Neural Stem Cell Transplant Treats Parkinson's in Rats
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The proximate cause of the most visible symptoms of Parkinson's disease is the progressive loss of a small but vital population of dopamine-generating neurons. This loss happens to everyone, but for a variety of underlying reasons, not all of which are clear at this time, people with Parkinson's experience a more rapid loss of these cells. This is the case for many age-related medical conditions: they are a more rapid progression of a process that is in fact happening to all of us, and so the development of therapies is worth keeping an eye on. One approach to the treatment of Parkinson's disease is to attempt to restore the failing population of dopamine-generating neurons via some form of cell therapy, as demonstrated here in rats:

Parkinson's disease (PD) is considered the second most frequent and one of the most severe neurodegenerative diseases, with dysfunctions of the motor system and with nonmotor symptoms such as depression and dementia. Compensation for the progressive loss of dopaminergic (DA) neurons during PD using current pharmacological treatment strategies is limited and remains challenging. Pluripotent stem cell-based regenerative medicine may offer a promising therapeutic alternative, although the medical application of human embryonic tissue and pluripotent stem cells is still a matter of ethical and practical debate.

Addressing these challenges, the present study investigated the potential of adult human neural crest-derived stem cells derived from the inferior turbinate (ITSCs) transplanted into a parkinsonian rat model. Emphasizing their capability to give rise to nervous tissue, ITSCs isolated from the adult human nose efficiently differentiated into functional mature neurons in vitro. Transplantation of predifferentiated or undifferentiated ITSCs led to robust restoration of behavior, accompanied by significant recovery of DA neurons within the substantia nigra. ITSCs were further shown to migrate extensively in loose streams primarily toward the posterior direction as far as to the midbrain region, at which point they were able to differentiate into DA neurons within the locus ceruleus. We demonstrate, for the first time, that adult human ITSCs are capable of functionally recovering a PD rat model.

Link: http://dx.doi.org/10.5966/sctm.2014-0078

Linking Mitochondrial DNA Damage and Glaucoma
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Damage to mitochondrial DNA is a consequence of the normal operation of cellular processes, and is one of the contributing causes of degenerative aging. It acts through a convoluted chain of circumstances to generate a population of malfunctioning cells that export harmful reactive molecules into surrounding tissue. Here, researchers provide evidence linking mitochondrial DNA damage, and consequent dysfunction, with the progression of glaucoma, a form of neurodegeneration causing blindness:

Glaucoma is a chronic neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Mitochondrial DNA (mtDNA) alterations have been documented as a key component of many neurodegenerative disorders. However, whether mtDNA alterations contribute to the progressive loss of RGCs and the mechanism whereby this phenomenon could occur are poorly understood. We investigated mtDNA alterations in RGCs using a rat model of chronic intraocular hypertension and explored the mechanisms underlying progressive RGC loss.

We demonstrate that the mtDNA damage and mutations triggered by intraocular pressure (IOP) elevation are initiating, crucial events in a cascade leading to progressive RGC loss. Damage to and mutation of mtDNA, mitochondrial dysfunction, reduced levels of mtDNA repair/replication enzymes, and elevated reactive oxygen species form a positive feedback loop that produces irreversible mtDNA damage and mutation and contributes to progressive RGC loss, which occurs even after a return to normal IOP.

Furthermore, we demonstrate that mtDNA damage and mutations increase the vulnerability of RGCs to elevated IOP and glutamate levels, which are among the most common glaucoma insults. This study suggests that therapeutic approaches that target mtDNA maintenance and repair and that promote energy production may prevent the progressive death of RGCs.

Link: http://dx.doi.org/10.1016/j.nbd.2014.11.014

Discussing Science and Aging: Aubrey de Grey and Cynthia Kenyon at NPR
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NPR recently ran a show interviewing a number of people who have given TED talks relating to aging, among them Aubrey de Grey, cofounder of the SENS Research Foundation and coordinator of rejuvenation research programs, and Cynthia Kenyon, whose work on single gene manipulations that extend nematode longevity back in the 1990s arguably kicked off the modern wave of interest in slowing aging. It makes for interesting listening; you should certainly take a little time and at least look at the transcripts.

In these short interviews you can see illustrated the most important division in the modern work aimed at intervention into the aging process: on the one hand the mainstream approach of altering the operation of metabolism so as to slow down aging, based on traditional drug discovery methodologies, and on the other hand the radical, disruptive approach of repairing the damage caused by the normal operation of metabolism, requiring the development of new biotechnologies. The strategy here is to avoid changing the operation of metabolism, because that is very hard and far too little is known of the important details, but rather periodically clean up the consequences of normal metabolic activity in order to prevent that damage from overwhelming and altering biological systems so as to cause degenerative aging.

As I'm sure all of you know by now, I'm greatly in favor of the latter approach because all the signs suggest it should be far more efficient and effective at extending healthy life spans, not to mention producing actual rejuvenation in the old. You can't greatly help the old by slowing down aging: better technologies are needed. Rejuvenation is needed. You can't bring aging under medical control by working on metabolic alteration to slow aging. Repair is needed, not merely dialing down the pace of new damage.

How Do You Make An Elderly Worm Feel Young Again?

Have you ever wanted to stay young a little longer and put off aging? This is a dream of the ages, but scientists have for a long time thought this was just never going to be possible. They thought, you know, you just wear out - there's nothing you can do about it, kind of like an old shoe. But if you look at nature, you see that different kinds of animals can have really different life spans. Now, these animals are different from one another because they have different genes. So that suggests that somewhere in these genes, somewhere in the DNA, are genes for aging, genes that allow them to have different life spans. So if there are genes like that then you can imagine that if you could change one of the genes in an experiment, an aging gene, maybe you could slow down aging and extend life span. And if you could do that then you could find the genes for aging, and if they exist, and you can find them then maybe one could eventually do something about it.

You would think to extend the life span of an animal for such a long time, you know, you'd have to kind of go around in a way and fix things or shore them up. You'd have to do something for the skin and something for the intestine, something for the nervous system. You'd have to - it would be really hard because old tissues all look old, but they all have their own separate problems. But what's the big surprise is that there are these systemic or system-wide control circuits that you can tap into. And what happens is that there are circulating factors, factors in the blood that can move through the animal and tell all the tissues to slow down their aging. Not to slow down their movement, but to slow down their aging. The great secret of all this is that, you know, all animals are much more similar to one another than they are different. Worms have muscles, they have nerve cells, they have serotonin, they have acetylcholine, they have all the neurotransmitters we have, the very same ones. So what that means is, you can easily interrogate the genome by making mutations to find genes that control things, things that you didn't even know were controlled, like aging. And there are actually hints that gene changes in humans that mimic the effects of these changes in animals may contribute to exceptional longevity to becoming a centenarian, in a human.

Can Aging Be Cured?

RAZ: And we just heard from Dan Buettner. He's an explorer and a researcher who studies Blue Zones. These are the areas of the world where people live much longer than anywhere in the...

AUBREY DE GREY: Well, let me stop you right there. How much? How much? It's very important to look at the numbers here.

RAZ: Aubrey de Grey would argue the handful of extra years you can get from, say, a Blue-Zone lifestyle is really pretty minor.

DE GREY: People often laugh at the U.S.A. on this kind of thing because the U.S.A. spends far more money per capita on healthcare than any other country in the world.

RAZ: Right.

DE GREY: And yet, if you look at the league table of life expectancy, it comes down in the 40s somewhere - like, 45 or whatever. But then if you look at the actual absolute numbers, the difference in lifespan between the U.S.A. and the number-one country, Japan, guess what it is? Just guess. Go on.

RAZ: I don't know - four years, five years.

DE GREY: Indeed, only four years. So you know - and these Blue Zones, you know, they might get another couple of years, but you know, the numbers are so small that we've got to do something that nobody has today.

RAZ: Aubrey is an Evangelist, probably one of the loudest voices for what might be described as the anti-aging movement. He's one of the leaders of a group called the SENS Research Foundation. It funds research into what he calls rejuvenation biotechnologies.

DE GREY: Which means new medicines that don't yet exist that will be able to repair the various types of molecular and cellular damage that the body does to itself throughout life and that eventually contribute to the ill health of old age.

RAZ: Aubrey basically looks at the human body in the same way he sees any other machine. You keep it oiled. You replace parts. You do preventative maintenance, and the machine can keep going a lot longer than it was ever meant to. So instead of just focusing on, say, a cure for cancer, he wants researchers to channel their energy into finding ways to prevent cancer and other diseases from ever developing in the human body in the first place. And he thinks if we could do that...

DE GREY: Basically, the types of things you could die of at the age of a hundred or 200 would be exactly the same as the types of things that you might die of at the age of 20 or 30.

RAZ: An accident, for example.

DE GREY: Exactly.

RAZ: Alzheimer's, dementia, cancer - these diseases occur because as you age, your body gets damaged. Molecules get damaged. Cells mutate. Junk accumulates in your body. All of this is natural. It happens to everyone. And Aubrey believes that that damage can be grouped into seven different categories, all of which could be prevented or at least slowed down.

DE GREY: So for illustration, let me just talk about one category.

RAZ: Sure.

DE GREY: Cell loss - what is cell loss? It's simply cells in a particular organ or tissue dying and not being automatically replaced by the division of other cells. Now, it turns out that that is actually an important contributor to certain aspects of aging - Parkinson's disease, for example. Now, the thing is, we know what the fix for that one is. We know that the right way to repair that kind of damage is stem cell therapy. Now, progress in that area has been patchy over the past 20 years that people have been thinking about this. But now, it's going really well. There are a couple of clinical trials going on. And I'm really optimistic. I think most people are very optimistic. I would say that we've got a very good chance of actually totally curing Parkinson's disease with stem cells in the next 10 years, even.

RAZ: But you're arguing that the right investment in certain scientific research couldn't just get us to a hundred or 110, but it could get us to 110, playing tennis.

DE GREY: That's exactly right - in fact, keeping up with your granddaughter on the dance floor.

RAZ: Is that going to happen?

DE GREY: Well, I've just told you it would. You sound as though you don't quite believe me.

RAZ: I do, but you can understand why it still, today, in 2015, sounds like science fiction, right?

DE GREY: Things that are only - have only a 50 percent chance of happening in 20 years from now are supposed to sound like science fiction.

GABA Neuron Transplant Enhances Neural Plasticity in Mice
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Neural plasticity, the ability of the brain to generate new neurons and reshape its pathways, declines with age. Finding ways to temporarily reverse this decline and induce a more youthful state of plasticity may prove helpful in treating many conditions, but research is still at a fairly early stage of exploration:

Researchers have successfully re-created a critical juvenile period in the brains of adult mice. In other words, the researchers have reactivated brain plasticity - the rapid and robust changes in neural pathways and synapses as a result of learning and experience. The scientists achieved this by transplanting a certain type of embryonic neuron into the brains of adult mice. The transplanted neurons express GABA, a chief inhibitory neurotransmitter that aids in motor control, vision and many other cortical functions. Much like older muscles lose their youthful flexibility, older brains lose plasticity. But in the study, the transplanted GABA neurons created a new period of heightened plasticity that allowed for vigorous rewiring of the adult brain. In a sense, old brain processes became young again.

In early life, normal visual experience is crucial to properly wire connections in the visual system. Impaired vision during this time leads to a long-lasting visual deficit called amblyopia. In an attempt to restore normal sight, the researchers transplanted GABA neurons into the visual cortex of adult amblyopic mice. "Several weeks after transplantation, when the donor animal's visual system would be going through its critical period, the amblyopic mice started to see with normal visual acuity." These results raise hopes that GABA neuron transplantation might have future clinical applications. This line of research is also likely to shed light on the basic brain mechanisms that create critical periods.

Link: http://news.uci.edu/press-releases/uci-neurobiologists-restore-youthful-vigor-to-adult-brains/

Trials of Cell Therapies for Heart Regeneration
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Stem cell therapies to repair heart damage were one of the first to become widely available via medical tourism, and have been underway in earnest for more than a decade now. There is evidence from their use that benefits can be attained for patients. Providers and researchers continue to refine their techniques. There are numerous studies. That evidence is not good enough for the conservative end of the scientific community, who require a complete and rigorous understanding of the mechanisms of action before proceeding with enthusiasm, and nor for regulatory bodies in the US and Europe. Thus trials continue, now into their late stages, and treatments remain unavailable in many countries:

Like any new branch of medicine, cardiac cell therapy has progressed in fits and starts. Despite dozens of clinical trials, there's no slam-dunk treatment for improving the cardiac function of heart failure patients, but marginal, statistically significant improvements observed in some of the studies are propelling the cell-based therapies to ever larger, more expensive, and more rigorous trials. Most cardiologists remain underimpressed, says the head of an ongoing Phase 3 trial in Europe that involves injecting bone marrow cells into heart attack patients. "If [the trial] is positive, that's great, but I still think we'll have quite a challenge to convince people. If it's negative, then you get most of the cardiac community saying, 'Yep, we expected that.'?"

Now, it's make or break. Some anticipate that the results of the trial and two other ongoing Phase 3s will finally provide definitive evidence supporting the efficacy of cell therapies for the heart - evidence that has so far been lacking. On the other hand, negative results could spell the end of the approach altogether. "If our Phase 3 doesn't work, I think there's little likelihood any program could succeed in this indication," says the CEO of a Belgium-based firm sponsoring a clinical trial involving bone marrow-derived cells. "In the event they don't work [this time], I think it will be the end."

The idea to pluck cells from a person's bone marrow and shoot them into the heart took root in 2001, when researchers showed that doing so in mice could help regenerate damaged heart tissue. Yet no one knew how the cells worked. At the time, the prevailing thought was that stem cells took up residence in the heart and proliferated to produce new tissue. But this idea has since become a matter of debate. While some researchers claim the cells can form new cardiac muscle, others assert that the cells only very rarely differentiate into cardiomyocytes and instead support cardiac regeneration by other means.

Many scientists now believe that the introduced cells perform a paracrine function, signaling the activation of reparative pathways via growth factors or other secreted messengers. On its own, the heart regenerates about one percent of its tissue per year via the division of cardiomyocytes; perhaps cell therapies simply boost that normal behavior. The absence of a concrete mechanism of action has been one of the main criticisms of the field. On the other hand, most patients don't care how a treatment works, just that it does. "We have more trials than we have meaningful basic science papers. You'd like it to be the other way round. But I understand why there was an explosion [of clinical trials] - because there is such a need." And many researchers disagree that a known mechanism is required for advancing the therapy. "Nothing moves a field forward like actual clinical trials." While mechanisms are important - knowing them can help optimize treatments, for instance - "you can't slow things down because the mechanism of action isn't agreed upon by everybody."

Link: http://www.the-scientist.com/?articles.view/articleNo/42842/title/Hearts-on-Trial/

On Social Media and Advocacy for Radical Life Extension
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Changing the world is an activity built atop a foundation of persuasion and relationships, whether is a matter of creating entirely new technology or ensuring the widespread use of existing technologies. It always moves more slowly than advocates would like, even when things are progressing well, such as at the present time with regard to the public view of research into the effective treatment of aging. The past couple of years have seen a real transition in public perception and media treatment of aging research, the result of more than a decade of hard work and investment behind the scenes, all largely unnoticed. There are never any breakthroughs or sudden sweeping reversals in life: it is all a matter of the pieces finally falling into place, of the finale to a play that you just weren't paying all that much attention to while it was taking place.

The great revolution of our era is the plummeting cost and increasing capacity of computation. That has enabled all of the other transformative revolutions presently underway, such as in the cost, capabilities, and availability of communications technology and biotechnology. In communication especially, the cost of near instantly delivering old-style text from one person to another has fallen so far as to be essential zero, minuscule in comparison to the opportunity cost of time taken in composition of the message. Similarly, the cost of publishing to an audience has fallen to be essentially zero in comparison to the cost of finding that audience.

It is no coincidence that advocacy for longevity research, just like every goal originally held by a tiny fraction of the populace, has taken off in parallel with the growth of the internet. Beforehand, how were the one in a hundred or one in a thousand interested enough to talk and do something ever going to find one another? Now a special interest group of just a few hundred or few thousand people can span the globe and yet still be organized and effective, and for next to no cost beyond the time taken to participate. This is ideally suited to non-profit and advocacy organizations, and the last few decades of initiatives relating to extending the healthy human life span have seen many such organizations assemble via connections made online.

In this sense social media, a term I detest, means nothing more than communication. Everyone today has a near-zero-cost printing press and mail room. When everyone can act as their own newspaper, most people will do just that. Most of the resulting output is trivial, of course, because most conversations are trivial. But of those who have something to say that is worth listening to, more of that message will find a willing audience rather than being lost to the void. Of course there is always a power law of attention, there are always the professionals sitting on top of the pyramid, but ultimately we are expanded and improved by our new capabilities, each of us our own media outlet.

There are always those who mistake the shell for the snail, however. You can't force a conversation, or indeed any sort of meaningful outcome, by turning a crank and sending links here and there aimlessly, by counting posts and metrics. If there is no conversation, all of those mechanical actions, "social media activity", are just hollow. In all of my experiments in that, and all of the other experiments I've had the dubious pleasure of watching in the course of gainful employment as a technologist, I've become convinced that the only thing to do is have conversations. Talk to people. Publish what you want, and let people talk about it at the pace they want to talk about it. You can't force growth in advocacy, and it's really hard to measure where exactly you are in that process with the tools that social media companies force upon you. Advocacy for a cause doesn't have conversions and funnels that can be measured on a website or in an email, no matter what those selling you metrics engines might say. You end up with a lot of numbers and no real way to connect those numbers to anything that actually matters as a bottom line. So why try? There are share buttons here at Fight Aging!, hidden, not loaded at all until you request the tool, because people kept asking for them, not because I'm hot on creating larger numbers in a report.

So: we live in an age of ever more pervasive communication. That is important, very important, to all endeavors, and in ways that we haven't yet figured out. A lot of the more active members of the longevity science advocacy community are engaged in trying out new modes of organization and communication, building the community, present in ever new form of social media. But this is all, ever and always, at heart a conversation. It goes at its natural pace. We shouldn't forget that just because the tools of the trade are shiny and in everyone's hands these days.

Longevity online: can social media take life extension ideas from the radical to the mainstream?

To confront death is to face our biggest fear, and unfortunately for advocates of life extension, this is something which the majority of people are not presently inclined to do. Like any industry, the level of investment in life extension technologies and the resultant supply of treatments are directly related to demand. Therefore, for governments, scientific institutions, and venture capitalists to invest within the field, the demand from consumers simply has to be there. Recent big budget ventures spearheaded by some of Silicon Valley's most high profile companies and individuals go a long way to speeding up the rate of research and development as well as raising awareness of the cause, but for those looking to really accelerate the rate of progress, the question is how to get enough of the population onboard to significantly impact upon the rate of change.

In the 21st Century, social media has emerged as by far the most efficient and accessible platform for engagement between like-minded individuals, promoting shared ideas, and ultimately mobilising the general population into action. In fact, in our increasingly globalised world, such is the centrality of social media and its capacity to facilitate instant worldwide communication, one can argue that without it any movement or form of promotion is likely doomed to fail.

As a characteristically tech-minded community, it is therefore no surprise that the power of networks such as Facebook, Twitter, Google+, Linkedin, and Reddit as tools for furthering the cause of life extension has not been lost upon its most engaged advocates. One only has to peruse the most popular channels Facebook and Twitter to find literally hundreds of groups and profiles dedicated to life extension and longevity, with thousands of members based all over the world. Such high-levels of activity, one would assume, can only be a good thing for the life extension movement, but in terms of really taking life extension ideas from the radical to the mainstream, how far does social media currently go?

Cryonics is Still in Search of Better Approaches to End of Life Management
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Cryonics is the industry and collection of technologies associated with low-temperature preservation of an individual upon death, necessarily carried out as soon as possible so as to prevent tissue damage in the brain. It is connected to research and development in forms of organ preservation associated with transplant medicine. A good cryopreservation of at least the brain ensures the best chance of future restoration with all the data of the mind intact, encoded in the fine structure of neurons and synapses: a preserved individual has all the time in the world to wait, after all. The odds of success are unknown, but infinitely better than is the case for all of the alternative options for those too old or too ill to wait for the advent of future rejuvenation therapies.

In an ideal world a good preservation would occur because it was scheduled ahead of time: a team and resources must be assembled and on the site, and this is hard and expensive to do at very short notice when there are so few qualified individuals and such a large territory to cover. This is why cryonics is strongly connected to legal issues surrounding self-determination in end of life choices, since in most countries people are forbidden to choose the time and manner of their own death, and doctors are forbidden to assist in enabling that death to be an easy one when the patient is in pain and dying, beyond the capacities of present medical technology. In that ideal world, the cryonics industry would also be large enough to ensure that first responders to medical emergencies, coroners, and other relevant individuals would as a matter of course be trained to understand and respect cryonics arrangements.

The present small size of the cryonics industry and the hostile nature of our legal systems means that we don't live in that world, unfortunately. We are not granted ownership over our own lives and bodies. Cryonics must occur as a last minute emergency effort at short notice in most cases, and the existing services and regulatory bodies must often be fought at the same time. Even people well connected within the cryonics community, who are well aware of the hurdles in the way, can succumb to sheer accident and as a result obtain a poor preservation with an unknown but probably large level of neural damage:

Dr. Laurence Pilgeram, a cryopreservation member of Alcor since 1991, was involved in cryonics early on. He gave a talk at the 1971 Cryonics Conference in San Francisco, California, on "Abnormal in-Vitro Oxidation and Lypogenesis Induced by Plasma in Patients with Thrombosis". Dr. Pilgeram was awarded his PhD. in Biochemistry at the University of California at Berkeley in 1953. In 1954-55 he served as an Instructor in Physiology at the University of Illinois College of Medicine in Chicago. After two years, he accepted an offer to develop and head an Arteriosclerosis Research Laboratory at the University of Minnesota School of Medicine. He later moved to Santa Barbara, California for a time before joining the Baylor College of Medicine in Houston, TX to develop and head the Coagulation Laboratory there.

On April 10, Dr. Pilgeram, collapsed outside of his home of an apparent sudden cardiac arrest. Despite medical and police personnel aware of his Alcor bracelet, he was taken to the medical examiner's office in Santa Barbara, as they did not understand Alcor's process and assumed that the circumstances surrounding his death would pre-empt any possible donation directives. Since this all transpired late on a Friday evening, Alcor was not notified of the incident until the following Monday morning.

Fortunately, no autopsy was performed which at least eliminated any invasive damage but the lengthy delay led to a straight freeze as the only remaining option. The medical examiner released the body to the mortuary that Alcor uses in Buena Park, California and he was immediately covered with dry ice, per our request. Aaron Drake and Steve Graber traveled to California to perform a neuro separation in the mortuary's prep room and then returned to Arizona for continued cool down which began on April 15, 2015.

Link: http://www.alcor.org/blog/dr-laurence-pilgeram-becomes-alcors-135th-patient-on-april-15-2015/

A Trial of Immunotherapy to Treat Multiple Myeloma
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Any proposed first generation rejuvenation toolkit of future decades must include a robust approach to cancer therapy, at the very least offering reliable detection methods and cures even if not providing outright prevention. An important part of cancer therapies presently under development is the ability to far more accurately target cancer cells, thereby greatly reducing the presently onerous, damaging side-effects of treatment. Of the numerous approaches to targeted therapies, immunotherapy is one of the most advanced towards widespread clinical adoption, as illustrated by the results of this early stage trial of a form of adoptive T cell therapy:

Researchers say they have safely used immune cells grown from patients' own bone marrow to treat multiple myeloma, a cancer of white blood cells. A trial was conducted involving a particular type of tumor-targeting T cell, known as marrow-infiltrating lymphocytes (MILs). "What we learned in this small trial is that large numbers of activated MILs can selectively target and kill myeloma cells." MILs are the foot soldiers of the immune system and attack foreign cells, such as bacteria or viruses. But in their normal state, they are inactive and too few in number to have a measurable effect on cancer.

For the clinical trial, the team enrolled 25 patients with newly diagnosed or relapsed multiple myeloma, although three of the patients relapsed before they could receive the MILs therapy. The scientists retrieved MILs from each patient's bone marrow, grew them in the laboratory to expand their numbers, activated them with microscopic beads coated with immune activating antibodies and intravenously injected each of the 22 patients with their own cells. Three days before the injections of expanded MILs, patients received high doses of chemotherapy and a stem cell transplant, standard treatments for multiple myeloma.

One year after receiving the MILs therapy, 13 of the 22 patients had at least a partial response to the therapy, meaning that their cancers had shrunk by at least 50 percent. Seven patients experienced at least a 90 percent reduction in tumor cell volume and lived, on average, 25.1 months without cancer progression. The remaining 15 patients had an average of 11.8 progression-free months following MILs therapy. None of the participants had serious side effects from the MILs therapy. The overall survival was 31.5 months for those with less than 90 percent disease reduction, but this number has not yet been reached in those with better responses. The average follow-up time is currently more than six years.

Link: http://www.eurekalert.org/pub_releases/2015-05/jhm-pct051915.php

Parabiosis Research Identifies β-catenin as a Target to Rejuvenate Bone Healing
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Heterochronic parabiosis has become a growing line of research these past few years. It involves connecting the circulatory systems of two individuals, such as two laboratory mice, of different ages. Researchers have shown that the old mouse of the pair regains somewhat more youthful characteristics in stem cell activity, healing, neurogenesis, cardiac health and other aspects linked to tissue maintenance. It doesn't turn back the clock by more than a fraction, but the benefits are large enough in comparison to what can be achieved via other avenues in medical science for researchers to investigate further. An outcome of partial rejuvenation of function during parabiosis must be triggered by a different balance of factors that is present in youthful blood versus aged blood. Thus researchers conclude that some fraction of the decline in tissue maintenance and diminished stem cell activity that occurs in aging has signaling changes in the tissue environment as its proximate cause. The next logical path of action for the mainstream research community is to undertake a drug discovery program, aiming for treatments that can override age-related changes in signaling to at least some degree, and with minimal side-effects.

These age-related changes in the amount or type of proteins present in circulating blood are not a root cause. They are themselves most likely a reaction to the accumulating cellular and tissue damage that drives degenerative aging. So it is worth bearing in mind that any treatment focused on spurring greater stem cell activity by overriding the natural aged signaling balance is essentially a matter of pushing the accelerator on a damaged engine. These and other related studies in mice have not yet seen the potential threat of cancer that would be expected to arise from greater activity undertaken by damaged cells, but caution is still merited. It may well be the case that the evolved balance of stem cell decline is far from optimal, and researchers could turn the dial a way without producing a high risk of cancer or other issues as a result. The fastest way to find out is to try. Equally it would be nice to see more attention given to repairing the damage that causes aging rather than trying to compensate for the consequences one layer up while ignoring the damage entirely.

Researchers have recently reported another potential success for heterchronic parabiosis, claiming the identification of β-catenin signalling as important in age-related decline of bone regeneration. Note that while the popular press is focusing on the parabiosis portion of the research, the scientists involved also produced the same benefits with a more conventional transplant of young cells into an old individual. Given the recent news about GDF-11, however, it might be worth waiting a couple of years for firm confirmation and clarification of the mechanism involved before celebrating this advance.

Old Bones Can Regain Youthful Healing Power

Broken bones in older people are notoriously slow to heal. In studies using mice, researchers not only traced what signals go wrong when aged bones heal improperly, they also successfully manipulated the process by both circulating blood and transplanting bone marrow from a young mouse into an older mouse, prompting the bones to heal faster and better. The work builds on earlier research which identified an important role for a protein called beta-catenin in the healing process. The protein requires precise modulation for successful bone fracture repair. In older people, beta-catenin levels are elevated during the early phases of bone repair, leading to the production of tissue that is more like scar than bone, which is not good for bone healing.

Using mice as a surrogate for humans, the researchers found that they could manipulate beta-catenin levels by exposing older animals to the blood circulation of younger animals, essentially correcting the intricate formula necessary for healthy bone repair. "It's not that bone cells can't heal as efficiently as we age, but that they actually can heal if they are given the right cues from their environment. It's a matter of identifying the right pathway to target, and that's what's exciting about this work. The next steps are to figure out what's making beta-catenin go up in older adults, so that we can target that cause, and to explore drugs that can be used in patients to change beta-catenin levels safely and effectively."

Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin

The capacity for tissues to repair and regenerate diminishes with age. We sought to determine the age-dependent contribution of native mesenchymal cells and circulating factors on in vivo bone repair. Here we show that exposure to youthful circulation by heterochronic parabiosis reverses the aged fracture repair phenotype and the diminished osteoblastic differentiation capacity of old animals.

This rejuvenation effect is recapitulated by engraftment of young haematopoietic cells into old animals. During rejuvenation, β-catenin signalling, a pathway important in osteoblast differentiation, is modulated in the early repair process and required for rejuvenation of the aged phenotype. Temporal reduction of β-catenin signalling during early fracture repair improves bone healing in old mice. Our data indicate that young haematopoietic cells have the capacity to rejuvenate bone repair and this is mediated at least in part through β-catenin, raising the possibility that agents that modulate β-catenin can improve the pace or quality of fracture repair in the ageing population.

Continued Investigations of Very Small Embryonic-Like Stem Cells in Adult Tissues
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It is important in the development of the present and the next generation of stem cell therapies to have cheap, reliable access to patient-specific pluripotent stem cells on demand. These are the basic starting point for generating therapeutic cells of a specific type, and only pluripotent cells have the capacity to create cells of any type. This is why there there is so much interest in developing the technology of induced pluripotency, for example, by which any cell sample from a patient can be used to create pluripotent cells. Some researchers believe that adult tissues contain populations of pluripotent stem cells necessary to continued tissue maintenance over a lifetime. If the case, these would be a useful source of cells for cell therapies. These proposed cell populations are given various names by various different research groups, such as very small embyronic-like stem cells. There is still some debate over whether such pluripotent cell populations actually exist in adult tissues, and whether researchers are accurately characterizing their observations. Research continues, however:

The pancreas is one of three organs (besides lung and liver) with huge regenerative ability. Mouse pancreas has a remarkable ability to regenerate after partial pancreatectomy, and several investigators have studied the underlying mechanisms involved in this regeneration process; however, the field remains contentious. Elegant lineage-tracing studies undertaken over a decade have generated strong evidence against neogenesis from stem cells and in favor of reduplication of pre-existing islets. Ductal epithelium has also been implicated during regeneration. We recently provided direct evidence for the possible involvement of very small embryonic-like stem cells (VSELs) during regeneration after partial pancreatectomy in mice.

VSELs were first reported in pancreas in 2008 and are mobilized in large numbers after treating mice with streptozotocin and in patients with pancreatic cancer. VSELs can be detected in mouse pancreas as small-sized LIN-/CD45-/SCA-1+ cells (3 to 5 μm), present in small numbers (0.6%), which express nuclear Oct-4 (octamer-binding transcription factor 4) and other pluripotent markers along with their immediate descendant 'progenitors', which are slightly bigger and co-express Oct-4 and PDX-1. VSELs and the progenitors get mobilized in large numbers after partial pancreatectomy and regenerate both pancreatic islets and acinar cells.

In this review, we deliberate upon possible reasons why VSELs have eluded scientists so far. Because of their small size, VSELs are probably unknowingly and inadvertently discarded during processing. Several issues raised in the review require urgent confirmation and thus provide scope for further research before arriving at a consensus on the fundamental role played by VSELs in normal pancreas biology and during regeneration, aging, and cancer. In the future, such understanding may allow manipulation of endogenous VSELs to our advantage in patients.

Link: http://dx.doi.org/10.1186/s13287-015-0084-3

Doubt Cast on GDF-11 Mechanism for Improved Health in Mice
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The path of scientific discovery is never direct, and if something appears simple in an investigation of biochemistry then it is perhaps time to wonder what was missed and when the other shoe will drop. In the past couple of years researchers have demonstrated improved health in aged mice through reactivation of stem cell activity via increased levels of GDF-11. The situation may well be more complex than first thought, however, as a second group is having issues replicating the effect. This work calls into question present hypotheses on the nature of the underlying mechanisms exhibited in previous work on GDF-11, and points to the need for a better and more complete analysis of what is going on under the hood. The observed improvements to health seen in past studies are not yet disputed, but clearly something is missing:

In 2013, a team found that levels of a protein called GDF11 decreased in the blood of mice as they grew older. When the researchers injected the protein into the heart muscle of old mice, it became 'younger' - thinner and better able to pump blood. Two subsequent studies found that GDF11 boosted the growth of new blood vessels and neurons in the brain and spurred stem cells to regenerate skeletal muscle at the sites of injuries. Those results quickly made GDF11 the leading explanation for the rejuvenating effects of transfusing young blood into old animals. But that idea was confusing to many because GDF11 is very similar to the protein myostatin, which prevents muscle stem cells from differentiating into mature muscle - the opposite effect to that seen.

Researchers set out to determine why GDF11 had this apparent effect. First, they tested the antibodies and other reagents used to measure GDF11 levels, and found that these chemicals could not distinguish between myostatin and GDF11. When the team used a more specific reagent to measure GDF11 levels in the blood of both rats and humans, they found that GDF11 levels actually increased with age - just as levels of myostatin do. That contradicts what the former group had found. The researchers next used a combination of chemicals to injure a mouse's skeletal muscles, and then regularly injected the animal with three times as much GDF11 as the former team had used. Rather than regenerating the muscle, GDF11 seemed to make the damage worse by inhibiting the muscles' ability to repair themselves.

Researchers suggest that there could be multiple forms of GDF11 and that perhaps only one decreases with age. Both papers suggest that having either too much or too little GDF11 could be harmful. The more recent research group injured the muscle more extensively and then treated it with more GDF11 than the former group had done, so the results may not be directly comparable. "We look forward to addressing the differences in the studies with additional data very soon."

Link: http://www.nature.com/news/young-blood-anti-ageing-mechanism-called-into-question-1.17583

Fight Aging! Finally Exports a Comments Feed
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There is no doubt a special circle of hell reserved for an individual who allows twelve years or more to lapse before adding a comments feed to his or her blog. I imagine that Dante would find a lot to say about the sins of our modern technological society, were he alive to be given the chance, but I've never claimed that things move rapidly around here. It took me five years of talking about it to get to the one and only redesign in the history of this site, for example.

This update is fairly simple and prosaic. Individual comments now have anchors within a page, and are directly linked in the feed. Many of you have by now worked out that comments allow a little HTML for formatting, such as italics and bold elements, and automatically convert pasted URLs into links. That HTML will transfer through into the feed. You'll find the new comments feed at the following URL:

https://www.fightaging.org/comments.xml

The new feed is also mentioned in the help page for Fight Aging! feeds. I should say that this feed is really just a stopgap for now to make life easier for people who like to keep up with conversations here. I know you that all have far better things to spend your time on than speculatively reloading posts here to see if anything new has arrived, but that was pretty much the only option. You do still have to set up a feed monitor or reader to keep tabs on the situation if you are participating: it does require a little work on your part to keep up, but this is still an improvement over the recent past.

In the future I am planning to move Fight Aging! from its present aging and unsupported platform to a standalone WordPress deployment, but the timing of this depends upon my finding the necessary free time to devote to the project. A start has been made, a lot of the fiddly setup and deployment issues completed. Given the more than ten years of increasingly baroque additions and customization to the present Fight Aging! platform, I have to say that it isn't a straightforward migration at the application level, however. It will be worth it once done. When set up in WordPress I will have a lot more latitude to add all sorts of useful features, such as subscription to comment threads, better presentation of recent comments on the site, and other items that would be quite painful to attempt today.

It looks increasingly likely that the WordPress migration will not happen prior to this year's Fight Aging! fundraiser for SENS research programs, given that the first phase of the fundraiser will be underway in a matter of a few weeks from now. While the fundraiser is going on I will have higher priority items to tackle than the migration; while a comment feed is a poor substitute to be going on with for the moment, it is considerably better than the nothing that was in place prior to today.

Progress in Engineering Digestive System Tissue
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It is becoming ever more common these days to see news of proof of concept work for the engineering of specific tissue structures throughout the body. Here is a recent example:

In developing tissue-engineered gut replacements the researchers use smooth muscle and nerve stem cells from human intestine to engineer innervated muscle sheets. The sheets are then wrapped around tubular chitosan scaffolds. The tubular structures were implanted just under the skin of rats for 14 days, a first step in assessing their performance. Researchers found that the implants developed a blood vessel supply and that the tube opening was maintained. In addition, the innervated muscle remodeled as the cells began the process of releasing their own materials to replace the scaffold. "It is the combination of smooth muscle and neural cells in gut tissue that moves digested food material through the gastrointestinal tract and this has been a major challenge in efforts to build replacement tissue. Our preliminary results demonstrate that these cells maintained their function and the implant became vascularized, providing proof of concept that regenerating segments of the gastrointestinal tract is achievable."

The group's second project, to engineer anal sphincters, also reached a new milestone with the successful implantation of the structures in rabbits. Sphincters are ring-like muscles that maintain constriction of a body passage, such as controlling the release of urine and feces. There are actually two sphincters at the anus - one internal and one external. A large proportion of fecal incontinence in humans is the result of a weakened internal sphincter.

To engineer the internal anal sphincters, researchers used a small biopsy from the animals' sphincter tissue and isolated smooth muscle cells that were then multiplied in the lab. In a ring-shaped mold, these cells were layered with nerve cells isolated from small intestine to build the sphincter. The mold was placed in an incubator, allowing for tissue formation. The entire process took about four to six weeks. The bioengineered sphincters mimicked the architecture and function of native tissue and there are no signs of inflammation or infection after implantation. The constructs demonstrated the presence of contractile smooth muscle as well as mature nerve-cell populations. The bioengineered sphincters restored fecal continence in the animals throughout the six-month follow-up period after implantation.

Link: http://www.wakehealth.edu/News-Releases/2015/Researchers_Make_Progress_Engineering_Digestive_System_Tissues.htm

Yet Another Approach to Blocking Telomerase Activity in a Broad Range of Cancers
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Meaningful progress in cancer research in the decade ahead will emerge from strategies that can be applied to many different types of cancer: the same cost in time and money goes into development as building a treatment that is applicable to only one type, but the end result is vastly more effective and useful. The one commonality shared by all cancer cells is the ability to extend telomeres to permit uncontrolled cell replication past the normal limits. Take that away and the cancer fades. This is the SENS approach to preventing cancer by striking at the root, and the same strategy is emerging elsewhere in the research community. A variety of different approaches are under development, most focused on interfering in the activity of telomerase:

Approximately 85 percent of cancer cells obtain their limitless replicative potential through the reactivation of a specific protein called telomerase reverse transcriptase (TERT). Recent cancer research has shown that highly recurrent mutations in the promoter of the TERT gene are the most common genetic mutations in many cancers. TERT stabilizes chromosomes by elongating the protective element at the end of each chromosome in a cell. Scientists have discovered that cells harboring these mutations aberrantly increase TERT expression, effectively making them immortal.

Researchers have identified that the mechanism of increased TERT expression in tumor tissue relies on a specific transcription factor that selectively binds the mutated sequences. A transcription factor is a protein that binds specific DNA sequences and regulates how its target genes are expressed (in this case the gene that expresses TERT). Thus, the TERT mutations act as a new binding site for the transcription factor that controls TERT expression. The newly identified transcription factor does not recognize the normal TERT promoter sequence, and thus, does not regulate TERT in healthy tissue.

The team's work further showed that the same transcription factor recognizes and binds the mutant TERT promoter in tumor cells from four different cancer types, underscoring that this is a common mechanism of TERT reactivation. The identified transcription factor and its regulators have great potential for the development of new precision therapeutic interventions in cancers that harbor the TERT mutations. A treatment that would inhibit TERT in a targeted cancer-cell-specific manner would bypass the toxicities associated with current treatments that inadvertently also target TERT in normal healthy cells. The team is now conducting a variety of experiments designed to test whether inhibiting the transcription factor activity would not only turn down TERT expression, but might also result in selective cancer cell death.

Link: http://engineering.illinois.edu/news/article/11131

Developmental Disorders Have Little To Do With Aging
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One of the challenges inherent in talking to the public about aging is that there are many well-popularized rare conditions that have the superficial appearance of accelerated aging or slowed aging, but are in fact nothing of the sort. Take progeria, for example: it is a comparatively simple genetic dysfunction that induces a great deal of cellular dysfunction and damage. Aging itself is a matter of specific forms of cellular dysfunction and damage, but any vaguely similar limiting of cell activities will produce some of the same outcomes, such as failure of tissue maintenance and a decline in organ function and integrity. Progeria patients die young from cardiovascular disease as a result of these issues, and appear prematurely aged. Yet the type of damage to cells that occurs in progeria has next to no role in normal aging, and vice versa, and the outcomes only appear similar at the large scale because the essential high level functions of tissue are disrupted in both cases. In fact the two conditions, progeria and aging, have nothing to do with one another, and it is probably the case that little learned in progeria research will be applicable in the treatment of normal aging.

This is a moderately complex set of ideas to explain in enough detail for it all to make sense to someone not versed in the underlying science. It takes a little time, and good explanations are all too often obscured by simplified media stories that talk about accelerated aging in ways that make sound like progress in progeria research is a direct and useful approach to learning about normal aging. Not the case at all, however.

Another example of the type that has been making the rounds in the media for the past few years is a rare developmental disorder in which the child does not develop: one individual lived for two decades while remaining an infant. The colloquial sense of the word "aging" includes growing up to adulthood as well as getting old, and so the media breathlessly calls this arrested aging, but these are two quite different processes. The degeneration and loss of function in later aging is caused by accumulated damage that occurs as a side-effect of the normal operation of metabolism. The passage from childhood to adulthood is an evolved developmental program of growth and change. If that developmental program is broken, the individual will still age, will still accumulate cellular and tissue damage for so long as their metabolism is operating. It seems unlikely that there is anything of practical use for aging to be learned here, despite the hopes expressed by some of the people involved:

Epigenetic age analysis of children who seem to evade aging

We previously reported the unusual case of a teenage girl stricken with multifocal developmental dysfunctions whose physical development was dramatically delayed resulting in her appearing to be a toddler or at best a preschooler, even unto the occasion of her death at the age of 20 years. The pediatrician who cared for her from birth described his patient's strange affliction, that did not fit any disease category, as an "unknown syndrome" later to be called "syndrome X". As the result of her persistent "toddler-like" appearance, she received extensive notoriety from the media, and was featured as the "girl who doesn't age" in press articles and television broadcasts.

While most of the individual defects she experienced are not uncommon in many children, it was her retaining toddler-like features while aging from birth to young adulthood that made the case particularly unusual. Even children with growth retardation or failure to thrive exhibit maturation of facial and other physical/functional features with passage of time, indicating that their developmental program is still functional. In contrast, the peculiar trait of the first case suggested that her rate of aging was dramatically delayed or even arrested. If so, then perhaps an etiological understanding of her pathology might lead to novel treatments for age related diseases.

The objectives of this study were two-fold. The first was to determine if other such cases of syndrome X actually exist and thus might represent a novel syndrome. Then, because the case's appearance remained that of a toddler despite the passage of time, our second objective was to determine if there was any evidence that the arrested development in such children is linked to a slowing down of aging at the molecular level.

We identified five new cases whose clinical presentations were similar to the first case. Thus, while extremely rare, the first case described was not unique in the world. Furthermore, since such children require extensive medical care to survive, especially during the first years after birth, it may be that most succumb before ever being diagnosed. All of the identified subjects were female. It is not known whether this occurrence was due to chance alone or is a sex linked aspect of the putative syndrome.

To objectively measure the age of blood tissue from these subjects, we used a highly accurate biomarker of aging known as "epigenetic clock" based on DNA methylation levels. Our results demonstrate that despite the clinical appearance of delayed maturation in children afflicted with syndrome X, the epigenetic clock indicates that the rate of development in blood and perhaps other tissues is normal. Thus, while we cannot exclude tissue-specific ageing as causal in syndrome X, the current findings suggest that the observed delay in whole body development results from other, yet undiscovered factors. Future studies should assess whether other tissue types from these subjects (or their bodies as a whole) evade epigenetic aging.