Via Maria Konovalenko, here is another attractive poster on the biology of aging from some of the folk behind the Russian Science for Life Extension Foundation. There are more of these documents out there than are translated to English, more is the pity, but the supply of people who can make good technical translations in cutting edge life science from Russian to English (and have both the time and motivation to do so) is limited at the best of times. The image below is low-quality - click through for the full size version.

You might look back in the Fight Aging! archives for a few more of these posters:

• A Regenerative Medicine Roadmap from the Science for Life Extension Foundation
• Biomarkers of Aging and Age-Related Conditions

You'll also find other documents at the Science for Life Extension Foundation website (scroll down for the links) and if you're up for reading the original Russian, you'll find a great deal of similarly interesting material at researcher Alexey Moskalev's blog.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

One of the ways in which major blood vessels decline in function with aging is that they lose their elasticity. The state of chronic inflammation that grows with aging contributes to this, as noted in this open access paper (in PDF format). This is probably connected to the fact that exercise helps improve the elasticity of arteries, given that exercise is shown to impact levels of inflammation: "Increased arterial stiffness is an independent predictor of cardiovascular disease independent from blood pressure. Recent studies have shed new light on the importance of inflammation on the pathogenesis of arterial stiffness. Arterial stiffness is associated with the increased activity of angiotensin II, which results in increased NADPH oxidase activity, reduced NO bioavailability and increased production of reactive oxygen species. Angiotensin II signaling activates matrix metalloproteinases (MMPs) which degrade TGF? precursors to produce active TGF?, which then results in increased arterial fibrosis. ... There is also ample clinical evidence that demonstrates the association of inflammation with increased arterial stiffness. Recent studies have shown that reductions in inflammation can reduce arterial stiffness. In patients with rheumatoid arthritis, increased aortic pulse wave velocity in patients was significantly reduced by anti tumor necrosis factor-? therapy. ... Thus, there is rationale for targeting specific inflammatory pathways involved in arterial stiffness in the development of future drugs. Understanding the role of inflammation in the pathogenesis of arterial stiffness is important to understanding the complex puzzle that is the pathophysiology of arterial stiffening and may be important for future development of novel treatments."

Link: http://dx.doi.org/10.3349/ymj.2012.53.2.258

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

From Maria Konovalenko: "I am proud to announce that Science for Life Extension Foundation is one of the organizers of the 2nd international Genetics of Aging and Longevity conference. It is going to be an amazing and actually unprecedented conference focused on genetic mechanisms of aging and longevity. Check out the list of our invited speakers. I can't wait to hear the prominent researchers sharing their experience in making model animals live longer. By the way, we are proud to have all the longevity-record braking researchers, who extended the lifespan of yeast, nematodes, fruit flies and mice. You can't miss this meeting. I encourage you to go ahead and register. It's the end of April, beautiful spring in Moscow. For those who have never been here before, here's your chance to kill two birds with one stone - learn a lot about aging and discover one of the most beautiful and dynamic cities in the world."

Link: http://aging-genes2012.ru/en/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Tissue printing startup Organovo, of the Methuselah Foundation's portfolio of early stage investments, received a new round of funding recently:

Organovo closed a private placement consisting of approximately 6.5 million units of its securities to qualified accredited investors, for total gross proceeds of $6.5 million. "Organovo's advanced bioprinting platform can replicate essential biology for research, drug discovery and development and, eventually, for therapeutic applications," stated Keith Murphy, chief executive officer of Organovo. "We have found success in achieving early revenue through strategic collaborations, and this funding will allow us to extend the reach and uses of 3D bioprinting through growth and innovation in the coming years."

Given that at this stage in their life cycle they are essentially a research equipment manufacturer, that sort of money - while small in terms of medical development in the mainstream - should be enough to get them to the next level. You might recall an h+ Magazine article from a couple of years ago that gives a good overview of what the company aims to achieve:

Dr. Forgacs ultimately foresees fully implantable organs printed from a patient's own cells. "You give us your cells: we grow them, we print them, the structure forms and we are ready to go," he says. "I am pretty sure that full organs will be on the market [one day]." A printed biological heart might not appear exactly like an embryonic heart with a pericardium, two superior atria, and two inferior ventricles. But it will perform the same function: pumping blood throughout the blood vessels.

The second item relates to the preservation of organs for later transplant: this is a big logistical hurdle. A great deal of the processes of present day transplantation and early tissue engineering are completely shaped by our inability to reliably store large, complex tissues for the long term, without damage. The process of decellularization may be a practical way to work around the issue, though it remains to be seen if the economics work out yet: donated organs can be decellularlized, the scaffold stored at low temperature, and then warmed up and repopulated with a patient's cells in a matter of days. Here is a note from ScienceDaily, which leads to an open access research paper that is available in PDF format:

[Researchers] studied various strategies for freeze-drying porcine heart valves. After the cellular material was removed, they freeze-dried the heart valve scaffolds with or without sucrose and hydroxyl ethylene starch, and then compared the stability and elasticity of the freeze-dried scaffolds to assess the effectiveness of these lyoprotectants in preventing degradation of the scaffold. ... Tissue freeze-dried with sucrose alone displayed less porosity compared to tissue freeze-dried with the sucrose/HES mixture, whereas no significant differences in biomechanical properties were observed. Decellularization decreased the elastic modulus of artery tissue. The elastic modulus of freeze-dried tissue without protectants resembled that of decellularized tissue. The elastic modulus values of freeze-dried tissue stabilized by lyoprotectants were greater compared to those of decellularized tissue, but similar to those of native tissue.

Lastly for today, an article on one of the challenges of tissue engineering that people outside the field don't tend to think all that much about, which is that it is exceedingly difficult to convince tissues to form exactly the desired shape, with exactly the right mechanical properties, and with the right cells in the right place in that shape. A lot of researchers are spending a lot of time on determining how to cultivate tissue of the right size and shape; the strategies needed vary greatly by tissue type and other circumstances. In any case, here is an article on tubes:

In another advance for the field, researchers have now demonstrated a strategy to fabricate tubular structures with multiple types of cells as different layers of the tube walls. This method may be widely used in simulation of many tubular tissues and enriches the toolbox for 3D micro/nanofabrication by initially patterning in 2D and transforming it into 3D. ... To demonstrate the capability of their method, the scientists successfully simulated the structure of a human vessel-like structure - the tubular wall has three layers, and in each layer there is one representative type of cells: endothelial cells, smooth muscle cells and fibroblast cells (from inside out).
This kind of tubular structure with multiple types of cells can be applied in tissue engineering such as arterial and venous grafts in vivo. And [the] preparation method of stress-induced rolling membrane can be applied to fabricate other self-assembled 3D structures.

You might compare the methodologies in the technology demonstration quoted above with the approach used in growing mouse teeth to get a sense of just how broad the range of necessary techniques is.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

I would take this as an indicator that simple, ongoing maintenance of fitness and avoidance of a sedentary lifestyle pays off: "Simple tests such as walking speed and hand grip strength may help doctors determine how likely it is a middle-aged person will develop dementia or stroke. ... More than 2,400 men and women with an average age of 62 underwent tests for walking speed, hand grip strength and cognitive function. Brain scans were also performed. During the follow-up period of up to 11 years, 34 people developed dementia and 70 people had a stroke. The study found people with a slower walking speed in middle age were one-and-a-half times more likely to develop dementia compared to people with faster walking speed. Stronger hand grip strength was associated with a 42 percent lower risk of stroke or transient ischemic attack (TIA) in people over age 65 compared to those with weaker hand grip strength. This was not the case, however, for people in the study under age 65. ... Researchers also found that slower walking speed was associated with lower total cerebral brain volume and poorer performance on memory, language and decision-making tests. Stronger hand grip strength was associated with larger total cerebral brain volume as well as better performance on cognitive tests asking people to identify similarities among objects." We might theorize that this is related to exercise and blood flow in the brain, and related effects on the heath of blood vessels in the brain.

Link: http://www.sciencedaily.com/releases/2012/02/120215185850.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Average telomere length in at least some tissues makes a good marker for general health, but the progressive shortening of telomeres may or may not be a root cause of aging. Telomere length results from a dynamic system of lengthening and shortening processes, which seems more likely to be a reflection of underlying function and dysfunction: "In an ongoing study of almost 20,000 Danes, a team of researchers [have] isolated each individual's DNA to analyse their specific telomere length - a measurement of cellular aging. ... The risk of heart attack or early death is present whether your telomeres are shortened due to lifestyle or due to high age ... The recent Copenhagen General Population Study involved almost 20,000 people, some of which were followed during almost 19 years, and the conclusion was clear: If the telomere length was short, the risk of heart attack and early death was increased by 50 and 25 per cent, respectively. ... That smoking and obesity increases the risk of heart disease has been known for a while. We have now shown, as has been speculated, that the increased risk is directly related to the shortening of the protective telomeres - so you can say that smoking and obesity ages the body on a cellular level, just as surely as the passing of time. ... one in four Danes has telomeres with such short length that not only will they statistically die before their time, but their risk of heart attack is also increased by almost 50 per cent. Future studies will have to reveal the actual molecular mechanism by which the short telomere length causes heart attacks. Does one cause the other or is the telomere length and the coronary event both indicative of a third - yet unknown - mechanism?" I lean towards the latter hypothesis, that both risk of catastrophic failure in bodily systems and telomere length reflect levels of accumulated damage at the level of cells and macromolecules in the body.

Link: http://news.ku.dk/all_news/2012/2012.2/cellular-aging-increases-risk-of-heart-attack/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Resources in research and medical development seems to be the unifying topic here for the past week or so. It is interesting to these accidental thematic collections of content come and go in passing, all without any deliberate intent; a reminder that we take small samples from a much broader, many-threaded conversation of millions of people, one that spans all media and has its tides and fashions at every timescale. So continuing the theme, here is a newly processed and posted video from the SENS5 conference:

Since rejuvenation therapies will ultimately offer many more years of life than traditional life-saving interventions, a problem emerges for existing principles of medical decision-making. Justice demands that all patients are due an equal standard of medical care. But if we measure medical care in terms of the amount of life it saves, or in terms of its cost relative to its effectiveness, or even in terms of its ability to save identified individuals rather than reduce statistical risk in groups, rejuvenation will eventually be far more valuable than life-saving. More broadly, effective rejuvenation medicines will effectively erode the boundary between curative and prophylactic medicines, as well as the boundary between treatment and enhancement.

The quote above is the more reasonable part of the abstract, which concurs with the sensible view that the dominant strategies in medicine must change: what happens today largely takes the form of trying to patch over late stage consequences without addressing root causes, and will thus always be expensive and ultimately unsuccessful. It is poor value in comparison to a strategy of consistently repairing low-level biological damage and thus effecting rejuvenation.

That said, I should note that the whole is a viewpoint I cannot agree with. The presentation builds upon an idealized, and already incorrect, view of the British governmental heath monolith on the one hand, and the meaning of "justice" that roughly translates to "equality maintained through theft, coercion, and destruction of progress is better than honestly earned inequality" on the other. The end result is just moving deckchairs on the Titanic, painting a poisonous, failing system a different color. It'll all come to the same in the end. All systems, like the government health services in Western nations, that divorce themselves from price signaling and patient accountability for costs incurred ultimately create shortages, enforce rationing, and stagnate. They turn relationships between patient and provider from mutually beneficial trade to hostile engagement at arms length, then remove the market incentives for participants to develop and offer better services and technologies, and later the incentives that cause people to offer any form of service at all. Finally, you reach the unhappy truth about other people's money: it runs out.

While they last, the current incarnation of government-run health systems will continue to greatly harm the progression of medical technology - the pace of development, the cost-effectiveness, and the directions taken. The effects of the FDA on research directions - such as the institutional discouragement of work on therapies for aging - are but one facet of this problem. The laws that remove freedom of choice in funding research and development, freedom to practice medicine, and the freedom to try new medical technologies are but another.

These systems are rotten to the core, and the best thing we can do is find practical ways to work around their constraints: engaging them, trying to change them by working within the system, will only prop up these corroded, toxic hulks for that little while longer. We will all be better off when the current regime of regulation and centralized control collapses.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Resveratrol in and of itself is likely not terribly interesting for work on longevity - and certainly not worthy of the hype surrounding it. The same probably goes for sirtuins in general. This, however, is still a good example of work on tracing back the pathways of action of a metabolic change agent: "Research has previously suggested that resveratrol acts through activation of the sirtuin (SIR) gene family. This gene pathway, though controversial, has been implicated in life extension across several species. It has been reported that SIR extends lifespan in much the same way as caloric restriction which itself in turn may activate SIR. It has remained unclear however if resevertrol directly activates SIR or if it acts on SIR indirectly via another intermediary biochemical pathway. The current study successfully answered that question. Using several cell biology techniques the authors were able to demonstrate that resveratrol actually functions to activate SIR indirectly. They showed that resveratrol is really a phosphodiesterase inhibitor (PDE4). They demonstrated that reducing PDE4 allows cyclic AMP (cAMP) levels in the cells to rise. cAMP then increases the activity of AMPK which next increases NAD+ which finally increases SIR. This elegant study then went on to prove that the same life extending benefits of resveratrol could be achieved in rats by administering them the PDE4 inhibitor rolipram. ... inhibiting PDE4 with rolipram reproduces all of the metabolic bene?ts of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. "

Link: http://extremelongevity.net/2012/02/13/resveratrol-study-finds-new-class-of-life-extension-molecules/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

An excellent article from CNBC looks at some of the few figures in the investment community who support progress towards extended healthy lifespans: "what if 'getting old' wasn't really 'getting old?' What if aging - at least the physical deteriorations that accompany it - was something that could be prevented? It's a lofty idea, but it's one that a new breed of biotech start-ups, scientists, and prominent investors are beginning to tackle. Peter Thiel is one of those investors. ... Back in 2006, Thiel gave Cambridge anti-aging researcher Aubrey de Grey $3.5 million under the auspices of the Methusaleh Foundation, a non-profit headquartered in Springfield, Virgina, that awards scientists who are working on life-extension therapies. 'Probably the most extreme form of inequality is between people who are alive and people who are dead,' Thiel told The New Yorker. In 2010, Thiel and his partners at Founders Fund, a Bay Area venture capital firm, invested $500,000 in Halcyon Molecular, a biotech start-up whose 28-year-old founder has a 'dream to create a world free from cancer and aging.' To understand the fund's investment, you have to appreciate what Founders Fund is - or, more specifically, what it is not. 'These are not guys who care about an extra million dollars,' says Brian Singerman, a partner at Founders Fund along with Thiel. 'These are guys who wanted to do something amazing for the world.' Singerman, an early employee at Google, [came] to Founders Fund after having what he describes as an 'epic six hour epic dinner with Sean Parker.' Equal parts brilliant and idealistic, Singerman is adamant that aging is a problem that can be solved. The fund's portfolio has invested in about 14 health and biotech companies all interested in solving life's ultimate problem: death. ... We have a company that's charged with curing all viral disease, we have a company that's charged with curing several types of cancer. These are not things that are incremental approaches. It's all fine and good to have a drug that extends life by a certain amount of months or makes living with a disease easier. That's not what we're looking for. We are not looking for incremental change. We are looking for absolute cures in anything we do."

Link: http://www.cnbc.com/id/46342312

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The end of last month marked the close of the eighth year of Fight Aging!, and here we are in year nine of this bullheaded endeavor - the idea that the good can eventually drive out the bad in the online world of information on aging, longevity, and what best to do about the degenerations that await us all. Optimism shines eternal, I know, but as the science of human rejuvenation becomes ever closer to reality, the shysters and the marketeers of the "anti-aging" industry must eventually go the way of the real snake oil salesmen of old, travelling cart and all. Along with them must go the apologists for aging, the people who would force death upon everyone, and the other malignant naysayers.

Eight years was more than long enough for me to traverse that interesting section of life during which one first starts to notice the signs of decay - the things that don't work quite so well anymore, the initial small signs of what will be a lot worse later on. It makes it a good deal harder to avoid dwelling upon just how lousy the human condition is, all things considered. But that's all relative: I can tell you that the human condition is a raw deal because I can look ahead and see just how much of an improvement is possible through well-envisaged future technologies - not that there's anything special about being able to do that, but in this era we can be a lot more specific than our visionary ancestors. We can explain in some detail how we will defeat all disease, eliminate suffering, and of course remove aging as a threat to life and health. No serious, knowledgeable thinker can argue against these goals as possible and plausible, given our present understanding of physics and biology. We are machinery, our malfunctions are only a matter of atoms out of place, and precision control of atoms will be the basis for all of our technologies sooner or later. The world is our oyster in the realm of what is possible, but as always the question is how soon that future will arrive.

To my eyes, and as I noted recently, I think that this is absolutely a question of when the serious funding turns up. Progress towards rejuvenation biotechnology - the real, make a big difference therapies, not this incremental mainstream drug development that makes up nearly all present day work - is limited far more by money now than by the will to get the job done. A decade ago, this wasn't the case; the money wouldn't even have been solicited because the research community was stuck in the conservatism of silence regarding aging. Speaking of rejuvenation through medical science was the quick road to losing your funding.

It has been a privilege to watch those old attitudes dissolve so rapidly, a great deal of which is thanks to the efforts of volunteer groups like the Methuselah Foundation, outspoken advocates like Aubrey de Grey, and the support of hundred of grass-roots donors and thousands more people who made their own modest contributions to changing the culture of aging research. Every time I come across a new abstract listed in PubMed in which the authors say of their research "and this merits further investigation as the potential basis for a therapy to slow aging and extend healthy life," I am reminded to just how great a battle was won - and how recently. It was nothing less than a sea change, absolutely necessary as a precursor to what will come next.

But we're not getting any younger, the wages of success are to be taken for granted, and next year it'll be "but what have you done for me lately?" Rightly so, really - resting on laurels never got anything accomplished. The near future is a matter of money, and more so than the recent past: how much is going towards the most successful organizations and those working most directly on rejuvenation biotechnology, like the SENS Foundation. Money is the limiting factor for the progress produced by those organizations, as they are still comparatively small, with much room for growth in the work they can usefully start on within weeks of a check being written.

As a final thought for today, I'll note that there are days when it really doesn't seem like it has been eight years I've been doing this. But when you stop to look at the details early 2012 is a whole different world from early 2004. It might not look all that different when you stick your head out of the door, but change is happening.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm