Fight Aging! Newsletter, November 19th 2012

November 19th 2012

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!



- More Thoughts on Regenerative Medicine Timelines
- Investigating the Agelessness of Hydra
- Mining for Longevity Genes
- Discussion
- Latest Headlines from Fight Aging!
    - The State of Bioprinting
    - Molecular Tweezers Versus Alzheimer's Disease
    - Eliminating Metastasis in Melanoma
    - Investigating a Longevity-Related Mitochondrial Polymorphism
    - Injectable, Compressible, Shaped Tissue Scaffold
    - Humanity+ 2012 Conference, December 1st in San Francisco
    - Digging Deeper into Zebrafish Brain Regeneration
    - SENS Foundation Hiring a Telomere Biology Research Lead
    - "Successful Aging" Seems a Little Ridiculous as a Concept
    - The Goal of Lifelong Perfect Health


Dr. Brooks Edwards [is the] deputy director of the Mayo Clinic Center for Regenerative Medicine and director of the Mayo Transplant Center. [His] goal, before retiring from Mayo, is to be able to treat most of those patients with regenerative strategies, so they don't have to wait for a catastrophe to happen to a healthy person to become an organ donor, he said.

"We're going to have strategies to repopulate cells in the heart for patients with heart failure to restore them to normal cardiac function, we're going to have regenerative medicine strategies to be able to restore diseased liver to healthy liver by re-growing a liver from the recipient," he said. "We're going to have regenerative medicine strategies for patients with chronic lung disease that could avoid lung transplant."

Those treatments are not available now, said Edwards, who is 55. "But I think when you talk about five- and ten-year horizon, I think some of these things are going to become reality and we're going to look back at the current era and say, 'can you imagine that they had to wait for a deceased donor to treat that patient with heart failure?'" he said.


Hydra are one of the few ageless species, or at least a good candidate for such: researchers have watched populations age for years with no signs of increased mortality rates or declining pace of reproduction. One might view these creatures as an incremental step up from bacteria or yeast: multicellular animals that can reproduce asexually via budding, and which are extremely proficient at regeneration.

One line of thought regarding the agelessness of hydra is that they simply consistently and relentlessly renew all the tissues in their body, which is accomplished by having very many stem cells that don't decline over time. Hydra might follow a strategy of eliminating the inevitable buildup of malformed proteins, aggregate waste products, and similar damage in individual cells by (a) sacrificing and then replacing damage-bearing cells, and (b) using the bacterial approach of moving as much damage as possible into one of the two daughter cells produced in any cell division. Since a hydra has no brain, any cell can be sacrificed at any time so long as it is replaced with an equivalent new cell - the whole organism can be replaced completely over any arbitrarily short period of time provided it can find the metabolic resources to do so.

There's nothing magical about making cell lineages last essentially forever. All bacteria do it, and even complex organisms like we humans are capable of it. There is, for example, the process that ensures that the first cells of a human child are biologically young and free from damage even though the parents bear decades worth of accumulated damage in their cells. It's also possible that hydra use an aggressive repair and renewal process of this nature, either when they bud or on an ongoing basis.

Aging doesn't happen because it has to, aging happens because it's almost always advantageous from an evolutionary perspective - that we age is an example of the success of the gene built upon the pain, suffering, and death of the individual who bears it. Though apparently this isn't the case for hydra, and many other types of life that are closer to what we might think of as self-replicating machines rather than populations of individual entities. One might argue that the big downside of individual entityhood is the need for brain cells that store data, and thus cannot simply be replaced at arbitrary times. Or perhaps one might argue that a necessary precondition for individual entityhood is a loss of the processes of aggressive regeneration and tissue replacement such that a thing like a brain might be able to evolve in the first place.

In any case, not everything that the aging research community works on is both interesting and potentially useful when it comes to intervening in human aging. Ongoing research into the biology of hydra is certainly interesting, but I'm dubious that we'll find anything that can inform us of a way out of our present predicament, the one in which we are aging to death. We and the hydra live in very different worlds, with very different requirements for success.


he intricate, reactive, self-regulating machinery of our cells is built from proteins. Those proteins are specified by the blueprints known as genes, coiled up in each cell nucleus. The operation of our metabolism proceeds as a dance of networks of related proteins, feedback loops and signaling cascades in which the amount of a given protein produced at any given time can rise and fall in response to the rise and fall of other levels of production. The full scope of how variations in metabolism and its response to environment and lifestyle can affect the pace of aging is a staggeringly complex system, and as yet poorly understood.

Still, researchers seek to fully understand metabolism and aging; this goal has broader support than any other in aging research. There are more researchers chasing that understanding at any given time than there are working on ways to intervene in the aging process. A post from last week took a look at one way in which that research can progress: given an established mutation or other single-gene or single-protein change that extends life, scientists then follow the effects of that change through the network of interactions that it impacts, in search of a greater understanding of the system as a whole.

This is a time-worn and well proven methodology in all sciences: if you want to understand how something works then change one small part of it and carefully watch what happens next. Repeat as necessary.

There are other ways in which a knowledge of protein networks and existing longevity genes can be used to further research. For example, the catalog of what is known today can be mined in order to guide the process of uncovering more of the relationship between aging and the operation of metabolism. In any given network of genes where one can be altered to increase longevity, it is to be expected that there may be others. The proteins produced by these genes existing in an interconnected system, and it is probably the case that you can change the behavior of such a system by intervening at more than one point.

Here is an example of this approach: "Intricate and interconnected pathways modulate longevity ... Because biological processes are often executed by protein complexes and fine-tuned by regulatory factors, the first-order protein-protein interactors of known longevity genes are likely to participate in the regulation of longevity. Data-rich maps of protein interactions have been established for many cardinal organisms such as yeast, worms, and humans. We propose that these interaction maps could be mined for the identification of new putative regulators of longevity. For this purpose, we have constructed longevity networks in both humans and worms. We reasoned that the essential first-order interactors of known longevity-associated genes in these networks are more likely to have longevity phenotypes than randomly chosen genes."


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!



Friday, November 16, 2012
The developing technology of bioprinting, producing tissue structures using inkjet or other print technologies, has a promising future: "Desktop 3-D printers can already pump out a toy trinket, gear set or even parts to make another printer. Medical researchers are also taking advantage of this accelerating technology to expand their options for regenerative medicine. Researchers have made great strides in coaxing cells to grow over artificial, porous scaffolds that can then be implanted in the body to replace hard tissue, such as bone. ... But now, instead of relying on poured molds, foam designs or donated biological materials, researchers can print custom scaffold structures with biocompatible, biodegradable polymers. ... These methods have allowed us to develop very complex scaffolds which better mimic the conditions inside the body. ... Engineers can carefully control the minute, internal structures of these porous scaffolds to best promote cellular growth. And these new printing methods also allow quick and cheap experiments that test various one-off designs. Advancing bio-printing technologies can also be used for the biological material itself. Like color printing, biomaterial printing can switch among different organic materials as well as produce gradients and blending. Inkjet printing is preferred for depositing cells themselves, and as a demonstration of this in the 1980s an unmodified HP desktop printer was used to print out collagen as well as tissuelike structures. Printing, however, is tough on cells. Some studies have successfully kept more than 95 percent of cells intact through the process, but others have not done as well - losing more than half from damaged membranes. The future of bio-printing may be the combination of these approaches - printing both highly specific scaffolds and cell structures. Recent research has shown that stem cell fate can be controlled by the surfaces onto which the cells are printed."

Friday, November 16, 2012
A range of age-related conditions are characterized by a buildup or clumping of harmful proteins, and research tends to focus first on ways to safely break down these compounds. Here researchers are testing a new candidate method of breaking down the beta amyloid and tau associated with Alzheimer's disease: "Last March, researchers at UCLA reported the development of a molecular compound called CLR01 that prevented toxic proteins associated with Parkinson's disease from binding together and killing the brain's neurons. Building on those findings, they have now turned their attention to Alzheimer's disease, which is thought to be caused by a similar toxic aggregation or clumping, but with different proteins, especially amyloid-beta and tau. And what they've found is encouraging. Using the same compound, which they've dubbed a "molecular tweezer," in a living mouse model of Alzheimer's, the researchers demonstrated for the first time that the compound safely crossed the blood-brain barrier, cleared the existing amyloid-beta and tau aggregates, and also proved to be protective to the neurons' synapses - another target of the disease - which allow cells to communicate with one another. Even though synapses in transgenic mice with Alzheimer's may shut down and the mice may lose their memory, upon treatment, they form new synapses and regain their learning and memory abilities. ... For humans, unfortunately, the situation is more problematic because the neurons gradually die in Alzheimer's disease. That's why we must start treating as early as possible. The good news is that the molecular tweezers appear to have a high safety margin, so they may be suitable for prophylactic treatment starting long before the onset of the disease."

Thursday, November 15, 2012
Arguably metastasis is what makes cancer so dangerous: that a single malignant tumor of any size can seed further tumors throughout the body; that a diaspora of metastasized cells is exceedingly hard to eliminate once let lose. If metastasis could be blocked many forms of cancer would become tractable and far less threatening, which is a fair-sized step towards a robust cure for cancer - very much needed as a part of any package of biotechnologies aimed at greatly extending healthy human life. Thus it is promising to see signs of early progress along these lines: "In laboratory experiments, scientists have eliminated metastasis, the spread of cancer from the original tumor to other parts of the body, in melanoma by inhibiting a protein known as melanoma differentiation associated gene-9 (mda-9)/syntenin. ... With further research, the approach used by the scientists could lead to targeted therapies that stop metastasis in melanoma and potentially a broad range of additional cancers. [Researchers] found that Raf kinase inhibitor protein (RKIP) interacted with and suppressed mda-9/syntenin. Mda-9/syntenin [was] shown in previous studies to interact with another protein, c-Src, to start a series of chemical reactions that lead to increased metastasis. ... Prior research suggests that RKIP plays a seminal role in inhibiting cancer metastasis, but, until now, the mechanisms underlying this activity were not clear. Now that the researchers have demonstrated the ability of RKIP to inhibit mda-9/syntenin-mediated metastasis, they are focusing their attention on developing small molecules imitating RKIP that could be used as new treatments for melanoma."

Thursday, November 15, 2012
Mitochondrial function is important in determining life span, and mitochondrial damage is one of the root causes of aging. Thus life span differences between similar species may to a large degree reflect differences in the damage resistance of mitochondria, and a number of studies in recent years have shown that some human mitochondrial haplogroups - which represent characteristic variations in mitochondrial DNA - can be correlated with increased longevity. The way in which mitochondria become damaged involves the production of reactive oxygen species (ROS) in the course of generating fuel to power the cell that contains them. Here researchers show that a longevity-associated difference in mitochondrial DNA reduces the pace of ROS production - which fits nicely with the present understanding of the role of mitochondria in aging: "Mitochondrial DNA (mtDNA) is highly polymorphic, and its variations in humans may contribute to individual differences in function. [Researchers] found a strikingly higher frequency of a C150T transition in the D-loop of mtDNA from centenarians and twins of an Italian population. The C150T transition is a polymorphism associated with several haplogroups. To determine whether haplogroups that carry the C150T transition display any phenotype that may be advantageous for longevity, we analyzed cybrids carrying or not the C150T transition. These cybrids were obtained by fusing cytoplasts derived from human fibroblasts with human mtDNA-less cells. We have found no association of respiratory capacity, mtDNA level, mitochondrial gene expression level, or growth rate with the presence of the C150T transition. However, we have found that the cybrids with haplogroups that include the C150T transition have in common a lower reactive oxygen species (ROS) production rate than the haplogroup-matched cybrids without that transition. Thus, the lower ROS production rate may be a factor in the increased longevity associated with [these] haplogroups."

Wednesday, November 14, 2012
Biodegradable scaffolds are an important part of tissue engineering, providing a way to hold cells in place and shape their growth in three dimensions, breaking down gradually as the new tissue builds its own supporting extracellular matrix. Here an intriguing advance in scaffold technology is noted: "Bioengineers [have] developed a gel-based sponge that can be molded to any shape, loaded with drugs or stem cells, compressed to a fraction of its size, and delivered via injection. Once inside the body, it pops back to its original shape and gradually releases its cargo, before safely degrading. "The simplest application is when you want bulking. If you want to introduce some material into the body to replace tissue that's been lost or that is deficient, this would be ideal. In other situations, you could use it to transplant stem cells if you're trying to promote tissue regeneration, or you might want to transplant immune cells, if you're looking at immunotherapy." Consisting primarily of alginate, a seaweed-based jelly, the injectable sponge contains networks of large pores, which allow liquids and large molecules to easily flow through it. [Researchers] demonstrated that live cells can be attached to the walls of this network and delivered intact along with the sponge, through a small-bore needle. [The] team also demonstrated that the sponge can hold large and small proteins and drugs within the alginate jelly itself, which are gradually released as the biocompatible matrix starts to break down inside the body. Normally, a scaffold like this would have to be implanted surgically. Gels can also be injected, but until now those gels would not have carried any inherent structure; they would simply flow to fill whatever space was available. [Researchers] pushed pink squares, hearts, and stars through a syringe to demonstrate the versatility and robustness of their gel."

Wednesday, November 14, 2012
This year's Humanity+ conference is near: "The Humanity+ conference in San Francisco takes place on December 1-2, 2012 at Seven Hills Conference Center at San Francisco State University. ... Revolving around the theme "Writing the Future", the conference will explore the world of media and communicating Transhumanism. ... Speakers include multi-award winning science fiction author Kim Stanley Robinson, acclaimed biomedical gerontologist Aubrey de Grey, designer and theorist Natasha Vita-More, futurist Jamais Cascio, science fiction author David Brin, philosopher and proactionary principle advocate Max More, national best selling author Sonia Arrison, artificial general intelligence researcher Ben Goertzel, and more. "Writing the Future" focuses on communicating how emerging and converging sciences and technologies are the tools for designing our future, based on the advances in robotics, nanotechnology, artificial intelligence, human enhancement, brain-computer integration, regenerative medicine, and radical life extension. The future and its many narratives, both written and spoken, are is created by people of the present. In many cases, notably the biomedical realm, the intrinsic costs of pioneering technological research mean that the rate of progress is strongly influenced by public enthusiasm for its goals. This creates a dilemma, in that the public are often ambivalent (at best) concerning such goals, even when by any rational standards they should not be. Should those involved in such work therefore understate their goals when writing proposals and addressing a general audience, making them less "scary" and thereby attracting funds to make initial progress?"

Tuesday, November 13, 2012
Zebrafish, like a number of lower animals, are far better at regenerating lost tissue than mammals. In recent years, researchers have been investigating the mechanisms by which this superior regeneration works. It is possible that mammals such as we humans still have the necessary machinery, but it is turned off - or if we have lost it, that there is a way to recapture some of that loss through genetic engineering or other advanced medicine. But first, far more must be learned of the way in which regeneration proceeds in species like the zebrafish: "The secret to zebrafish's remarkable capacity for repairing their brains is inflammation ... Neural stem cells in the fish's brains express a receptor for inflammatory signaling molecules, which prompt the cells to multiply and develop into new neurons. Zebrafish, like many other vertebrates, are able to regenerate a variety of body tissues, including their brains. In fact [mammals] are the ones that seem to have lost this ability - they are kind of the odd ones out. [Given] the therapeutic potential of neuron regeneration for patients with brain or spinal injuries, [we'd] like to figure out if we can somehow reactivate this potential in humans. Last year, [researchers] discovered that radial glial stem cells are responsible for producing new neurons during brain regeneration in zebrafish. But they didn't know what prompted these cells to spring into action. Inflammation seemed a good candidate, [as] it arises as an immediate response to injury. [Researchers] introduced Zymosan A - an immunogenic factor derived from yeast - into the brains of zebrafish to induce inflammation in the absence of injury. They found that, just like brain injury, Zymosan A induced significant glial cell proliferation and new neuronal growth. In fish with suppressed immune responses, however, brain injury did not induce regeneration, further suggesting a role for inflammation."

Tuesday, November 13, 2012
OncoSENS is the cancer-related project in the Strategies for Engineered Negligible Senescence (SENS). In typically ambitious fashion the plan is to remove the ability of humans to generate cancer by blocking all processes that can lengthen telomeres, as telomere lengthening is a function that all cancers must abuse in order to bypass normal limits on cell replication. No other commonality between all cancers is presently known, and this blocking of telomere lengthening looks very likely to work, but for my money I'd prefer a more traditional approach to building robust cancer therapies - or perhaps adapting the mechanisms by which mole rats render themselves immune to cancer. The reason for this preference is that a person unable to lengthen telomeres would, at a minimum, require replacement of all stem cell populations once a decade or so - and if you miss that procedure, you will decline pretty quickly with many of the symptoms of an accelerated aging condition. The SENS Foundation is presently hiring for a research group lead position in the OncoSENS project; pass it on to anyone you know who might be interested: "SENS Research Foundation is hiring for our research center located in Mountain View, CA. We are seeking a team lead for our OncoSENS group to work both on established projects and new independent research geared towards understanding the genetic mechanisms of telomerase-independent telomere elongation; for example, see the project Identifying and Disrupting Mediators of ALT. Research is focused on developing therapies against cancers that maintain their replicative potential using alternative lengthening of telomeres (ALT), and more generally the mission of the Foundation, toward overcoming the diseases and disabilities of aging. Qualified candidates will have a Ph.D. in the chemical/biological sciences. Duties will include bench work, management of a small team of lab researchers, the preparation of grant proposals, internal and external progress reports, individual and collaborative publication. The project lead will develop, interpret and implement standards, procedures, and protocols for the OncoSENS research program and may collaborate on determining strategic directions in the research program."

Monday, November 12, 2012
As I've pointed out in the past, the concept of "successful aging" looks more and more awkward and ill-thought the closer you examine it. At the high level the idea is connected to compression of morbidity, pushing disability and frailty further out into old age without extending life - but are these things even possible as goals for medical science? It seems likely not: either you extend life or you don't; either you treat aging by slowing its progression or reversing it or you don't. Aging itself is by definition a degenerative medical condition that causes pain, suffering, and death - so the idea of aging successfully seems a contradiction in terms at best, and at worst a sort of propaganda intended to deliberately cloud the issue of what should be done by the medical research community: "Increasing longevity is one of the great achievements of our civilization, but it has also given rise to discussion about good and successful aging. The concept of successful aging has attracted much debate, but there is still no universally accepted definition or standard measurement tool for it. The Encyclopedia of Aging defines successful aging as survival (longevity), health (lack of disabilities), and life satisfaction (happiness). It appears that the main sources of difficulty lay in the ambiguity of the meaning of "success," in the complexity of the aging process, the rapid changes taking place in society, and the changing characteristics of the older population. Discussions on successful aging have taken two main perspectives: one defines successful aging as a state of being, while the other understands it as a process of adaptation, described as doing the best with what one has. Studies taking the adaptation approach have often found that older people themselves feel they are aging successfully, even though traditional quantitative models say otherwise. Successful aging as a state of being, then, is an objective measurable condition at a certain point in time, demonstrating the positive extreme of normal aging. The most influential model of successful aging as a state of being was introduced by Rowe and Kahn, who characterize "success" as absence of disease and disability, maintained physical and mental functioning, and active engagement with life. Many studies and definitions take the view that successful aging is possible only among individuals without disease and impairment. Obviously such categorizations are likely to exclude most older people, typically the oldest-old, from the possibility of successful aging."

Monday, November 12, 2012
A short Slate article here looks at some comments made by Aubrey de Grey on the goals and outcomes of rejuvenation biotechnology research: ""I do not like to use the word immortality. It gives a very bad, a wrong impression about my work. I work on health. I am interested in ensuring that people will stay completely youthful, like young adults, for as long as they live," he said at a press conference at Ciudad de las Ideas, an annual conference about big ideas held in Puebla, Mexico. de Grey is the founder of the SENS Foundation, a nonprofit that, among other things, is funding projects intended to cure aging, if not dying. His goal: that everyone may stay a health 29 for as long as they may live. "It is quite likely that there will be a big side effect of doing that, which is that people will live a lot longer, but that is just a side effect," he says. Let's say that de Grey's research pans out - whether it's in the next 20 years, as he hopes may be possible; in the next 40, which he thinks is likely; or not for the next 100, which could happen "if we are unlucky or if we do not try hard enough." How would lifelong health change the way we live? ... "I think that actually society will be very different but ... mostly in ways that it is already moving as a result of technology, including health technologies, that are happening already," he says. "We see today many more people having multiple careers, moving from one to another; having multiple long-term partnerships one after another; generally much more equality between ages; people having partners that are very far distance from them in age. These things I think will simply continue to progress.""



How much money is estimated to be needed today to realize de Grey's goals in less than 20 years? What are the obstacles, other than money, standing in the way of significant progress in age rejuvenation today?

Posted by: Mike at November 29th, 2012 10:19 AM

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