Fight Aging! Newsletter, April 22nd 2013

April 22nd 2013

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!



- Converting this Newsletter to HTML Formatting
- Aubrey de Grey on "the Undoing of Aging"
- A Short Interview With Researcher João Pedro de Magalhães
- Longevity, Technological Progress, and Economic Growth
- At the Intersection of Aging, Cancer, and Cellular Senescence
- Audience Data for Fight Aging!
- Discussion
- Latest Headlines from Fight Aging!
    - Mitochondrial Functional Mutations and Worm Longevity
    - Indy Mutations and Fly Longevity
    - Sterilized Dogs Live Longer
    - Exploring Genetic Regulation of Heart Regeneration
    - The Other Side of CD47: a Way to Spawn Induced Pluripotent Stem Cells
    - A Popular Science Article on the Genetics of Human Longevity
    - Cell-Nanoparticle Hybrids, an Illustration of What is to Come
    - An Update on Protofection
    - A Look at Some of Ray Kurzweil's Predictions on Longevity
    - Decellularization Produces Partially Functional Kidneys in Rats


I would like to begin sending out the Fight Aging! Newsletter in HTML format rather than the present plain text. This would allow for the same general visual layout as the Fight Aging! website, which in theory will make the newsletter more attractive and easier to read - it will certainly improve separation between comments and quotes, for example. The last time I brought this up as a possibility, some years ago, it was greeted by a modest chorus of grumbles from the old school of mail readers, but I think that the state of email software has since advanced to the point at which everyone should be able to receive an HTML email and still read it as text without the formatting if they so choose.

If you have strong opinions either way on this topic, do let me know.


A recent short article from Aubrey de Grey of the SENS Research Foundation:

The desire to defeat aging is surely even more long-standing than the quest to reach the stars. Unfortunately, the idea that we will crumble and die is so crippling that most people evidently need to convince themselves, by whatever means, that it is not such a bad thing after all. Whether it's the existence of a joyous afterlife, or the presumption that a post-aging world would be unsustainably overpopulated, or the fear of immortal dictators, a conversation with nearly anyone about the idea of developing medicine to prevent age-related ill-health is almost certain to be derailed into arguments about whether such medicine would be a good thing at all.

A key pillar of many people's thinking about this topic is the misconception that "aging itself" is somehow a different sort of thing than the diseases of old age. There is actually no such distinction. Age-related diseases spare young adults simply because they take a long time to develop, and they affect everyone who lives long enough because they are side-effects of the body's normal operation rather than being caused by external factors such as infections. In other words, aging is simply the collection of early stages of the diseases and disabilities of old age, and treatment of aging is simply preventative medicine for those conditions - preventative geriatrics. It is thus logically incoherent to support medicine for the elderly but not medicine for aging.

I claim no originality for the above: it has long been the virtually universal view of those who study the biology of aging. I believe it is resisted by the wider world, despite those experts' energetic efforts, overwhelmingly because people don't believe there is much chance of significant progress in their or even their children's lifetimes and they don't want to get their hopes up. But in recent years, the justification for such pessimism has evaporated.

It has done so above all because of progress in regenerative medicine, which colloquially (but see below) consists of stem cells and tissue engineering. Regenerative medicine can be defined as the restoration of bodily function by restoration of structure. We may replace entire organs (tissue engineering), or we may repair organs by replacing their constituent cells (stem cell therapy). In a sense, regenerative medicine is maintenance for the human body. as such, it should in principle be capable of constituting preventative maintenance for the chronic, slowly progressive, initially harmless but eventually fatal processes that jointly make up aging and the diseases of old age. Regenerative medicine has only recently, however, become recognized as a promising avenue for postponing age-related ill-health. This is for two reasons. firstly, it was originally conceived and pursued for its potential to treat acute injury, such as spinal cord trauma, rather than chronic damage: thus, regenerative medicine pioneers and biologists of aging simply didn't talk to each other very much, with the result that those studying aging were insufficiently informed about progress in regenerative medicine to appreciate its potential. The second reason was equally important: in order to be plausibly applicable to aging, regenerative medicine must be broadened into a host of other areas, over and above stem cells and tissue engineering, and those areas are mostly at considerably earlier stages of development.

But not fancifully early. In the decade since I first laid out a putatively comprehensive classification of the various types of molecular and cellular "damage" that must be periodically repaired in order to stave off the decline of old age, and the specifics of how we might do it, progress has been gratifyingly rapid (though I estimate it could be at least three times faster if the potential of this approach were more widely understood and funding for it correspondingly elevated). Furthermore, that plan has abundantly stood the test of time, undergoing only minor adjustments.

In this short, general-audience piece I can only hint at the advances over the past year or two achieved by researchers worldwide in this space. SENS Research Foundation was created for this purpose, and alongside numerous other institutes and organizations, both commercial and nonprofit, we have achieved not only the retardation of aging but its actual repair, restoring youthful health to animals that were suffering widespread age-related decline. Much remains to be done to extend these results, before they can realistically be applied in the clinic. However, the removal of toxic metabolic by-products shows clear promise of completely eliminating cardiovascular disease, the Western world's foremost killer, and also macular degeneration, the leading cause of blindness in the elderly. Similarly, removing cells that have become dysregulated and toxic to the body was recently shown, in multiple models, to restore function to sick animals. Advances like these, in combination with traditional regenerative medicine, may in the next few decades deliver a truly comprehensive and dramatic postponement of age-related ill-health.


João Pedro de Magalhães is the researcher behind the excellent site, the Animal Aging and Longevity Database, the Aging Gene Database, and sundry other projects. He presently heads the Integrative Genomics of Ageing Group at the University of Liverpool, and is one of the modern generation of life scientists unafraid to declare in public that the goal of the field should be nothing less than to cure aging. Many more people of this vision and drive are needed in the field of aging research if we are to see more rapid progress towards rejuvenation biotechnology. I noticed a short iinterview with de Magalhães in the Argentinian Spanish language press today that gives an executive summary of some of his views. Follow the link above for a translated version.


Longevity and wealth go hand in hand. This association is very evident in many periods of history, such as the century leading up to the industrial revolution in England, or the more recent and very rapid transformation of South Korean society from rural poverty to industrialized wealth, accompanied by an equally rapid rise in life expectancy.

Thus economics should be a topic of at least passing interest for everyone who follows longevity science, or looks forward to a future of extended healthy life provided by new medical biotechnologies. Frankly, economics in the broadest sense of human action and its explanations should be of at least passing interest to everyone: societies rise and fall based upon the public understanding or lack of understanding regarding the origins of wealth and economic growth. There seem to be cycles in which those who understand dominate and thus build prosperity, only for their descendants to give it all back to waste and destruction because they fail to grasp why it is that their society is prosperous. Comparative wealth is very good at sheltering people from the realities of how the world works, sadly. These days the US seems to be on the downward slope of that cycle: there is a lot more of eating of seed corn and corruption than even as recently as twenty years ago.

On the grand scale this will slow down progress in technology across the board in comparison to what might have been. Corruption manifests itself most evidently as centralization of power and resulting regulation, which in turn attracts those who live to propagate control for the sake of control. Medicine and biotechnology are being choked beneath a mountain of red tape. One can hope that other regions of the world will take up the slack as the grand medical research community of the US is slowly crushed into an inability to produce and commercialize anything truly new and innovative.

But I hadn't intend this to be a gloomy post, and the very readable paper I want to bring to your attention today is, ultimately, an optimistic take on human progress - both in longevity and in wealth. And indeed, I am optimistic for the long term; empires rise and fall, the US only different in detail from those that came before, and humanity nonetheless marches onward, building new technologies at what seems to be an every-increasing pace, despite the politics, politicians, and parasites. What gloom there is stems from that fact that you and I don't have forever to wait for the just-around-the-corner biotechnologies that will enhance human longevity - there is plenty of room for ugly economic or political collapse to delay matters long enough to produce a poor outcome for us, while still winding up as just another fiddling detail of early 21st century history to the ageless folk of the 2100s and later.


The gene BubR1 is of interest to cancer researchers involved in the study of various forms of nuclear DNA damage, the intricate but usually very reliable DNA repair mechanisms that strive to revert that damage, dysfunction in those repair mechanisms, and how these items relate to cancer and aging. Cancer is quite clearly a condition spawned by damage to the DNA in the cell nucleus; the more of that damage you suffer, the more likely it is that one of your cells will undergo the right combination of mutations to turn it into an unfettered, self-replicating cancer seed - something that looks and acts a lot like a stem cell, spawning copies of itself and a legion of descendants prone to further mutation and causing havoc.

For those of us who follow longevity science, the gene BubR1 is of interest because altering its gene expression level is one of the few simple mechanisms than can both shorten and extend life in mice. Less BubR1 produces an accelerated aging condition, while more of it appears to slow aging, reducing the incidence of various common age-related conditions in the mice that have this gene therapy applied to them.

It is important to note that accelerated aging conditions are generally classed as DNA repair dysfunctions. The worse the dysfunction, the faster that the individual suffers what looks a lot like accelerated aging - but there is some debate in the research community as to whether what is happened should be described as accelerated aging. From the perspective of those of us interested in ways to extend healthy life, research results involving laboratory animals suffering from artificially induced forms of accelerated aging have to be viewed carefully, because they are rarely straightforwardly applicable to normal aging. When you alter genes in a way that causes accelerating aging, such as by reducing the efficiency of some crucial part of DNA repair, this is analogous to breaking a part of a machine - you shouldn't be surprised to find that it fails sooner and more readily than its unbroken peers. That doesn't necessarily say anything about how you might extend the working life of that type of machinery, however.

So you really have to look at each research result on a case by case basis; the ones that are interesting and do have something to say about normal aging are almost always those in which the mechanism causing accelerating aging can be turned around to extend life, as is the case for BubR1 levels.

As it so happens, this all ties in to cellular senescence, another topic of interest to those of us who follow developments in longevity science. Senescent cells are those that have left the cell cycle due to age or damage - such as damage to their nuclear DNA - and really should be destroyed, either by their own programmed cell death processes or by the immune system. Cellular senescence might be thought of as a part of the evolved balance between cancer risk and the need for cells to work and maintain tissues; the more damage there is in the cellular environment, the more cells become senescent, an adaptation that lowers the risk of cancer by preventing damaged cells from undertaking their normal range of activities.

Unfortunately senescent cells are still harmful in and of themselves, as they secrete all sorts of unwanted signals and remodel their local environment. The more of them there are, the more their presence damages the surrounding tissue. The growth in senescent cells with age is one of the root causes of degenerative aging, and getting rid of them on a regular basis is one of the proposed rejuvenation therapies in the SENS vision for reversing the course of aging.

A demonstration of improved health measures in mice through destruction of senescent cells was carried out two years ago. The study used BubR1 mutants suffering from accelerated aging - and thus a faster accumulation of DNA damage and senescent cells. Researchers often use accelerated aging as a way to enable studies to conclude more rapidly, and thus be conducted at an affordable cost; there is an enormous difference in cost between a study that runs a few months and one that runs a few years. Here, however, it is the case that the researchers involved are as much interested in cancer and DNA damage as they are in aging, and the BubR1 mice are their main object of study for many reasons. That they are producing results of interest to longevity science on the matter of cellular senescence is a side-effect of the main thrust of their research, and a consequence of the overlapping mechanisms involved: DNA damage, DNA repair, cancer, aging, accelerated aging, and cellular senescence.


I thought it time to one again say something about the Fight Aging! audience data; for all the numbers, follow the link above. I am occasionally asked about this, so I'm given to think that some of the other folk who run similar sites may benefit from this very infrequent series of posts. Other regular readers may take the information below as a data point to add to what is known about the size and scope of the longevity science community: researchers, advocates, and supporters. As is always the case, I should note that Fight Aging! is a niche concern: any hard science site is already a low traffic venture, and this is even more the case for specialist hard science sites that focus on small fields. Much as I would like to say otherwise, longevity science is a small subfield of aging research, which in turn is a small field within the medical life sciences, tiny in comparison to many of its peers. Neither human longevity nor aging research in general have the funding or attention they merit, given the possibilities for rejuvenation biotechnology that lie ahead and the level of harm caused by aging. We'd all like to see this change - and it needs to change if we are going to anything other than age to death like our ancestors did.


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, April 19, 2013
Many longevity mutations discovered in lower animals such as nematodes involve alterations to mitochondrial function - which only reinforces the apparent importance of mitochondria in determining life span. Mitochondria swarm within cells, working to produce the chemical energy stores used to power cellular operations. In doing so they emit reactive oxygen species, however, that can cause all sorts of harm to the molecular machinery of a cell if not neutralized by a cell's native antioxidants. It is damage to mitochondrial DNA, however, that seems to be one of the root causes of degenerative aging, via a Rube Goldberg sequence of consequences that causes cells to become dysfunctional mass exporters of reactive, harmful molecules. From a practical therapy standpoint, the research community should be working on ways to repair, replace, or back up mitochondrial DNA in our cells if we want this contribution to aging to go away. That work is very poorly funded, however, in comparison to the benefits it might deliver. Meanwhile, examination of longevity mutations in lower animals continues to reinforce the fact that this is an important direction for therapies to treat and reverse aging. Some mitochondrial longevity mutations work via hormesis; they cause a slight increase in the level of emitted reactive oxygen species, which in turn causes the cell to react with increased housekeeping and repair activities, resulting in a net gain - less damage over the long term translates into slower aging. Other mutations lower the level of emitted reactive oxygen species, which again means less damage over the long term. Yet more mitochondrial mutations extend life in less obvious ways, or cause mitochondrial dysfunction that appears at the high level to be broadly similar to that of longevity mutants, yet reduces life span. Once you start digging in to the mechanisms of the mitochondrial interior - the electron transport chain with it's multiple complexes - it's all far from simple Here is an example of research into the mechanisms of mitochondrial longevity mutations in nematode worms: "Many Caenorhabditis elegans mutants with dysfunctional mitochondrial electron transport chain are surprisingly long lived. Both short-lived (gas-1(fc21)) and long-lived (nuo-6(qm200)) mutants of mitochondrial complex I have been identified. However, it is not clear what are the pathways determining the difference in longevity. We show that even in a short-lived gas-1(fc21) mutant, many longevity assurance pathways, shown to be important for lifespan prolongation in long-lived mutants, are active. Beside similar dependence on alternative metabolic pathways, short-lived gas-1(fc21) mutants and long-lived nuo-6(qm200) mutants also activate hypoxia-inducible factor-1α (HIF-1α) stress pathway and mitochondrial unfolded protein response (UPRmt). The major difference that we detected between mutants of different longevity is in the massive loss of complex I accompanied by upregulation of complex II levels, only in short-lived, gas-1(fc21) mutant. We show that high levels of complex II negatively regulate longevity in gas-1(fc21) mutant by decreasing the stability of complex I. Furthermore, our results demonstrate that increase in complex I stability, improves mitochondrial function and decreases mitochondrial stress, putting it inside a "window" of mitochondrial dysfunction that allows lifespan prolongation."

Friday, April 19, 2013
The indy gene - named for "I'm not dead yet" - was one of the earliest longevity mutations to be uncovered in flies, and consequently is somewhat better studied than the many that have followed since then. Here is an open access paper on the subject: "Decreased expression of the fly and worm Indy genes extends longevity. The fly Indy gene and its mammalian homolog are transporters of Krebs cycle intermediates, with the highest rate of uptake for citrate. Cytosolic citrate has a role in energy regulation by affecting fatty acid synthesis and glycolysis. Fly, worm, and mice Indy gene homologs are predominantly expressed in places important for intermediary metabolism. Consequently, decreased expression of Indy in fly and worm, and the removal of mIndy in mice exhibit changes associated with calorie restriction, such as decreased levels of lipids, changes in carbohydrate metabolism and increased mitochondrial biogenesis. Here we report that several Indy alleles in a diverse array of genetic backgrounds confer increased longevity." The paper is a good example of the way in which calorie restriction muddies the water of longevity studies; the effects of calorie restriction on life span are very strong in lower animals like flies and worms, and many past studies failed to fully account for differing dietary calorie intakes between populations of these animals. The authors of this paper point out a number of past papers with results that may tainted due to differing calorie intake, and note that their own work tries to control for this.

Thursday, April 18, 2013
A range of research in laboratory animals associates alterations to the reproductive system with alterations in longevity. Nematode worms live longer if you remove their germ cells, for example. Transplanting younger ovaries into older mice extends life as well. There is some thought that these varied approaches work through common longevity mechanisms such as insulin-like signaling pathways, but that's by no means certain. Here is another set of data to add to the existing research on this topic: "Reproduction is a risky affair; a lifespan cost of maintaining reproductive capability, and of reproduction itself, has been demonstrated in a wide range of animal species. However, little is understood about the mechanisms underlying this relationship. Most cost-of-reproduction studies simply ask how reproduction influences age at death, but are blind to the subjects' actual causes of death. Lifespan is a composite variable of myriad causes of death and it has not been clear whether the consequences of reproduction or of reproductive capability influence all causes of death equally. To address this gap in understanding, we compared causes of death among over 40,000 sterilized and reproductively intact domestic dogs, Canis lupus familiaris. We found that sterilization was strongly associated with an increase in lifespan, and while it decreased risk of death from some causes, such as infectious disease, it actually increased risk of death from others, such as cancer. Although a retrospective, epidemiological study such as this cannot prove causality, our results suggest that close scrutiny of specific causes of death, rather than lifespan alone, will greatly improve our understanding of the cumulative impact of reproductive capability on mortality. Our results strongly demonstrate the need to determine the physiologic consequences of sterilization that influence causes of death and lifespan. Shifting the focus from when death occurs to why death occurs could also help to explain contradictory findings from human studies."

Thursday, April 18, 2013
Will it be possible in years ahead to temporarily adjust the programming of existing cell populations in the body to cause them to regenerate from damage and injuries more effectively than is presently the case? Most likely so, though it is a fair distance from present early explorations to a safe and effective therapy. Here is an example of work presently underway in the laboratory: ""We found that the activity of the Meis1 gene increases significantly in heart cells soon after birth, right around the time heart muscle cells stop dividing. Based on this observation we asked a simple question: If the Meis1 gene is deleted from the heart, will heart cells continue to divide through adulthood? The answer is 'yes.'" The research team demonstrated that deletion of Meis1 extended the proliferation period in the hearts of newborn mice, and also re-activated the regenerative process in the adult mouse heart without harmful effect on cardiac functions. This new finding demonstrates that Meis1 is a key factor in the regeneration process, and the understanding of the gene's function may lead to new therapeutic options for adult heart regeneration. The findings also provide a possible alternative to current adult heart regeneration research, which focuses on the use of stem cells to replace damaged heart cells. "Meis1 is a transcription factor, which acts like a software program that has the ability to control the function of other genes. In this case, we found that Meis1 controls several genes that normally act as brakes on cell division. As such, Meis1 could possibly be used as an on/off switch for making adult heart cells divide. If done successfully, this ability could introduce a new era in treatment for heart failure.""

Wednesday, April 17, 2013
CD47 is a cell surface marker that tells immune cells to leave a cell alone. Researchers are presently using CD47 as a target for next-generation cancer therapies - and quite effectively. The marker seems to be present to a greater level that usual in all cancers examined to date, and blocking it frees the immune system to attack the cancer cells. I noticed another research item today in which a group found that removing CD47 triggers the set of genes known to cause normal adult cells to become induced pluripotent stem (iPS) cells. This is a very interesting result given the cancer connection, and given that this manipulation doesn't seem to make cells prone to generating cancer: "In 2008 [researchers] were using agents that block a membrane protein called CD47 to explore their effects on blood vessels. When cells from the lining of the lungs, called endothelium, had been treated with a CD47 blocker, they stayed healthy and maintained their growth and function for months. [The] team continued to experiment with CD47 blockade, focusing on defining the underlying molecular mechanisms that control cell growth. They found that endothelial cells obtained from mice lacking CD47 multiplied readily and thrived in a culture dish, unlike those from control mice. [The researchers] discovered that this resulted from increased expression of four genes that are regarded to be essential for formation of iPS cells. When placed into a defined growth medium, cells lacking CD47 spontaneously formed clusters characteristic of iPS cells. By then introducing various growth factors into the culture medium, these cells could be directed to become cells of other tissue types. Despite their vigorous growth, they didn't form tumors when injected into mice, a major disadvantage when using existing iPS cells. "Stem cells prepared by this new procedure should be much safer to use in patients. Also, the technique opens up opportunities to treat various illnesses by injecting a drug that stimulates patients to make more of their own stem cells. These experiments indicate that we can take a primary human or other mammalian cell, even a mature adult cell, and by targeting CD47 turn on its pluripotent capability. We can get brain cells, liver cells, muscle cells and more. In the short term, they could be a boon for a variety of research questions in the lab.""

Wednesday, April 17, 2013
A great deal of work in the aging research community focuses on trying to untangle the relationship between genes, epigenetic patterns of gene expression, metabolism, and natural variations in human longevity. It's an enormously complex task, far harder than just trying to repair the known biochemical damage of aging - analogous to producing a general theory and full mathematical model of paint peeling rather than just repainting a wall. "In the dimly lit, chilly hallway outside Passarino's university office stand several freezers full of tubes containing centenarian blood. The DNA from this blood and other tissue samples has revealed additional information about the [study population]. For example, people who live into their 90s and beyond tend to possess a particular version, or allele, of a gene important to taste and digestion. This allele not only gives people a taste for bitter foods like broccoli and field greens, which are typically rich in compounds known as polyphenols that promote cellular health, but also allows cells in the intestine to extract nutrients more efficiently from food as it's being digested. Passarino has also found in his centenarians a revved-up version of a gene for what is called an uncoupling protein. The protein plays a central role in metabolism - the way a person consumes energy and regulates body heat - which in turn affects the rate of aging. "We have dissected five or six pathways that most influence longevity," says Passarino. "Most of them involve the response to stress, the metabolism of nutrients, or metabolism in general - the storage and use of energy." His group is currently examining how environmental influences - everything from childhood diet to how long a person attends school - might modify the activity of genes in a way that either promotes or curtails longevity. If nothing else, the plethora of new studies indicates that longevity researchers are pushing the scientific conversation to a new level. [But] genes alone are unlikely to explain all the secrets of longevity. Passarino made the point while driving back to his laboratory after visiting the centenarians in Molochio. "It's not that there are good genes and bad genes," he said. "It's certain genes at certain times. And in the end, genes probably account for only 25 percent of longevity. It's the environment too, but that doesn't explain all of it either. And don't forget chance.""

Tuesday, April 16, 2013
Work on nanoparticles and artificial cell structures for use in medicine is becoming more sophisticated. There is an emerging generation of simple but effective medical micro- and nanomachines, devices that will be manufactured in their millions and infused into the body to perform useful tasks, such as killing specific cells, or delivering specific signals to cells to cause them to regenerate more effectively, or clearing out unwanted metabolic byproducts that contribute to aging. A lot of interesting projects are presently underway, and this article is a good illustration of one branch of this work and its utility: "Nanoparticles could be used to neutralize toxins produced by many bacteria, including some that are antibiotic-resistant, and could counteract the toxicity of venom from a snake or scorpion attack. [The] "nanosponges" work by targeting so-called pore-forming toxins, which kill cells by poking holes in them. There are a range of existing therapies designed to target the molecular structure of pore-forming toxins and disable their cell-killing functions. But they must be customized for different diseases and conditions, and there are over 80 families of these harmful proteins, each with a different structure. Using the new nanosponge therapy [researchers] can neutralize every single one, regardless of their molecular structure. [Researchers] wrapped real red blood cell membranes around biocompatible polymeric nanoparticles. A single red blood cell supplies enough membrane material to produce over 3,000 nanosponges, each around 85 nanometers (a nanometer is a billionth of a meter) in diameter. Since red blood cells are a primary target of pore-forming toxins, the nanosponges act as decoys once in the bloodstream, absorbing the damaging proteins and neutralizing their toxicity. And because they are so small, the nanosponges will vastly outnumber the real red blood cells in the system. This means they have a much higher chance of interacting with and absorbing toxins, and thus can divert the toxins away from their natural targets. In animal tests, the researchers showed that the new therapy greatly increased the survival rate of mice given a lethal dose of one of the most potent pore-forming toxins. Liver biopsies several days following the injection revealed no damage, indicating that the nanosponges, along with the sequestered toxins, were safely digested after accumulating in the liver."

Tuesday, April 16, 2013
Here at Fight Aging! the most recent update on protofection, a possible basis for a way to replace damaged mitochondrial DNA (mtDNA) and remove its contribution to degenerative aging, was late last year. Since the first publication on protofection back in 2005 a number of other potential mechanisms for mitochondrial DNA repair or replacement have emerged, but none of these, protofection included, are moving as rapidly as would be liked. One problem is the regulatory environment in the biggest markets: you are only allowed to develop commercial therapies for named diseases, not for aging, and comparatively few people suffer from named diseases that involve specific, characteristic forms of mitochondrial mutation - as opposed to the general stochastic damage of aging. So there is little funding, and it's actually effectively illegal to try to treat aging this way, despite the great possibilities of this research. One of the potential target diseases is Leber's hereditary optic neuropathy (LHON), and if you have a good memory you might recall that one of the researchers involved in work on the SENS approach to mitochondrial DNA damage - move the vulnerable genes into the cell nucleus to create a secondary source of the necessary proteins - is primarily concerned with LHON rather than aging. Here is an open access paper on the use of protofection (among other options) as a LHON therapy, which is also of general interest to anyone looking at this sort of approach to mitochondrial gene therapy for aging or other conditions: "An optimal cure [for LHON] would be gene therapy, which involves introducing the missing gene(s) into the mitochondria to complement the defect. Our recent research results indicate the feasibility of an innovative protein-transduction ("protofection") technology, consisting of a recombinant mitochondrial transcription factor A (TFAM) that avidly binds mtDNA and permits efficient targeting into mitochondria in situ and in vivo. Thus, the development of gene therapy for treating mitochondrial disease offers promise, because it may circumvent the clinical abnormalities and the current inability to treat individual disorders in affected individuals. We successfully demonstrated introduction of labeled rhTFAM and healthy mtDNA complexed with rhTFAM into homoplasmic LHON cybrid cells containing the G11778A mutation. [Further] results in LHON cybrid cells, demonstrated an increase in mitochondrial genome replication, transcription, translation, and respiration initiated within a week when the complex was introduced into the mitochondria. We also observed the activation of the mitochondrial biogenesis (creation of new mitochondria) program in these human LHON cybrid cells. [It] is expected that this mitochondrial genome manipulation approach based on introduction of exogenous normal or pathogenic mtDNA provides hope for LHON patients afflicted with other mutations in the mitochondrial genome. The current studies indicate that the mitochondrial genome can be manipulated and lead to improvement in mitochondrial function in in vitro and in vivo models. Future coordinated efforts between scientists and clinicians are necessary to translate these findings towards development of therapies for LHON patients." This is far from a niche study, despite being related to a niche disease; mitochondrial DNA damage arguably causes a fairly large fraction of degenerative aging. It is incredible to think that regulators actively work to prevent greater funding and more work on this and other items that could help to reverse the effects of aging in the old.

Monday, April 15, 2013
Like many, I think that Ray Kurzweil is overly optimistic on the timeline for progress in technology. I don't think he's wrong in terms of his high level view on where our technology is going, just a few decades on the early side - which is unfortunate for those of us who will age to death before the advent of rejuvenation biotechnology. It is certainly the case that the first draft of technologies to repair the underlying biological damage that causes aging could arrive fairly soon, within two decades - but it's not just a matter of building them, even though there are detailed research and development plans for doing so. The issues are persuasion and fundraising; when it comes to aging, the mainstream of the research community is set on goals that either have nothing to do with human longevity, or will do very little to extend life even after being realized at great cost. So the comparatively tiny and underfunded shard of the scientific community whose members are interested in realizing effective means of rejuvenating the old will likely spend the next twenty years on laying the groundwork, prototyping the biotechnologies, proving their case ever more completely, growing funding, and persuading ever more researchers to do the same. If there were hundreds of millions of dollars devoted to this cause today, we could leap ahead twenty years in this timeline - but there are not. The money and large supportive community still has to be bootstrapped, building on the present early phase in the growth of modern rejuvenation research, underway successfully but slowly for the past decade or so, giving rise to organizations like the Methuselah Foundation and SENS Research Foundation. Here is Kurzweil's take on timelines, which are derived from his analysis of trends in technological capabilities: "To listen to Mr. Kurzweil or read his several books is to be flummoxed by a series of forecasts that hardly seem realizable in the next 40 years. But this is merely a flaw in my brain, he assures me. Humans are wired to expect "linear" change from their world. They have a hard time grasping the "accelerating, exponential" change that is the nature of information technology. "A kid in Africa with a smartphone is walking around with a trillion dollars of computation circa 1970," he says. Project that rate forward, and everything will change dramatically in the next few decades. "I'm right on the cusp," he adds. "I think some of us will make it through" - he means baby boomers, who can hope to experience practical immortality if they hang on for another 15 years. By then, Mr. Kurzweil expects medical technology to be adding a year of life expectancy every year. We will start to outrun our own deaths. And then the wonders really begin. Mr. Kurzweil's ideas on death and immortality, not his impressive record as an entrepreneur, are what bring TV newsmagazines and print reporters to his door these days. I suggest to him he's discovered the power of the prophetic voice and is borne forward by the rewarding feelings that come from giving people hope in the face of their profoundest fears. My insight does not impress him. He says he just gets satisfaction from seeing his ideas, like his inventions, wield a positive force in the world. People blame technology for humanity's problems, he says. They are much too pessimistic about its power to solve poverty, disease and pollution in our lifetimes."

Monday, April 15, 2013
Decellularization is the process of taking donor tissue, such as a complete organ, stripping out its cells to leave the extracellular matrix structure, and then repopulating that structure with another individual's cells to reform a functional organ. This produces donor tissue that will not be rejected by a transplant recipient, and has been successfully used in a few human transplants of less complicated tissue structures such as the trachea. This technology is an important stepping stone on the way towards organs created from scratch; it works around the present inability to build a sufficiently detailed and functional framework for complex tissue. The extracellular matrix from existing tissue provides chemical cues and other necessary items that allow cells to correctly form the many intricate structures, such as blood vessel networks, needed for a fully functional organ. In the laboratory, a number of complete animal organs have been successfully decellularized and transplanted - and kidneys are now included in that list, albeit only partially functional kidneys, a starting point for better results in years ahead: "[Researchers have] engineered functional rat kidneys by stripping donor kidneys of their cells and then repopulating the remaining collagen substructures with new cells. The bioengineered kidneys produced urine in laboratory dishes and when implanted in living animals. The advance could be good news for the 100,000 Americans waiting for donor kidneys for transplant, because it suggests that someday scientists might be able to grow custom-made kidneys for people, using a patient's own cells to seed tissues. The process at the center of his team's approach is called "decellularization." In a carefully calibrated process, researchers removed a kidney from a cadaver and then introduced a series of washing agents into its vascular system to remove the organ's cells. [Then] they introduced immature cells that could form kidney tissues and blood vessels into the acellular scaffold. After a short time, the new kidneys could produce urine. They didn't work as well as normal, healthy kidneys would - in the laboratory dish, they cleared creatinine (a blood component filtered by the kidneys) 23% as well as a native kidney; once implanted in animals, about 5% to 10% as well. But "the bottom line is, we saw urine production.""



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