Exploring Transdifferentiation in the Pancreas

Cellular differentiation is the process by which stem cells and other progenitor cells divide to form specialized cell populations - of which there are a great many different types in the body. Much of stem cell research to date has been focused on finding out how to first obtain stem cells and then differentiate them to form specific desired types of specialized cell. This has been a challenging process, but advances in biotechnology are making it easier and less costly as the years go by.

Cells are programmable machinery; it seems to be the case that any given type of cell holds the potential to produce any other type of cell, if researchers just understood the right chemical and genetic cues and instructions. Thus in addition to the work of reverting specialized cells into stem cells, and differentiating stem cells into desired specialized cells, there is also the possibility of achieving transdifferentiation - converting one type of cell directly into another without passing through a stem cell stage.

In recently reported research, researchers are making inroads in converting various types of cell in the pancreas - which offers the possibility of a fairly direct path towards providing new beta cells to diabetes patients:

While the current standard of treatment for diabetes - insulin therapy - helps patients maintain sugar levels, it isn't perfect, and many patients remain at high risk of developing a variety of medical complications. Replenishing lost beta cells could serve as a more permanent solution, both for those who have lost such cells due to an immune assault (Type 1 diabetes) and those who acquire diabetes later in life due to insulin resistance (Type 2).

"Our work shows that beta cells and related endocrine cells can easily be converted into each other," said study co-author Dr. Anil Bhushan, an associate professor of medicine in the endocrinology division at the David Geffen School of Medicine at UCLA and in the UCLA Department of Molecular, Cell and Developmental Biology.

It had long been assumed that the identity of cells was "locked" into place and that they could not be switched into other cell types. But recent studies have shown that some types of cells can be coaxed into changing into others - findings that have intensified interest in understanding the mechanisms that maintain beta cell identity.

This is as much the age of controlling cells as it is the age of biotechnology. Researchers are presently building the foundation for complete control over the component machinery of the human body. Along the way to that goal lies the production of ever more effective general repair kits for all forms of damage that originate in missing or damaged cell populations - including one portion of aging itself.

Calorie Restriction Increases Mitochondrial Biogenesis

Mitochondria are the cell's roving herd of bacteria-like power plants, and the damage they suffer in the course of their operation is strongly implicated as a contributing cause of aging. Here researchers show that calorie restriction appears to boost the rate at which new mitochondria are spawned: "mice with increased respiratory rates and reduced energetic conversion efficiency due to spontaneously uncoupled mitochondria lived longer than their counterparts. Indeed, different uncoupling strategies were able to extend lifespan in models ranging from yeast to mammals. ... uncoupling could be an approach to promote lifespan extension due to its ability to prevent the formation of reactive oxygen species (ROS). Indeed, mild mitochondrial uncoupling is a highly effective intervention to prevent the formation of ROS ... CR also increases the number of functional respiratory units (mitochondrial biogenesis) [and researchers] demonstrated that mitochondrial biogenesis was essential for many beneficial effects of dietary limitation in mice. ... We recently demonstrated that murine lifespan can be extended by low doses of the mitochondrial uncoupler 2,4-dinitrophenol (DNP) in a manner accompanied by weight loss, lower serological levels of glucose, insulin and triglycerides as well as a strong decrease in biomarkers of oxidative damage and tissue ROS release. Similar effects have been repeatedly reported using CR diets ... Based on the similarities between these two interventions, we hypothesized that DNP treatment could also lead to enhanced mitochondrial biogenesis. In this manuscript, we measured the effects of DNP treatment and CR on mitochondrial biogenesis and associated pathways. We observed that both DNP and CR increase mitochondrial biogenesis, [confirming] that signaling events in both treatments converge."

Link: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0018433

A Commentary on Metformin Studies

A fairly long open access commentary on metformin and its effects on slowing aging in mice: "A recent study [may] certainly establish that metformin should be defined as geroprotective or gerosuppressant rather than bona fide [calorie restriction mimetic]. Long-living female mice from the outbred SHR strain were fed metformin in drinking water beginning at 3, 9 or 15 months of age and they were then analyzed for reproductive aging, mean and maximal lifespan and incidence of malignant tumors ... In female SHR mice, [researchers] now confirm that metformin treatment, if started early in life, notably increases by 21% the mean lifespan of tumor-free mice. In contrast, if started late in life, metformin treatment appears to significantly reduce (by 13%) the mean lifespan of tumor-free mice. ... It is perhaps relevant to note that, if started early in life, metformin treatment decreased the risk of death compared to the control group whereas similar treatment with metformin at older ages did not affect the relative risk of death in SHR female mice. Metformin's ability to increase the mean lifespan of tumor-free mice while simultaneously decreasing the risk of death in an age-related manner somewhat recapitulate metformin's ability to reduce cancer incidence among type 2 diabetic individuals."

Link: http://www.impactaging.com/papers/v3/n4/full/100316.html

Potential Early Documentation Projects for the Vegas Group

UPDATE 05/21/2011: The Vegas Group initiative has been renamed to Open Cures, with a new website and a new mailing list. Please do drop by and take a look at what we're working on.

What is the Vegas Group initiative setting out to achieve, in a nutshell? I'm still working on that short explanation, but here is one attempt at it. Thanks to the present regulatory situation in the US - where aging is not recognized as a disease, and therefore no therapy for aging can be legally developed - there are any number of potentially useful biotechnologies presently languishing without further development. These are methods and techniques shown to extend life in mice or repair and reverse specific biochemical aspects of aging, but for which there is no further funding for clinical development. Nothing may be happening for these technologies in the US, but there are active biotechnology and medical development communities in other parts of the world who are not so encumbered by local regulation: many of the developed Asia-Pacific countries, for example. What the Vegas Group initiative ultimately aims to do is build a bridge between these undeveloped technologies and the developers who could bring them into the clinic for human use.

How will that bridge be built? I believe that the growing garage biotechnology and DIYbio communities will play a pivotal role in the US - validating, documenting, and lowering the cost for overseas ventures to pick up and further develop longevity therapies. From my perspective then, the very earliest actions for the first Vegas Group volunteers involve building the foundations for a repository of how-to documentation: guides that clearly explain how the garage biotechnology community could validate and further develop the best and latest techniques in longevity science.

At the outset this is less a matter of writing documents and more a matter of figuring out a sustainable process and organizational structure - the business of freelance writing is much akin to herding cats even when money is involved.

So I can envisage a guiding council of advisors putting together a plan for the hierarchy of topics they would like to see in the Vegas Group codex, from basic methods in biotechnology through to best attempt reverse engineering of things we know to be possible and that have been published: such as Cuervo's work on restoring youthful levels of autophagy, or protofection to replace mitochondrial DNA. The end result of that process might look something like a distillation of Fight Aging! mixed with the very elegant materials produced by the Science for Life Extension Foundation.

Codex project volunteers would then run an ongoing process of hiring post-graduates and interested researchers to write, and passing the results to starving authors who improve the output to a quality suitable for the open biotechnology community. There would of course be some back and forth between the post-graduates and the starving authors in order to reduce the inevitable translation errors, but I see this as a viable way to produce a body of knowledge that is sufficiently good to begin with - not perfect, not even necessarily very good, but sufficient.

I mentioned rejuvenation of autophagy above as one of the possible projects for documentation, and at present, the Vegas Group discussion list is focused on mitochondrial protofection - and we could certainly use another life science volunteer or two to help lay out the skeleton for full documentation, or work on one of the other potential projects. If you're interested, come on over and join in.

Some of the other possible projects that have been mentioned or came to mind include the following:

1) LysoSENS

LysoSENS isn't an established methodology, but it is an ongoing research program that aims to find bacterial enzymes capable of breaking down harmful aggregates that build up with age. This is a matter of synthesizing the chemicals to be broken down, digging up some dirt from likely locations, culturing bacteria, and matching them up against your unwanted chemicals to see if you have a hit. This seems like an excellent project for DIYbio enthusiasts - someone is going to find an existing bacterial strain containing enzymes that can be adapted to safely destroy lipofuscin in human cells, and there's no reason that person has to be working in an institutional establishment.

2) Manufacturing Targeted Mitochondrial Antioxidants

A number of research groups have been publishing in recent years on ingested targeted mitochondrial antioxidants that appear to slow aging in mice. It seems a viable sophisticated garage or shared lab-space chemistry experiment to replicate their published work, and then a biotech experiment to validate your synthesized antioxidants in cell cultures.

3) Upregulation of PEPK-C

This is a manipulation of gene expression show to increase longevity in mice. As gene engineering goes, this is about as straightforward as it is going to get - which is to say still a fair hurdle for the garage biotech community to work towards - a single gene altered, and an impressive result. Managing to document the process sufficiently well to recreate this intervention in cell cultures would be, I think, a real showpiece for a laboratory cooperative.

Now all of these items, when carried out as projects, can be expected to sit atop a pyramid of supporting techniques and documentation, some of which will be common to many different projects. Producing that material sufficiently well will, I think, help in the growth of the garage biotechnology and DIYbio communities. Documentation is key for newcomers and recruitment, and you can never have too much of it.

Centenarians and Oxidative Stress

A study of markers of oxidative stress in centenarians: "Human longevity is a complex phenotype that is determined by environment, genetics, and chance. Understanding the mechanisms by which aging leads to longevity, particularly healthy longevity would be of enormous benefit to our aging population. Unfortunately, most research on human aging has focused on phenomenological description of age-related diseases, and much less is known about the mechanisms of aging itself. Among the most promising theories about how and why we age is the Free Radical Theory, initially proposed by Denham Harman in 1956. Harman proposed that oxygen radicals produced during aerobic respiration induce oxidative damage in DNA, cells, tissues, and organisms that lead to aging and death. ... Harman hypothesized, based on observations of enzymatic redox chemistry, that oxygen radical generation occurs in vivo and that mechanisms exist to protect against such damage. Mitochondria were later found to be a principal source of these oxygen radicals ... Okinawa has among the world's longest-lived populations but oxidative stress in this population has not been well characterized. ... The low plasma level of [oxidized lipids] in Okinawan centenarians, compared to younger controls, argues for protection against oxidative stress in the centenarian population and is consistent with the predictions of the Free Radical Theory of Aging."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068305/

Thoughts on Protein Aggregation and Aging

An open access paper: "Aging is the single most important risk factor in human disease in developed countries but when it comes to research on prevention or cures, aging is seldom taken into account. Nevertheless if aging is a significant contributor to age-related conditions, we would hope that an understanding of aging mechanisms could prompt the design of rational therapies. Moreover, if aging causes multiple diseases then it is reasonable to think that pharmacological agents that slow aging could be also effective in preventing or slowing a wide spectrum of diseases. ... Protein aggregation is a hallmark of aging and several age-related pathologies, collectively known as conformational diseases (CD). This similarity strongly suggests a crosstalk between aging and disease. Although it is not clear how protein aggregation occurs, dramatic alterations in the balance of protein synthesis, protein folding and protein degradation (together representing 'protein homeostasis') are likely to play important roles in this process. As a consequence, modified proteins tend to accumulate into soluble oligomers and insoluble aggregates that may actively influence cell function. Neurodegenerative diseases are arguably the best studied CD and the aberrant aggregation of several insoluble molecules [has] long been associated with the development of these pathologies. ... The general picture that that has emerged is that conformationally-altered proteins escape the surveillance of repair and degradation systems, form aggregates, and this process contributes to aging; aging could be therefore a manifestation of a loss in protein homeostasis. This then prompts the question: to what extent could chemical modulation of protein aggregation alter the rate of aging? Furthermore, would such an intervention influence disease pathology? In a recent publication, we addressed this issue by identifying small molecules able to slow protein aggregation in the C. elegans model. We were then able to directly assess the degree to which protein aggregation influences normal aging rates."

Link: http://www.impactaging.com/papers/v3/n4/full/100317.html

SENS Foundation is Hiring for the LysoSENS Project

LysoSENS is the SENS Foundation initiative to build a platform for medical bioremediation capable of breaking down the damaging byproducts of metabolism that build up in old cells and degrade their ability to recycle garbage. The short of is that we know that out there somewhere are bacteria that can eat these compounds, such as the lipofuscin that contributes to many age-related conditions. There is no buildup of prominent components of lipofuscin in graveyards, for example - so something is consuming it. That bacterial something will be armed with enzymes, biological knifes and saws that might be turned into a therapy to destroy lipofuscin if identified and introduced into the human body.

You might recall that the early LysoSENS volunteers ran a contest for soil samples from obscure locations back in 2006, the better to get a good mix of bacterial origins for analysis.

The search for bacterial enzymes that can safely attack lipofuscin in the body presently gets the lion's share of research funding at the SENS Foundation, and, appropriately, they are hiring in the Bay Area, California:

SENS Foundation is hiring for our research center located in Mountain View, CA. We are seeking a team lead for our LysoSENS project, which contains both intra- and extramural components.

Qualified candidates will have an MS, or Ph.D. in the chemical/biological sciences and at least 5 years of work experience that must include prior project management experience. Duties will include the preparation of grant proposals, internal and external progress reports, individual and collaborative publication. The project lead will develop, interpret and implement standards, procedures, and protocols for the LysoSENS research program and may collaborate on determining strategic directions in the research program. Candidates must have a proven ability to lead other professionals.

Seems like the community has come a long way from the turn of the century, doesn't it? Raising enough money for formal hires is always a big organizational milestone, and congratulations are due to the SENS Foundation staff and volunteers who have worked hard to get to this point.

A German Interview with Aubrey de Grey

A translated interview with SENS Foundation co-founder Aubrey de Grey: "I have identified seven types of damage [that cause aging]. In five cases we can repair the damage in my opinion, by replacing irreversibly damaged cells by stem cells, or when garbage accumulates, we will remove [it]. In two cases, we need to engage in gene therapy, for example, through new DNA counteract mutations in the mitochondria. ... We should intervene as little as possible in the metabolic pathways themselves. This is too complicated, we do not know enough yet about it. I prefer the regenerative approach, the repair and maintenance. It is [sufficient] to repair the damage after it occurred. In this way, we do not [need to] understand all the molecular details and how they come about. But we have to intervene before the problems get out of control. ... A simple example is the stiffening of the extracellular matrix - this is the fibrous scaffold between cells. The stiffening occurs because certain molecules network with each other. There is a principal [agent], a molecule called [glucosepane], which has the largest share of the networking and reinforcement. We must find a way to break up about two-thirds of them again. If we break these reinforcements, it would eliminate about half of the damage. ... I think the probability is about 50 percent, that all of these therapies in 25 years actually show the desired results. The average life span might then be [increased by] about 30 years."

Link: http://translate.google.com/translate?u=http://www.heise.de/tr/artikel/Muell-entfernen-und-Zellen-erneuern-1230091.html

A Stable, Self-Renewing Supply of Neural Stem Cells

News from the field of stem cell research: "researchers [report] a game-changing advance in stem cell science: the creation of long-term, self-renewing, primitive neural precursor cells from human embryonic stem cells (hESCs) that can be directed to become many types of neuron without increased risk of tumor formation. ... It means we can generate stable, renewable neural stem cells or downstream products quickly, in great quantities and in a clinical grade - millions in less than a week - that can be used for clinical trials and, eventually, for clinical treatments. Until now, that has not been possible. ... Human embryonic stem cells hold great promise in regenerative medicine due to their ability to become any kind of cell needed to repair and restore damaged tissues. But the potential of hESCs has been constrained by a number of practical problems, not least among them the difficulty of growing sufficient quantities of stable, usable cells and the risk that some of these cells might form tumors. ... [Researchers] added small molecules in a chemically defined culture condition that induces hESCs to become primitive neural precursor cells, but then halts the further differentiation process. ... And because it doesn't use any gene transfer technologies or exogenous cell products, there's minimal risk of introducing mutations or outside contamination."

Link: http://www.sciencedaily.com/releases/2011/04/110425153554.htm

Ageless Animals, the Jellyfish Edition

The jellyfish Turritopsis nutricula is one of the few species whose members might be considered immortal, based on what is presently known of its biology. The life course of this jellyfish is very far removed from that of humans; even more so than that of the lobster, another marine species that might be immortal - though there researchers know far too little to make the call one way or another.

Immortality in the sea lasts right up until something larger eats you, of course. The form of agelessness enjoyed by Turritopsis nutricula appears to be an adaptation to periods of starvation: it can retreat to earlier stages of its life cycle, and in the process its cells alter their character in an usual way:

It starts out as a larva that eventually sinks to the bottom of the ocean and attaches to a sturdy substrate and continues development into a polyp that resembles a sea plant. The polyp then matures to become a free-floating medusa, what we commonly recognize as jellyfish resembling an upside down saucer with tentacles. ... However, during times of stress like a shortage of food, Turritopsis responds by beginning to reverse the process before eventually becoming a polyp again. From this point then, it can again develop into a sexually mature medusa when conditions become more favorable. Theoretically, it can repeat this process indefinitely as its cells undergo a process called transdifferentiation, a rare biological process whereby any non-stem cell can become a different cell entirely. It is still unclear whether only specific cells can only become other specific cells or if any cell in Turritopsis has the potential to become any other cell.

Unlike other long-lived or apparently ageless animals, the principle biological process of interest here is transdifferentiation - being able to produce any type of cell from any other type of cell without having to go through intermediary stages such as the generation and differentiation of stem cells. Modern stem cell medicine depends on techniques for controlling and changing the state of cells - to be able to engineer pluripotent cells from ordinary cells, for example, or produce unlimited numbers of a particular type of cell for research, transplantation, and tissue engineering.

When it comes to transdifferentiation, the hope is that we will eventually be able to learn how creatures like Turritopsis skip the stem cell step and go directly from one cell type to another.

Reliable control over that process for human cells would greatly improve the state of the art in the field of regenerative medicine - and in fact research groups in the space are headed in that direction already.

A Prize for Brain Preservation

An article on uploading and preservation of the brain: "Ken Hayworth, a cognitive neuroscientist, has the difficult task of juggling two hats on his head, or should we say brain. With the first one, he and his colleagues at Harvard University are working on enhancing the power of an instrument that automates the mapping of brain tissues to answer a fundamental question that still faces neuroscience: How are the 100 billion neurons wired in the brain and how they know what function to perform? If you think that's difficult to digest, ponder over the bigger objective that Hayworth has on his mind - not as a Harvard post-doctoral student but as the president of The Brain Preservation Foundation: 'My personal long-term goal is to upload a human mind into a machine. I think it's the larger conclusion of neuroscience. This means, I can put a specific mind into a robot.' ... In the next five years, he is confident of seeing an entire human brain preserved chemically and embedded in plastic. This brain, he explains, can eventually be automatically cut into ultra-thin strips and scanned at very fast rates and high resolutions. With these maps, neuroscientists can figure out how the neurons are wired and how they create memories, skills and personalities. ... Hayworth is convinced that once the scientific and medical community understands that brain preservation techniques (cryonics or plastination) are successful in preserving 'high-quality brains', people will come around the idea eventually. He admits, though, that legal problems will remain (currently, one can't preserve a brain before a person is legally dead). Regardless, he has announced a prize of $106,000 to anyone who can preserve a large mammalian brain such that all the synaptic connections are intact using today's technology. Two major laboratories are competing for the prize, says Hayworth, adding: 'We have to image that brain and verify that claim ourselves. For this, we will need the help of labs and more money. Currently, I have zero money in the bank.' But he is optimistic that "this message will resonate. 'I have been talking to some very wealthy people (who do not want to disclose their identities currently). They believe in this and want to see credibility. Once people start seeing results in brain preservation, there will be more converts.'"

Link: http://www.business-standard.com/india/news/resurrectingbrain-forbetter-afterlife/431904/

A Novel Method for Potentially Restoring Sight

An interesting technology demonstration noted at the Technology Review:: "Viruses can deliver light-sensitive proteins to specific cells in the retinas of blind mice, allowing rudimentary vision, according to new research. ... The new light-sensitive proteins were active for the length of the study, about 10 months, suggesting the treatment would work long-term. In addition, the therapy appeared safe; the proteins, which were derived from algae, remained within the eye, and they did not trigger inflammation. ... In my opinion, the biggest step forward in this paper is the use of viral delivery techniques, the same delivery techniques that would have to be used should the technique move on into human treatment. ... Recent gene-therapy studies, which used similar viruses to deliver different proteins, have shown preliminary success in treating a rare genetic form of blindness in patients.But the current approach could be applied to a much broader group of people because it could restore light-sensitivity to the retina regardless of the cause of degeneration. .. [Researchers] used a specially designed virus to deliver numerous copies of the gene that makes a protein called channelrhodopsin to the eye. The protein forms a channel that sits on a cell's membrane and opens when exposed to light. Positively charged ions then rush into the cell, triggering an electrical message that is transferred to other cells in the retina. The gene was modified so that it became active only in specific retinal cells called bipolar cells. In a healthy eye, these cells are activated when adjacent photoreceptor cells detect light. The researchers hope that making the bipolar cells directly responsive to light in an eye stricken by retinal degenerative diseases, such as retinitis pigmentosa or macular degeneration, could enable the altered cells to replace photoreceptors that have died off. "

Link: http://www.technologyreview.com/biomedicine/37467/

An Update on Early Vegas Group Discussions

UPDATE 05/21/2011: The Vegas Group initiative has been renamed to Open Cures, with a new website and a new mailing list. Please do drop by and take a look at what we're working on.

The Vegas Group is a recently launched initiative that aims to speed up translation of existing longevity-enhancing biotechnologies from the laboratory to human therapies. There is little incentive for commercial entities to work on these technologies in the US because the FDA does not recognize aging as a disease, and will therefore never approve a therapy for aging. But if these technologies, currently documented only in the prickly, dense scientific literature, can be brought into the open biotechnology arena, explained, and made accessible, they will be picked up by semi-professionals, developers, and commercial ventures in less restricted parts of the world.

Protofection, for example, is a technique for introducing replacement mitochondrial DNA into all the cells of the body - a way to repair the contribution to aging caused by accumulated defects in mitochondrial DNA. This was demonstrated in mice back in 2005, but the research group responsible has since been working on the commercialization of other aspects of this work. Protofection as a way to repair a fundamental part of the damage of aging will likely languish undeveloped in the US for years to come under the present regulatory regime.

Yet this is an era of medical tourism and near-free transmission of information - if we take currently esoteric but largely proven biotechnology and produce good, free, open instruction manuals, then this knowledge and its application will spread. We can all help to take advantage of the information age and biotechnology revolution that we are living through, and we can start to do this by engaging and persuading the growing open biotechnology and DIYbio community to pay more attention to longevity science.

The Vegas Group is presently a discussion list of a few active volunteers and a small crowd of interested folk. We are looking at the nuts and bolts of organization, focused on a proof of concept documentation project: take mitochondrial protofection and document it sufficiently well to make it accessible to the DIYbio community of enthusiasts and moonlighting biotech professionals who are building open-access devices and establishing shared laboratories. Along the way this means finding freelance life science writers, evangelizing the concept, proofing copy, making diagrams and layouts, and putting up a website - amongst other line items.

Here's a diagram of the early efforts that lie ahead, as I see them:

The Vegas Group, early work

If you take a look at the discussion list, you'll see some of the following threads underway:

We are looking for more life science and DIYbio volunteers, writers and editors, folk with connections that will help move things along, people with an understanding of the legalities of reverse engineering and intellectual property, and web developers who can help with the forthcoming website. Amongst others - if you think you can help make the Vegas Group a reality, then you probably can. So join the list and help!

An Update on GADD45 Research

A Russian group has been investigating the effects of GADD45 on life span in flies, which I noted last year. Here is a post from one of the researchers outlining the present state of research: "As I wrote earlier, we were able to do while his most important discovery - show that activation of the GADD45 gene by genetic methods leads to longer life of fruit flies up to 80%. Our research also showed that in old age animals are not able to activate their own GADD45, which leads to deterioration of stress resistance and aging (article forthcoming). Transcription factor FOXO, which plays a role in anti-aging generally known (it provides the ability to handle stress, suppressed IGF-1 signaling), causes DNA repair through GADD45. GADD45 is controlled by another gene of longevity - SIRT1. We are now looking for investors to look for substances capable of restoring expression of the gene GADD45 in older individuals to the level inherent in the young. ... Ability of cells to maintain a high level of inducible GADD45 with age could be an excellent marker for longevity of the individual. To prove this, it is necessary to conduct a screening study among different age groups and centenarians." We will see a lot of this in the years ahead: the financial success achieved by researchers in the field of sirtuins, despite a lack of practical results, will attract a great many research groups to try to slow aging through metabolic manipulation. Unfortunately this is the long, hard path to a poor end goal: as a strategy for tackling aging it is a bad choice when compared to the Strategies for Engineered Negligible Senescence.

Link: http://translate.google.com/translate?hl=en&sl=auto&tl=en&u=http://aging-genes.livejournal.com/41993.html

Horses Obtain Better Stem Cell Medicine than Humans

Thanks to the present restrictive state of medical regulation, horses have been getting better treatments than people for a few years now: "Take the case of SandSunSea, a 3-year-old colt by the late Pleasant Tap, bought for about $90,000 at a yearling sale in Canada. His trainer, Roger Attfield, elected not to try racing him at age 2. 'He was a horse that I gave time to because he was a big growing boy,' Attfield said. At 3, the colt was coming along nicely but then suffered a torn flexor tendon in his right front leg. 'He was just about ready to run when this happened.' ... Such an injury normally would take nine months to a year to recover from, and the horse might re-injure himself once he finally goes back into training. Attfield turned to stem-cell therapy. He shipped the horse from Payson Park training center in Florida to Woodford Equine Hospital in Versailles, where Dr. Joe Yocum removed a bit of the horse's tissue one morning in March. At the MediVet labs, which opened earlier this year in Nicholasville, 1.2 billion stem cells were pulled from 30 grams of fat taken from SandSunSea. ... That afternoon some of the cells were injected back into SandSunSea's leg. (The rest are stored frozen at the MediVet lab in case more treatments are needed one day.) The results surprised even Yocum, who is a partner in MediVet America, one of a handful of companies around the world that offer stem-cell therapy to veterinarians. 'I went back after two weeks and scanned him and could hardly even find the lesion. He looks perfect, really.' Normally it might take four months for the lesion to gradually disappear, he said. 'This thing was practically obliterated in two weeks.'"

Link: http://www.kentucky.com/2011/04/23/1716479/stem-cell-therapy-proves-successful.html

Older Parents, Probably Not So Good

One of the predictions of the reliability theory of aging and longevity is that we are all born damaged. Reliability theory evolved from the theories used to predict failure in mechanical systems; as such, it is a less an attempt to explain the roots of aging and more an attempt to frame an understanding of the way in which accumulating damage at the most fundamental levels of our biochemistry produces the observed patterns of aging.

The models of reliability theory only match up with reality if we assume that life starts with a certain level of preexisting biological damage, and that damage goes some way to determining later health and life expectancy. What happens in early life matters a great deal, it seems. This is why we are interested in such topics as the potential effects of solar radiation on the unborn, and the degree to which historical increases in longevity can be explained by a lower childhood burden of chronic disease.

I noticed another interesting data point today in an open access paper: a possible marker for the biological cost of being born to an older mother - something that we know bears an increased risk of health issues.

Parental ages and levels of DNA methylation in the newborn are correlated:

Changes in DNA methylation patterns with age frequently have been observed and implicated in the normal aging process and its associated increasing risk of disease, particularly cancer. Additionally, the offspring of older parents are at significantly increased risk of cancer, diabetes, and neurodevelopmental disorders. Only a proportion of these increased risks among the children of older parents can be attributed to nondisjunction and chromosomal rearrangements.

We found that methylation levels [associated with] 142 genes were significantly correlated with maternal age. A weaker correlation was observed with paternal age. ... Genes associated with [cancer] are significantly over-represented among the genes correlated with maternal age, and this suggests a link to known increased risks of cancer among the children of older parents. Similarly, gene functions related to neurodevelopment and neuroregulation are over-represented among the strongly correlated genes, and this may have relevance to the increasing risk of neurodevelopmental and psychiatric disorders in offspring as parental ages increase.

Biotechnology will be a great leveler of opportunity, a grand remover of adversity, offering the chance to repair deleterious consequences of ancestry, birth, and other biological circumstances beyond our control. Systematic alteration of DNA methylation will likely be a commonplace medical technology of the late 2020s, for example. This and many other potentially beneficial manipulations of DNA are almost within reach of the most advanced research groups today - and the biotechnologies of ten or fifteen years from today will far cheaper and more capable than the best machinery now available.

The CRONA Study

A look at current research on the definite health and potential longevity benefits of calorie restriction in humans: "Animals who consume fewer calories live longer and healthier lives. Now, a seminal study at the University of California, San Francisco (UCSF) is testing whether the same is true for extreme dieters. The calorie restriction study centers on two primary questions: What allows people to live in a manner many consider food deprived? And does it slow down aging? Called CRONA (Caloric Restriction with Optimal Nutrition and Aging Study), the investigation is probing the biological processes affected by extremely low caloric intake, including the impact on telomeres - tiny pieces of DNA that protect cell chromosomes. Short telomeres have been linked to a host of health problems including diabetes, heart disease and premature death. The UCSF study is the first to broadly examine the psychological profile of successful extreme dieters, gauging how their cognitive sharpness, impulse control, stress and personality differ from normal eaters and overeaters. ... Testing and data collection will continue through summer. The scientists are still recruiting control subjects who are either obese or 'free eaters' - not restricting food intake but not overweight. Interested parties can email cronastudy@gmail.com. ... We need information about what it takes to change your eating pattern for a long time. There are so many diets out there - people lose weight for six months, then regain it. We need to study what it is about the calorie restrictors that makes them able to do this for years and years." The new information on the biological response to calorie restriction is, I think, much more valuable than yet another study on willpower in humans.

Link: http://www.ucsf.edu/news/2011/04/9740/extreme-dieting-does-it-lead-longer-lives

A Look at Garage Biotechnology

Small scale efforts by a widespread people outside the academic and industry communities, and open and largely free access to plans and data are the future of biotechnology. It is a data-driven field, and will ultimately look just like the open source software community does today: "Following in the footsteps of revolutionaries like Steve Jobs and Steve Wozniak, who built the first Apple computer in Jobs's garage, and Sergey Brin and Larry Page, who invented Google in a friend's garage, biohackers are attempting bold feats of genetic engineering, drug development, and biotech research in makeshift home laboratories. ... For a few hundred dollars, anyone can send some spit to a sequencing company and receive a complete DNA scan, and then use free software to analyze the results. Custom-made DNA can be mail-ordered off websites, and affordable biotech gear is available on Craigslist and eBay. ... biohackers, like the open-source programmers and software hackers who came before, are united by a profound idealism. They believe in the power of individuals as opposed to corporate interests, in the wisdom of crowds as opposed to the single-mindedness of experts, and in the incentive to do good for the world as opposed to the need to turn a profit. Suspicious of scientific elitism and inspired by the success of open-source computing, the bio DIYers believe that individuals have a fundamental right to biological information, that spreading the tools of biotech to the masses will accelerate the pace of progress, and that the fruits of the biosciences should be delivered into the hands of the people who need them the most."

Link: http://www.technologyreview.com/biomedicine/37444/

The Importance of Improvement

It is unfortunate and noteworthy that the loudest institutional voices in Western culture seem to have an aversion to human enhancement. It is the ideal of equality run rampant, heading for its inevitable Harrison Bergeron endpoint - equality by leveling down to the lowest and preventing new heights from being achieved. Destruction is the only thing that politicians are really good at, sad to say, and egalitarianism, much like communism, is pretty in its abstract ideals but horrific when put into practice:

This rejection of human enhancement is in essence a rejection of the urge to improvement - and is thus one of a number of important hurdles standing in the way of widespread support for the development of rejuvenation biotechnology. Living longer than your parents did? That's an enhancement, and a great many talking heads would like to see laws written to prevent such technologies from ever seeing the light of day.

Yet the urge to improvement is everywhere else in evidence in our societies, as noted in this subtle injection of transhumanist ideals into the Discover Magazine website:

Just because I'm not ill [and] not injured, doesn't mean that I am, by default, as healthy as I could be. For some bizarre reason, we don't think about our bodies that way when it comes to health care and self improvement. We don't pursue excellent health the way we strive to be better in our hobbies and work. So, where did we get the idea that mediocre health is good enough?


But here's the interesting thing: neither the US nor the UK have regulations in place for prescription pharmaceuticals that are not therapeutic. Drugs that don't cure an illness but still have a beneficial effect have one of two paths: either find an illness they do cure or invent an illness that the drug seems to cure. An example of the latter is Viagra. I don't care what the DSM says, erectile dysfunction is not real illness. But Viagra works. It doesn't "cure" anything, but it sure makes a lot of people's lives better, which is [a] great thing. But it's a massive problem that there is no way for drugs that make our health better to find their way onto the market. And there in lies the problem. Save vaccines, modern medicine just doesn't know what to do with medicine that prevents disease or improves a person's life.


Prevent and improve. Those are the two words I'd argue are most underused in every other aspect of human health care. Why does self-improvement not include pharmaceuticals that make us smarter or stronger or happier? Because we've been convinced and told and reminded and scolded that taking a pill means something is wrong with you.

And so to aging and longevity. The bureaucrats of the FDA do not recognize aging as a disease, and so will not approve treatments for it. In a culture that is hostile to human enhancement, winning support for the reversal of aging will be that much harder. This is one of many ways in which freedom matters greatly in medical research. Under the systems of regulation in place in the largest markets of the world, researchers and commercial developers are far from free to turn proven science into commercial products, and far from free to convince their fellow countrymen to try something new.

We humans are the species that improves ourselves and creates value from our surroundings. That is our defining characteristic - and yet, paradoxically, so much time and effort in this day and age is devoted to sabotaging the engines of progress.

The Promise of Stem Cell Rejuvenation

Stem cell function, necessary to maintain tissue, declines with age. This most likely a part of the evolved balancing act between suppression of cancer and the need to keep tissues repaired and working - as you grow older, forms of molecular damage accumulate, increasing the risk of cancer resulting from the normal operations of cellular proliferation. That balance can already be shifted in mice in very beneficial ways, giving both less cancer and longer lives. While these are the early days yet, in our future lies a fusion of the fields of cancer research and stem cell science that will do the same for humans: "Adult stem cells exist in most mammalian organs and tissues and are indispensable for normal tissue homeostasis and repair. In most tissues, there is an age-related decline in stem cell functionality but not a depletion of stem cells. Such functional changes reflect deleterious effects of age on the genome, epigenome, and proteome, some of which arise cell autonomously and others of which are imposed by an age-related change in the local milieu or systemic environment. Notably, some of the changes, particularly epigenomic and proteomic, are potentially reversible, and both environmental and genetic interventions can result in the rejuvenation of aged stem cells. Such findings have profound implications for the stem cell-based therapy of age-related diseases."

Link: http://jcb.rupress.org/content/193/2/257.long

Time Waits for No One

A reminder: "Biological aging is the greatest health threat to humanity today. It causes more disease and suffering in the world than all infectious diseases (HIV, malaria, etc.) or any other cause (e.g. poverty, war, natural disaster, etc.). The inborn aging process causes cancer, heart disease, stroke, AD, joint pain, vision and hearing impairment, etc. The harms of senescence (even if we exercise and eat a healthy diet) are certain, severe and universal. The diseases of aging afflict both rich and poor, and developed and developing countries. And, unless the biological clocks we have inherited from our Darwinian past are modified, it is highly likely that all future generations of human beings that shall ever live on this planet will suffer one or more of the diseases of aging. In light of the unique health challenges facing the world's aging populations, the most important knowledge humans can acquire today is knowledge about the biology of aging: why do we, as a species, age at the rate we do? why does aging leave our bodies and minds susceptible to disease? And, most importantly, how can we retard or ameliorate the harmful effects of biological aging?"

Link: http://colinfarrelly.blogspot.com/2011/04/time-waits-for-no-one.html

Measuring the Benefits of Good Lifestyle Choices

For everyday, average, healthy people, leading a good lifestyle makes a sizable difference both to your life expectancy and your chances of suffering the common age-related diseases in years to come. Refrain from smoking, regular moderate exercise, and a diet low in calories that still provides optimal nutrition - thereby avoiding the build up of visceral fat that happens on the way towards obesity - and you will gain a greater benefit than any presently available medical technology can offer.

For example:

A study of more than 100,000 men and women over 14 years finds nonsmokers who followed recommendations for cancer prevention had a lower risk of death from cancer, cardiovascular disease, and all-causes.


The participants were scored on a range from 0 to 8 points to reflect adherence to the American Cancer Society (ACS) cancer prevention guidelines regarding body mass index, physical activity, diet, and alcohol consumption, with 8 points representing adherence to all of the recommendations simultaneously.

After 14 years, men and women with high compliance scores (7, 8) had a 42% lower risk of death compared to those with low scores (0-2). Risk of cardiovascular disease death were 48% lower among men and 58% lower among women, while the risk of cancer death was 30% lower in men and 24% lower in women.

The best we can presently do for our health and longevity in this grand age of biotechnology is still exactly the same as the best was for our grandparents, and that is disappointing. There is a gaping chasm between the exciting advances and technology demonstrations taking place in laboratories and what becomes available for commercialization - or rather what the regulators grudging permit to become available for commercialization. The future will include rejuvenation biotechnology that can repair the damage of aging. That technology is clearly envisaged and understood today, but progress towards its development and deployment remains frustratingly slow.

As always, the way to change this situation lies in money and action: help out, persuade people to help out, and give your time and resources to speed matters along.

Investigating Muscle Repair and Maintenance

A number of research groups are looking into ways to manipulate muscle regeneration and maintenance, and an advance here could be useful as a therapy to address age-related loss in muscle mass and strength: "Researchers have long questioned why patients with Duchenne muscular dystrophy (DMD) tend to manage well through childhood and adolescence, yet succumb to their disease in early adulthood, or why elderly people who lose muscle strength following bed rest find it difficult or impossible to regain. Now, researchers [are] beginning to find answers in a specialized population of cells called satellite cells. Their findings [suggest] a potential therapeutic target for conditions where muscle deterioration threatens life or quality of life. ... Suspecting a genetic switch that might turn off satellite cell proliferation in these circumstances, the scientists looked to a gene called Ezh2, known to keep the activity of other genes in check. When they genetically inactivated Ezh2 in satellite cells of laboratory mice, the mice failed to repair muscle damage caused by traumatic injury - satellite cells could not proliferate. Ezh2 expression is known to decline during aging, and the new research in mice suggests that therapies to activate Ezh2 and promote satellite cell proliferation might eventually play a role in treating degenerative muscle diseases. ... in the elderly, tweaking the gene in satellite cells would not increase their lifespan, but could increase their quality of life by helping to prevent falls and enabling them to move and walk better and go about their daily activities."

Link: http://www.nih.gov/news/health/apr2011/niams-15.htm

The Work of Michael Rose

A Science 2.0 article looks at the work of researcher Michael Rose over past decades: "Over the years, Rose and his lab have bred fruit flies to live four times the life span of an average fruit fly. Reasoning from those studies, Rose has proposed that, because the life spans of fruit flies have the genetic capability to be extensively prolonged, human life can be manipulated in the same way. ... Wattiaux was a French scientist working at the University of Leuven in Belgium. His study used the same fruit flies that Rose had been working with ... Wattiaux found that when he made each new generation of fruit flies that were the offspring of old parents exclusively, the flies showed an increased life span after each generation. But Wattiaux didn't know why his fruit flies lived longer. He felt that longevity increased because of a nongenetic effect, but he didn't have any direct evidence. Rose did. Wattiaux's results, he saw, showed the importance of the force of natural selection. He believed that, because natural selection stops working at a late age and fails to eliminate genes with detrimental effects, these bad genes would not be removed by natural selection. Instead, they would accumulate. In populations that reproduce early, natural selection declines early. Alternatively, populations that are old when they reproduce will continue to be subject to powerful selection until they begin to reproduce. Thus, by allowing older flies to reproduce over generations, natural selection would continue to choose the flies that are able to breed at a later age - the fittest flies."

Link: http://www.science20.com/forever_fly/forever_fly_forever_diet-78126

Muddy Waters When it Comes to Quahog Biochemistry and Longevity

Yes, we're back to clams again: four hundred year old clams in this case. The ocean quahog, Arctica islandica, is a very long-lived bivalve that, like other unusually long-lived species, is attracting the attention of researchers. How is it that these animals manage to live so much longer than their near relatives? You'll find some background reading in the archives:

Researchers to date have focused on resistance to oxidative damage in quahogs, but the more research is done, the more ambiguous that picture becomes. It doesn't seem to be the case that we can simply point to very high levels of antioxidants or an aggressive antioxidant response that preserves cells from the accumulating damage caused by oxidative byproducts of metabolism. In many ways this parallels research into the biochemistry of the naked mole-rat: the initial focus on examining natural antioxidants gave way to the present view that their comparatively long life span depends on differences in the construction of their vulnerable cell membranes. They are better built in the places where it matters - their cells are buzzing with reactive oxidant compounds, but their resistant cell membranes shrug it off.

That may be the case for the quahog as well, but researchers aren't there yet. This recent paper manages to continue the present trend of muddying the waters:

We assess whether reactive oxygen species production and resistance to oxidative stress might be causally involved in the exceptional longevity exhibited by the ocean quahog Arctica islandica. We tested this hypothesis by comparing reactive oxygen species production, resistance to oxidative stress, antioxidant defenses, and protein damage elimination processes in long-lived A islandica with the shorter-lived hard clam, Mercenaria mercenaria. We compared baseline biochemical profiles, age-related changes, and responses to exposure to the oxidative stressor tert-butyl hydroperoxide (TBHP).

Our data support the premise that extreme longevity in A islandica is associated with an attenuated cellular reactive oxygen species production. The observation of reduced protein carbonyl concentration in A islandica gill tissue compared with M mercenaria suggests that reduced reactive oxygen species production in long-living bivalves is associated with lower levels of accumulated macromolecular damage, suggesting cellular redox homeostasis may determine life span. Resistance to aging at the organismal level is often reflected in resistance to oxidative stressors at the cellular level.

Following TBHP exposure, we observed not only an association between longevity and resistance to oxidative stress-induced mortality but also marked resistance to oxidative stress-induced cell death in the longer-living bivalves. Contrary to some expectations from the oxidative stress hypothesis, we observed that A islandica exhibited neither greater antioxidant capacities nor specific activities than in M mercenaria nor a more pronounced homeostatic antioxidant response following TBHP exposure. The study also failed to provide support for the exceptional longevity of A islandica being associated with enhanced protein recycling.

Which is really saying little that is new and definitive - just better ruling out some of the options. The quahog could be producing fewer oxidants, or it could be efficiently mopping up oxidants at their source in the mitochondria due to a natural source of localized antioxidant compounds. In either case, that says nothing about how it or its cells might react to an externally provided and artificial source of oxidative stress like TBHP. Given the present pace of work, however, I'd expect that researchers will have developed a well-supported consensus explanation for the extreme longevity of this species and the naked-mole rat by the time 2020 rolls around.

Injectable Regenerative Filler for Wounds and Defects in Tissue

The use of nanoscale scaffolding material mixed with cells - to spur repair of wounds that would otherwise not heal - is becoming more sophisticated: "scientists have made star-shaped, biodegradable Polymer>polymers that can self-assemble into hollow, nanofiber spheres, and when the spheres are injected with cells into wounds, these spheres biodegrade, but the cells live on to form new tissue. ... The procedure gives hope to people with certain types of cartilage injuries for which there aren't good treatments now. ... To repair complex or oddly shaped tissue defects, an injectable cell carrier is desirable to achieve accurate fit and to minimize surgery. [Researchers have been] working on a biomimetic strategy to design a cell matrix - a system that copies biology and supports the cells as they grow and form tissue - using biodegradable nanofibers. ... the nanofibrous hollow microspheres are highly porous, which allows nutrients to enter easily, and they mimic the functions of cellular matrix in the body. Additionally, the nanofibers in these hollow microspheres do not generate much [in the way of] degradation byproducts that could hurt the cells. ... The nanofibrous hollow spheres are combined with cells and then injected into the wound. When the nanofiber spheres, which are slightly bigger than the cells they carry, degrade at the wound site, the cells they are carrying have already gotten a good start growing because the nanofiber spheres provide an environment in which the cells naturally thrive. This approach has been more successful than the traditional cell matrix currently used in tissue growth ... Until now, there has been no way to make such a matrix injectable so it's not been used to deliver cells to complex-shaped wounds."

Link: http://www.sciencedaily.com/releases/2011/04/110417185353.htm

NF-κB Inhibition Extends Life in Flies

NF-κB is associated with a range of interesting mechanisms: "Aging is associated with NF-κB-dependent pro-inflammation. Here we demonstrated that inhibition of NF-κB with pyrrolidine dithiocarbamate increases the median lifespan (13-20%) and the age of 90% mortality (11-14%) in Drosophila melanogaster females and males, respectively. ... NF-κB controls the expression of genes involved in innate immunity, inflammation and apoptosis. Such age-dependent pathologies as tissue inflammation and atrophy are caused by over-activation of the NF-κB signaling with age. ... Recent studies suggest that the NF-κB transcription factor controls age-dependent changes in inflammation genes expression. Donato et al showed that an increase of NF-κB dependent genes in human endothelium with age is primarily linked to [decreased] NF-κB inhibition. Age-associated expression of NF-κB-dependent genes cause progression of atherosclerosis in rat. Furthermore, selective inhibition of NF-κB activity in blood vessel endothelial cells prevents atherosclerosis progression. Genetic blockade of NF-κB in the skin of chronologically aged mice reverses the global gene expression program and tissue characteristics to those of young mice ... However, the effect of NF-κB inhibition on the lifespan was not studied before."

Link: http://www.impactaging.com/papers/v3/n4/full/100314.html

A Mailing List for Discussion of the Vegas Group Initiative

UPDATE 05/21/2011: The Vegas Group initiative has been renamed to Open Cures, with a new website and a new mailing list. Please do drop by and take a look at what we're working on.

I have created a mailing list - actually a Google group - for discussion on the Vegas Group initiative, as outlined in past posts here at Fight Aging!:

The Vegas Group: a so far fictional community of the next ten years that will merge the longevity advocacy and open biotech communities in order to (a) reverse engineer the most promising life-span-enhancing techniques demonstrated in the laboratory, (b) translate that work into human rejuvenation biotechnologies, and (b) make these therapies available for use via medical tourism to Asia-Pacific region clinics.

I suppose it's not quite so fictional now that a small group of people are talking about how to make it happen. The present focus - for me at least - is on kickstarting a narrow, exploratory project of documentation and reverse engineering:

Given a large idea, the challenge is often finding that starting point. From the broad high level outline of the Vegas Group, I focused on the codex: the necessary how-to documents and body of knowledge that will enable people to participate. ... The codex itself is a very large project [and thus] fairly narrow initial project for the codex must be identified, so that the first group of volunteers to work on it can run into all the brick walls and fall into all of the potholes without risking a great deal if it all fails. ... I propose that reverse engineering and documentation of mitochondrial protofection is a good candidate. This is a technique by which mitochondrial DNA is replaced throughout an individual's cells, and was first demonstrated in mice back in 2005.

But this isn't a project that is particularly owned at this point in time - it's just starting out, a collection of ideas and some people who would like to see them made real. If you have different priorities or interests, such as digging in to the DIYbio aspect of the Vegas Group concept, then by all means join in and run with it. If you feel you can contribute, or even if you would just like to keep an eye on progress from the sidelines, then please do join the mailing list.

Included in the (so far tiny) archive is a discussion on the to-do list: a list of topics for discussion and consideration, the very earliest thoughts on planning that will lead to later, more concrete to-do lists and collaborations. That may help frame the questions or ideas that you bring with you.

An Example of the Relevance of Autophagy

Time and again, autophagy, the process by which cells recycle their broken machinery, shows up as being important in methods of altering life span in lower animals: "The acetylase inhibitor, spermidine, and the deacetylase activator, resveratrol, both induce autophagy and prolong life span of the model organism Caenorhabditis elegans in an autophagy-dependent fashion. Based on these premises, we investigated the differences and similarities in spermidine and resveratrol-induced autophagy. The deacetylase sirtuin 1 (SIRT1) and its orthologs are required for the autophagy induction by resveratrol but dispensable for autophagy stimulation by spermidine ... SIRT1 is also dispensable for life span extension by spermidine. Mass spectrometry analysis of the human acetylproteome revealed that resveratrol and/or spermidine induce changes in the acetylation of 560 peptides corresponding to 375 different proteins. Among these, 170 proteins are part of the recently elucidated human autophagy protein network. Importantly, spermidine and resveratrol frequently affect the acetylation pattern in a similar fashion. In the cytoplasm, spermidine and resveratrol induce convergent protein de-acetylation more frequently than convergent acetylation, while in the nucleus, acetylation is dominantly triggered by both agents. We surmise that subtle and concerted alterations in the acetylproteome regulate autophagy at multiple levels."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21460620

Regenerating Blood Vessels

Researchers are making progress in understanding the signals needed to spur specific forms of regeneration: they "have discovered a strategy for stimulating the formation of highly functional new blood vessels in tissues that are starved of oxygen. ... a biological factor, called fibroblast growth factor 9 (FGF9), is delivered at the same time that the body is making its own effort at forming new blood vessels in vulnerable or damaged tissue. The result is that an otherwise unsuccessful attempt at regenerating a blood supply becomes a successful one. ... This potential treatment has been termed 'therapeutic angiogenesis'. ... Unfortunately and despite considerable investigation, therapeutic angiogenesis has not as yet been found to be beneficial to patients with coronary artery disease. It appears that new blood vessels that form using approaches to date do not last long, and may not have the ability to control the flow of blood into the areas starved of oxygen. [This latest work] provides a method to overcome these limitations. This strategy is based on paying more attention to the 'supporting' cells of the vessel wall, rather than the endothelial or lining cells of the artery wall. The research team found that by activating the supporting cells, new blood vessel sprouts in adult mice did not shrivel up and disappear but instead lasted for over a year. Furthermore, these regenerating blood vessels were now enveloped by smooth muscle cells that gave them the ability to constrict and relax, a critical process that ensures the right amount of blood and oxygen gets to the tissues. ... FGF9 seemed to 'awaken' the supporting cells and stimulated their wrapping around the otherwise fragile blood vessel wall."

Link: http://www.eurekalert.org/pub_releases/2011-04/uowo-ssd041411.php

Progress is Forged Over the Background Hum of Whining Ethicists

The problem with ethics as a profession is exactly that it has become a profession: the salaried ethicist knows that his continued employment depends upon finding problems with research and development. Money, even modest amounts of the stuff, is a powerful incentive. So where there are no problems, there are still groups of people who are effectively being paid to invent problems - and you wonder why medical science isn't moving as fast as it might be.

This form of institutional corrosion is well entrenched throughout the Western world now, of course, and so you'll see plenty of things like this open access whine-slash-justification-for-a-paycheck:

Optimistic predictions of the feasibility and effectiveness of life extension should be critically reviewed in the light of their ethical and social implications. Some anti-aging scientists claim that arguments against anti-aging medicine will simply be dismissed by research outcomes. We would claim that the problem is not with the availability of results, but with defining the nature of what we consider "results".

The idea that life extension research will necessarily translate into what some judges interpret as a result (i.e. the cure of aging) is problematic, because the translational process from potential life extension interventions into reality is not only a matter of science. Suppose we have laboratory advances that are promising for the future translation of laboratory work to the clinic. This result would matter scientifically, but would not solve the ethical and social questions of life-extending interventions. Even if we should succeed in the laboratory, the problems of equitable access to such interventions, the impacts of the future implementation of life extension on health care systems, the risk of pressure to make use of life extension techniques - all these issues will still be with us. Here, more than ever, it must be stressed that the "nature" of what we consider "results" matters not only scientifically, but also ethically and socially. Ethical and social debate on these issues is therefore much needed, along with scientific research and discussion.

Roughly translated: "I don't actually know enough about contemporary longevity science to write about it comprehensively or well, but I do know how to write successful grants. Please pay me and my colleagues more money rather than putting those resources to work on actual research." The middle section of the paper is particularly offensive on that count, an incomplete overview that plays up the bad and the unknown while failing to mention important topics such as SENS, systems biology, tissue engineering, and so on and so forth. There are admittedly far worse things going on in the world these days than the efforts of a legion of minor parasites who've manage to redirect research funding to build an industry that actively opposes research, but the noisy parasitism of the ethics profession manages to be more aggravating than its cost should make it.

Strange things happen to cultures when they lose sight of what matters, begin to value abstractions such as "society" over real individuals, and empty talk over tangible progress. I'd say it's a form of collective cabin fever brought on by the shrinking world and the absence of a frontier: with no hard-to-reach destination for the best, brightest, and most motivated to head for when matters become less than tolerable, there is no escape valve to prevent a network of diverse cultures from nonetheless degenerating in lockstep. The only form of protest that really matters in the long term - when it comes to applying pressure for change - is emigration to a remote region in order to build better lives. The sooner that the next new frontier is opened by technological progress in orbital flight the better in my view.

Calorie Restriction and Core Body Temperature in Humans

Another of the observed effects of calorie restriction in lower animals is shown to exist in humans as well: "Reduction of body temperature has been proposed to contribute to the increased lifespan in calorie restricted animals and mice overexpressing the uncoupling protein-2 in hypocretin neurons. However, nothing is known regarding the long-term effects of calorie restriction (CR) with adequate nutrition on body temperature in humans. In this study, 24-hour core body temperature was measured every minute by using ingested telemetric capsules in 24 men and women consuming a CR diet for an average of 6 years, 24 age- and sex-matched sedentary (WD) and 24 body fat-matched exercise-trained (EX) volunteers, who were eating Western diets. ... Mean 24-hour, day-time and night-time core body temperatures were all significantly lower in the CR group than in the WD and EX groups ... Long-term CR with adequate nutrition in lean and weight-stable healthy humans is associated with a sustained reduction in core body temperature, similar to that found in CR rodents and monkeys. This adaptation is likely due to CR itself, rather than to leanness, and may be involved in slowing the rate of aging."

Link: http://www.impactaging.com/papers/v3/n4/full/100280.html

Industrialization of Tissue Engineering

Economies of scale apply to all endeavors, including the production of human tissue: "The high-tech production lines of [a] laboratory in Germany began moving this week turning out a unique product - human skin. Nicknamed 'The Flesh Factory' by the boffins who work at the Stuttgarter Fraunhofer-Institute, it aims to produce 5,000 circles of skin as big as a one-euro cent every month. Costing around 45 pounds each, when the skin circles are perfected they will be sold to hospitals and clinics around the world for life-saving operations. Project leader Professor Heike Walles, 48, has devoted her whole life to the goal of reproducing human skin on an industrial scale - to save human life and protect animals; it can be used for the kind of testing currently requiring the sacrifice of live creatures. ... Until now, methods of culturing tissue like that used for skin transplants have been very expensive. Most of the steps are carried out manually, which means that the process is not particularly efficient. ... The new production line is entirely mechanical and controlled by computers. ... The process works like this; a biopsy - a sample of human tissue - is checked for sterility. A gripper arm then transports the biopsy into an automated cutting device. The machine snips the biopsy into small pieces, isolates the different cell types, stimulates their growth, and mixes the skin cells with collagen. A three-dimensional reconstruction of the different skin layers is produced with the aid of a special gel matrix - and the skin is ready. In the final step, the machine packages the cells for shipment. Alternatively, the tissue can be cryopreserved - that is, deep-frozen and stored for later use."

Link: http://germanherald.com/news/Allan_Hall's_Germany/2011-04-13/647/The_Flesh_Factory_goes_online

Reverse Engineering Protofection as a First Target for the Vegas Group

UPDATE 05/21/2011: The Vegas Group initiative launched soon after this post, and was quickly renamed to Open Cures, with a new website and a new mailing list. Please do drop by and take a look at what we're working on.

The Vegas Group is a yet-to-be-built community initiative intended to bring longevity science to the open biotechnology and DIYbio communities - and from there reverse engineer and make ready for human use the most promising longevity-enhancing technologies demonstrated in mice in the laboratory. We are entering an age of medical tourism, and the clinics and laboratories of Asia will be happy to accept business and open source biotechnologies generated by DIYbio work in the US. At this stage, I'm still thinking through the project: breaking it down into manageable chunks, and considering what I should work on first:

The path to this future involves networking and community building in a whole new and different direction from that taken by much of the longevity advocacy community - and the construction of a codex of information, a how-to manual of recipes for replicating specific products of the formal research community in longevity science. ... any step one for me will involve considering the codex: what it is, and how it will be constructed, maintained, and made useful to the seeds of what will be the Vegas Group - however that organization ultimately comes about, and whatever form it ultimately takes.

As the cost of biotechnology falls, so is the door opened to much wider development and innovation, wherein lab cooperatives host a mix of hobbyists, moonlighting professionals, and semi-professionals who collaborate on a range of their own projects. Ultimately, low-cost desktop biotech toolkits will be developed and a community of tens or hundreds of thousands of developers will contribute from their homes - just as is the case for open source software development today. With computers in mind, a good historical analogy for the present state of the small DIYbio community is in fact the Homebrew Computer Club in the mid 1970s, prior to the introduction of the first popular personal computer kit. Some small but enthusiastic individuals and groups are designing, building, and selling biotech hardware - such as PCR machines - that will ultimately be the components of a home laboratory, but matters are not yet at that stage of take-off that will see dozens of companies founded and many more people join the community in a short period of years. That lies ahead. The wave is coming, in its own time, and I would like to be positioned to take advantage of it.

All journeys start with the first steps, and I'm in favor of incremental approaches to development. Make something small, a minimum viable product that is the most elementary building block that can stand on its own and still contribute to the ultimate goal. Release it, obtain feedback, and then start on the next building block - and repeat that process until you have as fully as possible realized your initial vision. There will be much to learn along the way, and small building blocks coupled with "release early, release often" make that learning less painful.

Given a large idea, the challenge is often finding that starting point. From the broad high level outline of the Vegas Group, I focused on the codex: the necessary how-to documents and body of knowledge that will enable people to participate. As a general rule, technical communities are terrible at documentation - and that lack of documentation is a real hurdle to recruitment and growth. It could be argued that the DIYbio community isn't yet at the point where it could benefit greatly from a codex: there are other tasks to be completed first relating to hardware. But time is ticking, and progress is being made. The period of being too early won't last forever, and establishing even the skeleton of a practical longevity science codex at hobbyist or non-profit speed will be a process that takes years.

The codex itself is a very large project: something large enough to found a company on in and of itself. There are any number of questions: how best to discover the business models that work to efficiently produce accurate reverse engineering from published papers on longevity-related biotechnology; how best to structure the information presented; how to organize writers and researchers; how to even assemble and prioritize the list of materials needed; and so on ad infinitum.

Thus a fairly narrow initial project for the codex must be identified, so that the first group of volunteers to work on it can run into all the brick walls and fall into all of the potholes without risking a great deal if it all fails. Small projects are easy to scrap, rework, and start over if necessary - and that is a tremendous advantage when you don't yet know the detailed recipe for success. Along the way the volunteers will come to an understanding of how best to make assembly of the broader codex work as a process.

What is this first codex project, though? I propose that reverse engineering and documentation of mitochondrial protofection is a good candidate. This is a technique by which mitochondrial DNA is replaced throughout an individual's cells, and was first demonstrated in mice back in 2005. As you might know, progressively accumulated damage to mitochondrial DNA is one of the causes of aging, as described by the mitochondrial free radical theory of aging. Future rejuvenation biotechnology must include a way to either permanently work around this form of damage, such as through the methodology advocated by the SENS Foundation, or periodically repair it - say once every two to three decades.

Why protofection? In a nutshell:

  • It is comparatively easy to explain to a non-technical audience.
  • It fits with the SENS vision for rejuvenation biotechnology.
  • It has already been demonstrated to work, so at least one group of researchers knows exactly how to do it.
  • It is old enough that this and related knowledge may have spread somewhat, making it more amenable to reverse engineering.

Protofection works in mice, but since that demonstration six years ago next to nothing has been heard of it - just a few publications indicative of a slow exploration in search of possible FDA-approved applications. The FDA does not consider aging a disease, however, and therefore its regulators will not approve any treatment that aims to intervene in aging or achieve rejuvenation. That unfortunate fact is well known, and thus there is little funding available for attempts to treat aging: potential technologies are instead subverted into the development of limited treatments for late stage age-related diseases. The silence regarding protofection is probably another good example of the way in which the present regulatory apparatus holds back progress, as developing protofection for safe general human use is an obvious course of action based on the weight of evidence linking mitochondrial DNA damage and aging. Yet it isn't happening.

Given that a number of years have passed since the viability of protofection was demonstrated, it should be an easier target for reverse engineering and documentation of processes than more recent developments. By which I mean that it should be easier to find researchers and post-graduates unconnected with the work who nonetheless know enough to write on the topic.

Protofection is also (I hope) narrow enough not to generate a true mountain of supporting needs in terms of how-to documents. Part of the process of discovery is to understand how to develop the initial list of documents required for the codex, starting from a high-level goal like "let's reverse engineer protofection, make reproducing it comprehensible to the semi-professional DIYbio volunteer, and release that documentation under a Creative Commons license" and working all way down to the brass tacks and petri dishes. Protofection, while something that can be explained in a few short sentences, stands at the top of a sizable pyramid of techniques and knowledge in biotechnology: how to work with DNA, how to manage your own laboratory equipment, how to keep cell cultures, and so on for a long list of topics.

If this takes a few years to get right, that's fine by me. It will provide a blueprint for doing the same to other areas of biotechnology, and by that time there should be more people interest in helping out - both for longevity science and for their own areas of interest.

Vegetarianism, Or Less Body Fat?

Here is an example of a research commentary that misses the forest for the trees: "Vegetarians experience a 36 percent lower prevalence of metabolic syndrome than non-vegetarians, suggests new research ... Because metabolic syndrome can be a precursor to heart disease, diabetes, and stroke, the findings indicate vegetarians may be at lower risk of developing these conditions. Metabolic syndrome is defined as exhibiting at least three out of five total risk factors: high blood pressure, elevated HDL cholesterol, high glucose levels, elevated triglycerides, and an unhealthy waist circumference. ... while 25 percent of vegetarians had metabolic syndrome, the number significantly rises to 37 percent for semi-vegetarians and 39 percent for non-vegetarians. The results hold up when adjusted for factors such as age, gender, race, physical activity, calories consumed, smoking, and alcohol intake. ... On average, the vegetarians and semi-vegetarians were three years older than non-vegetarians. Despite their slightly older age, vegetarians had lower triglycerides, glucose levels, blood pressure, waist circumference, and body mass index (BMI). Semi-vegetarians also had a significantly lower BMI and waist circumference compared to those who ate meat more regularly." Given the broader context of what is known about the effects of body fat on long-term health, the plausible mechanism here looks to be related to the amount of visceral fat rather than anything to do with diet per se.

Link: http://www.eurekalert.org/pub_releases/2011-04/llua-vmb041311.php

Growing Kidneys From Stem Cells

Progress in tissue engineering: "scientists have created human kidneys from stem cells ... The artificial organs were created in a laboratory using human amniotic fluid and animal foetal cells. They are currently half a centimetre in length - the same size as kidneys found in an unborn baby. [Scientists] hope they will grow into full-size organs when transplanted into a human. ... It sounds a bit science fiction-like but it's not. The idea is to start with human stem cells and end up with a functioning organ. We have made pretty good progress with that. We can make something that has the complexity of a normal, foetal kidney ... The research team hope that doctors will eventually be able to collect amniotic fluid, which surrounds the growing embryo in the womb, when a baby is born. This will then be stored by scientists in case that person develops kidney disease later in life. The fluid can then be used to create a matching kidney. Creating an organ using a patient's own stem cells solves the problem of having to use powerful immunosuppressant drugs to stop the body rejecting a another person's kidney. ... the technology could be ready for use on humans in around 10 years." By which time it will probably be unnecessary to collect amniotic fluid, as the signals and chemicals it provides will be understood and reproduced.

Link: http://www.telegraph.co.uk/health/healthnews/8443740/Scientists-create-human-kidneys-from-stem-cells.html

Critiquing the Practice of Cryonics

Over at Chronosphere you'll find a weighty set of posts that aim to provide a foundation for critiquing cryonics at the organizational level of achieving consistently good cryopreservations, and the development of professional organizational cultures and processes - such as record-keeping - required to support that goal. All industries require ongoing initiatives that provide solid, constructive critiques of present practice, for otherwise how are the participants to progress and improve themselves?

You be the Judge: Understanding and Evaluating the Quality of Human Cryopreservations from Cryonics Organization Literature and Case Report Data, Part 1:

The goal of this series of articles is to equip the reader with the tools necessary to make an accurate assessment of the quality of care cryonics patients, both individually and as a group, are receiving from their respective cryonics organizations.

You be the Judge: Understanding and Evaluating the Quality of Human Cryopreservations from Cryonics Organization Literature and Case Report Data, Part 2:

In a very real sense, that care starts the moment the member/patient experiences his first contact with the cryonics organization that will ultimately cryopreserve him. The tenor of that first contact will likely determine the nature and course of the member's subsequent interaction both with cryonics and his cryonics organization. If cryonics is presented as a developed product that is costly but nevertheless fairly routine, say like buying a home or an automobile, that's very likely how it will be subsequently be treated. If, on the other hand, there is heavy emphasis on the lack of infrastructure to provide help in an emergency and the need to exercise both personal responsibility and personal preparedness, outcomes will likely differ - at least statistically, if not in each individual case.

You be the Judge: Understanding and Evaluating the Quality of Human Cryopreservations from Cryonics Organization Literature and Case Report Data, Part 3:

not only is it important that those caring for the patient know what is expected of them, the cryonics organization must also know what the family/caregiver's needs are, both logistically and psychologically. Cryonics is unfamiliar territory for family, and the procedures attending [the preparatory period immediately prior to cryopreservation] can perturb what in many cases will be a fragile emotional and psychological equilibrium in the patient's home life. Organizations that fail to establish rapport, and work to ascertain and meet the needs of the patient's family, risk non-cooperation, obstruction and even litigation. Seemingly small details, such as protecting flooring or furniture from water damage, or arranging for a few minutes of private "alone time" with the patient before he is removed from the home or care facility after acute stabilization, can mean the difference between heartfelt assistance, and bitter belligerence from the next of kin.

The quotes above hit some of the points I have had in mind in past years when discussing the need for cryonics organizations to (a) become more professional in character, and (b) form up a better product offering for customers, one that provides more in the way of service and guidance than is presently the case. That theme continues into the last of the four posts, linked below.

You be the Judge: Understanding and Evaluating the Quality of Human Cryopreservations from Cryonics Organization Literature and Case Report Data, Part 4:

Nevertheless, the real solutions to the problems discussed here are not easy, because they demand the acquisition of professionalism, knowledge, and skill in the context of cryonics as medicine. I personally believe that Jerry Leaf and I came very close to doing that in the decade between 1981 and 1991. But we failed. Why we failed will be discussed at a later time. Suffice it to say that the problem of maintaining professionalism is a nettlesome one in medicine, engineering and other demanding disciples that are vastly more developed than cryonics is today, and there will be no quick fixes.

"No quick fixes" is a conclusion I agree with. Nothing worthwhile is quick and painless to achieve, and even small industries change slowly when it comes to company cultures. The only reliable path to faster change involves money, as change follows rapid growth in the number of paying customers in any human endeavor. Unfortunately that growth remains elusive for cryonics providers, just as it has throughout that past decades. From where I stand, I'd say that the best near-term path to the goal of transformative growth in revenue lies in developing spin-off technologies in cryobiology and related fields - but that's an opinion offered without any great insight into the inner workings of the industry as it exists today. It is simply taken from the standard business texts: if you've consistently failed to achieve good growth with option A, then perhaps it's time to try options B, C, and D.

Klotho in Humans

You might recall the identification of klotho as a longevity-related gene in mice and other lower animals in recent years. Here is a study on levels of klotho in humans: "The aging-suppressor gene klotho encodes a single-pass transmembrane protein that in mice is known to extend life span when overexpressed and resemble accelerated aging when expression is disrupted. It is not known whether there is a relationship between plasma levels of secreted klotho protein and longevity in humans. ... We measured plasma klotho in 804 adults, greater than or equal to 65 years, in the InCHIANTI study, a longitudinal population-based study of aging in Tuscany, Italy. ... During 6 years of follow-up, 194 (24.1%) of the participants died. In a multivariate Cox proportional hazards model, adjusting for age, sex, education, body mass index, physical activity, total cholesterol, high-density lipoprotein cholesterol, cognition, 25-hydroxyvitamin D, parathyroid hormone, serum calcium, mean arterial pressure, and chronic diseases, participants in the lowest tertile of plasma klotho [had] an increased risk of death compared with participants in the highest tertile of plasma klotho ... In older community-dwelling adults, plasma klotho is an independent predictor of all-cause mortality. Further studies are needed to elucidate the potential biological mechanisms by which circulating klotho could affect longevity in humans." Given the number of adjustments there, I'd like to see a confirming study - and for preference one that explicitly took into account calorie intake as well. Just because you see the expected result is no reason to abandon the usual level of caution needed when reading the output of the scientific method.

Link: http://www.ncbi.nlm.nih.gov/pubmed/21474560

Never Too Late to Exercise: the PROOF Study

Even at older ages, exercise is a still very important - as demonstrated by the degree to which it influences ongoing health in later stages of life, just as it does in earlier stages in life. "It is not sufficient simply to live longer. One of the current priorities for public health is to how to maintain good quality of life for longer. This has given rise to the concept of 'successful aging' generating a turning point in our thinking about aging, which is no longer seen as an inevitable decline. ... Physical activity has a pleiotropic effect and is a significant factor in successful aging. This study aims to quantify the relationship between the physical activity of a 65-year-old cohort and the level of life satisfaction and self-rated health 7 years later. A total of 988 questionnaires were sent by mail to a representative sample of healthy pensioners. Life satisfaction and health status were estimated on two visual analogical scales in answer to the following questions: (1) How would you estimate your state of health? and (2) Are you generally satisfied with your life? The level of physical activity was estimated using a questionnaire which enabled us to calculate: Daily energy expenditure (DEE) [and] VO2 peak. ... Energy spent in activity and VO2 peak estimated from DEE, measured at the age of 65, appear to be strong predictors of well-being 7 years later."

Link: http://dx.doi.org/10.1089/rej.2010.1101

An Introduction to Targeting Cancer Stem Cells for Destruction

It remains plausible that many cancers will suddenly become curable at some point in the next decade or so - even in their later stages - through the identification and targeted destruction of the cancer stem cells that power the cancer's growth:

The promise - the hoped for possibility - of cancer stem cells is that they represent a small, manageable, less complex range of biochemical targets to prevent and destroy cancer. The biotechnology of this year and next can flip genetic switches and safely destroy cells with specific markers - if we just know where to look, what to destroy, what to change.

Over the past few years, researchers have started the long process of cataloging cancers with identifiable stem cells at their root, and the unique signatures of those cancer stem cells. Those biochemical signatures in theory provide a template for targeted cell destruction therapies currently under development: engineered viruses, nanoparticle assemblies, immune therapies, and so forth. Given a distinct cell type, researchers can deplete its population without harming other cells or damaging tissues elsewhere in the body - a far cry from the present brute force approach of chemotherapy, and something that has been demonstrated numerous times in the laboratory.

On this topic I noticed a good open access paper today that provides an introduction to - and overview of - the near future of this branch of medical research.

Therapeutics formulated to target cancer stem cells: Is it in our future?:

When discussing potential targets for the treatment of cancer today, the conversation will generally lean towards targeted therapy of cancer stem cells (CSCs). With the identification of potential defining characteristics for CSCs, there have also been more questions raised as to which of these characteristics may make better targets. For many years, research seemed to focus on isolating CSCs by specific identifying markers but the research has seemed to shift towards identifying the way in which these stem cells behave that make them different from bulk tumor cells. Limited efficacy has been seen with the use of cell surface markers in clinical trials; however, there have been recent advances that target other aspects such as signaling pathways or genetic alterations seen particularly in CSCs. The following is a review of what information is out there and what seem to be the most promising paths on this journey to identifying therapeutic targets of self-renewing CSC sub-populations.

For the other side of the debate on cancer stem cells, you might look back into the archives. Not all researchers think that cancer stem cells are a viable target for therapies, or that they are in fact a sustaining force for cancer:

From my outsider's perspective, the competing evidence for and against the cancer stem cell hypothesis might be resolved if it turns out that only some cancers have clearly identifiable stem cells at their root. But we shall see how it all turns out: the research community is certainly going to spend a great deal of time and money over the next decade trying to destroy cancer by identifying and targeting its stem cells.

Reversing B Cell Aging

Here are more indications that selective pruning of an aged immune system can restore at least some of its youthful potency. If researchers can understand why the pruning does this, then there is the possibility of skipping the selective destruction and directly manipulating the underlying signaling processes instead: "Age-related alterations in the cellular composition of the B lineage are a major cause of the poor antibody response to vaccination and to infectious agents among the elderly population. The mechanisms leading to these changes are poorly understood. Recently, we have shown that these changes reflect, at least in part, homeostatic pressures imposed by long-lived B cells that accumulate with aging, and that aging in the B lineage can be reversed upon alteration of B cell homeostasis by depletion. Here we discuss homeostatic causes for B lineage immunosenescence, and the potential for its rejuvenation. ... The major conclusion of our study is that age-related alterations in the B lineage are reversible and mediated [by] the long-lived B cells accumulating in the periphery with age ... These observations are the foundations of new paradigms for enhancing immune responsiveness in aging, which may be translated in the future for clinical use. The nature of these homeostatic regulation mechanisms and the cross-talk between peripheral B cells and progenitor cell populations in the [bone marrow] are yet to be identified. This will allow direct manipulation of B cell homeostasis by targeting the regulatory factor(s) rather than by depletion of B cells, to [enhance] immune competence in the elderly."

Link: http://www.impactaging.com/papers/v3/n4/full/100313.html

Alcor's Latest Cryopreservation

The cryonics provider Alcor publishes short summaries of cryopreservation activities, which are educational if you seek to better understand how the process of cryonics unfolds in practice: "In late March of this year, Alcor was notified that a member in Pennsylvania had entered into the hospital with severe abdominal pain and was critically ill. As her medical providers predicted that she would probably not survive, Alcor's Medical Response Director, Aaron Drake and Readiness Coordinator, Steve Graber were on a plane to the east coast within the next three hours. Upon arrival, the member's health condition had stabilized and appeared to have improved somewhat. While optimistic that a recovery might be possible, diagnostic tests and blood labs indicated that a terminal outcome was more probable. This pause in the patient's health decline provided an opportunity to request that Suspended Animation respond as well to help perform a field washout and perfusion. On the third day of the standby, the member succumbed to her illness. Highly cooperative hospital administrators and physicians allowed the Alcor team to perform stabilization and cool down procedures within the patient's private hospital room immediately following pronouncement. The patient was then transferred to a local mortuary where Suspended Animation was set up to complete the next step in the process. The family had pre-paid additional funds to Alcor for a private jet to eliminate the potential delays associated with commercial air travel. After a six and half hour flight, the patient arrived at the Scottsdale Airport, located just a few blocks from Alcor Central. Alcor's surgical team was standing by and performed vitrification procedures throughout the night. On Saturday, March 26th, member A-2478 became Alcor's 104th patient."

Link: http://www.alcor.org/blog/?p=1950

An Update on Leishmania and Mitochondrial DNA Repair

The ability to repair accumulated damage to our mitochondrial DNA is one necessary item in the rejuvenation biotechnology toolkit of the future. You can look back in the Fight Aging! archives to see why this the case, but the short version is that your mitochondria damage their DNA as a natural consequence of their operation, and this damage is the start of a chain of events that ultimately spreads harm and dysfunction throughout the body. Mitochondrial DNA damage is thus one of the causes of aging.

Fortunately, there are a number of promising avenues for repair technologies. One of the newer approaches involves adopting a mechanism observed in the tropical parasite Leishmania:

Dr. Samit Adhya of the Division of Molecular and Human Genetics at the Indian Institute of Chemical Biology is pursuing yet another innovative approach. He proposes to dispense with the need for mitochondrial DNA altogether, by instead providing the mitochondrial protein-making machinery directly with the "working instructions" (messenger RNA) that it normally receives in the form of a transcribed copy taken from the mitochondrial DNA originals. This would allow the mitochondria to continue their protein production even if the mitochondrial DNA were completely destroyed: they would still have their marching orders, even if the general himself were incommunicado. Dr. Adhya is accomplishing this goal by borrowing a trick used by a single-celled organism called Leishmania tropica. This organism, unlike mammals, generates another kind of RNA in the main cell body, and uses a specialized protein to move it into the mitochondria. Dr. Adhya reasoned that he could bind copies of our own RNA to the same protein and use it to deliver both kinds of RNA into mammalian mitochondria, bypassing the need for a DNA original. Very clever.

Over at the SENS Foundation - a group working on a different methodology of making mitochondrial damage irrelevant - you'll find an update on development of this Leishmania-derived mechanism. The article is fairly dense, but the gist of it is that Samit Adhya and company took mutant cells with massively broken mitochondrial DNA and temporarily fixed their operation by providing them with doses of RNA tailored to create the protein components that their damaged DNA couldn't produce. From the commentary:

This in vitro experiment is exciting, opening up an alternative means of restoring [necessary mitochondrial function to] cells that accumulate in aging tissues, areas associated with age-related diseases such as Parkinson's disease and sarcopenia, and that can strongly be argued to be contributors to the degenerative aging process. The method is rightly described by the authors as "inherently simple, efficient, and fast-acting, and appears to be of general applicability to a wide variety of [cells and tissues]." Indeed, it shows clear advantages relative to the low targeting to cells and/or mitochondria of previous attempts using pharmacological delivery systems, and appears to show a [greater effectiveness] than previous efforts using allotopic expression itself.

On the other hand, the effects of the [RNA based therapy were] transient, as would be predicted from the inherent nature of a therapy based on delivery of mRNA, which are routinely recycled within the cell ... there is substantial room for skepticism that normal function could be continuously sustained by such means on acceptable booster schedules.

But this work is a major advance, and clearly promising. The therapeutic potential [should] now be tested in animal models of inherited mitochondrial disease, [and] if successful, the more ambitious work of using it to restore [cells become damaged] as a result of the degenerative aging of wild-type mice. The biomedical rejuvenation of aging human mitochondrial function would not lie far behind, with the promise of muscles maintained, Parkinson's prevented, and an end to the rising systemic metabolic toxicity of [cells overrun with damaged mitochondria].

The more methods of mitochondrial repair that are actively worked on the better the long-term prognosis for all of us - though it should be noted that despite progress over the past few years, there is comparatively little funding for this field of research and development. Few groups are working in this area, and in comparison to hot fields like stem cell research, progress is slow and halting. The cure for that problem is as it always has been: funding, attention, advocacy.

Learning from the Salamander Brain

Salamanders can regenerate more than just limbs: "A study of the salamander brain has led [researchers] to discover a hitherto unknown function of the neurotransmitter dopamine. ... The study was conducted using salamanders which unlike mammals recover fully from a Parkinson's-like condition within a four week period. Parkinson's disease is a neurodegenerative disease characterised by the death of dopamine-producing cells in the mid-brain. As the salamander re-builds all lost dopamine-producing neurons, the researchers examined how the salamander brain detects the absence of these cells. ... What they found out was that the salamander's stem cells are automatically activated when the dopamine concentration drops as a result of the death of dopamine-producing neurons, meaning that the neurotransmitter acts as a constant handbrake on stem cell activity. ... As in mammals, the formation of neurons in the salamander mid-brain is virtually non-existent under normal circumstances. Therefore by studying the salamander, scientists can understand how the production of new nerve cells can be resumed once it has stopped, and how it can be stopped when no more neurons are needed. It is precisely in this regulation that dopamine seems to play a vital part. Many observations also suggest that similar mechanisms are active in other animal species too. Further comparative studies can shed light on how neurotransmitters control stem cells in the brain, knowledge that is of potential use in the development of therapies for neurodegenerative diseases."

Link: http://ki.se/ki/jsp/polopoly.jsp?l=en&d=130&a=120420&newsdep=130

Atherosclerosis Happens Rapidly and Late

Many of the characteristic signs and conditions of aging arrive in a rush in later life. The buildup to that point has been going on for a while, but there is a threshold past which matters suddenly accelerate. Here is one example: researchers "have determined the age of atherosclerotic plaques by taking advantage of Carbon-14 (14C) residues in the atmosphere, prevailing after the extensive atomic bomb tests in the 50ties and 60ties. The findings, published in the scientific online journal PLoS ONE, suggest that in most people plaque formation occurs during a relatively short and late time period in life of 3-5 years. ... We suspected that the plaque would be substantially younger than the patients, who were on average were 68 years old at surgery, but we were surprised when we found that the average age of these plaques was less than 10 years. ... If proven true, the growth of atherosclerotic lesions may be interrupted to prevent clinical manifestation, like [stroke], even in late stages of life, at 60 years of age or possibly later. ... The age of plaques was also found to be associated to blood levels of insulin, and plaques with lower age (formed more recently) were found to be more unstable than older plaques and therefore more likely to cause clinical complications." All of which is characteristic of a suddenly runaway process.

Link: http://ki.se/ki/jsp/polopoly.jsp?d=130&a=120475&l=en&newsdep=130

A Few Large Numbers

Some numbers to consider, since everyone and their dog seems to be talking about the disposition of inordinately large sums of money - and little else - at the moment:

We all have our ideas as to how to spend money in ways better than the choices made by its current owner. It can be frustrating when the course ahead is so very clear indeed, yet not taken ... but that is what advocacy is for. When you have a vision, share it, persuade others, and make it happen. When you don't like the numbers you see in front of you, work to change them.

Mitochondria as a Therapeutic Target for Aging and Neurodegeneration

It is good to see some of the larger and better funded life science research communities showing interest in targeting mitochondria - the more people working on this the better, as mitochondria are important in degenerative aging, but there is presently relatively little ongoing research into the practical approaches to mitochondrial repair: "Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal models, postmortem brain studies of and clinical studies of aging and neurodegenerative diseases suggests that mitochondrial function is defective in aging and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Several lines of research suggest that mitochondrial abnormalities, including defects in oxidative phosphorylation, increased accumulation of mitochondrial DNA defects, impaired calcium influx, accumulation of mutant proteins in mitochondria, and mitochondrial membrane potential dissipation are important cellular changes in both early and late-onset neurodegenerative diseases. Further, emerging evidence suggests that structural changes in mitochondria, including increased mitochondrial fragmentation and decreased mitochondrial fusion, are critical factors associated with mitochondrial dysfunction and cell death in aging and neurodegenerative diseases. This paper discusses research that elucidates features of mitochondria that are associated with cellular dysfunction in aging and neurodegenerative diseases and discusses mitochondrial structural and functional changes, and abnormal mitochondrial dynamics in neurodegenerative diseases. It also outlines mitochondria-targeted therapeutics in neurodegenerative diseases."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21470101

Mitochondrial Mechanisms and Aging

The evidence points toward mitochondrial structure and function being very important in the progression of aging within a species and differences in life span between species. Here researchers review some of the mechanisms involved: "Mitochondria are considered major regulators of longevity, although their exact role in aging is not fully understood. Data from different laboratories show a negative correlation between reactive oxygen species (ROS) generated by complex I and lifespan. This suggests that complex I has a central role in the regulation of longevity. Here, we review data that both support and refute the role of complex I as a pacemaker of aging. We include data from our laboratory, where we have manipulated ROS production by the electron transport chain (ETC) in Drosophila melanogaster. The by-pass of complex I increases the lifespan of the fruit fly, but it is not clear if this is caused by a reduction in ROS or by a change in the NAD+ to NADH ratio. We propose that complex I regulates aging through at least two mechanisms: (1) an ROS-dependent mechanism that leads to mitochondrial DNA damage and (2) an ROS-independent mechanism through the control of the NAD+ to NADH ratio. Control of the relative levels of NAD+ and NADH would allow the regulation of (1) glyco- and (2) lipoxidative-damage and (3) the activation of sirtuins." Amongst other things, the NAD+ / NADH ratio determines how much in the way of damaging free radicals a cell exports into the surrounding environment.

Link: http://www.ncbi.nlm.nih.gov/pubmed/21471732

Growing a Retina in a Dish From Embryonic Stem Cells

The process of understanding how to manipulate stem cells goes hand in hand with being able to coax them into forming more complex structures, recapitulating the path taken during the original development of the body when young. The state of the art at the present time is crude in comparison to what takes place in our bodies: the only way that researchers can presently obtain complex tissues is by using the extracellular matrix extracted from donor tissue as a guide for new growth. That guidance is as much chemical as structural, which is illustrated in the following recently announced research.

'Retina in a Dish' is the Most Complex Tissue Ever Engineered in the Lab:

Researchers in Japan have grown a retina from mouse embryonic stem cells in a lab, but this isn't just another incremental advance in tissue engineering. Scientists claim their "retina in a dish" is by no small degree the most complex biological tissue yet engineered.

If the breakthrough can be adapted to work with human cells, it could provide a retina that is safe for transplantation into human eyes, providing a potential cure for many kinds of blindness. That's still years away, but in the meantime the lab-grown mouse tissue could provide researchers with a wealth of information on eye diseases and potential treatments for them.

Cultured mouse embryonic stem cells self-organize into a complex retinal structure:

Starting with the culture conditions they had established for retinal differentiation, the researchers added matrix proteins that they hoped would encourage the formation of the more rigid retinal epithelial structures. They then seeded the culture with mouse [embryonic stem] cells. Within a week, the cells began to form small vesicles and differentiate into two different tissue types: Cells on one side of the vesicles formed the mechanically rigid pigment epithelium, while cells on the other side differentiated into a more flexible tissue that folded inward in the shape of an embryonic optic cup - the retina's precursor.

As you can see, researchers remain a long way away from growing a transplant-ready human retina from cells alone - but this is still an important step forward in the path towards producing such a thing. What is learned here will also inform efforts to build the thousand other tissue types we'd like to be able to produce from scratch.

Progress in Methuselah Foundation's Silverstone Investment

The Methuselah Foundation invests in a variety of companies, and one of them is Silverstone Solutions. Here the Foundation notes a demonstration of the company's product: "In what is the largest single-hospital kidney swap in the history of California, five patients received five kidneys from healthy donors in a marathon series of operations on Friday, April 1st 2011 ... 'Paired donation' is the procedure that makes it possible, a relatively new phenomenon in transplantation surgery that allows for a live kidney going to someone who has a friend or relative willing to donate an organ not compatible for them but a match for someone else. The donor matches one who needs a kidney and that patient's incompatible donor matches someone else and so on, like a chain. ... Imagine that - multiple lives being extended in one fell swoop! This is one of many reasons why Methuselah Foundation has proudly invested in Silverstone Matchmaker, a break-through computer software that makes the pairings possible. It quickly computes the myriad of possible matches in a pool of prospective donors and recipients, minimizing time and effort that the transplant center needs to reach this goal. ... That is why we proudly extend an angel financing arm, funding the development of the bleeding-edge improvements to the Silverstone technology called MatchGrid. This event is in keeping with Methuselah Foundation's strategy of making investments in life-extending technologies that work RIGHT NOW (dangit!) and that also have long term positive implications for general life extension in the tissue engineering realm. Our long term vision for this technology? We hope that its massive and super performance data management system will eventually play a role in the an envisioned 'Postscript' language that can send printing instructions for creating new tissues and eventually organs to be used by tissue printers such as Organovo's sci-fi worthy 3D tissue printer, another founding angel investment by you, the donors of Methuselah Foundation."

Link: http://blog.methuselahfoundation.org/2011/04/hot_dog_a_record-breaking_5-transplant_kidney_swap.html

A Modest Step Towards Limb Regrowth in Mammals

Researchers continue to investigate how to replicate the limb regeneration found in lower animals: "Move over, newts and salamanders. The mouse may join you as the only animal that can re-grow their own severed limbs. Researchers are reporting that a simple chemical cocktail can coax mouse muscle fibers to become the kinds of cells found in the first stages of a regenerating limb. Their study, the first demonstration that mammal muscle can be turned into the biological raw material for a new limb ... their 'relatively simple, gentle, and reversible' methods for creating the early stages of limb regeneration in mouse cells 'have implications for both regenerative medicine and stem cell biology.' In the future, they suggest, the chemicals they use could speed wound healing by providing new cells at the injured site before the wound closes or becomes infected. Their methods might also shed light on new ways to switch adult cells into the all-purpose, so-called 'pluripotent' stem cells with the potential for growing into any type of tissue in the body. The scientists describe the chemical cocktail that they developed and used to turn mouse muscle fibers into muscle cells. [They] then converted the muscle cells turned into fat and bone cells. Those transformations were remarkably similar to the initial processes that occur in the tissue of newts and salamanders that is starting to regrow severed limbs."

Link: http://www.eurekalert.org/pub_releases/2011-04/acs-scc040611.php

He'll Let Folk Know When the Worm Zapping Commences

You might recall that the Immortality Institute raised funds for a test of laser ablation of lipofuscin, to run on nematode worms using commercially available laser equipment:

The good news for today is that the longevity science grassroots centered at the Immortality Institute have successfully raised $8,000 to fund research into laser ablation of lipofuscin. Those funds will be matched up to $16,000 at the SENS Foundation and put towards work on a method of eliminating one form of damaging metabolic byproducts that build up with age.

Lipofuscin is the name given to a collection of various waste products of metabolism that are hard for the body to break down. They build up inside cells, collecting in the recycling mechanisms of lysosomes and causing cellular housekeeping to progressively fail over time. Ways to safely break down lipofuscin are very much required as a part of the envisaged package of future rejuvenation biotechnology that can prevent and reverse aging.

One proposed methodology for tackling lipofuscin is the use of pulsed laser light targeted at very specific molecules and molecular bonds: in theory, it should be possible to significantly impact lipofuscin levels without harming the cells that contain this gunk. Whether this is the case in practice remains to be seen, but it is an approach well worth testing: after all, lasers are already routinely used in dermatology to achieve conceptually similar goals, and the cost of this test is minimal in the grand scheme of things. Hence the laser ablation project funded by forward-looking donor and organized by the Immortality Institute.

You'll find recent updates on the state of the laser ablation test in the Longecity thread for the project:

Here is the basic agenda for the remainder of the project:

1) Test the effect of 8ns pulses on worm lifespan, at many different intensities. ... The beam coming straight out of the laser has terrific coherence and a nice tophat profile, which although it is 8ns, which is a little harsh, it is wonderfully consistent, great at destroying pigments, and we can rest assured that all worms on the slide are getting the exact same exposure every time.

2) Examine effect on worm activity/livelihood. Since the worms grow distinctively and progressively less active in the 2nd half of their life, this can be used to roughly assess quality of life changes; i.e. if worms are all dying at the same time, but at 75% lifespan, laser-treated groups are still quite active, this could be seen as a definite extension of useful lifespan.

3) Examine changes in pigmentation, if any. I may even be able to rig up a crude blacklight setup and get some fluorescence going. Or we could lop two months of the end of the 8-month project and buy a basic fluorescence scope with the extra $2500


4) Assess the effect of laser treatment on a more long-lived strain of worms (such as DAF-16 mutants), as well as the wild-type. This could provide useful clues as to what is going on, whichever way the results go.


It's still taking awhile to breed more DA1116 worms. I can see how this is going to go - things are going to stretch out a bit, partly due to my schedule and partly due to using long-lived worms, and the nature of lifespan experiments in general. Therefore I propose using experiments as milestones instead of sticking to a fixed weekly or monthly schedule. Thus the project will span at least 8 complete lifespan experiments, regardless of how long it takes to complete them. The remaining 'monthly' salary and expense checks could be sent at the start of experiments 3, 5 and 7 - which will doubtless end up being more than one month apart. This definitely seems more appropriate to me - that way all of our gracious donors get the same amount of science for their money, regardless of how long it takes.

The fluorescence scope may or may not be purchased for this project, depending on how our financial situation pans out on this end. It may end up being budgeted as part of a future project proposal instead; but we can cross that bridge when we get there.

I'll let everyone know as soon as the worm zapping begins.

One of the Immortality Institute volunteers visited the lab recently, and so you'll find photographs of the equipment, work area, and researcher in the thread to go along with the updates.

By way of a reminder, the Institute continues to raise funding for their next project, an investigation of microglia transplantation as a therapy for age-related neurodegeneration. $5,500 of the needed $8,000 has been raised, and futher donations are very welcome. Every dollar donated will be matched by an additional dollar from the Institute and its sponsors, so that the completed fundraiser will send $16,000 to the laboratory that will carry out the research:

Cognitive functions of the brain decline with age. One of the protective cell types in the brain are called microglia cells. However, these microglia cells also loose function with age. Our aim is to replace non-functional microglia [in mice] with new and young microglia cells derived from adult stem cells.


The full PDF format research proposal is available: the work will be carried out by a graduate research assistant and will cost $16,000. This is the essence of our present era of biotechnology: a task that would have occupied a whole laboratory and its equipment in the 1980s, and cost a great deal of money if it was even possible at all, is now something that a skilled graduate-level life scientist can organize and run himself within an established lab.

Muscle Regeneration via Stem Cells

Researchers have demonstrated that "damaged muscle tissues treated with satellite cells in a special degradable hydrogel showed satisfactory regeneration and muscle activity. Muscle activity in repaired muscle in a mouse model was comparable with untreated muscles. ... Satellite cells (SCs), freshly isolated or transplanted within their niche, are presently considered the best source for muscle regeneration. They are located around existing muscles. Hence, a patient's own cells can be used, from a muscle biopsy. ... A key issue for regeneration is how cells grow as a structure, as they usually require some form of framework. A hard framework would impede muscle growth and muscle cell penetration. The hydrogel, by contrast, provides a supportive structural skeleton but degrades quickly as muscle tissue returns and the support becomes unnecessary. The gel is initially liquid, hardens in place under UV light, and is easily penetrated by muscle cells. ... This is using the patient's own cells, without any lengthy culturing process, which means we could take a biopsy, produce the cells in a couple of hours, and implant them where needed - it can be done in theatre as one process. Using the patient's own cells eliminates any tissue rejection. ... The focus for initial clinical research in humans will be relatively small muscles at first, like deformities in the face and palate, or in the hand. It will be technically more demanding to grow larger muscles with more structure, which would require their own nerves and blood supply."

Link: http://www.ucl.ac.uk/news/news-articles/1103/31031101

The Methuselah Generation

The Methuselah Generation is a documentary film in progress, far enough along that the filmmaker is putting out early versions: "Is aging a disease that can be cured? Is it possible to live forever? Even if we could, should we? The Methuselah Generation (working title) is a 3D verite documentary about the science and philosophy of Life Extension - the scientific hypothesis that individuals may be capable of extending human life beyond anything humans have yet imagined. The story will follow a select few individuals at the forefront of this movement as well as those skeptical and antagonistic toward the goals of life extension. The film will follow five protagonists as they progress with their movement to change humanity. Through intimate interviews, observational shooting and provocative imagery, this character-based 3D documentary will explore the big philosophical ideas of Life Extension, while also examining the scientific feasibility - the film will explore the what, how and (most significantly) the WHY of long-lived humans."

Link: http://davidalvarado.info/le.html

p16 and the Balance Between Cancer and Aging

The evolutionary view of cancer and aging is that these end points stand in opposition: complex organisms such as mammals evolve to some point of balance between risk of cancer and certainty of accelerated aging. This happens because the mechanisms that suppress cancer also inhibit the necessary regenerative capacity to maintain tissue function: it's largely a matter of how free cells are to divide and multiply, taking into account the increasing levels of damage and mutation with age - which increase the chance of a cancer developing.

In research focused on this balance between aging and cancer, two genes - and the proteins they produce - are especially important: p53 and p16. Both can suppress cancer, but at the cost of accelerated aging:

p16 has been particularly interesting of late because it appears to be a plausible candidate for the cancer immunity observed in naked mole rats:

the mole rat's cells express a gene called p16 that makes the cells 'claustrophobic,' stopping the cells' proliferation when too many of them crowd together, cutting off runaway growth before it can start. The effect of p16 is so pronounced that when researchers mutated the cells to induce a tumor, the cells' growth barely changed

Unfortunately, as recent research illustrates, making use of this knowledge isn't as easy as just ramping up p16 gene expression in other mammal species:

"I didn't anticipate that increased production of the p16 tumor suppressor protein would so readily promote aging," says Enders, who led the study. "The p16 protein has been previously associated with aging, and we know its expression increases during late stages of aging. But the idea that its expression would be sufficient to generate features of aging was surprising."

Although scientists know that loss of p16 is associated with numerous human tumors, they know much less about the function of p16 in normal cells and tissues. To explore this, Enders' team engineered a strain of mice that enables them to control p16 expression in various tissues and at various times in an animal's lifespan. They quickly found that turning on p16 blocked cell proliferation in normal tissues.

The implications of blocked cell proliferation emerged when they expressed p16 in animals that were not yet fully mature. "They developed features of premature aging," Enders says. "To my knowledge, this is the first model that induces striking characteristics of premature aging where there is no macromolecular damage. The premature aging appears to be the result of blocking cell proliferation."

In this respect, p16 is very similar in behavior to p53. But that in fact means that there is great promise inherent in p16 research: a few years ago, Spanish researchers engineered their way around the aging-cancer balance in mice for p53, producing mice that suffered less cancer and lived 50% longer than normal. Trying a similar approach with p16 sounds very plausible. It is also possible that their work is analogous to the biology of naked mole-rats, animals that manage to live vastly longer than the members of other similarly sized rodent species, and this despite their evolved usage of p16 and apparently complete immunity to cancer. Equally, mole-rats might exhibit yet another completely different configuration of mammalian biology - one that it may soon be possible to reverse engineer and test in mice.

Answers to this sort of speculation still lie in the near future, but research into the biochemistry of p16 and p53 is worth keeping an eye on. Few other methodologies can claim to have extended healthy life in mice by as much as that mentioned above, and, furthermore, somewhere in the biology of these species lies a way to simply turn off cancer.

Calling Stem Cells to Work

Understanding how to manipulate the signaling systems that command stem cells into action will enable many of the same beneficial results as stem cell transplants: "The chemical which summons stem cells from bone marrow to the site of a wound has been discovered by scientists. The study identified the distress signal - HMGB1. The authors believe it can be used to put 'a megaphone in the system' to improve the treatment of injuries such as burns and leg ulcers. ... Bone marrow was thought to play a role in repairing damaged skin, but the exact process was unknown. Scientists [gave] mice bone marrow cells that glow green - which can be tracked while moving round the body. They then wounded the mice and some were given skin grafts. In mice without grafts, very few stem cells travelled to the wound. Those with grafts had many stem cells travelling to the wound. ... grafted skin tissue has no blood vessels and therefore no oxygen. ... this environment leads to the release of HMGB1 [which] results in stem cells moving to the wound. ... Researchers [are] developing a drug to mimic HMGB1. They hope to begin animal testing by the end of the year and human clinical trials shortly afterwards."

Link: http://www.bbc.co.uk/news/health-12956636

A Review of Telomere Studies

Telomere length seems to correlate with general levels of wellbeing. This article reports on: "several studies showing that psychological stress leads to shorter telomeres - the protective caps on the ends of chromosomes that are a measure of cell age and, thus, health. The findings also suggest that exercise may prevent this damage. ... [Researchers] examined telomeres in leukocytes, or white blood cells, of the immune system, which defends the body against both infectious agents and cell damage. ... Our findings suggest that traumatic and chronic stressful life events are associated with shortening of telomeres in cells of the immune system, but that physical activity may moderate this impact ... the current research [followed] for two years 63 healthy postmenopausal women who were the primary caregivers for a family member with dementia. In an earlier analysis of 36 of these women, pessimism was associated with high levels of a pro-inflammatory protein often associated with aging and disease states, and with short telomeres. In a recent and separate analysis of the full group of women, an increase in perceived stress was related to an increase in the odds of having short telomeres only in the non-exercising women. Among those who exercised, perceived stress was unrelated to telomere length. In the current analysis of the larger group, it was revealed that an increase in perceived stress over the course of one year was associated with a decrease in telomere length during that time. ... A third study [analyzed] data from 251 healthy, non-smoking women ages 50-65 of varying activity levels. The findings showed that non-exercising women with histories of childhood abuse had shorter telomeres than those with no histories of abuse. But, in those women who exercised regularly, there was no link between childhood abuse and telomere length, after controlling for body mass index, income, education and age."

Link: http://www.eurekalert.org/pub_releases/2011-04/uoc--emp040111.php

Finally Redesigned

As you may have noticed, Fight Aging! now looks somewhat better than it used to. This major overhaul and redesign has been on my list for a very long time, but it seems to take a good few years for an idea to work its way through the pipeline into actualization around here.

Redesigning a website is a little more of a process than an event: with nearly 8000 posts and a variety of pages, it's a given that there are things lurking in the depths of Fight Aging! that now look worse than they did before. There will be a long list of minor tweaks and edits to make as I uncover the necessity for each. Equally, while I have made the best reasonable effort to ensure that Fight Aging! looks the same in every modern combination of browser and operating system, I'm sure there are one or two of you left with a slightly suboptimal experience.

The first step to fixing issues is to let me know about them - if you see something out of place, the odds are good that it's not something I know about. Otherwise I'd have fixed it already. In particular, it would be good to know that visitors are all seeing the right condensed fonts in the header and the post titles. Custom fonts, and condensed fonts especially, are a horribly broken area of web development, and getting it right for everyone requires some fiddly work. Which should all be in hand and accomplished, but you never really know for sure until you meet that last edge case in person. What you folk should be seeing is shown in the image below - click for a larger version:

If that doesn't reflect what is on your screen now, then let me know.

In the course of working with the designer who put this present layout together, I obtained a good half-dozen variations on the theme: different color palettes, different header images, different navigation styles, and so forth. Now that the basic structure is done, swapping these themes in and out is just a matter of switching the stylesheets that declare the look and feel rules for the site. They are all good-looking variants, and it seems a shame to let them go to waste. So expect to see some changes and experimentation over the next few weeks, insofar as my time allows.

Ultimately I will place a small widget of some sort in the header that will let you choose whichever of the available themes you like the best, and that will be how Fight Aging! appears to you. We'll see how long that takes me.

An Interview with the Cytori Therapeutics CEO

Some interesting quotes can be found in this short piece: "We are at the beginning of a new age in medicine called Regenerative Medicine. The foundation of this is the living cell, although the emerging field will encompass a broad array of technologies. Remember the early days of the Computer Age circa 1978 where there were these new potentially powerful tools, but not a lot of software or applications? Today, almost everything we use or touch is in some way an offspring of this technology. Regenerative Medicine will explode in a similar way with new tools and applications and treatments, many of which are rapidly being developed around the world and I expect will ultimately impact the lives of billions of people. I predict that the innovations around these cell therapies will have as much impact on medicine as the silicon chip has had on technology. ... Medical tourism is gaining momentum worldwide. As the world becomes more 'flat,' medicine becomes somewhat of a commodity. With ever-increasing access to information, patients are doing more research on their conditions, and instead of only having access to treatment at their local medical facility, their reach becomes global. So when new technology is developed and available in one country and not another, savvy patients with the means to access it are able to identify, research, and ultimately receive the care they might not have otherwise. This hopefully will drive down the cost of care, speed the access to innovations, and raise the standard of care globally."

Link: http://www.theatlantic.com/life/archive/2011/04/a-conversation-with-christopher-j-calhoun-ceo-of-cytori-therapeutics/73338/

Recellularization Attempted in Human Hearts

The technique of recellularization has been used to prepare heart valves for transplant, and here researchers are attempting the whole heart: "US researchers have revealed they made the hearts by stripping cells from the hearts of people who had died, leaving behind the organ's tough protein skeleton, known as a 'ghost heart'. The researchers seeded eight ghost hearts with living human stem cells, which successfully stuck to them and then, crucially, started turning into heart cells. ... The hearts are growing and we hope they will show signs of beating within the next week. There are many hurdles to overcome to generate a fully functional heart, but the hope is that it may one day be possible to grow entire organs for transplant. ... It follows a series of successes by [researchers] in growing beating animal hearts. The team has also taken the ghost hearts of rats and pigs and seeded them with human stem cells. Again, the cells multiplied, colonised the structure and started to beat independently. The beating strength was up to 25 per cent that of a normal heart, but the fact the hearts were beating at all was seen as a triumph."

Link: http://www.theaustralian.com.au/news/health-science/story-e6frg8y6-1226032923689

Resting Metabolic Rate Predicts Human Mortality

Allow me to point you to the results of a long-running study on metabolic rate and mortality:

Higher metabolic rates increase free radical formation, which may accelerate aging and lead to early mortality. ... Our objective was to determine whether higher metabolic rates measured by two different methods predict early natural mortality in humans. ... Twenty-four-hour energy expenditure (24EE) was measured in 508 individuals, resting metabolic rate (RMR) was measured in 384 individuals.

The study ran with hundreds of participants over more than twenty years and concluded that there is a good correlation between these measures of metabolic rate and risk of death:

For each 100-kcal/24 h increase in EE, the risk of natural mortality increased by 1.29 in the 24EE group and by 1.25 in the RMR group, after adjustment for age, sex, and body weight in proportional hazard analyses.

The higher your resting metabolic rate, the greater your expected chance of death by aging or disease sometime soon - a cheerful prospect. My first thought was that these measurements should reflect levels of physical fitness achieved through exercise, which we know has a strong effect on mortality, but apparently not:

Studies published in 1992 and 1997 indicate that the level of aerobic fitness of an individual does not have any correlation with the level of resting metabolism. Both studies find that aerobic fitness levels do not improve the predictive power of fat free mass for resting metabolic rate.

There's a lesson there concerning the practice of quickly leaping to what might seem to be sensible conclusions. My slower second thought involved calorie intake: even mild levels of calorie restriction have measurable impacts on health in humans and on longevity in lower animals. Possibly also on longevity in humans, though that study will likely never be undertaken - if started tomorrow, by the time it was even half-way complete we'd be well into the era of rejuvenation biotechnology, making the whole exercise rather pointless.

In any case, the practice of calorie restriction does lower resting metabolic rate, and does so across a range of species: stick insects, rhesus monkeys, and humans, to pick a few. So it seems reasonable to theorize that differences in mortality seen in the study quoted above are reflections of the natural variance of calorie intake amongst the participants, and the biochemical - and existential - consequences of lower versus higher calorie diets.

Towards Enhanced Liver Regeneration

The liver has the greatest capacity for regeneration amongst human organs - but there's always room for improvement. Here, cancer researchers incidentally uncover a potential mechanism to safely boost regenerative capacity: "During chronic liver damage repetitive waves of hepatocyte cell death and compensatory proliferation take place, eventually culminating in chronic liver failure and often in the development of hepatocellular carcinoma (HCC). A misregulated regenerative response to chronic liver injury may represent the base for development of HCC. Therefore, a more detailed understanding of signaling pathways involved in proliferation control of hepatocytes not only holds the great promise of informing new therapies to increase the hepatic regenerative potential but also to deduce new strategies for the treatment of HCC. We have established a unique system to perform in vivo RNAi screens to genetically dissect cellular signaling networks regulating hepatocyte proliferation during chronic liver damage. ... we identified shRNAs which showed strong enrichment during regeneration, therefore pinpointing new regulators of liver regeneration. Our top scoring candidate represents a kinase, which is accessible to pharmacological inhibition. Functional in vivo validation studies show that stable knockdown of the candidate gene by different shRNAs can significantly increase the repopulation efficiency of mouse hepatocytes and also increases the regenerative capacity of chronically damaged mouse livers. Despite the fact that some human HCCs show focal deletion of the candidate gene, a therapeutic window for regenerative therapy exists, as mice stably repopulated with shRNAs against the candidate did not develop liver tumors."

Link: http://www1.easl.eu/easl2011/program/Orals/261.htm

The Cost of a Bad Lifestyle

Type 2 diabetes is a lifestyle disease, avoidable for vast majority of people. If you overeat, become fat, and live a sedentary life then the odds are good you'll develop the condition, or at least its precursor, metabolic syndrome. The cost of this neglect of health basics is measurable: "Middle-aged adults with diabetes are much more likely to develop age-related conditions than their counterparts who don't have diabetes, according to a new study ... Adults between 51 and 70 with diabetes developed age-related ailments like cognitive impairment, incontinence, falls, dizziness, vision impairment and pain at a faster rate than those without diabetes, the study found. ... Our findings suggest that middle age adults with diabetes start to accumulate these age-related problems. Because diabetes affects multiple organ systems, it has the potential to contribute significantly to the development of a number of issues that we associate with aging ... For adults aged 51-60 with diabetes, the odds of developing new geriatric conditions were nearly double those of their counterparts who didn't have diabetes, the researchers found. By the time people with and without diabetes reach 80, the overall effects of aging and impact of other diseases start to reduce the disparities between the two groups. ... The findings suggest that adults with diabetes should be monitored for the development of these conditions beginning at a younger age than we previously thought." Though of course your odds of making it to 80 to be compared to your healthier cohorts are not as good if you're diabetic. So don't get fat, don't stay fat, and exercise sounds like good advice.

Link: http://www.eurekalert.org/pub_releases/2011-03/uomh-acd033111.php