reverting to a larval state under stress, then beginning life again with a fresh start. Baudisch coined the term "negative senescence" for a phenomenon that is not the same thing as this: most trees and some turtles and lobsters just grow ever larger and more fertile over decades or even centuries.

Closing the conference was a keynote address by Steven Austad. Austad warned us that much of what we have long assumed about the biology of aging is not to be taken literally without exception; and some of it is merely persistence of myth. He showed us the classic plot of animal size versus lifespan. In mammals, life span rises slowly, with about the 1/4 power of an animal's weight, which corresponds to a slope of 0.25 in the log plot. There are outliers where animals have managed to find strategies to suppress their death rates from predators and disease. Most birds live longer than comparably-sized mammals, and the most dramatic examples are people and bats. I had known that mice are outliers on the downside. Since mice provide food for a great number of predators, and they freeze to death over the winter; their life spans are below the trend line. What I learned from Austad is that the exceptions extend to all small rodents. For rodents less than 8 kg, there is no correlation at all between size and life span. No one, to my knowledge, has explained this.

As in his past work, Austad offers so much useful good sense in his keynote, and yet he clings to a view that aging is driven by an accumulation of damage, that it can be slowed but never reversed, that there are no genetic mechanisms that have evolved solely for the purpose of assuring a fixed (shorter) life span. The three points are related but not identical. Curiously the idea that damage is the root of aging is not the influence of evolutionary theorists, but far older, rooted in ancient concepts of impermanence. I know it is theoretically possible, and hope that it will prove generally true in practice, that the body knows how to repair all the important kinds of damage that accrue in aging, and is capable of restoring itself to a youthful state, given the appropriate signaling environment.

Austad's present research is based on the observation that misfolded proteins tend to accumulate in our cells, and are related to dysfunction and disease, most prominently Alzheimer's. Long-lived varieties need to keep proteins in the right conformation, with "chaperone" molecules that are particularly effective. Austad is isolating and transplanting some of these chaperone molecules from his menagerie of 500-year-old clams. Despite differences in theoretical perspective, I have found the community of aging biologists to be especially personable and gracious. I have known Austad and Kirkwood in the deep past, and Baudisch more recently because she belongs to the next generation. Before I had any reputation or credibility in the field, all of them responded to me personally and respectfully.

Wednesday, October 21, 2015

Here I'll point out an article on research into nutrition and some of the aspects of aging that contribute to neurodegenerative conditions, such as chronic inflammation. The article discusses one representative program in a broader field that devotes significant resources to the study of nutrition and aging, something that I think is a waste of potential given what could be done instead with all that time, training, knowledge, and funding. We are in the midst of a revolution in biotechnology. Are investigations of altering diet really worth it? I think not.

It is my conjecture that there is a deep conceptual chasm separating science from the application of science. Science in medicine is the business of mapping what is, the bounds of the present situation, how things progress, how things work. The application of science to construct new medical technologies is all about changing all these things for the better. People enmeshed in the scientific community, the research funding community, and the ethos of the scientific method are largely absolutely terrible at stepping beyond what is to what might be. I think that's probably true of the population at large, as well, but in this particular portion of the larger human endeavor the result is a selection of very inefficient, stumbling strategic approaches to the application of science.

One of these, I think, is any attempt to consider nutrition a useful approach to manipulating aspects of aging. It is true that this is probably helpful if you are interested in mapping metabolism and the way in which metabolism and aging interact to cause disease and death due to accumulating damage and dysfunction. It provides points of comparison, slightly different paths of progression, and that's always a benefit when trying to decipher a very complex system. Calorie restriction research has certainly produce mountains of data on this front. But it has also failed to produce meaningful ways to extend healthy life after billions in funding and two decades of research. In principle the approach of developing calorie restriction mimetic drugs cannot do more than slightly slow aging in humans, even if that line of research was going anywhere these days, and this is the absolute best of what can be done with altered nutrition. We have examples all around us, a century or more of very good data on what exactly the bounds of the possible are in terms of altering human aging via diet. The results are marginal, tiny in the grand scheme of things.

In summary these are all distractions. They are not legitimate paths towards healthy life extension, but in reality bad strategic choices by people who have not stepped beyond their primary goal, the scientific goal of obtaining more data on how aging happens here and now, in the present situation. If you don't like how aging happens today, then you need to look elsewhere for people who are trying to do something about it, such as to SENS research.

There has been widespread speculation that stem cells could be used to repair neurons damaged by degenerative diseases such as Alzheimer's and Parkinson's. In other cases, however, these cells could be part of the problem. "They do try and repair disease and aging. But when they do that too much, they can lead to brain tumors." The question was how could these neural stem cells be stimulated to produce more healthy cells without overproducing and creating tumors - and how could they continue to make cells as they aged? "Their aging involves many, many gene and protein networks, and to try and get a handle on that influence through a single gene or protein is very difficult." While some drugs have been shown to be effective in stimulating growth of new brain cells, results have been inconsistent.

A few years ago, the researchers began investigating a new angle: nutrition. "Food is medicine. Nutrition has the ability to affect many of those pathways at the same time. When we went looking for a director for our new laboratory, we were looking for a translational scientist who was conducting cutting-edge research related to nutrition and prevention of age-associated cognitive impairments - someone who would bring in new areas of research to the center and help move the field of nutrition and brain disease forward. I believe we found exactly the right person we are looking for. What's become very clear is that the regenerative capacity diminishes as you age. The question we will probably ask and answer is how do these nutritional requirements change and how do they tie into the regenerative ability. Once we answer that question, we can ask how we alter nutrition to achieve that."

To home in on those questions, researchers have focused on the role that inflammation plays in the aging of stem cells, as well as in neurodegenerative diseases. Research has shown that inflammation produces small proteins, or cytokines, in brain cells. Two of these types of proteins - amyloid and tau proteins - have been associated with Alzheimer's disease. "Particular genetic mutations can't process these proteins very well. The cells try and spit them out to get rid of them, but when they can't do that, the cells themselves can die." When they are able to expel them into the environment in the brain, they can affect other cells, which may not function properly, contributing to Alzheimer's. A similar protein called alpha-synuclein may be associated in a similar way with Parkinson's. The researchers have focused on the role that inflammation plays in the aging of stem cells, as well as in neurodegenerative diseases such as Alzheimer's and Parkinson's. By changing diet and nutrition, patients may be able to limit inflammation of brain tissue and prevent or even reverse these degenerative diseases by giving neural stem cells the ability to heal the damage.

Thursday, October 22, 2015

I had no idea that the the Milken Institute included a Center for the Future of Aging. In nature it is more AARP than Healthspan Campaign, which might explain the oversight. Here I'll point out an article published by the organization earlier this year, one of a number on the future of retirement that appeared around the same time. The bottom line is that change is upon us, and younger adults are largely planning for a future that won't happen: they will live far longer and in better health than the present common wisdom suggests, and most likely far longer than is predicted by the current actuarial models based on a continuing gentle upward trend in life expectancy. This is a time of great progress in biotechnology and medicine, a leap upwards and fundamental shift in the relationship between medicine and aging. In the past researchers were not trying to treat the causes of aging. Now they are.

Many see aging only in negative terms, with the talk about entitlement costs, dependency ratios, and the challenges of disease and financial insecurity. But increased longevity has contributed to unprecedented economic growth and opportunities for personal fulfillment that previous generations could only dream of. Innovations in genomics, personalized medicine, and digital health will mean more time to work, learn, contribute, and recreate. Respected leaders in science are focused on the possibilities of dramatic life extension. The odds are that millennials and the generations that follow will experience significantly longer lives. So conversation about the future of aging is not just about "boomers." It's about all of us. While there is no certainty that scientists will succeed in enabling radical life extension, that possibility alone should change the thinking of millennials about their futures. How should members of this generation prepare? Here are a few points to consider.

Plan for lifelong learning. Whether on campus or on-line, millennials will return to school several times in their lives to learn new skills, develop fresh perspectives, and expand their general knowledge and relationship networks. They'll benefit by learning with and from older adults, and older adults will, in turn, benefit from lessons they learn from millennial teachers. The habit of establishing intergenerational relationships and shared learning experiences will bring lifetime benefits.

Plan for lifelong work. Traditional retirement is ready to be retired. Millennials will continue to work for financial security in longer life and because the stimulus of work can enhance both health and well-being. Many millennials already understand the challenges of changing workplaces and professions. Flexibility and comfort with new environments will serve this generation well. Millennials should join with older adults to fight workplace ageism and advocate for part-time, shared, and flexible work options, knowing they'll be the beneficiaries of progressive workplace policies as they age.

Save and invest for the long term. Many in the current generation of older adults have not saved enough to support themselves and their families, with devastating consequences. Millennials came of age during the Great Recession, and many carry the burden of student loan debt. But by planning responsibly and effectively, and investing early, millennials can be better prepared than their parents for longer lives. Big cars and bigger houses may be appealing to some, but there are far more important priorities in life for all of us.

Thursday, October 22, 2015

Resulting from parabiosis studies in mice, GDF-11 is one of the significant proteins identified to vary with age in blood. When augmented to youthful levels in old mice it produces partial reversal of some measures of degeneration via boosted stem cell activity. The underlying mechanisms for these findings were disputed, however, and here is the latest in that discussion:

Back in the 1950s scientists first showed that connecting the circulatory systems of old and young mice seems to rejuvenate the more elderly animals. A handful of labs have recently been racing to find factors in young blood that may explain this effect. Researchers claim that a specific protein, GDF11, may explain young blood's beneficial effects. They have reported that blood levels of GDF11 drop in mice as the animals get older and that injecting old mice with GDF11 can partially reverse age-related thickening of the heart.

Last May, however, another group reported that the antibody the Harvard team used to measure levels of GDF11 also detected myostatin (also known as GDF8), a similar protein that hinders muscle growth. This group concluded from a different assay that GDF11 levels in blood actually rise with age in rats and people. And in their lab, GDF11 injections inhibited muscle regeneration in young mice. Now, the original researchers say that this assay used to detect GDF11 and GDF8 was itself flawed. They found that the main protein detected by the antibody test is immunoglobulin, another protein that rises in blood level with age. Mice lacking the gene for immunoglobulin tested negative for the active form of GDF11/8 that the assay was thought to reveal. "They actually had very consistent findings to ours with respect to the blood levels of GDF11/8 with the antibody we all used, but their interpretation was confused by this case of mistaken identity."

A recently published study finding that GDF11/8 blood levels decline with age in people and are low in those with heart disease supports the contention that GDF11 has an antiaging role. To back up their earlier results, the original researchers again show in a new paper that daily GDF11 injections can shrink heart muscle in both old and new mice. But this time they note another observation: The mice also lost weight. "We don't have much insight into that right now, but we're looking into it." The findings suggest that as with other hormones, GDF11 may have "a therapeutic window" for beneficial effects - too much may cause harm.

Friday, October 23, 2015

An interesting study here correlates physical fitness to a specific measure of cognitive function and age-related change in brain activity in older individuals. There are numerous mechanisms that might link degree of fitness to the pace of change and neurodegeneration in aging, such as the structural integrity of blood vessels in the brain, which in turn connects to blood pressure, degree to which stiffening occurs in blood vessel walls, and so forth:

A new study shows, for the first time, the direct relationship between brain activity, brain function and physical fitness in a group of older Japanese men. They found that the fitter men performed better mentally than the less fit men, by using parts of their brains in the same way as in their youth. With tasks involving the temporary storage and manipulation of memory, long term memories and inhibitory control, young adults favor the right side of the prefrontal cortex (PFC), while older adults engage both the right and left PFC. In fact, with aging, we tend to use both sides of the PFC during mental tasks, rather than just one. This phenomenon has been coined HAROLD (hemispheric asymmetry reduction in older adults) and reflects the reorganisation of the brain as compensation for reduced brain capacity and efficiency due to age-related structural and physiological decline.

60 older men (aged 64-75 years) underwent an exercise test to measure their aerobic fitness. The men, whose physical fitness was found to vary widely, then performed a test to measure their selective attention, executive function and reaction time. This well-known color-word matching Stroop test involved showing the men words meaning color, such as blue, green, red, but asking them to name the color of the letters rather than read the word itself. When the color of the letters does not match the word - blue, red, green - it takes the brain longer to react. This reaction time is used as a measurement of brain function. Activity in the PFC region of the mens' brains was measured throughout the test.

As predicted for older adults, during the Stroop test both sides of the PFC are active, with no difference between right and left, verifying the HAROLD phenomenon amongst this group of men. Previous studies have shown that young adults favour the left side of the PFC for this task. Analysis of the relationship between brain activity and Stroop reaction time revealed that those men that favored the left side of the PFC while performing the Stroop test had faster reaction times. This indicates that older adults who use the more youth-like, task-related side of the brain perform better in this test. Next, the association between aerobic fitness and Stroop reaction time was analysed. Fitter men had shorter reaction times. Based on these findings, the researchers correctly predicted that higher aerobic fitness would be associated with higher left-PFC activity. In other words, fitter men tend to use the more youth-like side of their brains, at least while performing the Stroop test. "One possible explanation suggested by the research is that the volume and integrity of the white matter in the part of brain that links the two sides declines with age. There is some evidence to support the theory that fitter adults are able to better maintain this white matter than less fit adults, but further study is needed to confirm this theory."

Friday, October 23, 2015

Researchers here demonstrate a more efficient path to the production of large numbers of patient-matched immune cells. Delivering large numbers of immune cells via infusion on a regular basis may prove to be a useful treatment for older individuals suffering the characteristic immune dsyfunction that accompanies aging, a near-term way to restore vital immune functions ranging from clearance of unwanted cells to defense against pathogens, a stop-gap to be used until the underlying causes of immune aging can be reversed. The cost of generating the necessary cells is a big determinant of whether or not a therapy is developed for widespread use, however.

Though immune therapy and regenerative medicine are promising areas of research for future medical therapies, they are limited today by the difficulty of creating stem cells, and scientists around the world are searching for ways to create somatic stem cells in the easiest way possible. Researchers have now found that in immune cells, simply blocking a transcription factor that leads to differentiation is sufficient to keep cells in a multipotent stem cell-like state where they can continue to proliferate and can later differentiate into various cell types. Efforts in the past to create stem cells have typically involved finding ways to take target cells and "dedifferentiate" them into multipotent cells, but this is typically a painstaking process.

The team took mouse hematopoetic progenitor cells - cells that give rise to white blood cells - and modified them to overexpress a protein called Id3. Id3 inhibits the expression of E-proteins, which are involved in differentiation in somatic cells. They then placed the cells into culture conditions containing certain cytokines, and instead of differentiating into B-cells, the cells continued to divide as stem cells. When placed in a culture that did not contain those cytokines, the cells differentiated into various immune cells. To test whether the cells would maintain their multipotency in living animals, the researchers transplanted them into mice whose white blood cells had been depleted, and showed that the new cells could expand and differentiate into various types of white blood cells.

To explore the potential for application, the group then attempted a similar experiment using human blood stem cells taken from umbilical cords, which they transfected with a vector encoding human Id3. They found that like the mouse cells, these human cells could be maintained in a dividing state and then prompted to differentiate by changing the conditions. "This is both a useful tool for giving us a better understanding of the genetic and epigenetic program controlling the self-renewal of stem cells, and on a practical side, it could allow us to inexpensively produce large numbers of immune cells, which could then be used for regenerative medicine or immune therapy."


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