Fight Aging! Newsletter, January 27th 2014

January 27th 2014

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!

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  • The 2010s in Biotechnology Reflect the 1960s in Computing
  • A Few Papers Related to the Structural Aging of the Adaptive Immune System
  • Genetics of Aging and Longevity Conference in Sochi, April 2014
  • The Immorality of Seeking to Halt Progress in Longevity Science
  • Recent Attention Given to SENS Rejuvenation Research
  • Latest Headlines from Fight Aging!
    • Manufacturing Synthetic Tracheas
    • A Review of Intermittent Fasting Research
    • Exploring AMPK as a Potential Exercise Mimetic Target
    • Theorizing on the Consequences of Learning
    • Inhibiting Myostatin Increases Muscle Mass in Old Mice
    • Gene Silencing PHD2 to Enhance Tissue Regeneration
    • Damage, Not Free Radicals, Should Be the Focus
    • Stem Cells Supplying Mitochondria to Other Cells
    • Repairing Retinal Tissue in Mice With Stem Cells
    • Immune Cell Dynamics and Variations in Heart Healing


Drawing on historical analogies is a common practice when trying to figure out where we are and where we're going. We're all still human, and development today proceeds according to human nature first and foremost, just the same as in the past: great progress has taken place, but when comes down to the basic organization of research, development, and commercialization of products, there are still far more similarities than differences in comparisons with any given yesteryear. We can recognize the elements of our present work in the way the Victorians and the Romans did business - so a mere few decades past into the last century seems quite safe to mine for examples.

Biotechnology is the application of the life sciences, and the foundation of medicine. At present progress in biotechnology is rapid and revolutionary. The groundwork for a series of disruptive, factor-of-ten improvements in a variety of medical technologies has already been accomplished: think of the attention given to gene sequencing over past years, for example, the world watching as costs plummeted even while capabilities increased year over year. That is just one of many, many applications in biotechnology that are improving in similar ways.

I've pointed out in the past that this present stage bears considerable resemblance to the dawn of the age of powered flight: decades in which the necessary technologies for aircraft as we recognize them were developed in isolation, for other uses, or assembled into noble failures. Then, suddenly the leap was made and in just a few further decades following that the whole nature of travel underwent a revolution - a disruptive advance in the speed and opportunity to move from place to place was achieved.

A different sort of leap occurred over the 1960s and 1970s in the development of modern computing: the move from expensive, large computing devices to cheap, small computing devices. A mere change in price is far from prosaic and boring: it drives sweeping changes in adoption and expansion in the forms of application for any given technology. The lower the barrier to entry - price in this case - the more experimentation and thinking takes place, leading to greater application of a given technology for the benefit of all. In the past I've pointed out the parallels between the early personal computing societies of the 1970s and the present diybio community: enthusiasts, hobbyists, and professionals merging their efforts as costs fall to the point at which anyone can join in and build.

If you look at the Computer History Museum's entries for 1960, 1965, and 1970, it's not unreasonable to suggest that we're somewhere in the middle there when it comes to biotechnology today. The present trend I have in mind is the move towards small, portable, low-cost laboratory equipment that can accomplish most of what was possible in a large lab ten years ago. A lab in a box by that metric is years away still, but numerous groups are making significant inroads towards that goal.

But why care about this? In truth it isn't all that important to me whether or not 2010 in biotechnology is 1960 in computing, but is important to me to have some model for the next few decades of work in medical science, and in particular the ability to make progress towards treatment and reversal of aging. How much progress is likely in the foundations, the capabilities in biotechnology (other people have looked at that exhaustively from a different angle)? Should we expect and plan for disruption of the research process to the point at which the barrier between trained professional and effective self-educated contributor blurs to nothing, as has happened for software development?

We can ask these and other questions so as to have some idea as whether matters are proceeding as fast as they might, and what new directions in effective advocacy and funding will arise in the near future. Clearly at some point if the institutions are not funding the research and development work we feel is important, it will be possible to do it ourselves. Given smart, motivated collaborators and crowdfunding complex problems can be solved in software development today. Creating applications of new knowledge in molecular biology and medical science is no more complex than constructing big software projects - the differences between these two types of undertaking are the degree to which regulation obstructs change, raises costs, and prohibits participation, and the anemic, expensive nature of the presently publicly available tools for life science work. The latter will change, rapidly, and the former will simply mean that development will occur most readily in regions outside the US.

But these are things to think on as we watch and support our favored research into aging and longevity. In past decades we could only have watched - the amounts of money involved were too large for any ordinary individual to help with. But the cost of life science research is plummeting, and here and now crowdfunding of research projects that advance the state of the art is a very real thing. Medical research for your favored causes isn't just a spectator sport anymore: the times are changing.


The adaptive immune system that we are all born with is structurally unsound for long term use. Even if we did not accumulate any of the known forms of cellular and molecular damage thought to cause degenerative aging, the adaptive immune system would still grind itself down into a state of continual malfunction. In this it is unusual: absent damage, a liver or a heart would continue to function as well as it did in youth far beyond the present human life span.

Why would the immune system fail even absent damage? From a mechanistic standpoint - and simplifying a complex situation considerably - it fails because it has a limited supply of new T cells in adulthood, but is programmed to assign some of its T cells to remembering every new threat that it encounters. Some threats, such as otherwise largely harmless herpesviruses like CMV, are exceedingly persistent and come back again and again. Eventually there are too many memory T cells and not enough naive T cells capable of attacking new pathogens or destroying senescent and precancerous cells. The outcome is frailty: inability to resist diseases, a greater toll on the body due to cellular senescence, and a rising risk of cancer.

(There are other structural issues, such as the fact that the immune system falls into a state of chronic low-level activation, producing inflammation: it is on alert, imposing the costs of inflammation on the body, but at the same time ever more ineffective at actually doing anything useful while being on alert. But for the same of this discussion, I'll skip over that, as it may be more of a consequence of forms of low-level tissue damage that accompanies aging rather than an inherent property resulting from the composition and activities of the immune system).

I thought I'd point out a couple of papers from the research community presently focused on T cell dynamics and the aging of the immune system, all from a recent issue of Experimental Gerontology. As you take a look, bear in mind that there are many plausible near-future ways in which these problems of the aging immune system might be addressed, some of which are already well within the capabilities of the research community. For example, we might regularly treat old people with infusions of immune cells grown from their own stem cells. Or we might aim to rejuvenate the thymus through tissue engineering: it atrophies in early adulthood, and restoring it would provide a flow of new immune cells created in the body. Another option is to target and destroy the excess population of memory cells. Many are useless, duplicates fixated on CMV or other non-threatening targets. Targeted cell killing technologies under development by the cancer research community are well suited to this task.

All in all there are many options, and most are either presently possible or a bare few years away - if there is just sufficient funding and interest in moving forward to rejuvenation the aged immune system. There is far from any sort of unified consensus on what approach to take, however, or even that the sketch I provided above is in fact an important part of the overall picture. You might see the first of the papers below, for example, in which the authors propose that promising results for thymic restoration in mice will probably not translate to humans. Other researchers are much more interested in developing drugs to manipulate the organization and activities of the immune system than in targeted destruction of excess memory cells or cell therapies to deliver new immune cells. So it goes - this is par for the course in any field.

Mechanisms shaping the naïve T cell repertoire in the elderly - Thymic involution or peripheral homeostatic proliferation?

The ability of the human immune system to repel infections is drastically diminished with age. Elderly individuals are more susceptible to new threats and are less able to control endogenous infections. The thymus, which is the sole source of new T cells, has been proposed as a target for regenerative efforts to improve immune competence, as thymic activity is dramatically reduced after puberty.

In this review, we review the role of the thymus in the maintenance of T cell homeostasis throughout life and contrast the differences in mice and humans. We propose that in humans, lack of thymic T cell generation does not explain a decline in T cell receptor diversity nor would thymic rejuvenation restore diversity. Initial studies using next generation sequencing are beginning to establish lower boundaries of T cell receptor diversity. With increasing sequencing depth and the development of new statistical models, we are now in the position to test this model and to assess the impact of age on T cell diversity and clonality.

Naive T cells: The crux of cellular immune aging?

When encountering foreign antigens, naïve T cells become activated and differentiate into effector and memory T cells. They represent therefore the primary source to mount an immune response against pathogens or tumors. Recent evidence of both quantitative and qualitative alterations of naïve T cells has accumulated in aged mice, indicating that the successful generation of primary T cell responses from the naïve T cell pool may be compromised with old age.

However, the vast majority of the data supporting compromised naïve T cell priming efficacy with old age have been produced in animal models, and the situation is much less clear in humans. In the elderly, the involution of the thymus and the associated decline in thymic output result in a decreased number of naïve T cells, which is partially compensated by homeostatic proliferation. Emerging evidence suggest that alterations of the TCR repertoire diversity and intrinsic defects of old CD4+ naïve T cells may impact on their responsiveness to antigenic stimulation. Increasing focus on the study of naïve T cells (in particular CD8+) in old humans are needed to fill the gaps in our understanding of reduced cellular immunity with aging.

CD4 T cell defects in the aged: Causes, consequences and strategies to circumvent

Aging leads to reduced immunity, especially adaptive responses. A key deficiency is the poor ability to mount robust antibody response. Although intrinsic alterations in B cells with age are in part responsible, impaired CD4 T cell help makes a major contribution to the poor antibody response. Other CD4 effector responses and memory generation are also impaired.

We find delayed and reduced development of CD4 T follicular help (Tfh) cells in aged mice in response to influenza infection with reduction of long-lived plasma cells. We summarize strategies to circumvent the CD4 T cell defect in aged, including adjuvants and proinflammatory cytokines. We find that we can strongly enhance responses of aged naïve CD4 T cells by using Toll-like receptor (TLR) activated dendritic cells (DC) [and] that this leads to improved [antibody responses].


Via Maria Konovalenko, I see that the Third International Conference on the Genetics of Aging and Longevity will be held in Sochi, Russia, in April. This is one of the more visible results of the work undertaken by the community of Russian advocates and researchers focused on the extension of health human lifespan. They have a vision for needed research and development that is different from both that of the US mainstream and the disruptive repair-based focus of SENS rejuvenation research, as it is largely informed by programmed aging theories. You can peruse some of the translated downloadable materials at the English language site of the Science for Life Extension Foundation to get an idea of this focus. Alexei Moskaliev's blog is another good resource, though not everything available for viewing there is in English.

While I might not agree with the viability of work based on an assumption of programmed aging, the energetic Russian contingent of the broader community does great work, and helps to bring greater attention to the field as a whole. Their unabashed and straightforward focus on radical life extension and the end of degenerative aging as logical and desirable goals of aging research is very welcome, and I'd like to see more of that from the English language scientific community. The Genetics of Aging and Longevity conference series in particular is turning into an influential event, and the list of those involved looks like a Who's Who of noteworthy figures in mainstream aging and longevity research.

Third International Conference on the Genetics of Aging and Longevity

The third international conference "Genetics of aging and longevity" will take place in Sochi, Russia from 6th till 10th of April, 2014. The event is held by "Science for Life Extension" foundation and Institute of Biology of Ural department of Russian Academy of Science.

With this conference being held once in two years, it is the fourth time for it to happen and the third time to be international. As a result of the previous conference in 2012, this event has become the central discussing board of longevity and aging issues in Russia, uniting the field's leading scientists from all over the world. Having received wide international recognition, it has become a must-see point in longevity science agenda.

Back in 2012, more than 700 people visited the conference in four days of its work, including genetics scientists, bio-informatics specialists, biologists, doctors, journalists, entrepreneurs and investors. Conference of 2014 will bring together some of the most well-known scientists and representatives of the world's leading longevity laboratories and institutions from the US, Europe, Russia and Asia. The program committee consists of thirty experts responsible for delivering the highest level of scientific content possible and providing the latest data.

Experts, business representatives, public figures and authorities will join together to discuss fundamental science as well as more practical applied science issues. Along with the unique scientific content, round tables and informal meetings with world's leading experts will be held, giving everyone a chance to discuss a large variety of questions, including investment opportunities in the field of slowing aging and treating age-related diseases.

The event will reveal the on-growing demand on longevity research both in science and in business. Some of the materials for the "Genetics of aging and longevity" conference have never been published before and will be first presented on the conference, forecasting the future of longevity science. We welcome you to one of the most exciting science events of 2014!


We humans are capable of the most mundane of evils. Perhaps the most pervasive in this age in which no decision is permitted to be private and individual any more, in which government is used as a lever to open up access to the minutiae of everyone's lives and pour them onto the public stage to be regulated and inspected, is the evil of seeking to deprive others of a benefit that the seeker would readily make use of were it theirs. Money, and all the trappings of wealth, are the classic example. There is no evil as boring and ubiquitous as the person who works to tear down those who have more than he does, even as he strives to accumulate more for himself.

When it comes to enhancing human longevity, there is no harm done to the world by the personal choice to stand to one side, not participate, and age and die. It seems a waste and a shame, but freedom comes with the option to shun potential and refuse opportunity: it wouldn't be freedom if it didn't. All too many people who declare their intent to do this are clearly availing themselves of all the advantages of modern medicine, however. Their position is incoherent. Put them fifty years in the past and they would be arguing against the very technologies that are keeping them alive in good health. Put them fifty years into the future and they would be taking advantage of rejuvenation treatments just like the majority of the population. But again, it is a choice to act and think this way, and for so long as it is a personal choice it doesn't harm progress.

The real problem is those who seek to forge the world to their view: who would use the state as a lever to block and hold back work on rejuvenation treatments for everyone. This is a great evil, the consequences of its success measured in millions of lives for each month of delay, and the ongoing suffering and pain of hundreds of millions more.

The Moral Bankruptcy of Deathism

As research related to life extension has progressed and the concept has begun to register with the mass public mind, we increasingly face objections arguing not that we can't achieve it, but that we shouldn't. In-vitro fertilization, therapeutic cloning, stem-cell research, and other medical innovations of recent times have met with the same agitated yammering about going against nature. The objections to anti-aging research are just the latest incarnation of the same old mentality.

Another tack some people take is to insist that they personally would not want to extend their lives indefinitely. I doubt this - very few people, in practice, refuse an opportunity to save their own lives when death is staring them in the face - but even if they're telling the truth, it's perfectly irrelevant to the larger issue of whether research in the field should keep going. Even when radical life extension becomes a reality, anyone who seriously objects to the idea will be free to refuse whatever therapies are involved, just as adults today are free to refuse blood transfusions or other medical treatments to which they object on whatever grounds. The fact that some people and religious sects have such objections is not a basis for arguing that blood transfusion should not have been invented.

And this is the key point: the deathist moral position is an abominable one. It boils down to saying that I need to die because of your visceral discomfiture with something.

We're already quite some ways down this road. During the [19th and 20th centuries], life expectancy at birth in developed countries roughly doubled, from about 40 years to about 80, due to vaccines, antibiotics, and various other innovations. All the clichéd objections that are now made to radical life extension - overpopulation, cultural stagnation due to having too many old people around, widening the gap between rich and poor countries, etc. - could just as easily have been made in 1900 against these achievements. But it would be an audacious deathist indeed who would argue today that we should not have invented vaccines, or should stop using them now.


Gathering support for any cause in medical research is a slow process of bootstrapping. This is just as much the case for research into extending human life as for any other form of medical technology. Treatments and capabilities presently taken for granted were all bootstrapped at some point in the past, and the pioneers all had to climb the cliffs of skepticism and inertia. No matter how beneficial, new ideas and technologies are resisted and ignored at first. People don't like change.

Funds raised is one way to measure support for research, and another is the amount of time and energy people put into writing on the topic. In both cases SENS rejuvenation research - and even the broader and less promising efforts to work on enhancing human longevity - has a long way to go to reach the enthusiastic levels of support enjoyed by the stem cell or cancer research communities. Rejuvenation research will ultimately have to rise to those heights to achieve clinical application and widespread availability of treatments, but it is quite possible that demonstrations of rejuvenation in mice will precede that point by decades.

So attention, discussion, and writing is important. I'm always pleased to see new faces talking about SENS and other aspects of longevity science, and look forward to the day on which I don't recognize the origin of most of what I read online about rejuvenation biotechnology and the broader field of longevity science.

The scientific pursuit of eternal youth

"I resolve to not get any older." This may seem like a somewhat outlandish New Year's resolution, a desire more grounded in the realm of science fiction than science itself. But a growing group working in the field of biogerontology would argue that it is not. I was able to get an update on the state of the science at a session organized by Dr. Aubrey de Grey, Chief Scientific Officer of the anti-aging organization SENS (Strategic Engineering Negligible Senesence) Research Foundation, last month at the World Stem Cell Summit in San Diego.

Dr. de Grey was careful to make an important distinction about this vein of research and addressed what is known as the "Tithonus Error" - an assumption that postponing aging would extend ill-health rather than health span. In the Greek legend, Tithonus was granted immortality by Zeus at the bequest of his Titan lover and kidnapper, Eos, who in an unfortunate twist forgot to ask for Tithonus' eternal youth, cursing him to living forever in a "loathsome old age...unable to move nor lift his limbs". This public misconception thus mistakes the goal of biogerontology to extend the unhealthy phase of our life rather than the healthy. The therapeutic goal is to shift the balance between how much of our lives are lived as healthy and productive members of society and delay or prevent the onset of age-related disorders such as cancer, cardiovascular disorders and neurodegenerative disease (to name a few).

Dr. de Grey recently examined the state of messaging related to biogerontology and expounded upon the risks in promising too much in the field, lessons that have certainly been learnt in the field of stem cell research and gene therapy. It is clear from the highly accomplished scientific advisory board of SENS Research Foundation that there is considerable conceptual backing behind their goals, but a clear takeaway from the session was that they have only recently begun to enter the area of realistically achieving their goals and meeting expectations.

Do You Want To Live To Be 1,000? Better Listen Real Hard To Aubrey de Grey.

Q: What do you mean when you say ageing is no longer immutable?

A: I don't say that: I say that we are in striking distance of making it no longer immutable. What that means is that we have a good chance of developing, in the next few decades, medicines that can not only slow down the accumulation of the damage of ageing but actually repair that damage, thereby greatly postponing the disease and disability that it causes.

Q: Do you still believe the "first person to live to 1,000 is already alive"?

A: Yes I do, with high probability (note that I've only ever said "probably"). The same logic I always set out - that the first-generation rejuvenation therapies which we may well have within a couple of decades will only extend healthy life by maybe 30 years, but that that will be enough to let us figure out what to do next to re-rejuvenate the same people 30 years later, etc - is still valid.

Q: You said in a recent talk that ageing is the world's "most important problem". Is it more important than all of the problems we face (of which overpopulation, pollution, energy shortage, climate crisis, mass species extinction, desertification, ocean acidification, overfishing, general scientific illiteracy and human nature itself are but a few) which threaten the quality of our life? And why?

A: Yes, obviously it's more important than any other problem. How is any other problem even a problem at all, if you're already dead? The right way of thinking about this is that defeating ageing will give us a proper perspective on the long-term importance of other problems.

Q: What is your retort to those who say extending life is "unnatural"?

A: I simply point out that by the same token one can say that all medicine - or even all technology, all the way back to fire and the wheel - is unnatural. Or, conversely, that it is natural for humans to seek to create the unnatural as ways to improve their quality of life, and unnatural for humans to submit to living with nature as they find it.

Q: Finally, are you optimistic about the future?

A: I don't like the word "optimistic" because so many people interpret it to mean "over-optimistic". I'm realistic about the future: I have a more optimistic view than many other people, but only for very rational reasons based on actual data.


Monday, January 20, 2014

The state of clinical development for tissue engineering of less complex parts of the body is far advanced beyond organ engineering. Organs like hearts, livers, and lungs are far more structurally diverse than, say, a trachea, and thus an acceptable biological substitute trachea is easier to build - well within the capabilities of today's laboratories. That translates into faster progress towards broader availability in the clinic:

Since 2008, eight patients have been given a new chance at life when surgeons replaced their badly damaged tracheas with man-made versions. This highly experimental technology is now moving from research labs to a manufacturing facility as a Boston-area company prepares to produce the scaffolds for growing the synthetic organs on a large scale.

Harvard Apparatus Regenerative Technology, or HART, is testing its synthetic trachea system in Russia and has plans for similar tests in the European Union this year. The company is working with the U.S. Food and Drug Administration to set up a trial in the United States as well. The synthetic windpipes are made by growing a patient's own stem cells on a lab-made scaffold. In the future, this technique could be adapted to create other organs, such as a replacement esophagus, heart valve, or kidney.

HART creates the scaffolds by spinning fibers about a hundredth of the width of a human hair into a tube that is made to fit each patient. Stem cells taken from a patient's bone marrow are then "rained down over the top of the scaffold, much like a chicken in a rotisserie." The cells grow on the scaffolds in a specialized rotating incubator for about two days before they are transplanted. About five days after the transplant, new cell types appear on the organ, including important cells that line the inner surface and help move mucous from the lungs by coughing. Eventually, blood vessels grow into the synthetic organ.

Monday, January 20, 2014

The evidence for intermittent fasting to improve health and extend life is pretty good, but nowhere near as solid as that for calorie restriction. There appear to be separate mechanisms at work: researchers have demonstrated at least some benefits to result in laboratory animals for intermittent fasting without reduction in dietary calorie levels, for example. Additionally, the gene expression profiles of intermittent fasting and calorie restricted mice are noticeably different. Still, it seems likely that in most cases some of the benefits of intermittent fasting are derived from a reduction in overall calorie intake.

Thousands of people deliberately practice calorie restriction on the basis of the scientific evidence to date, and over the past decade or two the Calorie Restriction Society has spurred research programs that have produced pretty compelling human data. Given that intermittent fasting is in many ways an easier sell to the public in this age of obesity and low-cost food, I imagine that we'll see a similar growth in research and awareness in the years ahead. That says nothing about the relative merits or level of scientific support for outcomes at this point, of course - and on that count calorie restriction is far ahead.

Periods of deliberate fasting with restriction of solid food intake are practiced worldwide, mostly based on traditional, cultural or religious reasons. There is large empirical and observational evidence that medically supervised modified fasting (fasting cure, 200-500 kcal nutritional intake per day) with periods of 7-21 days is efficacious in the treatment of rheumatic diseases, chronic pain syndromes, hypertension, and metabolic syndrome. The beneficial effects of fasting followed by vegetarian diet in rheumatoid arthritis are confirmed by randomized controlled trials.

Further beneficial effects of fasting are supported by observational data and abundant evidence from experimental research which found caloric restriction and intermittent fasting being associated with deceleration or prevention of most chronic degenerative and chronic inflammatory diseases. Intermittent fasting may also be useful as an accompanying treatment during chemotherapy of cancer.

A further beneficial effect of fasting relates to improvements in sustainable lifestyle modification and adoption of a healthy diet, possibly mediated by fasting-induced mood enhancement. Various identified mechanisms of fasting point to its potential health-promoting effects, e.g., fasting-induced neuroendocrine activation and hormetic stress response, increased production of neurotrophic factors, reduced mitochondrial oxidative stress, general decrease of signals associated with aging, and promotion of autophagy. Fasting therapy might contribute to the prevention and treatment of chronic diseases and should be further evaluated in controlled clinical trials and observational studies.

Tuesday, January 21, 2014

At some point researchers will begin earnestly trying to develop the means to replicate some of the beneficial effects of exercise via drugs, in the same way as they are presently trying to replicate the beneficial effects of calorie restriction. At the moment research is still largely exploratory, based on the handful of targets known to be related to the metabolic response to exercise:

Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging-associated frailty can preclude physical activity.

In young sedentary animals, pharmacological activation of AMP-activated protein kinase (AMPK), a transcriptional regulator important for muscle physiology, enhanced spatial memory function, and endurance. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (5- to 7-wk-old) and aged (23-mo-old) female C57Bl/6 mice, and in young (4- to 6-wk-old) transgenic mice with muscle-specific mutated AMPK α2-subunit (AMPK-DN).

Mice were injected with AICAR (500 mg/kg) for 3-14 d. Two weeks thereafter animals were tested in the Morris water maze, rotarod, and open field. Improved water maze performance and motor function were observed, albeit at longer duration of administration, in aged (14-d AICAR) than in young (3-d AICAR) mice. In the AMPK-DN mice, the compound did not enhance behavior, providing support for a muscle-mediated mechanism.

In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus, genes relevant to neuronal development and plasticity were enriched. Altogether, endurance-related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions.

Tuesday, January 21, 2014

Researchers here propose that, regardless of other forms of physiological damage that degrade the brain with age, we might consider that simply having a longer period of learning behind you could cause a decline in cognitive ability. This is plausible in the theoretical sense; there are plenty of other systems in the body, such as the immune system, that experience declining effectiveness over time not only because of damage or wear and tear but also due to the way in which they are structured. Evolution doesn't produce perpetual operation, but rather systems that have peak performance for just long enough to get by - and that can result in a system that eventually grinds itself into self-destruction simply through continued normal operation.

Theoretically plausible and a meaningful effect are two very different things, however. The weight of evidence linking forms of physiological damage in the brain with levels of cognitive decline strongly suggest that damage is the overwhelming cause. These researchers are arguing from the point of view of models of how the brain works, rather than any more robust data. So I'm not giving this line of thinking too much serious consideration at this point in time. But we shall see:

In what follows, we consider the question of whether one might reasonably expect that performance on any measure of cognitive performance could or should be expected to be age- or, more specifically, experience-invariant. We shall suggest that, since the answer to this question is no, many of the assumptions scientists currently make about "cognitive decline" are seriously flawed and, for the most part, formally invalid.

We will show that the patterns of response change that are typically taken as evidence for (and measures of) cognitive decline arise out of basic principles of learning and emerge naturally in learning models as they acquire more knowledge. These models, which are supported by a wealth of psychological and neuroscientific evidence, also correctly identify greater variation in the cognitive performance of older adults, and successfully predict that older adults will exhibit greater sensitivity to the fine-grained properties of test items than younger adults.

[These] patterns of performance reflect the information-processing costs that must inevitably be incurred as knowledge is acquired. Once the cost of processing this extra information is controlled for in studies of human performance, findings that are usually taken to suggest declining cognitive capacities can be seen instead to support little more than the unsurprising idea that choosing between or recalling items becomes more difficult as their numbers increase.

Wednesday, January 22, 2014

A range of different manipulations of myostatin have been shown to safely and significantly increase muscle mass and strength in mice. Some rare natural myostatin mutants exist in our species and other larger mammals. All in all it seems like a promising line of research to ameliorate age-related muscle loss, whether or not it rises to the level of diagnosis as sarcopenia. This doesn't address the underlying causes, but it could greatly increase the buffer of muscle tissue to resist those causes: a patch, but not a bad patch, given the large degree to which muscle mass is gained in these experiments.

Mammalian aging is accompanied by a progressive loss of skeletal muscle, a process called sarcopenia. Myostatin, a secreted member of the transforming growth factor-β family of signaling molecules, has been shown to be a potent inhibitor of muscle growth. Here, we examined whether muscle growth could be promoted in aged animals by antagonizing the activity of myostatin through the neutralizing activity of the myostatin propeptide.

We show that a single injection of an AAV8 virus expressing the myostatin propeptide induced an increase in whole body weights and all muscles examined within 7 weeks of treatment. Our cellular studies demonstrate that muscle enlargement was due to selective fiber type hypertrophy, which was accompanied by a shift toward a glycolytic phenotype. Our molecular investigations elucidate the mechanism underpinning muscle hypertrophy by showing a decrease in the expression of key genes that control ubiquitin-mediated protein breakdown. Most importantly, we show that the hypertrophic muscle that develops as a consequence of myostatin propeptide in aged mice has normal contractile properties. We suggest that attenuating myostatin signaling could be a very attractive strategy to halt and possibly reverse age-related muscle loss.

Wednesday, January 22, 2014

Researchers are trying a new approach to speeding regrowth of tissue guided by a scaffold structure:

Studies suggest that increasing angiogenesis - the formation of new blood vessels - may help to heal wounds. One way to enhance the development of blood vessels is through the delivery of growth factors directly to wounds; yet multiple growth factors are needed to produce mature blood vessels, and their concentration as well as the timing of their application must be carefully orchestrated to facilitate proper growth. An alternative approach involves delivering siRNA - short, double-stranded RNA molecules designed to silence a gene of interest - to cells in order to influence genes that induce the formation of new blood vessels.

[Researchers used] a novel tissue scaffold that can deliver siRNA to nearby cells over a period of several weeks. Using an siRNA dose 10-100-fold lower than previous studies, the research team efficiently silenced the expression of PHD2 - a protein that normally inhibits blood vessel formation - locally within a biodegradable tissue scaffold. At 33 days post-implant, the scaffolds that delivered PHD2 siRNA had a three-fold increase in the volume of local blood vessels.

To achieve sustained delivery, the researchers first packaged siRNA into nanoparticles, which protect siRNA from being degraded by enzymes found in the extracellular environment. They then combined these nanoparticles with varying amounts of a substance called trehalose. This nanoparticle-trehalose combination was then embedded into a biodegradable tissue scaffold, which they implanted under the skin of a mouse. Trehalose acts as a porogen, meaning it creates pores in the tissue scaffold. As a result, the rate at which nanoparticles are released from the scaffold is directly influenced by the amount of trehalose added. Based on the quantity of trehalose, the system can be tuned to release the nanoparticles to the surrounding cells immediately or over a period of several weeks.

Thursday, January 23, 2014

The free radical theory of aging had a long time in the sun, but - like so many other narrow theories of aging that led to the present diversity of understanding - it is clearly neither the whole picture nor even particularly correct in its original formulation. This researcher is thinking along these lines, with a viewpoint similar to that of the SENS program for rejuvenation research:

The free radical theory of aging posits that aging is caused by accumulation of damage inflicted by reactive oxygen species (ROS). Although this concept has been very useful in defining the contribution of oxidative damage to the aging process, an increasing number of studies contradict it. The idea that oxidative damage represents only one of many causes of aging also has limitations, as it does not explain causal relationships and inevitability of damage accumulation.

Here, it is discussed that infidelity, heterogeneity, and imperfectness of each and every biological process may be responsible for the inevitable accumulation of by-products and other damage forms. Although ROS are prototypical by-products, their contribution to aging is governed by the metabolic organization of the cell, its protective systems, and genotype. These factors are controlled by natural selection and, like dietary and genetic interventions that extend lifespan, change the composition of cumulative damage and the rates of accumulation of its various forms.

Oxidative damage, like other specific damage types viewed in isolation or in combination, does not represent the cause of aging. Instead, biological imperfectness, which leads to inevitable accumulation of damage in the form of mildly deleterious molecular species, may help define the true root of aging. Free radical and other specialized damage theories served their purpose in the understanding of the aging process, but in the current form they limit further progress in this area.

Thursday, January 23, 2014

Mitochondria are important in aging. Each cell has its self-replicating herd of mitochondria, which play a vital role in many processes. Unfortunately they become damaged over time. Most damage to individual mitochondria can be rescued since they have limited repair processes, are recycled by other cellular processes when damage is detected, and can divide and merge like bacteria. Further they are more like enclosed bags of liquid than fixed machines, and promiscuously swap component parts with with another inside a cell. Cells can even deliver whole mitochondria to one another when in close contact.

Thus mitochondrial dynamics are pretty complex, all told, and researchers continue to discover new aspects even now. Some forms of mitochondrial damage are persistent, however: they interfere with the process of culling damaged mitochondria, and so replicate throughout a cell making it dysfunctional and harmful to the surrounding tissue. This is one of the causes of aging.

There are a number of proposed ways to treat and reverse this problem, most quite close to realization, and some of which are more robust than others. Delivery of new unbroken mitochondria or mitochondrial parts will bring short-term benefits but it won't last - the damaged forms of mitochondria will win out again, just as they did in the first place. Nonetheless, more researchers are looking into this sort of approach than are working on the SENS strategy of creating backup sources of mitochondrial parts in the cell nucleus. This research is of interest to this line of work:

A research team has identified a protein that increases the transfer of mitochondria from mesenchymal stem cells to lung cells. [The] delivery of mitochondria to human lung cells can rejuvenate damaged cells. The migration of mitochondria from stem cells to epithelial cells also helps to repair tissue damage and inflammation linked to asthma-like symptoms in mice.

"Our results show that the movement of mitochondria from stem cells to recipient cells is regulated by the protein Miro1 and is part of a well-directed process. The introduction of mitochondria into damaged cells has beneficial effects on the health of cells and, in the long term, we believe that mesenchymal stem cells could even be engineered to create more effective therapies for lung disease in humans."

Earlier work revealed that mitochondria can be transferred between cells through tunneling nanotubes, thread-like structures formed from the plasma membranes of cells that bridge between different types of cells. Stem cells can also use tunneling nanotubes to transfer mitochondria to neighboring cells and the number of these nanotubes increases under conditions of stress.

Friday, January 24, 2014

An example of ongoing experiments and improvements in methodology for stem cell treatments:

[Researchers] report they have developed human induced-pluripotent stem cells (iPSCs) capable of repairing damaged retinal vascular tissue in mice. The stem cells, derived from human umbilical cord-blood and coaxed into an embryonic-like state, were grown without the conventional use of viruses.

"We began with stem cells taken from cord-blood, which have fewer acquired mutations and little, if any, epigenetic memory, which cells accumulate as time goes on." The scientists converted these cells to a status last experienced when they were part of six-day-old embryos. Instead of using viruses to deliver a gene package to the cells to turn on processes that convert the cells back to stem cell states, [the] team used plasmids, rings of DNA that replicate briefly inside cells and then degrade.

Next, the scientists identified high-quality, multipotent, vascular stem cells generated from these iPSC that can make a type of blood vessel-rich tissue necessary for repairing retinal and other human material. They identified these cells by looking for cell surface proteins called CD31 and CD146. [The] team injected the newly derived iPSCs into mice with damaged retinas, the light-sensitive part of the eyeball. Injections were given in the eye, the sinus cavity near the eye or into a tail vein. When the scientists took images of the mice retinas, they found that the iPSCs, regardless of injection location, engrafted and repaired blood vessel structures in the retina.

Friday, January 24, 2014

Researchers here dig in to the details of one of the mechanisms that might explain variations in the ability to heal from heart injuries - and which might be manipulated to improve the situation:

The immune system plays an important role in the heart's response to injury. But until recently, confusing data made it difficult to distinguish the immune factors that encourage the heart to heal following a heart attack, for example, from those that lead to further damage. Now, [researchers] have shown that two major pools of immune cells are at work in the heart. Both belong to a class of cells known as macrophages. One appears to promote healing, while the other likely drives inflammation, which is detrimental to long-term heart function.

"Macrophages have long been thought of as a single type of cell. Our study shows there actually are many different types of macrophages that originate in different places in the body. We found that the heart is one of the few organs with a pool of macrophages formed in the embryo and maintained into adulthood. The heart, brain and liver are the only organs that contain large numbers of macrophages that originated in the yolk sac, in very early stages of development, and we think these macrophages tend to be protective."

Healthy hearts maintain this population of embryonic macrophages, as well as a smaller pool of adult macrophages derived from the blood. But during cardiac stress such as high blood pressure, not only were more adult macrophages recruited from the blood and brought to the heart, they actually replaced the embryonic macrophages. The complex interplay between these immune cells in the heart may provide an explanation for why some people experience healing following a heart attack but others don't.

"Now that we can tell the difference between these two types of macrophages, we can try targeting one but not the other. We want to try blocking the adult macrophages from the blood, which appear to be more inflammatory. And we want to encourage the embryonic macrophages that are already in the heart to proliferate in response to stress because they do things that are beneficial, helping the heart regenerate."


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