Fight Aging! Newsletter, March 17th 2014

March 17th 2014

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

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  • Sifting the Epigenetic Sea in Search of Sense and Meaning
  • Cryptocurrency Donations to Alcor and the Brain Preservation Foundation
  • Yet Another Study Pointing to the Costs of Visceral Fat
  • Data, Ambiguity, and p66shc
  • Low IGF-1 Predicts Survival in the Oldest Women, But Not in the Oldest Men
  • Latest Headlines from Fight Aging!
    • Stem Cell Transplants as a Treatment for Degenerative Disc Disease
    • Mortality Risks and Classification Issues
    • Cross-Links Can Harm Tendon Collagen Structure
    • Shrinking Gel as a Method of Tooth Tissue Engineering
    • An Interview With Craig Venter on Human Longevity
    • Generating New Neurons in Mouse Brains to Treat Alzheimer's
    • DNA Methylation Patterns Correlate With Socioeconomic Status
    • MicroRNA-29 and Age-Related Muscle Senescence
    • Suggesting the Use of Osteoclasts to Revert Heart Calcification
    • An Unanticipated Result in Cancer Immunotherapy


The SENS Research Foundation (SRF) has enough of a budget these days to be funding a fair number of distinct research projects relevant to aging and longevity - too many for me to be familiar with all of them at this point. Some are fairly indirect, fundamental research that aims to build the foundations needed to even start in on projects that cut to the heart of the matter, the construction of rejuvenation biotechnologies that can reverse the course of degenerative aging. Bear in mind that as research progresses, it will not be the Foundation that funds or accomplishes the bulk of the work needed to make human rejuvenation a reality: these are still the early days, and it is as important to provide groundwork that opens the doors for other groups, or makes a field more financially attractive for development, as it is to make direct headway.

One of the Foundation's areas of interest is cancer and its causes, and this is where you'll find a lot of the more indirect work. There is a broad outline in WILT - whole body interdiction of lengthening of telomeres - as a path to build the ultimate cure for cancer, but it is also the case that a large amount of fundamental genetic science and tool-building is needed to validate and make progress on that path. For my money, I see cancer research as being in much the same state as stem cell research, by which I mean that a massive research edifice is already heading in roughly the right direction, making fair progress towards therapies that a few decades from now will be good enough to get by for the foreseeable future. Stem cells and cancer treatments are not presently set to be the limiting factors for the future of treating and reversing aging, in my opinion.

I'm not running the SRF, of course, and if you look over the Foundation's annual reports you'll see quite a lot of interest in specific tool-building at the intersection of genetics and cancer to arrive at more radical solutions for cancer than those pursued by the present mainstream. (The next generation of cancer therapies emerging from that mainstream are based on selective targeting of cancer cells, offering the promise of few side-effects and high effectiveness - which sounds pretty good to me). You can read an introduction to this area of work at the SENS website, and note that it may well also overlap with means of generating data relevant to questions on aging that are of greater interest than rejuvenation to the research mainstream, such as whether there is any merit at all in programmed aging theories, or whether there are any significant and widespread genetic contributions to longevity in humans.

One area of interest here is the generation and analysis of epigenetic data, something that I'm generally not so hot on as a point of relevance to human longevity, given its usual association with the development of drugs to slow aging or other ways to manipulate metabolism without addressing the underlying causes of dysfunction. Those are the slow roads, unlikely to produce great gains in healthy life span. But here is a piece by philanthropist Jason Hope on the way in which one SRF-funded research program is using epigenetic tools to arrive at a potentially better grasp on cancer at the opening stage, in its very earliest development:

Epimutations  -  Identifying Changes in Structures Controlling the Genetic Code

With funding from SENS Research Foundation, Albert Einstein College of Medicine (AECOM) Team members Dr. Vijg and Dr. Gravina have developed novel ways of identifying changes in the "scaffolding" that structures and controls the expression of the genetic code. These innovative approaches also help scientists determine if these changes in DNA are a response to environmental exposure or the result of damage to the scaffolding, leading to accumulating errors in the regulation of the DNA code. These methods may someday change the way doctors diagnose illnesses, such as cancer, and slow or reverse some of the debilitating effects of aging.

Dr. Gravina and the team tested the new evaluation method by analyzing DNA methylation in thousands of single liver cells, each from a different mouse. The researchers looked at specific locations in DNA scaffolding that control whether the genes are methylated or demethylated. This approach allowed scientists to compare the distinctive methylation and demethylation of individual cells with the widespread patterns of methylation occurring in a larger scale throughout the entire liver.

In other words, Dr. Gravina and his team found a way to determine whether changes in methylation were responses to environmental conditions common to many cells in the liver or were aberrant patterns unique to individual cells  -  widespread changes are likely the response to environmental stimuli whereas single cell deviations from the wider pattern are likely to be the result of damage to the epigenetic structure. The new approach developed with the support of SENS Research Foundation funding could be the foundation for new technologies for identifying cancers at their earliest stages.

You can probably see how this work will be of interest to researchers studying genetics and longevity, especially those who think that aging is a programmed set of epigenetic changes. As to cancer: the advantage of very early detection of cancer is that we don't need radical new technologies to eliminate early cancers with a high degree of reliability and comparatively little trauma. That goal is achievable with incremental advances in medical technology in the near term. Getting rid of very early stage cancer is very possible for many cancers even today, but the trouble is that by the time cancer is discovered it is almost always well past that stage. So there is a path here towards making the mainstream initiatives in targeted cancer treatment far, far more effective than would otherwise be the case. But again, I see this all happening on a good schedule with or without the help of the SRF: work on early detection of cancer is already an established line of research. This thus looks like tool-building, a process of making technologies that are needed for other Foundation work, and which also happen to have much broader applications in mainstream medicine.


Bitcoin is the best known of the now numerous distributed cryptography protocols that are usually represented in the form of a currency or commodity. Use in payments is probably the least of the future applications that will arise from the ability to use cryptography to solve important problems in trust and coordination - consider decentralized arbitration and escrow wherein there is no need for any third party to be trusted with funds, for example - but for now the trading of coins is where much of the attention lies.

With the growth of Bitcoin, all of the other various cryptocurrencies have seen their values rise. In effect, to my eyes, what is being valued here is the current or potential ability of a given cryptocurrency network to perform trust operations - such as payment, arbitration, escrow, validation of identity, and so forth - more efficiently than the old-fashioned methodologies, largely by removing the need for a central trusted party and single point of failure. A lot of early adopters are suddenly doing rather well for themselves, and that includes charities fortunate enough to have supporters who helped them to receive bitcoins or other cryptocoins prior to the present level of attention. The Lifeboat Foundation, for example, found themselves with several hundred thousand dollars in bitcoins, and more power to them.

I note that one of the initial investors in another cryptocurrency, NXT, has made praiseworthy donations in coin to some of the cryonics and cryonics-related charities in the community. Good for him:

Androklis Polymenis Donates 1 Million NXT to Alcor

Androklis Polymenis, a digital currency entrepreneur, has recently donated 1 million NXT coins to the Alcor Life Extension Foundation located in Scottsdale, Arizona. After Alcor converted the 1 million NXT coin donation by Polymenis to bitcoins (and then to dollars) the end result was an approximately $44,000 donation to Alcor. The donation will be used to enhance marketing efforts, special projects and continued day to day operations at Alcor.

Alcor President, Max More, said that "This was a wonderful surprise to our foundation. Alcor would like to extend our sincerest gratitude to Mr. Polymenis for his kindness and generous financial contribution. This donation will help us continue our research and bring greater awareness of the possibilities of cryonics to a wider audience."

Androklis Polymenis Donates 1 Million NXT Coins to Brain Preservation Foundation

The Brain Preservation Foundation (BPF) has received a one million NXT coin ($43,000) donation from the digital currency entrepreneur Androklis Polymenis. The donation goes toward supporting its research into the development of a scientifically-proven medical procedure capable of preserving a person's unique neural circuitry at death with the hope of allowing that person to eventually be brought back to life by future technology.

This large donation will be used by the BPF to help fund its electron microscopic evaluation of cryonically and chemically preserved animal brains which are provided to the BPF by the research groups competing in its Brain Preservation Technology Prize. This is a challenge prize offered to any research group which can rigorously demonstrate a technique capable of preserving an entire human brain with such fidelity that the structure of every neuronal process and synaptic connection remains intact and traceable using today's electron microscopic imaging techniques.

Mr. Polymenis' generous donation will also help fund targeted research grants to scientific labs with the skills needed to overcome current limitations in cryonic and chemical preservation protocols.

It is worth noting that NXT is very different to Bitcoin in near all of its fundamental aspects, and some of those differences are not viewed well by all within the cryptocoin community. Your opinions may differ, but caveat emptor is always the rule of the day. A great deal of experimentation is presently underway in cryptocurrencies, and I suspect that only a small percentage of those currently in circulation will survive the test of time - as is the case for most traditional ventures in business and collaboration. This is the way in which progress works; a great deal of trial and error accompanies each new discovery.


There are a range of mechanisms associated with the health costs of becoming fat, some of which are much more iron-clad than others when it comes to the supporting evidence. On the leading edge, there is the comparative lack of exercise usually associated with gaining weight. It is also probably the case that increased levels of methionine intake that come with a larger calorie intake lead to an unfavorable adjustment of metabolism. Once you have excess visceral fat tissue, the inner fat tissue that accumulates around your abdominal organs, this acts to further alter metabolism in harmful ways - it is much more active in this respect than other fat tissue in the body. It also leads to increased levels of chronic inflammation, and is associated with higher mortality and a raised risk of suffering most of the common fatal age-related conditions.

This visceral fat is so damaging to health that you can pick out its effects just by looking at measures of body shape that preferentially capture visceral fat over other aspects of weight gain. Body mass index is useful but a little too insensitive to weight distribution, for example, which is why researchers tend to come up with other proposed categorization systems for epidemiological studies such as the body shape index noted last month. But even very simple approaches such as measuring waist circumference can distinguish the impact of visceral fat on health in large studies:

Large Waist Linked to Poor Health, Even Among Those in Healthy Body Mass Index Ranges

Having a big belly has consequences beyond trouble squeezing into your pants. It's detrimental to your health, even if you have a healthy body mass index (BMI). Men and women with large waist circumferences were more likely to die younger, and were more likely to die from illnesses such as heart disease, respiratory problems, and cancer after accounting for body mass index, smoking, alcohol use and physical activity.

The researchers pooled data from 11 different cohort studies, including more than 600,000 people from around the world. They found that men with waists 43 inches or greater in circumference had a 50 percent higher mortality risk than men with waists less than 35 inches, and this translated to about a three-year lower life expectancy after age 40. Women with a waist circumference of 37 inches or greater had about an 80 percent higher mortality risk than women with a waist circumference of 27 inches or less, and this translated to about a five-year lower life expectancy after age 40.

Importantly, risk increased in a linear fashion such that for every 2 inches of greater circumference, mortality risk went up about 7 percent in men and about 9 percent in women. Thus, there was not one natural "cutpoint" for waist circumference that could be used in the clinic, as risk increased across the spectrum of circumferences. Another key finding was that elevated mortality risk with increasing waist circumference was observed at all levels of BMI, even among people who had normal BMI levels.

All in all getting fat seems like a poor plan and staying fat a worse one. Medical science may well advance rapidly enough to rescue you from the consequences at some point later in your life, and almost certainly so if you are presently young, but why roll the dice and endure those consequences at all if you don't have to?


The trouble with trying to slow down aging by manipulating metabolism is that the interaction of day to day metabolism and the processes driving aging is fantastically complex. So much so that the investigation of even tiny little slices of it by multiple research teams can span a decade or more, consume millions of dollars, and yet produce no great advance in understanding of the big picture over that time. This is the story for the role of p66shc in aging and mitochondrial metabolism: data is gathered and scientists are at work, but the high level explanation of what is known remains much the same as it was ten years ago. Reducing or removing the protein p66shc may or may not extend life in mice, and may or may not be a meaningful target for age-slowing drugs in humans.

The researchers quoted below, like other teams, investigate p66shc in the context of mitochondria and aging. As in past research, the fact that p66shc has an influence on reactive oxygen species production in mitochondria makes it plausible that it might have some role in the pace of aging. Numerous genetic alterations that extend life in lower animals are accompanied by either an increase or reduction in the production of reactive oxygen species. The theory here is that a reduction means less oxidative damage to cellular components and an increase means that cellular housekeeping mechanisms are spurred into greater action, with the same end result of a net lowering of oxidative damage. (This is to be compared with other alterations that reduce life span while either lowering or raising generation of reactive oxygen species. Nothing is ever simple). The reality under the hood is probably more complicated than present theories in many of these cases, and there is plenty of room for new data, new interpretations, and new arguments as to how these established means of life extension via slowing aging actually work.

Again, it comes back to the fact that this is all enormously complex. Adjusting metabolism in a desired way is very hard at our present level of technology and understanding. Consider, for example, that we have calorie restriction and exercise as examples of ways to reliably reproduce desirable alterations in metabolism. They are right in front of us to study whenever we want, in as much detail as we want, and yet despite that fact, some fifteen years of work and billions of dollars have so far failed to find ways to safely and reliably recreate even a fraction of these altered metabolic states.

In any case, this paper is more grist for the mill of plausibility when it comes to p66shc levels influencing the course of aging. The researchers also make some interesting comments on the differences between mice and humans in the discussion:

Prooxidant Properties of p66shc Are Mediated by Mitochondria in Human Cells

p66shc is a protein product of an mRNA isoform of SHC1 gene that has a pro-oxidant and pro-apoptotic activity and is implicated in the aging process. Mitochondria were suggested as a major source of the p66shc-mediated production of reactive oxygen species (ROS), although the underlying mechanisms are poorly understood.

We studied effects of p66shc on oxidative stress induced by hydrogen peroxide or by serum deprivation in human colon carcinoma cell line RKO and in diploid human dermal fibroblasts (HDFs). An shRNA-mediated knockdown of p66shc suppressed and an overexpression of a recombinant p66shc stimulated the production of ROS in the both models. This effect was not detected in the mitochondrial DNA-depleted ρ0-RKO cells that do not have the mitochondrial electron transport chain (ETC). Mitochondria-targeted antioxidants SkQ1 and SkQR1 also decreased the oxidative stress induced by hydrogen peroxide or by serum deprivation. Together the data indicate that the p66shc-dependant ROS production during oxidative stress has mitochondrial origin in human normal and cancer cells.

Noteworthy, most studies challenging functions of p66shc in mitochondria were performed in mouse models. However, the impact of oxidative stress that hypothetically may serve as a rheostat for the lifespan regulation differs substantially in the mouse and the human models. Human cells are more resistant to oxidative stresses and have at least two-fold lower mitochondria ROS production rate. Therefore, some mechanisms related to p66shc and their significance could also differ in human cells. More focused studies on p66shc mechanisms in human cells would provide valuable clues for treatment and prevention of accelerated aging and numerous diseases associated with elevated ROS.


As I mentioned yesterday, the biology of aging, the actual dance of proteins and mechanisms and environment that progressively kills us, is enormously complex in its progression from day to day and year to year. Decades and billions of dollars have only scratched the surface, even in this age of rapidly advancing biotechnology. Researchers have focused on a handful of starting point proteins and their roles and are making painstaking inroads into greater understanding, year by year, but we stand a very long way from being able to use modern medicine safely and effectively adjust the operation of metabolism to slow aging - because that would require reproducing or at least understanding a fair fraction of the great complexity of the ongoing dance. Exercise and calorie restriction remain by far the best presently available options if slowing aging is your goal, and I don't expect to see them greatly improved on for a good fifteen to twenty years yet.

Fortunately there is an entirely different and much better path towards lengthening healthy life, which is to identify and repair the forms of cellular and molecular damage that cause aging. Researchers know what these forms of damage are because comparing the detailed structure of old and young tissue has been well within our capabilities for several decades. Remove all the differences between old flesh and young flesh and old cells and young cells and what you have is young flesh and young cells: a process of rejuvenation by biochemical repair. The old could be restored to youthful health and function, and young never become damaged by age. The big deal about this approach is that (a) we know very well how to go about building treatments to do it, and (b) it doesn't require any further understanding of how aging actually happens at the detail level. We know enough now.

But I'm not talking about that today. Today is a return to one of the proteins under investigation by researchers whose primary goal is understanding, and whose slowly growing secondary goal is to try to build some sort of treatment to slow aging that looks enough like a drug to be palatable to the FDA - where the bureaucrats don't accept treatment of aging as a valid activity and will not presently approve any sort of approach to lengthening life through tackling the aging process itself. That is well known and echoes all the way back down the funding chain from commercial development to primary research. What this means in practice is that it is much harder to try to build a great way of preventing age-related disease by tackling aging than it is to try to build yet another mediocre advance in patching over the consequences of age-related disease after the fact. It's a messed-up world that we live in.

The protein of interest is IGF-1, long known to be involved in a range of mechanisms of interest to aging. As for most such culprit proteins it has many roles, as evolution likes reuse. The picture is very complex and challenging to pick apart into its component pieces, but here is a representative human study in which researchers identify a correlation between IGF-1 levels and remaining life expectancy in the elderly. As for most such things it isn't a straightforward correlation, however, and in this case it exists for women only.

Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity

Individuals with exceptional longevity comprise an advantageous group for the study of mechanisms that promote healthy aging, as many of them have delayed onset or have been spared from age-related diseases. Diminished IGF-1 signaling may be one such mechanism. Our group showed that a functional mutation in the IGF-1 receptor, which confers partial IGF-1 resistance, was more prevalent in centenarians, as compared to controls without familial longevity. Based on these observations in humans and other species, we hypothesized that lower IGF-1 levels are predictive of extended survival in generally healthy nonagenarians.

We tested the hypothesis that IGF-1 levels in nonagenarians (n = 184), measured at study enrollment, predict the duration of their incremental survival. In the Kaplan-Meier analysis, females with IGF-1 levels below the median had significantly longer survival compared with females with levels above the median. However, this survival advantage was not observed in males.

If you look back in the Fight Aging! archives you'll find a paper showing a correlation between high IGF-1 and increased survival in old men:

In this study, researchers evaluated 376 healthy elderly men between the ages of 73 and 94 years. A serum sample was taken from each subject at the beginning of the study and researchers were contacted about the status of the participants over a period of eight years. Subjects with the lowest IGF-1 function had a significantly higher mortality rate than subjects with the highest IGF-1 bioactivity. These results were especially significant in individuals who have a high risk to die from cardiovascular complications.

But in general, yes, the bulk of animal studies on IGF-1 lean the other way: less is better. Still, is this simple, clear, and well understood? No, of course not. Don't hold your breath waiting for ways to significantly extend life to emerge from this field - most of the participants are not interested in that outcome, and even if they were this is an expensive, long, confusing road to the poor end result of merely slowing aging, not reversing it.


Monday, March 10, 2014

Researchers review the evidence from animal studies suggesting that stem cell transplants are a beneficial treatment for degenerative disc disease. This is a treatment that has been available via medical tourism for some years now, though it is still only just entering clinical trials in the US:

Stem cell transplant was viable and effective in halting or reversing degenerative disc disease of the spine, a meta-analysis of animal studies showed, in a development expected to open up research in humans. Recent developments in stem cell research have made it possible to assess its effect on intervertebral disc (IVD) height. Not only did disc height increase, but stem cell transplant also increased disc water content and improved appropriate gene expression. "These exciting developments place us in a position to prepare for translation of stem cell therapy for degenerative disc disease into clinical trials."

The increase in disc height was due to restoration in the transplant group of the nucleus pulposus structure, which refers to the jelly-like substance in the disc, and an increased amount of water content, which is critical for the appropriate function of the disc as a cushion for the spinal column. What they found was an over 23.6% increase in the disc height index in the transplant group compared with the placebo group. None of the 6 studies showed a decrease of the disc height index in the transplant group. Increases in the disc height index were statistically significant in all individual studies.

"A hallmark of IVD degenerative disease is its poor self-repair capacity secondary to the loss of IVD cells. However, current available treatments fail to address the loss of cells and cellular functions. In fact, many invasive treatments further damage the disc, causing further degeneration in the diseased level or adjacent levels. The goal of tissue engineering using stem cells is to restore the normal function and motion of the diseased human spine."

Monday, March 10, 2014

Data on the degree to which various age-related conditions contribute to mortality is actually a lot less precise than most people assume it to be. Cause of death in old age is often either ambiguous or ambiguously recorded, leading to the need for estimation and correction via statistical methods. This opens the door to arguments as to the plausibility of data for any particular age-related condition, claiming that it is either more or less of a threat than previously thought. Here, for example, epidemiologists argue that Alzheimer's disease causes far more deaths than are officially reported as being due to this condition:

Data came from 2,566 persons aged 65 years and older (mean 78.1 years) without dementia at baseline from 2 cohort studies of aging with identical annual diagnostic assessments of dementia. Because both studies require organ donation, ascertainment of mortality was complete and dates of death accurate. Mortality hazard ratios after incident AD dementia were estimated per 10-year age strata from proportional hazards models. Population attributable risk percentage was derived to estimate excess mortality after a diagnosis of AD dementia. The number of excess deaths attributable to AD dementia in the United States was then estimated.

Over an average of 8 years, 559 participants (21.8%) without dementia at baseline developed AD dementia and 1,090 (42.4%) died. Median time from AD dementia diagnosis to death was 3.8 years. The mortality hazard ratio for AD dementia was 4.30 for ages 75-84 years and 2.77 for ages 85 years and older (too few deaths after AD dementia in ages 65-74 were available to estimate hazard ratio). Population attributable risk percentage was 37.0% for ages 75-84 and 35.8% for ages 85 and older. An estimated 503,400 deaths in Americans aged 75 years and older were attributable to AD dementia in 2010.

[Thus] a larger number of deaths are attributable to AD dementia in the United States each year than the number (less than 84,000 in 2010) reported on death certificates.

Given that there were overall 2.5 million deaths in the US in 2010, with the largest attributed causes being cancer and heart disease, this paper is suggesting that a large systematic miscategorization exists, not just the need for a modest correction.

Tuesday, March 11, 2014

Cross-links between proteins are formed by advanced glycation end-products and become a growing problem with advancing age. The best understood consequences are the degradation of elasticity in skin and blood vessels, but there are many other forms of harm that result from this interference with tissue structure. There is too little research presently taking place on methods of safely breaking cross-links, but this is something that the SENS Research Foundation seeks to change - the means to make an impact on aging here is one of the forms of rejuvenation treatment that might be developed comparatively rapidly, given the funding.

Here is an example of another form of harm created by cross-links, this time in the structure of tendons. The molecular structure of tissues determines their properties, such as mechanical strength and elasticity, and damage to that structure leads to loss of function:

Recent molecular modeling data using collagen peptides predicted that mechanical force transmitted through intermolecular cross-links resulted in collagen triple helix unwinding. These simulations further predicted that this unwinding, referred to as triple helical microunfolding, occurred at forces well below canonical collagen damage mechanisms. Based in large part on these data, we hypothesized that mechanical loading of glycation cross-linked tendon microfibers would result in accelerated collagenolytic enzyme damage.

This hypothesis is in stark contrast to reports in literature that indicated that individually mechanical loading or cross-linking each retards enzymatic degradation of collagen substrates. Using our Collagen Enzyme Mechano-Kinetic Automated Testing (CEMKAT) System we mechanically loaded collagen-rich tendon microfibers that had been chemically cross-linked with sugar and tested for degrading enzyme susceptibility. Our results indicated that cross-linked fibers were more than 5 times more resistant to enzymatic degradation while unloaded but became highly susceptible to enzyme cleavage when they were stretched by an applied mechanical deformation.

Tuesday, March 11, 2014

A novel approach in the tissue engineering of teeth is covered in this piece. It shows promise, but is still in the early stages of development in comparison to other methodologies in which researchers have actually created whole functional teeth:

[Researchers] investigated a process called mesenchymal condensation that embryos use to begin forming a variety of organs, including teeth, cartilage, bone, muscle, tendon, and kidney. In mesenchymal condensation, two adjacent tissue layers - loosely packed connective-tissue cells called mesenchyme and sheet-like tissue called an epithelium that covers it - exchange biochemical signals. This exchange causes the mesenchymal cells to squeeze themselves tightly into a small knot directly below where the new organ will form. By examining tissues isolated from the jaws of embryonic mice, [researchers] showed that when the compressed mesenchymal cells turn on genes that stimulate them to generate whole teeth composed of mineralized tissues, including dentin and enamel.

[The researchers then] set out to develop a way to engineer artificial teeth by creating a tissue-friendly material that accomplishes the same goal. Specifically, they wanted a porous sponge-like gel that could be impregnated with mesenchymal cells, then, when implanted into the body, induced to shrink in 3D to physically compact the cells inside it. They chemically modified a special gel-forming polymer called PNIPAAm that scientists have used to deliver drugs to the body's tissues. PNIPAAm gels have an unusual property: they contract abruptly when they warm. Ultimately, they developed a polymer that forms a tissue-friendly gel with two key properties: cells stick to it, and it compresses abruptly when warmed to body temperature.

[Researchers worked to] load mesenchymal cells into the gel, then implant the gel beneath the mouse kidney capsule - a tissue that is well supplied with blood and often used for transplantation experiments. The implanted cells not only expressed tooth-development genes; they also laid down calcium and minerals, just as mesenchymal cells do in the body as they begin to form teeth. In the embryo, mesenchymal cells can't build teeth alone - they need to be combined with cells that form the epithelium. In the future, the scientists plan to test whether the shrinking gel can stimulate both tissues to generate an entire functional tooth.

Wednesday, March 12, 2014

Below is a pointer to a recent radio interview with Craig Venter on the subject of his new venture Human Longevity, Inc. It is my belief that genetic data and analytics at the large scale will benefit medicine as a whole, the quality of cancer treatments especially, but the direct utility of this field to radical life extension is limited. Beyond a few narrow applications it does not have a large role in the creation of a toolkit of rejuvenation treatments, which is the best road ahead. On the other hand, it will be very helpful to attempts to identify longevity-associated genes and genetic variations, or slow aging via metabolic manipulation, but those have never been very plausible paths to greatly extend human life. Slowing aging is an expensive, slow road to a poor outcome: treatments that won't produce a large effect, have to be applied constantly over an entire life span, and which cannot greatly help anyone already old.

Aging. It's a universal disease, and an inescapable killer. As more of us escape traumatic deaths, life expectancy has grown dramatically in our time. As more and more individuals in the developed world manage to escape premature death, life expectancy has grown dramatically in our time. Diseases like cancer and dementia can be understood as consequences of a deteriorating body for reasons science still doesn't understand. We're exploring what might be considered the natural limits of the human body, and some believe that we can choose to push those limits out. What is a human lifespan? Is there any reason why we can't function biologically and mentally for 200 years?

One of the best known and respected genomic and synthetic life scientists, J. Craig Venter, says aging is a phenomenon we can control and arrest through genomic science. He believes that by aggressively accelerating human mapping we can better understand - and prevent - the consequences of human aging. His new project is called Human Longevity Inc., and the company aims to combine genetic and medical data at a massive scale to come up with new ways to predict, prevent and treat diseases of aging, such as cancer, heart disease and Alzheimer's.

To crack the question of aging, Venter says his new project will connect layers of information that have never been put together, starting with the entire human genome and then layering in the genetic code of the microbes, in addition to measuring proteins and chemicals. "We'll be doing tests that people won't necessarily be able to get anywhere else, and combining that all together. We're trying to get the whole picture and create a database that can actually become really predictive of what's associated with disease and what's associated with health."

Wednesday, March 12, 2014

The brain does generate new neurons over a lifetime, a process known as neurogenesis, but at a sedate pace. Various methods have been shown to boost the rate of neurogenesis in laboratory animals, in order to somewhat reverse age-related loss of memory or turn back some of the other symptoms of neurodegenerative conditions. It isn't always clear that the generation of new neurons is in fact the direct cause of such benefits, however:

[Researchers] have discovered that by reestablishing a population of new cells in the part of the brain associated with behavior, some symptoms of Alzheimer's disease significantly decreased or were reversed altogether. The research [was] conducted on mouse models; it provides a promising target for Alzheimer's symptoms in human beings as well. "Until 15 years ago, the common belief was that you were born with a finite number of neurons. You would lose them as you aged or as the result of injury or disease. We now know that stem cells can be used to regenerate areas of the brain."

After introducing stem cells in brain tissue in the laboratory and seeing promising results, [researchers] leveraged the study to mice with Alzheimer's disease-like symptoms. The gene (Wnt3a) was introduced in the part of the mouse brain that controls behavior, specifically fear and anxiety, in the hope that it would contribute to the [expression] of genes that produce new brain cells. Untreated Alzheimer's mice would run heedlessly into an unfamiliar and dangerous area of their habitats instead of assessing potential threats, as healthy mice do. Once treated with the gene that increased new neuron population, however, the mice reverted to assessing their new surroundings first, as usual.

"Normal mice will recognize the danger and avoid it. Mice with the disease, just like human patients, lose their sense of space and reality. We first succeeded in showing that new neuronal cells were produced in the areas injected with the gene. Then we succeeded in showing diminished symptoms as a result of this neuron repopulation."

Thursday, March 13, 2014

A big mess of correlations exists between social status, wealth, intelligence, education, stress, life expectancy, and a range of aspects of our biology linked to variations in longevity, such as telomere length, epigenetic patterns of DNA methylation, and so forth. There are many moving parts here and the situation is complex enough that I imagine people will still be gathering data and arguing over interpretations long after the research community has created means of rejuvenation, ways to extend healthy life by far greater amounts than the present natural variations in human life span, that will make all of this irrelevant:

Epigenetic programming and epigenetic mechanisms driven by environmental factors are thought to play an important role in human health and ageing. Global DNA methylation has been postulated as an epigenetic marker for epidemiological studies as it is reflective of changes in gene expression linked to disease. Insufficient maternal care or diet can be reflected in the methylation status of their offspring. Indeed, an inherited sensitivity to stress, influenced by the mood of the mother during pregnancy, has also been reported. These observations suggest that there may be an adaptive mechanism which allows for epigenetic plasticity in response to environmental changes. A broad range of environmental factors may therefore impact on global DNA methylation status and consequently health. This is important to the understanding of the impact of socio-economic drivers of ill health, which may be predominant in communities where there is also a higher prevalence of classical risk factors for disease.

The aim of this study was to investigate the relationship between socio-economic and lifestyle factors and epigenetic status, as measured by global DNA methylation content, in the pSoBid cohort, which is characterized by an extreme socio-economic and health gradient. Global DNA hypomethylation was observed in the most socio-economically deprived subjects. Job status demonstrated a similar relationship, with manual workers having 24% lower DNA methylation content than non-manual. Additionally, associations were found between global DNA methylation content and biomarkers of cardiovascular disease (CVD) and inflammation, including fibrinogen and interleukin-6 (IL-6), after adjustment for socio-economic factors.

Thursday, March 13, 2014

Many research groups around the world are all gnawing away at their own little pieces of the very large and complex web of interactions between proteins in particular areas of age-related degeneration. Here is work focused on a narrow portion of the biochemistry of progressive loss of muscle mass and function:

The loss of muscle mass in older subjects, termed sarcopenia, not only decreases muscle strength, contributing to a high incidence of accidental falls and injuries but also compromising the quality of life of elderly subjects. Identification of mechanisms and contributors to aging-induced muscle loss could lead to new therapeutic strategies for preventing and treating sarcopenia. Thus, we examined mechanisms causing sarcopenia and the development of muscle cell senescence in both mice and rats, [and] found that the microRNA miR-29 can initiate muscle cell senescence leading to aging-induced sarcopenia. miR-29 was increased in muscles of both mice and rats and it was associated with the presence of higher levels of cellular arrest proteins and lower levels of cell proliferation.

Expression of miR-29 suppressed the expression of IGF-1 and p85α and B-myb and led to induction of senescence in vivo. Thus, the presence of senescent cells that are derived from muscle progenitor cells (MPCs) would contribute to an exhaustion of MPCs regeneration, contributing to the development of muscle atrophy and sarcopenia. In vivo, electroporation of miR-29 into muscles of young mice suppressed the proliferation and increased levels of cellular arrest proteins, recapitulating aging-induced responses in muscle. A potential stimulus of miR-29 expression is Wnt-3a since we found that exogenous Wnt-3a stimulated mir-29 expression 2.7-fold in primary cultures of MPCs. The increase in miR-29 provides a potential mechanism for aging-induced sarcopenia.

Friday, March 14, 2014

The whole cardiovascular system becomes increasingly calcified with advancing age. As is also the case for the accumulation of advanced glycation endproducts (AGEs) this process increases vascular stiffness and otherwise degrades the functionality of heart and blood vessel tissues. A few researchers have proposed a similar strategy to that adopted for AGEs, which is to find drugs to remove the calcification. Here, however, an alternative approach is suggested:

Cardiovascular calcification (deposits of minerals in heart valves and blood vessels) is a primary contributor to heart disease, the leading cause of death among both men and women in the United States. "Unfortunately, there currently is no medical treatment for cardiovascular calcification, which can lead to acute cardiovascular events, such as myocardial infarction and stroke, as well as heart failure. We have not found a way to reverse or slow this disease process, which is associated with aging and common chronic conditions like atherosclerosis, diabetes, and kidney disease."

A team of [researchers] has discovered certain proteins in osteoclasts, a precursor to bone, that may be used in helping to destroy cardiovascular calcification by dissolving mineral deposits. The research suggests a potential therapeutic avenue for patients with cardiovascular calcification. Mature osteoclasts are not typically found in the vasculature. Using unbiased global proteomics (study of proteins), the researchers were able to examine osteoclast-like cells in the vasculature to determine which proteins induced osteoclast formation. They identified more than 100 proteins associated with osteoclast development. Follow-up study validated six candidate proteins, which serve as targets for possible medications that may help promote osteoclast development in the vasculature.

"To advance this research, we need to further understand why osteoclasts are not prevalent in the vaculature, despite active calcification of the heart valves and blood vessels, and determine the difference between calcification in vasculature compared with calcification in bone. Then, we may examine ways to form osteoclasts in the vasculature."

Friday, March 14, 2014

Researchers working on viral immunotherapy for cancer have uncovered an unexpectedly beneficial mechanism:

The study evaluated a combination therapy in which the Newcastle disease virus (NDV), a bird virus not ordinarily harmful to humans, is injected directly into one of two melanoma tumors implanted in mice, followed by an antibody that essentially releases the brakes on the immune response. The researchers report that the combination induced a potent and systemically effective anti-tumor immune response that destroyed the non-infected tumor as well. Even tumor types that have hitherto proved resistant to checkpoint blockade and other immunotherapeutic strategies were susceptible to this combined therapy.

[Researchers] found that an inflammatory immune response induced in the tumor by NDV primarily accounts for the efficacy of the therapy. The checkpoint blockade antibody used in this study binds CTLA-4, a molecule found on immune cells that acts like a brake (or "checkpoint") on the immune response. A version of this antibody is already used for cancer therapy, and it has proved potent in a clinical trial evaluating its combination with another immunotherapy as well. The researchers noticed that when NDV was injected into a tumor implanted in mice, cancer-killing immune cells flooded into that tumor. "But we also found, to our surprise, that a similar infiltration of activated immune cells occurred in a distant tumor, one in which the virus was never detected."

The researchers show that NDV infection alerts T cells of the immune system to the presence of cancer cells, which otherwise suppress immune surveillance and attack. Subsequent injection of the anti-CTLA-4 antibody dials up the incipient anti-tumor response so dramatically that it overcomes the tumor's immune suppression and destroys both NDV-exposed tumors and unexposed tumors. And the effect appears to be durable. When the same tumors are reintroduced into treated animals, they are swiftly eliminated.


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