Longevity Meme Newsletter, March 22 2010

March 22 2010

The Longevity Meme 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 the Longevity Meme.



- A New Look for the SENS Foundation
- Single Gene Deletion Causes Mouse Regeneration
- Calorie Restriction Reduces Lipofuscin Buildup
- Psychological Stress, Telomeres, and Aging
- Discussion
- Latest Healthy Life Extension Headlines


The SENS Foundation, the umbrella organization for Strategies for Engineered Negligible Senescence research, has launched a new, more functional website. A forum is included, so register an account and let the Foundation volunteers know what you think:


"The new site is organized around a series of projects, which are in progress at our Research Center, in the facilities of our collaborators, or under the auspices of our Academic Initiative. Blogs and news items relating to all these projects will be added regularly, giving you an up-to-date picture of the work we do. News items from outside the Foundation, which relate to our mission, will be available here. Publications and proceedings of past conference are also available, and we'll be creating a wider media library over the coming months."


Some years ago, scientists accidently discovered that MRL mice, an engineered breed, could regenerate damage that does not normally heal in mammals, leaving no scars. This process happens in a manner similar to regeneration in salamanders: a mass of cells reverts to a more embryonic-like state in a coordinated way to rebuild missing tissue. Researchers have now pinned this result down to a single gene deletion:


"One line of research into regenerative medicine is based on understanding and then recreating in mammals the regenerative powers of lower animals like the salamander or zebrafish. The existence of MRL mice, a laboratory breed originally created for quite different reasons, provides hope that the required genetic or other alterations to mammalian biochemistry are not in fact insurmountably large or complex. Some researchers believe that mammals retain much of the salamander's regenerative capabilities encoded within their genomes, and that it is currently only unused or inaccessible rather than completely lost. ... The determination of a single gene of interest in this matter will lead researchers to investigate a narrow range of potential underlying mechanisms in order to explain why the MRL mice heal as they do. Those mechanisms can then be manipulated directly, one by one, to establish a better picture as to what exactly is going on here."


Lipofuscin is a catch-all category for many different varieties of chemical gunk that build up in the long-lived cells of your body over the years. The lysosomes, roving garbage recyclers within your cells, can't break down the lipofuscin they collect, and so eventually become too bloated and damaged to do their job. This ongoing process is especially important in the degeneration of eyes and nerve cells with age. Ideally, researchers would be further along the path of developing a regularly applied treatment to break down lipofuscin - but that advance still lies in the future, and few groups are currently working on it. Here at least is some good news, however:


"I noticed a paper today that demonstrates another benefit of calorie restriction in rats: it reduces lipofuscin buildup and the consequent damage to lysosomes, the cell's recycling units. ... Calorie restriction essentially keeps your cells in better shape, amongst its other effects, and that helps to keep the functional structures of your body in better shape. It really is well worth your time to look into the practice of calorie restriction, and how you might make it work in your life."


Chronic psychological stress is convincingly associated with poor health in general, and in recent years has also been correlated with shorter telomeres. Telomeres, you might recall, are the protective caps at the end of your chromosomes which become, on average, progressively shorter as life goes on.


"So does psychological stress over time cause what amounts to somewhat accelerated aging? This is plausible, but still unclear. While research results strongly suggest that psychological stress leads to a less robust, more damaged immune system, with all that this implies for health and aging, the role of telomeres in the biochemical and cellular damage that accumulates with aging is not yet firmly established. They may be a root cause of age-related degeneration, or they may be a secondary marker of other processes, such as mitochondrial damage. Further, note that studies have generally looked at telomere length in only a limited population or subset of the body's different cell types. But the data on stress and telomere length continues to arrive. At some point a firm conclusion will emerge."


The highlights and headlines from the past week follow below.

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The early human trials of recellularized transplants continue to go well: "A 10-year-old British boy has become the first child to undergo a windpipe transplant with an organ crafted from his own stem cells. ... The world's first tissue-engineered windpipe transplant was done in Spain in 2008 but with a shorter graft. Doctors say the boy is doing well and breathing normally. ... In order to build him a new airway, doctors took a donor trachea, stripped it down to the collagen scaffolding, and then injected stem cells taken from his bone marrow. The organ was then implanted in the boy and over the next month, doctors expect the stem cells to transform into specialised cells which form the inside and outside of the trachea. ... more clinical trials were needed to prove the technique worked but that the team was also thinking about transplanting other organs, such as the oesophagus. ... The advantage of the new approach is that it can be performed quickly and cheaply and so if successful it could be made available to large numbers of patients at relatively low cost." The downside of recellularization is that it doesn't eliminate the need for a donor organ - but it does open up the possibility of using animal organs instead of human organs, with no threat of rejection, and it certainly contributes to advancing the state of the art. I expect to see recellularized heart transplants tested in humans within the next few years.

With the launch of the new SENS Foundation website, a range of photographs and presentation videos from the most recent SENS conference are available for viewing: "The purpose of the SENS conference series, like all the SENS initiatives (such as the journal Rejuvenation Research), is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem: not seeking elusive and probably illusory magic bullets, but instead enumerating the accumulating molecular and cellular changes that eventually kill us and identifying ways to repair - to reverse - those changes, rather than merely to slow down their further accumulation. ... Videos of a number of talks are now available. The footage of the remaining talks is still being processed by our volunteers, but will be published as soon as possible." You might also dig into the Fight Aging! archives for the conference converage from the folk at Ouroboros.

This paper shows researchers beginning to be able to distinguish between the genetic machinery that causes different parts of the calorie restriction effect on health and longevity: "The FoxO transcription factors may be involved in the antiaging effect of calorie restriction (CR) in mammals. To test the hypothesis, we used FoxO1-knockout heterozygotic (HT) mice, in which the FoxO1 mRNA level was reduced by 50%, or less, of that in wild-type (WT) mouse tissues. The WT and HT mice were fed ad libitum (AL) or 30% CR diets from 12 weeks of age. Aging- and CR-related changes in body weight, food intake, blood glucose and insulin concentrations were similar between the WT and HT mice in the lifespan study. ... Several of the selected FoxO1-target genes for cell cycle arrest, DNA repair, apoptosis, and stress resistance, were up-regulated in the WT-CR tissues, [while] the effect was mostly diminished in the HT-CR tissues. Of these gene products, we focused on the nuclear p21 protein level in the liver and confirmed its up-regulation only in the WT-CR mice in response to oxidative stress. The lifespan did not differ significantly between the WT and HT mice in AL or CR conditions. However, the [cancer resistance] effect of CR, as indicated by reduced incidence of tumors at death in the WT-CR mice, was mostly abrogated in the HT-CR mice. The present results suggest a role for FoxO1 in the [anti-cancer] effect of CR through the induction of genes responsible for protection against oxidative and genotoxic stress."

From Singularity Hub: "Hans Keirstead used embryonic stem cells to help paralyzed rats walk again. His research is the basis for the first FDA approved clinical trial for the use of embryonic stem cells (ESC) - currently underway by Geron and aimed at treating spinal cord injuries. After years of controversy in the first part of the decade, ESC trials have finally started on the path that may let them deliver on the vast promises of stem cell enabled medicine. Yet we have already seen how autologous stem cell therapies (those which use a patient's own cells) are becoming available in the U.S and all over the world. Why the hold up on ESC treatments? Autologous therapies are part of the medical practice of individual doctors, given to their individual patients. Geron's clinical trials hope to usher in a new wave of globally used drugs and procedures. The rigorous science needed to obtain FDA approval for such widespread treatments is not easily achieved, but many still lament the slow process. To all of us wondering why ESCs are not yet available in every hospital across the world, Hans Keirstead has an explanation. He doesn’t make an impassioned plea, or take a rhetorically defensive stance. In just 5 minutes Keirstead walks us through the fundamental hurdles that scientists face as they try to bring ESC therapies to fruition. Everyone who wants an intellectual and scientific explanation of stem cell research should watch the video."

As noted at In the Pipeline, researchers have recently generated a line of induced pluripotent stem (iPS) cells with long telomeres. Though no-one yet knows the precise cause, now that these cells exist as a point of comparison determining how to do it for all iPS cells will follow in time. Unfortunately, it has been somewhat overhyped in the press: this is just a promising step forward in the search for a solid, cheap source of patient-specific stem cells for regenerative medicine, not a sign of aging-reversal. "It seems to be interesting work that's a long way from application. Briefly [what] they're looking at is telomere length in various stem cell lines. Telomere length is famously correlated with cellular aging - below a certain length, senescence sets in and the cells don't divide any more. What's become clear is that a number of 'induced pluripotent' cell lines have rather short telomeres as compared to their embryonic stem cell counterparts. You can't just wave a wand and get back the whole embryonic phenotype; their odometers still show a lot of wear. [Researchers] induced in such cells a number of genes thought to help extend and maintain telomeres, in an attempt to roll things back. And they did have some success - but only by brute force. The exact cocktail of genes you'd want to induce is still very much in doubt, for one thing. And in the cell line that they studied, five of their attempts quickly shed telomere length back to the starting levels. One of them, though, for reasons that are completely unclear, maintained a healthy telomere length over many cell divisions. So this, while a very interesting result, is still only that."

LabLit publishes an interview with biomedical gerontologist Aubrey de Grey, heavier on the human interest side than usual: de Grey moved from computer science to gerontology "because I met the right woman. There is a 19-year difference between us; I met her when she was 45 while I was at Cambridge. As scientists we spoke about science a lot. And we spoke a lot about the problem of aging and the more I read about it the more I got worked up about the problem. Now, 100,000 people die every day because of aging, which is not a joke. ... Luck has played an important role. When I wrote the first Bioessay in 1997, the editor of the journal was highly impressed with the essay and asked me to write a book. I finished the book before the deadline in Spring 1998 but the publishing house was in trouble. It took them a whole year to stand up on their feet and before they could publish my book they asked me to review it. In a year, I knew a lot more biology than before. I changed the bad job I had done into something that I am proud of even now. ... I believe that scientists can change fields easily and sometimes make a bigger impact in the new fields they enter. I think it's because people who move do not look at the same problem from the traditional point-of-view. This enables them to come up with unique solutions. We are not trapped by dogma and if we are bold we can rise quickly."

Via EurekAlert!: "Bone marrow stem cells suspended in X-ray-visible microbubbles dramatically improve the body's ability to build new blood vessels in the upper leg - providing a potential future treatment for those with peripheral arterial disease or PAD ... They offer a future novel method to help PAD patients by increasing the number of blood vessels to replace or augment those choked off by plaque buildup ... With this treatment, the body was able to provide a more normal blood supply to the toes - possibly offering the hope of dramatically reducing - or avoiding - amputation. ... Because many treatments like stenting are done using X-rays, this microbubble stem cell treatment could be performed when an interventional radiologist is performing a dye study to look at a patient's arteries. Since an interventional radiologist can see where he or she puts the stem cells and whether they remain in the leg, the stem cells could be administered potentially where they can do the most good. The treatment could be repeated, if needed. ... researchers used a technique that encloses stem cells derived from bone marrow (not embryonic stem cells) in an alginate capsule or microbubble made from seaweed that contains stem cells to create factors to recruit the building of new vessels along with an X-ray-visible contrast agent. Tested [in rabbits], the bubble prevents the body's immune system from reaching and attacking the transplanted cells."

A VIEW OF AGING BONE (March 16 2010)
The aging of bone stems in part from the wear and tear of a very old cell population, according to this paper: "The adverse effects of aging of other organs (ovaries at menopause) on the skeleton are well known, but ironically little is known of skeletal aging itself. Evidence indicates that age-related changes, such as oxidative stress, are fundamental mechanisms of the decline of bone mass and strength. Unlike the short-lived osteoclasts and osteoblasts, osteocytes - former osteoblasts entombed in the mineralized matrix - live as long as 50 years, and their death is dependent on skeletal age. Osteocyte death is a major contributor to the decline of bone strength with age, and the likely mechanisms are oxidative stress, autophagy failure and nuclear pore "leakiness". Unraveling these mechanisms should improve understanding of the age-related increase in fractures and suggest novel targets for its prevention." The accumulating damage suffered by long-lived cell populations that are not replaced is an issue in many parts of the body, especially the nervous system.

This researcher's view is that the major problems in stem cell therapies for the old have yet to be solved: "Despite a wide range of therapeutic interventions, the prognosis for most patients with heart failure remains poor. The identification of stem cells with the ability to generate cardiomyocytes and vascular cells and promote local repair and survival pathways has highlighted the ability of the heart to undergo regeneration and potentially provides a new therapeutic strategy for treatment of the failing heart. In recent years, however, clinical trials aimed at exploiting the beneficial effects of stem and progenitor cells to treat patients with cardiovascular disease have resulted in mild improvements at best, suggesting that these cells and/or the conditions in which they find themselves are not conducive to cardiac repair. Heart failure is most prevalent among older individuals, and a growing body of evidence suggests that with increasing age, cardiac stem and progenitor cells undergo senescent changes that impair their regenerative capacities. Moreover, environmental alterations over time appear to impact the capacity of these cells to improve cardiac function. Understanding these senescent changes may lead to the development of new and improved approaches to exploit the potential of stem cells to repair the aging heart."

Early progress towards artificial organs results in tools that are often only applicable to diagnosis and research, as is the case here - but you can see the course of the future in their form and function: "A research group in Korea have developed a method to engineer artificial liver tissue using microfluidics. The liver is one of the most important organs in the human body. ... Transplants are [presently] the only way to compensate if the liver fails, therefore research is being carried out to develop a method to create artificial 3D liver tissues which can regulate specific functions. ... Chitosan is a natural polymer with a similar structure to the components found in the liver's extracellular matrix and has been widely used for liver tissue engineering. But it's mechanical weakness limits control of the shape and size of the tissue scaffold. ... [Researchers have now] developed a microfluidic method to allow thin, pure chitosan fibres to be prepared continuously without breaking. ... Using this method, the team has been able to create a bio-artificial liver chip by culturing [liver cells] on the pure-chitosan fibres. Tests show that vital liver functions including enzyme secretion and urea synthesis were carried out by the cells on the chip."



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