FIGHT AGING! NEWSLETTER
October 24th 2011
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!
- Adjusting Your Own Mortality Risk
- Groundwork for the Ultimate Cure for Cancer
- On Xenotransplantation
- Latest Headlines from Fight Aging!
ADJUSTING YOUR OWN MORTALITY RISK
Large-scale studies of health and longevity demonstrate the degree to which we can choose to shift our own risk of disease and death, and along with it the likely level of necessary medical expenditures in our future. A few examples can be found in the following Fight Aging! posts:
"One longevity-related line item that doesn't come up often enough in discussion is the matter of the expected state of your wallet as you move through life. Given that you have a fair degree of control over your long-term health, do you also have the same degree of control over the funds needed for future medical treatment? Reliability theory, a consideration of aging as damage, suggests that the only paths to a longer life are those which reduce or repair the accumulated biological damage that leads to aging. Reliability theory also tells us that this will lead to a lower chance of systems failure - which we might interpret as a lower chance of the need for medical intervention at any given time.
"Thus it makes sense to look at the foreseeable biotechnologies of enhanced longevity as a way to reduce long term expenditures on medicine, on average, for individuals. One might hope that everyone - and not just those who have nursed an aging car through its last years - understands the difference in maintenance costs for a well-repaired machine versus one that's showing all the signs of accumulated wear and tear. Damaged machines spiral down into ever more expensive breakdowns, and that's just as true of people as it is of the things people build. Yet much of the public debate over medicine seems to focus on the idea that living longer implies greater medical expenditure - possibly another aspect of the Tithonus Error, the naive belief that living longer though biotechnology means being old for longer rather than being young for longer."
"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 %)."
GROUNDWORK FOR THE ULTIMATE CURE FOR CANCER
All cancers depend on finding ways to abuse existing mechanisms in our biology to lengthen telomeres past the normal constraints - to find a way to permit runaway replication of cells, in other words. This is the one commonality shared by all of the wildly diverse forms of cancer:
"One of the longer term research projects that is a part of the Strategies for Engineered Negligible Senescence (SENS) is the technical basis for what might be described as the ultimate cure for cancer. It goes by WILT, or Whole-body Interdiction of Lengthening of Telomeres. The short version of the idea is to turn off the ability of the human body to do the one thing that all cancers depend upon, which is lengthening telomeres beyond their normal limits. Telomeres are the protective caps at the end of chromosomes that progressively shorten with each cell division: one of their functions is to prevent runaway division of cells (i.e. cancer), but that roadblock can be evaded by a cancer that evolves any one of a number of ways to abuse mechanisms that the body normally uses to repair and lengthen telomeres in the few cell populations that need it.
"The not inconsiderable downside of WILT is that a person who has undergone this treatment will have a reduced life span without access to procedures for regularly replacing their entire stem cell populations - turning off telomere lengthening will kill the possibility of cancer, but also put a short timer on the stem cells that need that process in order to keep repairing the body and replenishing cells. To my eyes this seems like an unnecessary risk when balanced against the future robustness of cancer therapies under development - but it's hard to argue against WILT as an ultimate cancer therapy.
"That is, provided all of the scientific assumptions about WILT are correct. For example, that we know all of the biological processes by which telomeres can be lengthened, and that shutting them all down doesn't cause any other harm beyond the loss of stem cell longevity. So there is a certain amount of groundwork to be done to seal the case for WILT as ultimate-cancer-therapy-with-big-but-possibly-acceptable-downside, and the SENS Foundation has been funding some of it, whilst keeping an eye on other related research already ongoing."
Practical ways to use animal tissue and organs for transplantation into humans are emerging in the laboratory, and researchers expect trials to begin within a few years. One of the adjunct technologies that will prove useful is decellularization, wherein a donor organ is chemically stripped of cells to leave behind the scaffolding of the extracellular matrix - ready to be colonized by the patient's own cells. Interestingly, that organ doesn't have to come from a human in order for its scaffold to provide a viable home for human cells:
"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. ... 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."
The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!
LATEST HEADLINES FROM FIGHT AGING!
WORKING ON BUILDING BLOOD VESSELS WITH BIORAP
Friday, October 21, 2011
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."
THE LOGICAL NEXT STAGE OF TARGETED CANCER THERAPIES
Friday, October 21, 2011
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."
A REVIEW OF THE STATE OF TISSUE ENGINEERING OF CARTILAGE
Thursday, October 20, 2011
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."
ANOTHER LOOK AT EPIGENETIC INHERITANCE OF LONGEVITY
Thursday, October 20, 2011
Researchers investigating calorie restriction have noticed that its effects on longevity can be inherited through epigenetic variations - which makes sense, given the reasons why individual longevity variations in response to available food evolved in the first place. If it is advantageous for a given individual at a given time to shift metabolism into a mode that allows it to live longer due to a decline in available food, then it's probably also advantageous for the children to do that from birth as well: "The tiny soil-dwelling worms C. elegans, when given mutations that make them live longer, transmit that trait even when their progeny don't inherit the life-extending mutations. ... Although much more research remains to be done, the new study raises the tantalizing possibility that if Grandma practiced caloric restriction - which affects the expression of longevity-enhancing genes - her descendants might reap the benefits. The inheritance occurs through "epigenetics": alterations not in the coding sequence of DNA (those ubiquitous A's, T's, C's, and G's) but in chemical changes that affect whether genes are expressed. ... [A] protein complex called ASH-2 [alters] histones in C. elegans, reconfiguring the histone-DNA complex into an 'open' state that promotes gene expression. Deficiencies in ASH-2 extend the worm's life span by as much as 30 percent. ... [researchers] blocked the three key proteins that make up the ASH-2 complex by mutating their genes. As expected, the worms lived longer - typically, an extra seven days beyond their lab life span of 20. [Researchers] bred the mutated worms with normal worms until their descendants no longer had the mutations. Nevertheless, the progeny still lived longer, as did their own descendants: even though their genes for the key proteins were normal, an epigenetic memory of longevity persisted."
STUDYING METHIONINE RESTRICTION
Wednesday, October 19, 2011
The response of metabolism to lowered methionine intake appears to be a major component of the mechanisms of calorie restriction: "Methionine dietary restriction (MetR), like dietary restriction (DR), increases rodent maximum longevity. However, the mechanism responsible for the retardation of aging with MetR is still not entirely known. As DR decreases oxidative damage and mitochondrial free radical production, it is plausible to hypothesize that a decrease in oxidative stress is the mechanism for longevity extension with MetR. In the present investigation male Wistar rats were subjected to isocaloric 40% MetR during 7 weeks. It was found that 40% MetR decreases heart mitochondrial ROS production at complex I during forward electron flow, lowers oxidative damage to mitochondrial DNA and proteins, and decreases the degree of methylation of genomic DNA. ... These results indicate that methionine can be the dietary factor responsible for the decrease in mitochondrial ROS generation and oxidative stress, and likely for part of the increase in longevity, that takes place during DR. They also highlight some of the mechanisms involved in the generation of these beneficial effects."
Wednesday, October 19, 2011
An example of present work in growing skin from stem cells: scientists "are participating in research to study how to make use of the potential for auto regeneration of stem cells from skin, in order to create, in the laboratory, a patient's entire cutaneous surface by means of a combination of biological engineering and tissue engineering techniques. Skin is a tissue that naturally renews itself throughout our lives thanks to the existence of epidermic stem cells. ... We have found that this regenerative potential can be preserved in vitro (in the laboratory) if the cells are joined and become part of generated skin using tissue bioengineering techniques. ... The researchers have already been able to join together these epidermic stem cells into skin created by means of bioengineering, and they have observed that the cells preserve the regenerative potential that they normally have in our skin. That is, using a small biopsy from a specific patient, they can generate almost the entire cutaneous surface of that individual in the lab. ... The regenerative capacity of epidermic stem cells in these conditions is overwhelming, and it leads to the possibility of using these cells as a target for even more complex protocols, such as gene therapy. ... In fact, these researchers have already demonstrated, at the pre-clinical level, that it is possible to isolate epidermic stem cells from patients with different genetic skin diseases, cultivate them and, using molecular engineering as a first step, incorporate the therapeutic genes into each patient's genome to take the place of the one that the patient does not have or that functions abnormally. Afterwards, in the second step, the stem cells would be assembled into patches ready to be transplanted onto the patients."
DISCUSSING THE NEAR FUTURE OF TISSUE ENGINEERING
Tuesday, October 18, 2011
From MSNBC: "The latest science and schemes for achieving long life and the "singularity" moment of smarter-than-human intelligence came together at the Singularity Summit held [in New York] October 15-16. Some researchers explored cutting-edge, serious work about regenerating human body parts and defining the boundaries of consciousness in brain studies. ... The most immediate advances related to living longer and better may come from regenerative medicine. Pioneering physicians have already regrown the tips of people's fingers and replaced cancer-ridden parts of human bodies with healthy new cells. ... Success so far has come from using a special connective tissue - called the extracellular matrix (ECM) - to act as a biological scaffold for healthy cells to build upon. Badylak showed a video where his team of surgeons stripped out the cancerous lining of a patient's esophagus like pulling out a sock, and relined the esophagus with an ECM taken from pigs. The patient remains cancer-free several years after the experimental trial. The connective tissue of other animals doesn't provoke a negative response in human bodies, because it lacks the foreign animal cells that would typically provoke the immune system to attack. It has served the same role as a biological foundation for so long that it represents a 'medical device that's gone through hundreds of millions of years of R&D'. ... If work goes well, Badylak envisions someday treating stroke patients by regenerating pieces of the functioning human brain."
P38 MAP KINASE AND FLY LONGEVITY
Tuesday, October 18, 2011
Researchers report another longevity gene: "Scientists have previously found mutations that extend fruit fly lifespan, but this group of genes is distinct because it acts specifically in muscles. The findings could help doctors better understand and treat muscle degeneration in human aging. [Researchers] started investigating a pair of genes called "p38 MAP kinase" in fruit flies with the expectation that they could play a role in learning and memory. Along the way, they discovered that mutations in these genes speed up the process of aging and make the flies more sensitive to oxidative stress. ... It was really just dumb luck, because we found a mutant that had almost completely lost gene activity, but had enough activity to be born. ... If both genes are defective in the same fly, the flies die very early. ... The experiment that made us nervous was when we asked whether having more p38 could increase lifespan. You can make flies sick and shorten their lives in a hundred different ways easily, but finding one gene that makes a big change in lifespan is more significant. ... Fruit flies normally live about fifty days in [this] laboratory, depending on temperature and conditions. Some strains of fly that overproduce p38 MAP kinase live on average about 75 days, 50 percent longer than regular flies ... For this effect, it is sufficient that p38 is overproduced in muscles only. ... a protein that protects cells against oxidative stress that is found in mitochondria, superoxide dismutase (MnSOD), is responsible for at least some of p38 MAP kinase's effects on aging." That last point makes this look rather like the mouse studies in which life span was extended by genetic engineering to boost levels of natural antioxidants present in the mitochondria.
FGF AND STEM CELL AGING
Monday, October 17, 2011
Researchers are spending more time these days on the mechanisms by which stem cell populations decline with age - understanding the controlling processes that stop stem cells from working so well in later life will be the key to restoring their effectiveness. For example; "The aging process decreases tissue function and regenerative capacity, which has been associated with cellular senescence and a decline in adult or somatic stem cell numbers and self-renewal within multiple tissues. The potential therapeutic application of stem cells to reduce the burden of aging and stimulate tissue regeneration after trauma is very promising. Much research is currently ongoing to identify the factors and molecular mediators of stem cell self-renewal to reach these goals. Over the last two decades, fibroblast growth factors (FGFs) and their receptors (FGFRs) have stood up as major players in both embryonic development and tissue repair. Moreover, many studies point to somatic stem cells as major targets of FGF signaling in both tissue homeostasis and repair. FGFs appear to promote self-renewing proliferation and inhibit cellular senescence in nearly all tissues tested to date. ... The effects of FGF signaling can be in part attributed to the stimulation of self-renewal in endogenous somatic stem cells within these organs, but there is also much evidence that FGF signaling also plays a role in the concomitant inhibition of cellular senescence in stem cell. The evidence presented here also suggests a role of FGF signaling in the more committed cells downstream of stem cells, a role that appears to stimulate differentiation. Moreover, in most cell types studied, FGF seems to play a permissive role rather than a direct inductive or instructional role, usually by modifying the responsiveness of the cells to other factors or by potentiating and synergizing with other signals. That seems to hold true in both stem cells self-renewal and differentiation of more committed cells."
ANOTHER LARGE STUDY SHOWS NO BENEFIT FROM ANTIOXIDANT SUPPLEMENTATION
Monday, October 17, 2011
The idea that you can do something positive for long term health by consuming presently available antioxidant supplements is a myth, not backed up by scientific evidence at all: "A study of vitamin E and selenium use among 35,000 men found that the vitamin users had a slightly higher risk of developing prostate cancer ... A separate study of 38,000 women in Iowa found a higher risk of dying during a 19-year period among older women who used multivitamins and other supplements compared with women who did not ... The findings are the latest in a series of disappointing research results showing that high doses of vitamins are not helpful in warding off disease. ... You go back 15 or 20 years, and there were thoughts that antioxidants of all sorts might be useful. There really is not any compelling evidence that taking these dietary supplements above and beyond a normal dietary intake is helpful in any way, and this is evidence that it could be harmful. ... Everyone needs vitamins, which are essential nutrients that the body can't produce on its own. But in the past few years, several high-quality studies have failed to show that high doses of vitamins, at least in pill form, help prevent chronic disease or prolong life." Antioxidants specifically targeted to the mitochondria have been shown to produce benefits to health and life span in mice, but running out to eat antioxidants from a bottle because of that is nothing more than magical thinking. In the case of currently available antioxidant supplements, there is every reason to think that they interfere with the beneficial mechanisms of exercise, causing a net loss in long term health.