Fight Aging! Newsletter, November 11th 2013

November 11th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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  • Prana Biotech's PBT2 Versus Cognitive Decline
  • Those Lucky Haplogroup H Bearers
  • Speculation on FOXO in Organismal Complexity and the Evolution of Aging
  • Recent Discoveries in Regenerative Research
  • Really There is No Such Thing as Healthy Aging
  • Latest Headlines from Fight Aging!
    • Potential for Photoacoustic Therapy to Target Protein Aggregates in Neurodegenerative Disease
    • A Popular Science Article on the Comparative Study of Aging in Short-Lived and Long-Lived Species
    • The Science of Staying Younger Longer
    • Born Too Early?
    • Evaluating Autologous Stem Cell Therapy for Peripheral Artery Disease
    • Treating Traumatic Brain Injury With Stem Cells
    • An Interesting Approach to Finding Longevity-Associated Genetic Variations
    • Considering Impairment of Regeneration in Aging
    • More on Lin28a and Enhanced Regeneration
    • A Scaffold Patch Combined With Gene Delivery Regrows Bone


The research company Prana Biotechnology has been touting the results of a recent study in which one of their drug candidates demonstrated a meaningful impact on cognitive decline in old mice:

Prana's PBT2 Reverses Memory Loss in Normal Aging (PDF)

Typically mice live for 24 to 30 months, developing progressive cognitive impairment from 16 to 18 months. Age related cognitive decline is associated with measurable structural and biochemical changes in the brain, which were significantly improved by PBT2. In the study 22 month old mice were treated with PBT2 for a total of 12 days. PBT2 restored learning and memory. The old mice treated with PBT2 performed learning and memory tasks to the same level exhibited by young mice and significantly better than untreated old mice. PBT2 Increases markers of neurogenesis and neuron number [and] increases numbers of synapses in the hippocampus.

So what is going on here under the hood? Prana researchers focus on the biochemistry of interactions between metals and proteins, in particular the role of what are known as metal chaperones, and they theorize that disruption of the normal adult state of these interactions is a significant contribution to age-related neurodegeneration. An open access position paper from last year outlines this viewpoint with a particular focus on Alzheimer's disease (AD):

Metal Chaperones: A Holistic Approach to the Treatment of Alzheimer's Disease

Metal chaperones (or metallochaperones) are compounds that function to shuttle metal ions to specific intracellular target proteins. This facilitation of metal transport is distinct from metal chelators or buffers, which function to exclude or deplete metals from discrete cellular compartments to thereby limit biological interactions of key metal ions. Cumulatively, however, these processes serve to maintain tight regulatory control over cellular metal ion homeostasis such that the intracellular concentration of freely available metal ions (such as copper and zinc) is close to zero.

Such a high level of control at many cellular "levels" is essential in limiting potentially deleterious interactions of redox active transition metal ions, which are implicated in the pathogenesis of a number of disorders including AD. The involvement of metal ions in disease extends the breadth from being involved in creating an adverse cellular milieu (which among other things, may promote cell death through the activation of particular pathways that lead to degeneration) through to direct involvement in the generation and toxicity of the principle toxic moiety in diseases such as AD.

Metal chaperones (which have also variously been referred to as "ionophores" and "metal-protein attenuating compounds") may represent the "sweet spot" of metal-targeted therapeutics for AD because they foster the maintenance and/or restoration of metal ion homeostasis which then impacts a raft of "healthy" and "pathological" cellular pathways that ultimately promotes "normal" function. Such context-dependent modulation of metal levels may prove critical for long-term therapeutic strategies that target metal ions.

The recent press and mouse study is accompanied by an open access paper. By the sound of it the mechanism of action here remains to be pinned down, but the outcomes are good enough to move this forward in the development process. So this compound may in the end turn out to work via means that have little to do with metals. It may or may not be in any way reducing levels of the fundamental cellular and molecular damage that cause aging, either directly or indirectly, and it may or may not be minimizing harmful responses to that damage. We shall see - only further research can determine the answers.

A Novel Approach To Rapidly Prevent Age-Related Cognitive Decline

The loss of cognitive function is a pervasive and often debilitating feature of the ageing process for which there are no effective therapeutics. We hypothesized that a novel metal chaperone (PBT2) would enhance cognition in aged rodents. We show here that PBT2 rapidly improves the performance of aged C57Bl/6 mice in the Morris water maze, concomitant with increases in dendritic spine density, hippocampal neuron number and markers of neurogenesis.

There was a breadth of biological effects within the brain following PBT2 treatment in the aged mice. While it is not possible to discern which of these was the principal driver of the cognitive benefit observed, it is likely to have resulted from a PBT2-mediated improvement in the function of different cellular pathways that are critical to synaptic plasticity and cognitive function. In the longer term, these improvements are likely to synergise with the effects observed on neuronal health and connectivity to foster a long-term improvement in both brain and cognitive health. As deficits in many of these same pathways are implicated in a variety of disorders, this also establishes a landscape where PBT2 may be efficacious in the treatment of a broad spectrum of diseases.

That this activity has also translated to improved cognition in a short-term Phase IIa human clinical trial of AD provides strong support for the efficacy of this compound in restoring normal brain function. The use of metal chaperones, such as PBT2, as novel therapeutic compounds for the treatment of both "normal" and "pathological" cognitive decline is strongly endorsed by these findings and warrant further mechanistic investigation into the precise mechanism of action of this class of compound, as well as human clinical trials to validate these rodent data.


Mitochondria are the power plants of the cell, working in herds to produce the energy stores that power other cellular processes. They are the evolved descendants of symbiotic bacteria and as such the blueprints for some of their protein machinery are encoded in their own DNA, separate from the DNA in the cell nucleus. This mitochondrial DNA is inherited wholesale from the mother, and numerous common variants known as haplogroups are distributed among the world's cultures and population.

Mitochondrial damage and function appears to be very important in the aging process and many common age-related diseases. In recent years evidence has accumulated to suggest that some variants of mitochondrial DNA are just plain better than others, but linking these genetic variations to damage and function remains a work in progress. Still, the genetic lottery we all participate in very definitely applies to the mitochondria we inherit, and not just our nuclear DNA. So far the widespread variant known as haplogroup H looks like a winner:

Variations in Human Response to Calorie Restriction

Before 1920 there is no significant difference between the longevity of individuals in haplogroup H and U. During the caloric restriction of the Great Depression, 1920-1940, haplogroup H shows significant increase in longevity compared to haplogroup U [with a] mean difference [of] 2.6 years.

Mitochondrial Haplotypes Correlate With Dementia Risk

Participants from haplogroup T had a statistically significant increased risk of developing dementia and haplogroup J participants experienced a statistically significant 8-year [cognitive decline], both compared with common haplogroup H.

Here is another paper demonstrating a possible facet of the superiority of haplogroup H mitochondrial DNA:

Increased intrinsic mitochondrial function in humans with mitochondrial haplogroup H

It has been suggested that human mitochondrial variants influence maximal oxygen uptake (VO2max). Whether mitochondrial respiratory capacity per mitochondrion (intrinsic activity) in human skeletal muscle is affected by differences in mitochondrial variants is not known. We recruited 54 males and determined their mitochondrial haplogroup. Haplogroup H showed a 30% higher intrinsic mitochondrial function compared with the other haplogroup U. There was no relationship between haplogroups and VO2max.

Interestingly, we are moving into an era in which wholesale replacement of mitochondrial DNA throughout the body is a practical possibility. This was accomplished in mice via protofection eight years ago, and since then numerous research groups have achieved mitochondrial DNA replacement in cell cultures via other mechanisms. In the future you will have optimal mitochondrial DNA, periodically replaced to clear out any damage that might have occurred.

But it is of course that damage that is the important factor here, not the details of your mitochondrial haplogroup. We age in part because our mitochondrial DNA becomes damaged, that being the start of a long chain of cause and effect that leads to dysfunctional cells, floods of harmful reactive compounds, and eventually fatal manifestations such as atherosclerosis. So work on mitochondrial DNA replacement is important because it will lead to a way to mitigate and reverse one facet of degenerative aging, not because you will be able to have an athlete's mitochondria as the result of a simple clinical procedure.


Only lower organisms seem able to prosper via evolutionary strategies that involve some combination of agelessness, radical transformation of body structure, and hyperefficient regeneration. The candidates for truly immortal animals are few and far between: species such as Turritopsis dohrnii, a tiny jellyfish that runs its development cycle in reverse rather than age and die, and hydra, which might achieve immortality through exceedingly effective always-on tissue regeneration. Strategies of this nature can work because these are comparatively simple organisms, lacking the specialization and complexity of higher animals such as we mammals. Gaining a complex neural network and brain seems to go hand in hand with losing exceptional regenerative capabilities - which seems reasonable, although it is still an open question as to exactly why this is the case.

One thing to consider as a result is that while studying these apparently immortal species might teach us interesting things about biology, it probably won't result in anything of practical use in medicine in the near term. Bear in mind that it will be a long haul to mine useful medical applications from the far better funded and more advanced study of long-lived mammals such as naked mole rats and whales, which are very close relatives to us in comparison to jellyfish and hydra. But the biochemistry that keeps a hydra going is more likely to result in destruction and cancer than benefits if implemented in a human: many of our structures, especially those in the brain, need to be around for the long-term, not constantly replaced with new tissue, or discarded in the course of a radical change of body structure.

Here researchers make an early and speculative hypothesis on the role of FOXO in the move from simple, highly regenerative organisms to complex, less regenerative organisms. FOXO genes (the O category of the forkhead box family) have been studied for some years by researchers seeking to understand and catalog the means by which metabolism determines longevity. Like many other longevity-related genes they influence broad collections of central and important processes related to genetic transcription, cell proliferation, and stress tolerance. There is no simple set of dots to join between point A and point B: these are networks of interlinked feedback loops.

FOXO in aging: Did evolutionary diversification of FOXO function distract it from prolonging life?

In this paper we contrast the simple role of FOXO in the seemingly non-aging Hydra with its more diversified function in multicellular eukaryotes that manifest aging and limited life spans. From this comparison we develop the concept that, whilst once devoted to life-prolonging cell-renewal (in Hydra), evolutionary accumulation of coupled functionality in FOXO has since 'distracted' it from this role. Seen in this light, aging may not be the direct cost of competing functions, such as reproduction or growth, but the result of a shift in emphasis in a protein, which is accompanied by advantages such as greater organismal complexity and adaptability, but also disadvantages such as reduced regeneration capacity. Studying the role of FOXO in non-aging organisms might, therefore, illuminate the path to extend life span in aging organisms.

Stem cells and aging from a quasi-immortal point of view

Understanding aging and how it affects an organism's lifespan is a fundamental problem in biology. A hallmark of aging is stem cell senescence, the decline of functionality, and number of somatic stem cells, resulting in an impaired regenerative capacity and reduced tissue function. In addition, aging is characterized by profound remodeling of the immune system and a quantitative decline of adequate immune responses, a phenomenon referred to as immune-senescence. Yet, what is causing stem cell and immune-senescence?

This review discusses experimental studies of potentially immortal Hydra which have made contributions to answering this question. Hydra transcription factor FoxO has been shown to modulate both stem cell proliferation and innate immunity, lending strong support to a role of FoxO as critical rate-of-aging regulator from Hydra to human. Constructing a model of how FoxO responds to diverse environmental factors provides a framework for how stem cell factors might contribute to aging.


As the research community continues to improve our understanding of the mechanisms of regeneration, ever more potential ways to improve healing and regrowth should emerge as a result. Stem cell therapies are one outcome of this research: having found the cells that do much of the work to keep our tissues in shape, we can now think about directing them, growing more of them, reversing their decline in aging, transplanting them between individuals, and so forth. But this is far from the only type of approach that might arise. Evolution doesn't tend to produce systems that are optimized for the best possible outcome for individuals: we can see that in the ease with which researchers can adjust any one of a handful of genes to extend healthy life in laboratory mice. Similarly we should expect there to exist numerous small genetic or metabolic changes that produce improved regeneration in mammals, but which have not been selected for by evolution in most species.

On this topic a couple of research results were publicized today, illustrating the sort of work that kicks off further investigations aimed at improving human regeneration, either globally or in specific tissue types:

Scientists identify clue to regrowing nerve cells

Axons are the branches of nerve cells that send messages. They typically are much longer and more vulnerable to injury than dendrites, the branches that receive messages. In the peripheral nervous system cells sometimes naturally regenerate damaged axons. But in the central nervous system, comprised of the brain and spinal cord, injured nerve cells typically do not replace lost axons.

Working with peripheral nervous system cells grown in the laboratory, [researchers] severed the cells' axons. [They] learned that this causes a surge of calcium to travel backward along the axon to the body of the cell. The surge is the first step in a series of reactions that activate axon repair mechanisms. In peripheral nerve cells, one of the most important steps in this chain reaction is the release of a protein, HDAC5, from the cell nucleus, the central compartment where DNA is kept. The researchers learned that after leaving the nucleus, HDAC5 turns on a number of genes involved in the regrowth process. HDAC5 also travels to the site of the injury to assist in the creation of microtubules, rigid tubes that act as support structures for the cell and help establish the structure of the replacement axon.

When the researchers genetically modified the HDAC5 gene to keep its protein trapped in the nuclei of peripheral nerve cells, axons did not regenerate in cell cultures. The scientists also showed they could encourage axon regrowth in cell cultures and in animals by dosing the cells with drugs that made it easier for HDAC5 to leave the nucleus. When the scientists looked for the same chain reaction in central nervous system cells, they found that HDAC5 never left the nuclei of the cells and did not travel to the site of the injury. They believe that failure to get this essential player out of the nucleus may be one of the most important reasons why central nervous system cells do not regenerate axons.

"This gives us the hope that if we can find ways to manipulate this system in brain and spinal cord neurons, we can help the cells of the central nervous system regrow lost branches. We're working on that now."

Researchers reactivate gene to rejuvenate tissue repair

[An] RNA-binding protein, Lin28a, promotes tissue repair by reactivating a metabolic state reminiscent of the juvenile developmental stage. [Researchers] showed that reactivation of Lin28a - a gene that is normally turned on in fetal but not adult tissues - substantially improved hair regrowth and accelerated tissue repair after ear and digit injuries. "Our work found that Lin28a promotes regeneration through a metabolic mechanism. This finding opens up an exciting possibility that metabolism could be modulated to improve tissue repair, whereby metabolic drugs could be employed to promote regeneration."


I'm not a big fan of the phrase "successful aging." It is a popular shorthand among researchers who investigate means of slowing aging and reducing incidence of age-related disease, but who do not wish to talk in public about extending human life span. So it is a problematic fig leaf on that count, but it is also a contradiction in terms. Aging is damage and degeneration, and so what if you manage to die, slowly and painfully, a shadow of your former self, just a little later than your peers? Why is that counted a success?

When we look elsewhere in the medical community, this lack of ambition and acceptance of disease is not what we see. Take cancer research, for example: it doesn't matter how many months that scientists manage to add to a terminal patient's life span, you'll never hear them talking about "successful terminal cancer" as a desired outcome. The measure of success in cancer research is to produce a cure, and that should also be the measure of success for aging, so that the research community aims to prevent and reverse age-related degeneration and disease, such as through implementation of the SENS proposals. Anything less is ridiculous: it is to say that degeneration, pain, and suffering are acceptable, and we should do nothing much about it. That is clearly the antithesis of what should mean to be involved in medical research and development.

I think that Maria Konovalenko of the Science for Life Extension Foundation is correct in noting here that the phrase "healthy aging" has essentially all of the same issues given the way it is presently used in the research and medical communities. It is a contradiction in terms: aging is explicitly the process of becoming less healthy. The fundamental definition of aging is that it is a rise in the chance of dying due to increasing tissue dysfunction, which doesn't sound a great deal like health to me.

There Can Be No Healthy Aging

[Craig Venter's institute] has received 1.25 million dollars from the Ruggles Family Foundation to study the biomarkers of healthy aging. This study makes no sense to me, because they want to look at the differences in health between sick people and even sicker people and call the results of the study markers of healthy aging. They propose to measure the right things, but what the study planners are missing here is the fact that aging itself is a disease. Aging can't be healthy, because the underlying biological mechanisms that are causing age-related pathologies are active also in those aged individuals, who don't have those diseases.

These people are considered to be just old, but not sick. That's exactly what's wrong with perception of aging. Everyone who reached a certain age is considered to be simply old, but not ill. However this person is 100% not healthy in a biological sense, because a lot of detrimental processes have already started their poisonous actions and altered the youthful state of the organism.

Here's what important - we need to change the perception of aging, so there would be no confusing terms like "healthy aging", which is an oxymoron. It's like "dignified poverty", or "merciful tyrant". Aging is not and can not be healthy. Aging is itself a disease. It is also the cause of many other maladies like Alzheimer's and stroke, and many others. We have to stop using the term healthy aging, because it is already making us conduct poorly designed research experiments.


Monday, November 4, 2013

Photoacoustic therapy involves the use of carefully modulated laser light to rapidly dump energy into very specific locations in a tissue, where flash heating will destroy the intended target. Work to date involves, for example, delivering carbon nanotubes to cancer cells and then using laser light to explode the nanotubes. Researchers are now considering the potential for forms of photoacoustic therapy to destroy aggregrates of misfolded proteins associated with neurodegenerative disease:

[Researchers] have made a discovery that may lead to the curing of diseases such as Alzheimer's [and] Parkinson's through photo therapy. [It] is possible to distinguish aggregations of the proteins, believed to cause the diseases, from the the well-functioning proteins in the body by using multi-photon laser technique.

If the protein aggregates are removed, the disease is in principle cured. The problem until now has been to detect and remove the aggregates. The researchers now harbor high hopes that photo acoustic therapy, which is already used for tomography, may be used to remove the malfunctioning proteins. Today amyloid protein aggregates are treated with chemicals, both for detection as well as removal. These chemicals are highly toxic and harmful for those treated. With multi photon laser the chemical treatment would be unnecessary. Nor would surgery be necessary for removing of aggregates. Due to this discovery it might, thus, be possible to remove the harmful protein without touching the surrounding tissue.

These diseases arise when amyloid beta protein are aggregated in large doses so they start to inhibit proper cellular processes. Different proteins create different kinds of amyloids, but they generally have the same structure. This makes them different from the well-functioning proteins in the body, which can now be shown by multi photon laser technique.

This may be overly optimistic on a few counts: firstly that the amyloid is definitely the disease agent in all cases, versus a secondary effect - though the research community should still work to remove it, as it is an enumerated difference between healthy and diseased tissue. Secondly it may not be as straightforward as hoped to deliver heat via laser only to amyloid without causing secondary damage to delicate nearby structures in neurons and synapses. You might recall that a community-funded attempt to break down liposfuscin through modulated laser light didn't go so well on that count. It proved more challenging than expected to keep the heat and damage constrained to just the lipofuscin. Still, this should just be another technical hurdle to overcome.

Monday, November 4, 2013

Looking for longevity-assurance mechanisms in long-lived animals is a growth concern these days, though it is still largely an aspect of the slow road in longevity science. It is possible that researchers will make discoveries that will help the development of means to repair specific forms of cellular and molecular damage that cause aging in humans, but the focus is usually on determining ways to alter the operation of human metabolism so as to gently slow down aging. Look at the community who investigate the biochemistry of calorie restriction so as to develop drugs to mimic its beneficial effects on health and longevity, for example.

Slowing aging safely by creating a new operating state for our cellular biology is a very challenging and expensive endeavor, and one which will yield little benefit for people who are already old. In comparison keeping the metabolism we have while working to periodically remove the damage that degrades its operation sounds like a much better plan, and one that will help the old by actually rejuvenating them.

Here is a popular science piece that looks at the work of one of the researchers involved in comparative studies of the genetics of aging in varied animal species:

Accumulating damage in cells is commonly thought to result in aging, but Gladyshev doesn't think even that assumption has been carefully tested. He pointed to the trash can in his fourth-floor office and noted that it could fill up with garbage, but that would not mean that his ability to do work would change.

So Gladyshev came up with a new way to probe aging. Instead of looking for clues by studying longer- and shorter-lived individuals of a particular species, why not look at the diversity of an entire class of organisms? Evolution, he notes, has been better at tweaking the life spans of organisms than any laboratory researchers have been: among mammals, there can be a gigantic variation in life span between different species. What, he wonders, are the genetic differences that mean an elephant can live for 70 years, a squirrel can reach its 20th birthday, but a shrew may expire after just one?

Gladyshev will collect samples from 50 mammals whose natural lives vary, from the longest- to the shortest-lived. Recently, for example, he enlisted a team of Russian scientists to gather samples from the Brandt's bat, a five-gram mammal that has been documented to live 41 years. Gladyshev and the Russian researchers described the bat's genome, and compared it with other mammals. They identified genetic alterations in genes that may be involved in lifespan, and Gladyshev hopes to examine those genes in greater detail to see whether they play a role in the tiny creature's remarkable longevity.

By eventually comparing gene activity in many mammals, he hopes to identify genes and control mechanisms that might control aging - and provide potent targets for researchers hoping to develop therapies that could extend life or combat diseases of aging.

Tuesday, November 5, 2013

It is pleasant to see larger, more conservative research institutions being much more aggressive in publicizing longevity science and the goal of extending the healthy human life span. It shows that the old scientific and funding institution culture of hiding and suppressing any work on aging that might be relevant to extending life is done with and over. When the research community talks openly about their goals, levels of funding and public support rise.

Nowadays the more important battle is fought to ensure that the best strategies for extending life are those that are funded: for example none of the lines of research mentioned in the article below are in any way relevant to the SENS vision of rejuvenation through damage repair. Despite the talk of rejuvenation they instead reflect the mainstream focus on altering genes and metabolism to slow down the progression of aging, which is a harder, slower, less certain road to a less useful outcome.

Eleven leading scientists from the California Institute for Quantitative Biosciences (QB3) - a state-funded consortium founded by UC San Francisco, UC Berkeley and UC Santa Cruz - presented their latest research findings and anti-aging strategies at a daylong symposium earlier this month called "The Science of Staying Younger Longer." The goal of this research area is rejuvenation: longer, healthier life, free from the costly and debilitating chronic diseases associated with aging and a too-early demise. Better living in old age is a growing priority as a bulging population of baby boomers enters their golden years.

Thanks primarily to better control over infectious diseases through improved sanitation, vaccines and antibiotics, Americans live on average more than three decades longer than they did a century ago. But today tantalizing research findings from different scientific disciplines - including genetics, immunology, cell biology, diabetes research and microbiology - are raising hopes for another revolutionary increase in life expectancy.

"Perhaps rejuvenation therapies will appear in less than a decade, if we pool our resources and skills," said Regis Kelly, PhD, director of QB3 and organizer of the event on the UCSF Mission Bay campus. At UCSF, researchers have led important research to identify the treatment needs of elderly patients, including disabled patients and individuals with HIV infection; they have made breakthroughs in accurately diagnosing dementias, a major malady of old age; and they have identified what may be biological underpinnings for aging at the genetic and biochemical level.

Tuesday, November 5, 2013

Practical human rejuvenation lies in the near future: the means to reverse age-related degeneration and restore youthful function to the old, thereby extending healthy life and eliminating age-related disease. With the right sea changes in scientific funding, so that organizations like the SENS Research Foundation become the mainstream of the aging research community, rejuvenation therapies could well arrive by the late 2030s. If the present mainstream focus on gently slowing aging continues as is, however, then it will take much longer to realize rejuvenation. But however long it takes, some fraction of those people presently alive will have been born too early.

A friend of mine in the life extension movement who is approaching age 65 once lamented that he might be part of the last generation that will not be able to take advantage of the rejuvenation biotechnologies that become available to the next generation. I wish I could believe him because it means that I may still be in time! Unfortunately, interest in anti-aging research and cryonics is rather low (to put it mildly), even among baby boomers who one might expect to be painfully aware of the aging process. It is rather disturbing to me that the aging process itself is not being identified as a source of misery, disease, separation, and oblivion. Then again, perhaps I am just too impatient and unable to see the larger picture.

The practical production of liquid nitrogen from liquefied air was first achieved by Carl von Linde in 1905, although liquid nitrogen only became widely available commercially after World War II. The idea of cryonics was introduced to the general public in the mid-1960s. Since liquid nitrogen (or liquid helium) is an essential requirement for human cryopreservation it is interesting to recognize that there was only a difference of roughly 20 years between cryonics being technically possible and the first efforts to practice cryonics. Is this an outrageously long delay? I doubt anyone would argue this.

Similarly, while the idea of rejuvenation has always appealed to humans, I doubt anyone can credibly claim that there has been a long delay between our recognition of biological senescence and the desire to see aging as a biotechnological challenge to overcome. While there is no massive global movement to fight aging yet, the desire to conquer aging is as old as the exposition of (secular) modern evolutionary biology itself. Are we too impatient?

What is disappointing, however, is the widespread passive acceptance of aging and death by the majority of people. Thinking about this issue, it struck me that until recently our (educational) institutions and research programs were shaped by generations that were perhaps eminently amenable to accepting the inevitability of aging. Expecting these institutions and research programs to change their objectives overnight may not be completely realistic. It is undeniable, however, that the idea that aging is not something that is to be passively accepted but something that can be stopped and reversed is gradually winning more converts.

From where I stand, the best thing to do is not to agonize over the odds but rather work to help shape the odds. Donate to research, persuade your friends, advocate for rejuvenation science, help make cryonics an ever more viable alternative for those who do not have enough time to wait for life-extending therapies, and more. There is plenty that can be done, and still all too few people working on it.

Wednesday, November 6, 2013

VesCell was one of the first of the present generation of commercialized stem cell therapies in which a patient's own cells are taken, expanded, and then returned to the body. The company was notable for marketing in the US while setting up clinics elsewhere in the world to evade onerous FDA restrictions on stem cell therapies: medical tourism at its finest. These sorts of treatments are only now becoming available in the US thanks to the fact that over the past fifteen years a range of pioneers successfully developed commercial clinical applications beyond the reach of US regulators. Otherwise we'd still be waiting and FDA bureaucrats would still be forbidding commercialization of stem cell research, demanding ever more trials and data.

Regeneration of the occluded peripheral arteries by autologous stem cell therapy is an emerging treatment modality for no-option patients with peripheral artery disease (PAD). The purpose of this study was to assess safety and efficacy of in vitro-expanded, peripheral blood-derived, autologous stem cells (VesCell) in no-option patients with PAD. A phase II, open-label, randomized clinical study was performed on 20 patients to investigate the safety and efficacy of VesCell therapy at 1 and 3 months of follow-up. The long-term (2 years) efficacy of the therapy was also evaluated.

No side effects of VesCell therapy were found. During the 3 month follow-up in the control group, one death occurred and six major amputations were performed; in the treated group, there were no deaths or major amputations. The difference of limb loss is significant between the two groups. At 2-year follow-up in the control group, two deaths and six major amputations occurred; in the treated group, there were three major amputations. At 3-month follow-up, the change in hemodynamic parameters showed a significant increase in the treated group over the control group; in the treated group, further improvement was detected at 2 years. As the result of the VesCell treatment, change in pain score, wound healing and walking ability test showed an improvement compared with the control group; at 2 years, incremental improvement was observed.

Peripheral blood-derived, in vitro-expanded autologous angiogenic precursor therapy appears to be a safe, promising and effective adjuvant therapy for PAD patients.

Wednesday, November 6, 2013

Here is one example drawn from many ongoing lines of research aimed at the development of stem cell treatments for a broad variety of injuries. Enhanced regeneration will be a strong theme in the new medical technologies of the next two decades:

A stem cell therapy previously shown to reduce inflammation in the critical time window after traumatic brain injury also promotes lasting cognitive improvement, according to preclinical research. Cellular damage in the brain after traumatic injury can cause severe, ongoing neurological impairment and inflammation. Few pharmaceutical options exist to treat the problem. About half of patients with severe head injuries need surgery to remove or repair ruptured blood vessels or bruised brain tissue.

A stem cell treatment known as multipotent adult progenitor cell (MAPC) therapy has been found to reduce inflammation in mice immediately after traumatic brain injury, but no one had been able to gauge its usefulness over time. [Researchers here] injected two groups of brain-injured mice with MAPCs two hours after the mice were injured and again 24 hours later. One group received a dose of 2 million cells per kilogram and the other a dose five times stronger.

After four months, the mice receiving the stronger dose not only continued to have less inflammation - they also made significant gains in cognitive function. A laboratory examination of the rodents' brains confirmed that those receiving the higher dose of MAPCs had better brain function than those receiving the lower dose. "Based on our data, we saw improved spatial learning, improved motor deficits and fewer active antibodies in the mice that were given the stronger concentration of MAPCs."

Thursday, November 7, 2013

Researchers here use dead people as their initial study group, an approach which has some advantages. One could imagine setting up a very large and cost-effective study based on introducing a simple skin sample procedure into standard end of life medical care, and then matching those results to genetic data drawn from existing large studies of old people. Researchers would only have to match age and gender between the deceased and living individuals from another body of study results in order to start producing value.

To investigate longevity-associated genes based on a comparison between dead and surviving populations, a total of 71 cases of dead individuals were treated as the death group, and healthy volunteers who were matched with the dead individuals based on sex and age were recruited as the survival group. Alleles of 13 CODIS short tandem repeats loci were determined. The cross-validation was performed based on differences between the two groups in both frequency values and ages.

The frequency value of the D18S51-17 alleles was significantly higher in the dead group than in the survival group, and the frequency value of the D2S1338-18 allele was statistically lower in the dead group than in the survival group. The mean age of the subjects with the D2S1338-18 allele was also significantly higher than that of the subjects without D2S1338-18, and no significant difference was observed with respect to the other three alleles. The results suggest that D2S1338-18 is associated with longevity.

Thursday, November 7, 2013

There is much debate over the origins and causes of the well-known decline in regenerative capability with age, characterized by reduced numbers of stem cells and reduced stem cell activity in tissue maintenance, among other mechanisms. A mainstream position is that this is an evolved response to damage, lengthening life by reducing the risk of cancer that might result from damaged stem cells, but at the cost of increasing frailty. There are other views, of course:

There is a viewpoint that suppression of the proliferative capacity of cells and impairment of the regeneration of tissues and organs in aging are a consequence of specially arisen during evolution mechanisms that reduce the risk of malignant transformation and, thus, protect against cancer. We believe that the restriction of cell proliferation in an aging multicellular organism is not a consequence of implementing a special program of aging.

Apparently, such a program does not exist at all and aging is only a "byproduct" of the program of development, implementation of which in higher organisms suggests the need for the emergence of cell populations with very low or even zero proliferative activity, which determines the limited capacity of relevant organs and tissues to regenerate. At the same time, it is the presence of highly differentiated cell populations, barely able or completely unable to reproduce (neurons, cardiomyocytes, hepatocytes), that ensures the normal functioning of the higher animals and humans.

Apparently, the impairment of regulatory processes, realized at the neurohumoral level, still plays the main role in the mechanisms of aging of multicellular organisms, not just the accumulation of macromolecular defects in individual cells. It seems that the quality of the cells themselves does not worsen with age as much as reliability of the organism control over cells, organs and tissues, which leads to an increase in the probability of death.

Friday, November 8, 2013

Here is a better set of publicity materials describing recent research in which scientists demonstrated enhanced regeneration in mice:

By reactivating a dormant gene called Lin28a, which is active in embryonic stem cells, researchers were able to regrow hair and repair cartilage, bone, skin and other soft tissues in a mouse model. Lin28, first discovered in worms, functions in all complex organisms. It is abundant in embryonic stem cells, expressed strongly during early embryo formation and has been used to reprogram skin cells into stem cells. It acts by binding to RNA and regulating how genes are translated into proteins. [The] researchers found that Lin28a also enhances the production of metabolic enzymes in mitochondria, the structures that produce energy for the cell. By revving up a cell's bioenergetics, they found, Lin28a helps generate the energy needed to stimulate and grow new tissues.

"Efforts to improve wound healing and tissue repair have mostly failed, but altering metabolism provides a new strategy which we hope will prove successful. Most people would naturally think that growth factors are the major players in wound healing, but we found that the core metabolism of cells is rate-limiting in terms of tissue repair. The enhanced metabolic rate we saw when we reactivated Lin28a is typical of embryos during their rapid growth phase."

"We already know that accumulated defects in mitochondrial metabolism can lead to aging in many cells and tissues. We are showing the converse - that enhancement of mitochondrial metabolism can boost tissue repair and regeneration, recapturing the remarkable repair capacity of juvenile animals." Further experiments showed that bypassing Lin28a and directly activating mitochondrial metabolism with a small-molecule compound also had the effect of enhancing wound healing. This suggests the possibility of inducing regeneration and promoting tissue repair with drugs.

Friday, November 8, 2013

One branch of tissue engineering focuses on the creation of scaffolds that mimic enough of the features of the extracellular matrix or local cellular environment to encourage regrowth. With suitable chemical signals a scaffold can guide the normal processes of regeneration to fill out its structure with suitable tissue, as demonstrated here for bone regrowth:

Researchers [have] created a bio patch to regenerate missing or damaged bone by putting DNA into a nano-sized particle that delivers bone-producing instructions directly into cells. The team started with a collagen scaffold. The researchers then loaded the bio patch with synthetically created plasmids, each of which is outfitted with the genetic instructions for producing bone. They then inserted the scaffold on to a 5-millimeter by 2-millimeter missing area of skull in test animals. Four weeks later, the team compared the bio patch's effectiveness to inserting a scaffold with no plasmids or taking no action at all.

The plasmid-seeded bio patch grew 44-times more bone and soft tissue in the affected area than with the scaffold alone, and was 14-fold higher than the affected area with no manipulation. Aerial and cross-sectional scans showed the plasmid-encoded scaffolds had spurred enough new bone growth to nearly close the wound area, the researchers report.

The plasmid does its work by entering bone cells already in the body - usually those located right around the damaged area that wander over to the scaffold. The team used a polymer to shrink the particle's size and to give the plasmid the positive electrical charge that would make it easier for the resident bone cells to take them in. "The delivery mechanism is the scaffold loaded with the plasmid. When cells migrate into the scaffold, they meet with the plasmid, they take up the plasmid, and they get the encoding to start producing PDGF-B, which enhances bone regeneration."


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