The cancer stem cell hypothesis suggests that a majority of cancers are driven and supported by a small population of errant stem cells, and that these cells are characteristic in ways allowing them to be identified and destroyed. Without the cancer stem cells, a cancer would whither. In other words, cancer stem cells offer the hope that there are in fact broad commonalities in the mechanisms of different forms of cancer, and that this fact will lead to a unified, single technology platform and robust cures for even late-stage cancers.

The existence and universality of cancer stem cells is a hotly debated topic in medical research, and rightly so for the reasons given above. Good evidence and arguments can be found on either side. Is cancer something that can be solved through a single mechanism or group of very similar mechanisms? Or only some cancers? Or only few cancers? These are important questions, and the answers, when they arrive, will tell us whether the prospects are for many cures arriving soon or for a slow and incremental flow of therapies over decades.

Today I noticed a good introductory popular science article that walks through the present state of research and scientific thought on this topic, and provides copious references along the way. You might find it interesting:

Take some cells from a tough-to-treat tumor, sort them, and inject each fraction into a different immunodeficient mouse, and only a small percentage of those cells will thrive and form tumors. This sort of experiment illustrates a concept that has been gaining traction within the cancer research community. Tumors contain a diverse mixture of cells, and only a handful of them can bounce back after treatment. That deadly minority can reproduce indefinitely and differentiate into a wide variety of cell types, just like stem cells. And often they express many of the same genes that are active in induced or embryonic stem cells and inactive in mature tissue.

...

The logic of pursuing therapies that might zero in on cancer stem cells is compelling to many. But the methods to evaluate such therapies' effectiveness, or to personalize cancer treatments according to stem cell markers, are not nearly as well developed. Without an array of proper markers, it's hard to tell whether drugs that target cancer stem cells are working as intended. ... Things are looking up for genetic analysis, but the poor reliability of cancer stem-cell-surface markers remains a confounding problem. For nearly a decade, biologists have known that antigens such as CD133 can be found on the surfaces of cancer stem cells. But these markers are not particularly specific.

...

But for solid tumors, which account for about 85% of all cancer diagnoses, the search for such stem-cell-surface markers is still in the early days. In such [cancers] cell-surface markers can vary from one type of cancer to another or even from one cell within a tumor to another. Until better markers are discovered [the] cancer stem cell field will remain somewhat embryonic.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A number of different research teams have recently demonstrated epigenetic markers that can be used to establish chronological age or predict life expectancy to various degrees. Here is another: "Aging has been associated with accumulation of cellular defects such as DNA damage and telomere shortening. On the other hand, there is accumulating evidence that aging rather resembles a developmentally regulated process which is tightly controlled by specific epigenetic modifications. ... All tissues of the organism are affected by aging. This process is associated with epigenetic modifications such as methylation changes at specific cytosine residues in the DNA (CpG sites). Here, we have identified an Epigenetic-Aging-Signature which is applicable for many tissues to predict donor age. ... This Epigenetic-Aging-Signature was tested on a validation group of eight independent datasets corresponding to several cell types from different tissues. ... The average absolute difference between predicted and real chronological age was about 11 years. ... It has to be noted, that chronological age is not identical with biological age and it is conceivable that some of the discrepancy between predicted and real age can be attributed to this difference - further research might facilitate determination of the biological age for personalized medicine."

Link: http://impactaging.com/papers/v3/n10/full/100395.html

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

There are a number of different lines of research focused on developing artificial blood or culturing blood to order from stem cells: "Clinical trials using blood created from adult stem cells are set to begin within the next two or three years, raising the prospect it could soon become routinely used where real blood is unavailable. Scientists are also developing alternative bloodlike substances which could be injected into the body as a 'stopgap' until an actual blood transfusion could be performed. ... modern doctors have minimised the risk of patients receiving infections such as Hepatitis A and C during transmission [but] blood produced from stem cells would avoid these risks and could be manufactured as type 'O-negative', which is produced by just 7 per cent of the population but is suitable for use in into up to 98 per cent of patients. ... It could also be used in certain hospital situations, for example in elective surgery, and save hundreds of thousands of lives in parts of the world where blood banks are not available. [Researchers have] developed a method of taking adult stem cells from bone marrow and growing them in the laboratory to produce cells which look and act almost identically to red blood cells. Once their technique is fine-tuned the team may consider using stem cells taken from embryos, or reprogrammed skin cells, instead of adult cells because although the end product does not mimic red blood as closely, they can be grown in much greater quantities in the lab. ... A more radical solution, which [researchers] say could be perfected within five to 10 years, is to develop a completely artificial alternative to blood which performs the same key functions and would be safe to use in patients of every blood type. This could involve packing haemoglobin - which carries oxygen around the body - into a synthetic cell-like structure, or using a chemical to hold the haemoglobin together so that it can be injected without the need for red blood cells."

Link: http://www.telegraph.co.uk/science/science-news/8850684/Artificial-blood-could-be-used-within-next-decade.html

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

SENS Foundation co-founder Aubrey de Grey recently presented at a meeting of the MIT Club of Northern California, and a two-part video record of the event was uploaded for those of us too distant in time and space to be there:

Join us for a fascinating discussion with Dr. Aubrey de Grey, Chief Science officer of the SENS Foundation (SENS stands for "Strategies for Engineered Negligible Senscence"), on the topic of "Regenerative Medicine Against Aging."

Dr. de Grey has been a provocative and polarizing figure in the scientific and medical communities' dialogue on the topic of life extension, and the approaches that will
lead to dramatic increases in quantity and quality of life.

According to Dr. de Grey, "the first human who will live up to 1,000 years is probably already alive now, and might even be today between 50 and 60 years old."

You might look back into the archives for an explanation of the 1,000 year life span: this is an estimated life expectancy for someone who does not age to death, thanks to a rolling series of advances in rejuvenation medicine that eventually add more than a year of additional life with each passing year of research and development. If you examine mortality rates due to other causes projected out over time, you see that an effectively ageless person will live for at least a millennium under the mortality rates of today, not considering any future reductions in the rate of death by accident thanks to advances across the board in technology.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The SENS Foundation has published a series of posts over the past year or so that follow progress in the development of immunotherapies to remove the age-related buildup of amyloid in the brain - much of it intended as treatments for Alzheimer's disease. Success here will, however, lead to a broader technology platform that might ultimately be turned against any damaging aggregate that builds up in the body with age. These aggregates contribute to aging itself, and so removing them is one necessary part of any comprehensive rejuvenation biotechnology package: "soluble and insoluble aggregates of beta-amyloid protein (Aß) and other malformed proteins accumulate in brain aging and neurodegenerative disease, leading progressively to neuronal dysfunction and/or loss. These have long been widely accepted to be drivers of Alzheimer's disease (AD) and other age-related dementias and neurological disorders such as Parkinson's disease, and it has recently become increasingly clear that neuronal protein aggregates are the main driver of 'normal' cognitive aging. To prevent and reverse the course of neurodegenerative disease and age-related cognitive dysfunction, the regenerative engineering solution is therapeutic clearance of extracellular aggregates (such as Aß plaques) and intracellular aggregates (such as soluble, oligomeric Aß). Immunotherapeutic Aß clearance from the brain is a very active field of Alzheimer's research, with at least seven passive, and several second-generation active, Aß vaccines currently in human clinical trials. ... . We now have a published report of preliminary findings from the first Phase I trial in an Aß-targeting vaccine with novel properties, and with the benefit of preliminary findings of outcomes that have only emerged with the experience of its forerunners in previous clinical trials."

Link: http://sens.org/node/2437

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Via ScienceDaily: "Exceptional cognitive and physical function in old age leaves a tell-tale immunologic fingerprint, say researchers ... Likewise, older adults who have mild impairments bear a distinct immunologic pattern, too. ... Our study indicates that getting older does not necessarily mean that the immune system gets weaker, as many of us assumed. The immune system is dynamic, and the changes it undergoes over time very much influence function. ... For the project, the team collected blood samples from 140 participants who had been followed in the Cardiovascular Health Study (CHS) for nearly two decades and were 78 to 94 years old. With only two participants younger than 82, the average age of the group was 86. The team also gathered information about the participants' health and function, medical history and hospitalizations, and self-rated health, and assessed their cognitive and physical function using standard tests. Previous research has shown that with age, immune cells called T-cells become more like natural killer (NK) cells, which typically target tumor cells and virus-infected cells ... A closer look in the new study shows that participants who were most physically and cognitively resilient had a dominant pattern of stimulatory NK receptors on the T-cell surface, and that these unusual T-cells can be activated directly through these NK receptors independently of the conventional ones. The functionally resilient elders also have a distinct profile of blood proteins called cytokines that reflect an immune-enhancing environment. ... Conversely, the group that showed mild health impairment had a dominant pattern of inhibitory NK receptors on their T-cells, and they have a cytokine profile indicating a pro-inflammatory environment. Both of these immunologic features could suggest a greater susceptibility to illness."

Link: http://www.sciencedaily.com/releases/2011/10/111021125808.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The present work on tissue engineering of large structures, such as printing blood vessels and organs, or creating patient-specific organs for transplant using decellularization, will produce end results that rely on surgery - major surgical procedures in the case of organ transplants.

The trouble with surgery is that it is risky: major, involved surgeries bear a non-trivial risk of death even in the most advanced clinical surroundings, and that risk grows with age. Old people suffer a general frailty due to the damage of aging that makes it progressively less likely for them to survive any given surgical procedure. When you consider that every major organ is going to have issues if we live long enough without access to general biological repair technologies that remove the cellular and molecular damage that lies at the root of tissue dysfunction in aging, that's a bunch of major surgeries to look forward to.

So I believe we should look on the forthcoming phase of tissue engineering as a transitional period: organs will be built from scratch and transplanted until such time as the state of the art allows our existing organs to be incrementally repaired and rebuilt in situ instead. Eliminating the need for surgery is a big deal, and so in the long term I think that the future belongs to the branch of regenerative medicine that delivers populations of tailored stem cells into damaged tissue. As the research community becomes every better at precisely controlling the behavior and activities of cells, even that step of delivering new cells into the body may go away, to be replaced with adaptive drug-like therapies that issue commands to the body's existing cells through signaling pathways or induced epigenetic alterations, and which react to guide the ongoing state of repair.

Either way, surgery is not a desirable outcome - it's a least worst path at the best of times. In the future of medicine and aging, everything that can be achieved without surgery should be achieved without surgery, and we'll all be better off for it.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Xenotransplanation is the use of animal organs, possibly genetically modified, in place of human organs for transplantation in cases of organ failure or damage. This is one of the developing technologies that will compete with electromechanical or bioartificial organs and tissue engineering of whole organs to make organ replacement a far more viable, effective, and low-cost prospect than it is today. To my eyes xenotransplantation was always going to be a transitional technology, economically viable for a period of years in which tissue engineering was still finding its feet, but the development of decellularization has made animal organs look like a far more interesting long term source of raw materials.

a valve from a human or animal donor is removed of all cells using tissue engineering, so that only its outer framework remains. This valve matrix is then colonised with cells that have been obtained from the blood of the recipient and propagated. Within a few weeks, a quasi-natural heart valve then emerges in this bioreactor, that exhibits no rejection response or other faults, but instead grows with the patient after the implantation. ... Recellularization makes xenotransplantation a much more viable technology to fill the tissue engineering gap prior to the ability to grow complex organs from scratch.

The use of the patient's own cells in a donor scaffold removes issues of immune rejection, wherein the patient's immune system attacks and destroys the donor organ. When immune rejection is removed from the equation, not only does the entire process become much safer and cheaper, we are left with the extracellular matrix organ scaffold as the actual raw material required. A full organ scaffold is presently too complex for researchers to construct from scratch, and even when this can be done at some point in the next decade or two, it will be expensive for a time thereafter. Obtaining the decellularized scaffolds from human organs puts you right back to where you started with the difficulties of sourcing donor human organs when needed, but using animal organs can work around that issue.

I noticed a recent article that discusses the timelines for present work on xenotransplanation without decellularization, which is largely focused on transferring cells and small sections of tissue rather than whole organ structures. Organs are clearly on the agenda, however:

During the past decade xenotransplantation, the use of animal organs, tissues or cells in humans, has made great advances. Due to the fact that more and more genetically modified pigs are available with genes to protect them from human immune response, has alleviated earlier problems in helping humans to accept such transplants. ... at this time the longest time of survival for pig organs in non-human primates varies from a few days in lung transplants to approximately 6-8 months in hearts transplants. Although research is still years away from conducting human trials of solid organ transplants of this nature, lifesaving transplants of a pig heart or liver could pose as an alternative solution until a human organ becomes available. At present researchers are investigating strategies to incorporate human anticoagulant or antithrombotic genes into genetically modified pigs, and additional genes to regulate the human inflammatory response.

...

The authors also discussed in terms of organs, that stages of other strategies are currently more advanced than xenotransplantation, such as left ventricular assist devices for cardiac support. However, they agree that given time, transplanting a pig's heart will prove to be the better option compared to using a mechanical device.

...

Although remaining issues are delaying clinical implementation, experimental results obtained with pig islet, neuronal-cell, and corneal xenotransplantation have been encouraging. With new genetically modified pigs becoming available that are likely to improve the outcome of cellular and corneal xenotransplantation further, we believe that clinical trials will be justified within the next 2-3 years. No safety concerns that would prohibit such clinical trials have been reported...With regard to pig tissues and cells, as opposed to organs, it would seem that clinical xenotransplantation could soon become a reality.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Another group working on machinery to produce tissue engineered blood vessels: "German researchers have been working at growing tissue and organs in the laboratory for a long time. These days, tissue engineering enables us to build artificial tissue, although science has still not been successful with larger organs. Now researchers at the Fraunhofer group of applied research institutes are applying new techniques and materials to come up with artificial blood vessels in their BioRap project that will be able to supply artificial tissue and, perhaps, even complex organs in the future. ... The aim of tissue engineering is to create organs in the laboratory for opening up new opportunities in the field. Unfortunately, researchers have still not been able to supply artificial tissue with nutrients because they do not have the necessary vascular system. Five Fraunhofer institutes joined forces in 2009 to come up with biocompatible artificial blood vessels. It seemed impossible to build structures such as capillary vessels that are so small and complex and it was especially the branches and spaces that made life difficult for the researchers. But production engineering came to the rescue because rapid prototyping makes it possible to build workpieces in line with any complex three-dimensional (3D) model. Now scientists at Fraunhofer are working on transferring this technology to the generation of tiny biomaterial structures by combining two different techniques: 3D printing technology established in rapid protoyping and multiphoton polymerisation developed in polymer science."

Link: http://www.engineeringnews.co.za/article/when-ink-becomes-an-artificial-vessel-system-2011-10-21

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A look at what comes after merely targeting cancer cells: "Several decades from now we hope to have sophisticated medical nanorobots, produced by molecular manufacturing, that can enter cells, analyze the state of the cell, and initiate appropriate therapy, such as killing cancer cells. A team of scientists [has] taken an important step in that direction by demonstrating a synthetic circuit that, when incorporated into a cell, detects the presence or absence of five specific small RNA molecules,processes that information, and then, based upon that result, either kills or does not kill the cell. ... [The] long-term goal is to construct biocomputers that detect molecules carrying important information about cell wellbeing and process this information to direct appropriate therapeutic response if the cell is found to be abnormal. ... The researchers constructed what they describe as a 'classifier' gene circuit that is transiently expressed inside a cell and then integrates information from five molecular markers to determine the state of the cell, and then produces a protein that sets off the cellular suicide cascade if the cell is determined to be cancerous. The DNA circuit they constructed contains numerous control sequences chosen from standard genetic engineering toolkits that respond to specific miRNAs such that only the combination that identifies the particular cancer cell line used in the experiments activates the circuit and triggers the onset of cellular suicide. The results presented do show some false positives and some false negatives, so further optimization of the genetic circuit would be needed. Nevertheless, the results are impressive. Also, in principle, this method could be adapted to different cell types by choosing the combination of miRNAs appropriate to distinguish that cancerous cell from neighboring cells."

Link: http://www.foresight.org/nanodot/?p=4813

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Much as none of us like to think about it, we all have an ongoing, changing mortality risk - the flip side of the statistics of life expectancy at any given age. This largely involves cars in younger years, but then goes on to be dominated by the unpleasant and varied consequences of aging to death. I have no sage advice when it comes to cars, but I can point out the science that backs up the idea that we have a modest degree of control over our risk of death at any given age, and hence over our life expectancy.

There are three line items here:

• Exercise
• Calorie restriction
• Working to speed development of rejuvenation biotechnology

I don't expect to see significant additions to this list become widely available for another twenty years or so. Aside from the fact that we can do a great deal to speed up the advent of ways to repair the cellular and molecular damage of aging - which is a very big deal - the healthy person interested in putting a thumb on the scales of mortality risk is presently stuck with much the same narrow array of methods as our immediate ancestors. There's an anti-aging marketplace shouting loudly that they have plenty of new things to try, but their marketing folk are largely lying through their teeth, hyping things with no scientific basis, or selling goods that have statistically negligible effects in comparison to exercise and calorie restriction.

But so it goes - there are always people who want answers now, and never mind whether they are the right answers, and so there will always be other people selling immediate answers. Fools and their money, and so forth.

By way of following on from yesterday's post on exercise, mortality, and medical costs, I thought I'd point out a couple of other recent items that clearly point to the obvious ways in which the vast majority of us can adjust our own life expectancy.

Early mortality risk reduced up to 40 percent through increased physical activity and sports:

The researchers identified about 7,000 potentially relevant reports, of which a total of 80 cohort studies with more than 1.3 million study participants from Europe, Canada, United States, and Asia fulfilled the strict inclusion criteria. At study onset participants had to be free of cardiovascular disease, cancer and other chronic conditions. Study participants were followed up by a median of 11 years. 'The results of the included studies were combined and controlled for other potential influential factors, e.g. cigarette smoking, alcohol uptake, body mass index, blood pressure, nutrition, education and social factors,' explained Guenther Samitz.

...

For light- to moderate intensity activities of daily living, e.g. housework, gardening, stair climbing, walking and bicycling for transportation, an increase of one hour per week compared to no physical activity was associated with a reduction in mortality of four percent. Dr. Samitz said that with moderate-intensity leisure activities (e.g. Nordic walking, hiking, social dance) the risk reduction increased to six percent, and with vigorous-intensity aerobic activity or sports (e.g. jogging, bicycling (>10 miles per hour), tennis, ball sport), the reduction in all-cause mortality was even nine percent per one hour increment per week. Meeting the WHO´s recommended level of 150 minutes per week of moderate physical activity of daily life or during leisure was associated with a reduction in mortality risk by ten percent. For vigorous exercise and sports the reduction in mortality risk was more than twofold higher (22 %).

High to moderate levels of stress lead to a higher mortality rate:

A new study concludes that men who experience persistently moderate or high levels of stressful life events over a number of years have a 50 percent higher mortality rate. ... This is the first study to show a direct link between stress trajectories and mortality in an aging population. Unlike previous studies that were conducted in a relatively short term with smaller sample sizes, this study was modified to document major stressors - such as death of a spouse or a putting a parent into a retirement home - that specifically affect middle-aged and older people.

You might look back in the Fight Aging! archives for more on the material links between psychological stress and biomarkers of health, such as telomere length in immune cells.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

An open access review paper: "In tissue engineering fields, recent interest has been focused on stem cell therapy to replace or repair damaged or worn-out tissues due to congenital abnormalities, disease, or injury. In particular, the repair of articular cartilage degeneration by stem cell-based tissue engineering could be of enormous therapeutic and economic benefit for an aging population. ... Many people over the age of 40 suffer from degeneration or injury of their cartilage, leading to a reduced workforce and increased medical expenses. Thus, improvements in cartilage repair using a cell-based tissue engineering approach will greatly benefit public health and the economy. Personalised cell therapy for cartilage repair using cell-based tissue engineering technologies would provide clinically practical methods for producing a cartilage tissue equivalent. A number of biomaterials are available as scaffolds, and research continues to help us understand more details about how tissues develop and which cell type should be applied. These studies have provided details of how tissues grow in vitro and in vivo, but clinical applications depend on working with surgeons and the translation of these materials and technologies to in vivo models that are more relevant to patients. When cell-based cartilage tissue engineering technologies are applied to new animal models, we attempted to find better functional compositions for successful applications than were observed in previous studies. Although stem cell-based cartilage tissue engineering systems may demonstrate success even in animal models, there are a number of new challenges when the technologies are applied to humans. Further research on in vivo application must address immunological issues, integration of host and stem cell-based engineered cartilage, and the variability of tissue development in an in vivo environment, depending on surrounding disease processes, age, or physical activity. Therefore, interdisciplinary studies are not only necessary but crucial before cell-based cartilage tissue engineering can reach its full potential in cartilage repair and regeneration."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191858/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm