You're all, I hope, familiar with the Fable of the Dragon-Tyrant - easily the best modern fable about the scientific quest to build rejuvenation biotechnology and thereby defeat age-related frailty, suffering and death. If you have not yet read it, shame on you. Go and read it:

Once upon a time, the planet was tyrannized by a giant dragon. The dragon stood taller than the largest cathedral, and it was covered with thick black scales. Its red eyes glowed with hate, and from its terrible jaws flowed an incessant stream of evil-smelling yellowish-green slime. It demanded from humankind a blood-curdling tribute: to satisfy its enormous appetite, ten thousand men and women had to be delivered every evening at the onset of dark to the foot of the mountain where the dragon-tyrant lived. Sometimes the dragon would devour these unfortunate souls upon arrival; sometimes again it would lock them up in the mountain where they would wither away for months or years before eventually being consumed...

I see that some folk across the way a little in the longevity science community have the great idea that a web animation of the fable should be produced - something that could be dropped into many, many websites and seen by a large audience.

My friend Kent Kemmish, at Halcyon Molecular, has offered to put up $50 for someone who does the best animated flash version of Nick Bostrom's classic essay "The Fable of the Dragon-Tyrant" ... Let's say that the challenge stands for one month, until August 7th. My other friend Kevin Fischer is also putting in $50 for a total of $100. Would anyone else be interested in adding to that purse?

I think that this is a good idea with a great deal of merit, but that these folk are not going about it in quite the right way. From my point of view, producing a fair animation - let's say something that looks like the silhouette stop-motion techniques used in some older Eastern European animations of folktales - is going to take a little organization, a few months in total elapsed time from start to finish, and at minimum a few thousand dollars. If you expect to pull in donations through word of mouth and in $50 increments, then this is exactly the sort of project you'd want to run via a tool like Kickstarter. You need some form of way to track and communicate with donors, a way to accept donations, and a web page to showcase your idea and progress to date - why build all that yourself, when you could use Kickstarter?

So the folk who are pushing this should pick a leader, have him set up and manage a Kickstarter project, produce a few specification documents and showy sample pictures, and then reel in enough in the way of funds to get started with a developer who has a good portfolio, found via a contract marketplace like oDesk or 99designs. That's the way this is done. A wide range of indie developers in the writing world use Kickstarter to crowdsource funding for their work using ransom models and other fundraising methods. An alternate approach to the one above is if someone with deeper pockets were to simply commission the work on the simple animated version of the fable, they could then place it in escrow until the costs were recouped through donations, and finally release it online.

Step one would be to validate the cost - and that's as simple as finding someone who builds animations for websites (in Flash, Canvas, or whatever the cool kids are using nowadays) and then asking.

Via EurekAlert!: "injections of adult patients' own CD34+ stem cells reduced reports of angina episodes and improved exercise tolerance time in patients with chronic, severe refractory angina (severe chest discomfort that did not respond to other therapeutic options). The phase II prospective, double-blind, randomized, controlled clinical trial was conducted at 26 centers in the United States ... The objective of the trial was to determine whether delivery of autologous (meaning one's own) CD34+ stem cells directly into multiple targeted sites in the heart might reduce the frequency of angina episodes in patients suffering from chronic severe refractory angina, under the hypothesis that CD34+ stem cells may be involved in the creation of new blood vessels and increase tissue perfusion. ... While we need to validate these results in phase III studies before definitive conclusions can be drawn, we believe this is an important milestone in considering whether the body's own stem cells may one day be used to treat chronic cardiovascular conditions. ... At six months after treatment, patients in the low-dose treatment group reported significantly fewer episodes of angina than patients in the control group (6.8 vs. 10.9 episodes per week), and maintained lower episodes at one year after treatment (6.3 vs. 11 episodes per week). Additionally, the low-dose treatment group was able to exercise (on a treadmill) significantly longer at six months after treatment, as compared with those in the control group (139 seconds vs. 69 seconds, on average)." If you want access to this sort of treatment now, and are resident in the US, going abroad as a medical tourist is your only realistic option. Otherwise you may still be waiting five or ten years from now: the FDA moves to approve treatments very slowly, when it moves at all.

Link: http://www.eurekalert.org/pub_releases/2011-07/nu-asc070711.php

Another example of calorie restriction slowing a specific aspect of the damage of aging: "restricting the caloric intake of adult female mice prevents a spectrum of abnormalities, such as extra or missing copies of chromosomes, which arise more frequently in egg cells of aging female mammals. ... We found that we could completely prevent, in a mouse model, essentially every aspect of the declining egg quality typical of older females. We also identified a gene that can be manipulated to reproduce the effects of dietary caloric restriction and improve egg quality in aging animals fed a normal diet, which gives us clues that we may be able to alter this highly regulated process with compounds now being developed to mimic the effects of caloric restriction. ... The long-term effects of a caloric restriction (CR) diet in humans are being investigated in ongoing studies, but some health improvements, including reductions in cholesterol levels and other cardiovascular risk factors, have already been reported. ... While the mechanisms by which caloric restriction produces its effects are still being investigated, several of the metabolic pathways involve a regulator of DNA transcription called PGC-1a, which is known to modulate genes involved in controlling mitochondrial number and function. [The researchers] also found that egg cells from female mice lacking a functional PGC-1a gene who were allowed to free feed through adulthood maintained the same egg-cell quality as seen in the CR mice. However, combining CR with PGC-1a inactivation did not increase the effects beyond those achieved separately, which suggests that the two approaches work in a common pathway."

Link: http://www.laboratoryequipment.com/news-Calorie-Reduction-May-Prevent-Infertility-070811.aspx

It seems that this is a week for announcing significant progress in tissue engineering. You might recall that one of the groups involved in recellularization research transplanted a trachea into a human recipient a couple of years ago. The organ was from a donor, stripped of all its cells, and the remaining natural scaffold of the extracellular matrix repopulated with cells from the recipient. The end result was a transplanted organ that would not be rejected by the immune system. The same researchers have now gone one step further and successfully transplanted an entirely synthetic trachea grown from the patient's cells on an artificial scaffold - no donor organ required.

Surgeons have performed the first transplant operation using an organ wholly grown in a laboratory to give a man a new windpipe. The 36-year-old is recovering after surgeons implanted the world's first wholly lab-grown organ into his body.

...

Professor Paolo Macchiarini, a Spanish expert in regenerative medicine who led the groundbreaking operation, designed the Y-shaped synthetic trachea scaffold with Professor Alexander Seifalian, from University College London. The Y-shaped structure was made from a plastic-like "nanocomposite" polymer material consisting of microscopic building blocks. Two days after stem cells were placed into the scaffold they had grown into tracheal cells ready for transplantation. Since the organ was built from cells originating from the patient, there was no risk of it being rejected by his immune system.

In conjunction with lines of research like organ printing, this pace of work bodes well for the 2030s as a time in which failing or badly injured organs are no longer automatically fatal or the cause of lifelong disability for the young. There is still the question of how best to take advantage of this for the old, however: the frailty that comes with aging brings with it a much lower survival rate and success rate for major surgery - and any significant transplant is major surgery. Regrowth of organs alone is not the way to greatly extend the maximum human lifespan on a timescale that matters. Other technologies are needed as well:

There are many whole-body, multi-organ, or regional biochemical feedback and control loops in the body. There are types of age-related damage that involve the intracellular accumulation of biochemical junk - simply replacing cells doesn't get rid of that. If your only tool is bioprinting (which won't be the case, but let us think inside the box for a while here), then the solution to these problems starts to look like replacing more of the body at one time.

You can't just replace the brain, of course, which remains an important limiting factor and the real driving need for in situ repair technologies that operate at the level of cells, buildup of protein aggregates, and broken cellular machinery.

The quality of the immune system in later years has a strong impact on mortality rates and frailty - and that quality varies with different genetic profiles. Thus it follows that among the genetic variants known to affect human longevity, some are involved with the immune system: "The ageing process is very complex. Human longevity is a multifactorial trait which is determined by genetic and environmental factors. Twin and family studies imply that up to 25% of human lifespan is heritable. The longevity gene candidates have generally fallen into the following categories: inflammatory and immune-related factors, stress response elements, mediators of glucose and lipid metabolism, components of DNA repair and cellular proliferation and mitochondrial DNA haplogroups. Because of the central role of HLA molecules in the development of protective immunity and the extraordinary degree of polymorphism of HLA genes, many studies have addressed the possible impact of these genes on human longevity. Most of the data available so far demonstrated a possible role of HLA class II specificities in human longevity but definitive evidence has remained elusive. Although the data are limited and controversial, it has been hypothesized that longevity could be associated with cytokine gene polymorphisms correlating with different levels of cytokine production, thereby modulating immune responses in health and disease. Because of the essential role of cytokines in immune responses, the regulation of cytokine gene expression and their polymorphic nature, the genetic variations of these loci with functional significance could be appropriate immunogenetic candidate markers implicated in the mechanism of successful ageing and longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21726414

Some work here on IFG-1, not to be confused with IGF-1, which is also of interest in longevity: "When researchers at the Buck Institute dialed back activity of a specific mRNA translation factor in adult nematode worms they saw an unexpected genome-wide response that effectively increased activity in specific stress response genes that could help explain why the worms lived 40 percent longer under this condition. ... Scientists have identified a number of so-called 'longevity' genes active in many species. However, the mechanisms by which those genes impact lifespan remain poorly understood. ... the majority of research involving those genes has focused on transcription, the first level of cellular activity whereby DNA produces RNA. This research focuses on translation, whereby RNA specifies the production of proteins. ... [Researchers] inhibited expression of the mRNA translation factor, IFG-1, in adult worms. IFG-1 is important for growth and development ... "Turning down ifg-1 expression flips a switch that turned down growth and reproduction, but increased their healthspan as well as their lifespan. ... Our primary interest is to understand the biological basis of aging. This will help identify molecular targets that can be used to develop therapeutics that would slow age-related diseases and extend the healthy years of life."

Link: http://www.sciencedaily.com/releases/2011/07/110705123340.htm

Publicity materials for a good-looking incremental advance from the tissue engineering community are doing the rounds in the press at the moment.

Researchers at The Saban Research Institute of Children's Hospital Los Angeles have successfully created a tissue-engineered small intestine in mice that replicates the intestinal structures of natural intestine - a necessary first step toward someday applying this regenerative medicine technique to humans.

...

Working in the laboratory, the research team took samples of intestinal tissue from mice. This tissue was comprised of the layers of the various cells that make up the intestine - including muscle cells and the cells that line the inside, known as epithelial cells. The investigators then transplanted that mixture of cells within the abdomen on biodegradable polymers or "scaffolding."

What the team wanted to happen did - new, engineered small intestines grew and had all of the cell types found in native intestine. Because the transplanted cells had carried a green label, the scientists could identify which cells had been provided - and all of the major components of the tissue-engineered intestine derived from the implanted cells. Critically, the new organs contained the most essential components of the originals.

The original paper is also available, for those who are interested. The normal caveats apply here - it's a promising advance for researchers to show that they can make lengths of intestine grow correctly inside a living mouse, using scaffolds seeded with cells. But bear in mind that this is only a demonstration: the new section of intestine isn't hooked up or being put under load. It'll be a few more years, I'd guess, before we see mice (or perhaps pigs) with tissue engineered and functional replacement small intestines.

If you'd like to learn more, I noticed an educational set of pages on the topic put up by the students at UCI:

In tissue engineering, there are two fundamentally different approaches that can be taken. The first is to replicate the organanatomically, with the expectation that the function of the engineered organ will therefore be the same. The second approach is simply to replicate its function. Researchers who aim to engineer intestine have adopted the anatomical approach with the key problems including the development of a muscular layer and neuronal innovation are major challenges to its success. On the other hand,if the aim is to develop an absorptive surface with neointestinal epithelium, it is possible to be more imaginative about how this can be achieved.

A confirming review of studies: "Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting. ... A dataset composed of 11,255 cases and 13,101 controls from 21 publications was included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and the relative telomere length. ... The results showed that shorter telomeres were significantly associated with cancer risk compared with longer telomeres. ... Studies have showed that telomeres are critical for maintaining genomic integrity and that telomere dysfunction or shortening is an early, common genetic alteration acquired in the multistep process of malignant transformation. In addition, telomere dysfunction has been found to be associated with decreased DNA repair capacity and complex [cellular] abnormalities. Both of animal studies and clinical observations have shown that shorter telomeres were associated with increased risk of cancers, such as epithelial cancers. However, telomere shortening might play conflicting roles in cancer development. For example, the progressive loss of telomeric repeats with each cell division can induce replicative senescence and limit the proliferative potential of a cell, thus functioning as a tumor suppressor. But, once telomeres reach a critical length, it will result in chromosome break, causing genome instability and enhancing potential for malignant transformation."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3112149/

Altering cells used in tissue engineering so as to obtain a better result is a very viable prospect, as demonstrated in a recent investigation of tendon regeneration: "The basic function of tendon is to transmit force from muscle to bone, which makes limb and joint movement possible. Therefore tendons must be capable of resisting high tensile forces with limited elongation. ... the mechanical properties of tendons are related to the fibril diameter distribution, large fibrils could withstand higher tensile forces. ... In the healing tendon, a uniform distribution of small diameter collagen fibrils has been found with poorer mechanical properties than native tissue and shows no improvement of mechanical properties with time ... The present study for the first time demonstrated the use of a scaffold-free tissue engineered tendon model for investigating the biological function of collagen V in tendon fibrillogenesis. ... Conclusively, it was demonstrated that Col V siRNA engineered tenocytes improved tendon tissue regeneration. ... These findings present a good example of in vitro tissue engineering model for tendon biology investigation and may provide basis for future development of cell or gene therapy for tendon repair."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119690/

Prioritizing the few exceptionally long-lived mammal species for full genome sequencing has been a few years in the making as a project, but I see that the researchers who initiated that effort have now completed the first item on their list:

Naked mole rat's genome 'blueprint' revealed

The industrious but unlovely naked mole rat is the latest creature to have its genome sequenced by scientists. A genetic blueprint for this bizarre-looking rodent could help researchers understand why it is so long-lived.

Scientists sequence DNA of cancer-resistant rodent

For the first time, scientists have sequenced the genome of the naked mole-rat to understand its longevity and resistance to diseases of ageing. Researchers will use the genomic information to study the mechanisms thought to protect against the causes of ageing, such as DNA repair and genes associated with these processes. To date, cancer has not been detected in the naked mole-rat. Recent studies have suggested that its cells possess anti-tumour capabilities that are not present in other rodents or in humans. Researchers at Liverpool are analysing the genomic data and making it available to researchers in health sciences, providing information that could be relevant to studies in human ageing and cancer.

Dr Joao Pedro Magalhaes, from the University of Liverpool's Institute of Integrative Biology, said: "The naked mole-rat has fascinated scientists for many years, but it wasn't until a few years ago that we discovered that it could live for such a long period of time. It is not much bigger than a mouse, which normally lives up to four years, and yet this particular underground rodent lives for three decades in good health. It is an interesting example of how much we still have to learn about the mechanisms of ageing. We aim to use the naked mole-rat genome to understand the level of resistance it has to disease, particularly cancer, as this might give us more clues as to why some animals and humans are more prone to disease than others. With this work, we want to establish the naked mole-rat as the first model of resistance to chronic diseases of ageing."

It will likely take a few years for the first interesting results to emerge from the genomic data - grants must be written, teams formed, studies carried out. Science, while fast, isn't yet instant. While researchers have a good idea as where in naked mole rat biochemistry they should be looking for both cancer resistance and longevity, molecular biology is an inordinately complex field of study. On the longevity side of the house, the composition of cellular membranes appears to be of greatest interest. You might look back into the Fight Aging! archives at these posts:

• Built Differently, Down in the Membranes
• Comparative Biology and the Membrane Pacemaker Hypothesis

The membrane pacemaker hypothesis predicts that long-living species will have more peroxidation-resistant membrane lipids than shorter living species.

Resistance to oxidative damage is of particular importance in mitochondria, cellular power plants that progressive damage themselves with the reactive oxygen species they produce as a byproduct of their operation - and that gives rise to a chain of further biochemical damage that spreads throughout the body, growing ever more harmful as you age. Less damage to the mitochondria should mean slower aging, and thus more resistant mitochondrial membranes should also mean slower aging.

The fifth Strategies for Engineered Negligible Senescence (SENS) Conference, SENS5, draws closer. It will be held from 31st August to 4th September at Queens' College in Cambridge - so there's still time to register.

The purpose of the SENS conference series, like all the SENS initiatives (such as the journal Rejuvenation Research), is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem: not seeking elusive and probably illusory magic bullets, but instead enumerating the accumulating molecular and cellular changes that eventually kill us and identifying ways to repair - to reverse - those changes, rather than merely to slow down their further accumulation. This broadly defined regenerative medicine - which includes the repair of living cells and extracellular material in situ - applied to damage of aging, is what we refer to as rejuvenation biotechnologies.

The program of presentations links to a range of interesting abstracts describing some of the important work that has taken place in the couple of years since SENS4, such as:

Tissue engineering of the liver using decellularised scaffolds

Here, we describe the fabrication of three-dimensional, naturally derived scaffolds with an intact vascular tree. ... The vascular network was used to reseed the scaffolds with human fetal liver and endothelial cells. These cells engrafted in their putative native locations within the decellularized organ and displayed typical endothelial, hepatic and biliary epithelial markers, thus creating a liver-like tissue in vitro.

MitoSENS: Allotopic expression of mitochondrial genes using a co-translational import strategy

The mitochondrion contains its own genome and encodes 13 proteins that are essential for the respiratory chain to function properly, [but] somatic mutations also accumulate in the mitochondria with normal aging. ... Thus far, we have stably transfected 5 of the 13 mitochondrial genes into the nuclear genome of human cell lines and are characterizing the expression and function of these exogenously expressed genes.

I also note that the group in Florida who are running a trial of granulocyte transplant therapy for cancer - based on the impressive results achieved by Zheng Cui - will also be presenting. On the whole, the program is well worth browsing. If you are interested in this field of science and biotechnology and you are not yet signed up for the conference, you should give some thought to attending.

An open access paper: "One of the most important and complex diseases of modern society is metabolic syndrome. This syndrome has not been completely understood, and therefore an effective treatment is not available yet. We propose a possible stem cell mechanism involved in the development of metabolic syndrome. This way of thinking lets us consider also other significant pathologies that could have similar [or shared biological pathways], like lipodystrophic syndromes, progeria, and aging. All these clinical situations could be the consequence of a progressive and persistent stem cell exhaustion syndrome (SCES). The main outcome of this SCES would be an irreversible loss of the effective regenerative mesenchymal stem cells (MSCs) pools. In this way, the normal repairing capacities of the organism could become inefficient. ... Stem cell restoration has already demonstrated therapeutic activities in certain systems. For example, it is known that after a stroke, endogenous stem cells are mobilized from the bone marrow in an attempt to heal the damaged neural tissue. Most interestingly, a recent study demonstrated that stroke patients who exhibit a high level of stem cell mobilization have better functional outcomes as opposed to patients with a lower mobilization. ... If [MSCs exhaustion syndrome] is true, then a stem cell therapy approach could be feasible. For instance, ex vivo expansion and reinfusion of MSCs from the patient's own or from allogeneic donors, as evidence shows that MSCs are not immunogenic at all, have been already tested in many clinical trials .... In the best case scenario, MSCs therapy could retard the onset of irreversible lesions associated with metabolic syndrome or at least partially improve those already present."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118295/

It is worth watching the prevalence of longevity insurance offerings, as this is a measure of the degree to which the actuarial community and insurance industry believes that increases in human life span will happen in the near future, but that they will not be large. For the insurer, longevity insurance is a bet on earlier than anticipated death: "Most people buy life insurance to protect against the risks of dying too soon. Now, there are new products offering the same protection if you live too long. It's known as longevity insurance, and there's clearly a huge market for it: Life expectancies are on the rise, cushy pensions are on the decline, and most people don't have enough savings to carry them through two decades or more of retirement. This is not lost on insurance companies, which would like you to think about the product as a pension of sorts - albeit one that you have to buy with your own money. ... But what happens if Merck invents the magic pill and we all live until 105? ... Continued improvements in medicine that allow people to live longer could create losses on our individual annuity business. but these would be more than offset by higher gains on the life insurance. ... Still [if] something like that were to happen, 'at some point, capacity might be limited.'" Companies that bet against large increases in longevity are likely to suffer greatly in decades to come - which is unfortunate for the rest of us, because these concerns are large enough to run to the nearest government for a bailout, and thus we all end up paying for collective bad bets.

Link: http://bucks.blogs.nytimes.com/2011/06/28/longevity-insurance-buying-down-the-risks-of-living-too-long/

There should be no such thing as "I don't know what to do with my life." Scratch that statement away and erase it, as it should be "I will aid the development of life extension technology until I do know."

It should be no surprise to anyone that many, or perhaps even a majority of people at any given time have no real idea as to what they want to do with their lives. No vision, no grand dream that captures them, no burning desire to achieve a specific great work. That isn't because they are incapable - far from it, it is because they haven't found their own personal blue touch paper yet. The space of ideas and ideals is vast, and even the most aggressively autodidactic internet-addicted polymath cannot embrace more than a fraction of the sphere of human knowledge. Yet you cannot know your grand vision, the one that resonates with everything your life has led to up until that point, if you never encounter its roots.

Which is where we come back to time. We tell the younger folk that it doesn't matter if they don't know what they want to do with their lives, as that knowledge will come with time. The rituals and mythology that spring from the passage from childhood to adulthood, repeated billions of times over the course of history, are as much about expanding horizons as they are about anything else. In our comparatively wealthy modern society, that process of expansion doesn't have to stop when you stop growing in body - except for the fact that we are all limited by the realities of the human condition, and aging in particular.

Our lives have a timer, and we are all well aware of it, for all that many of us prefer not to think about it at all. The whole structure of life and society revolves around the existence of that timer, as it ticks away the freedom we have remaining in which to find and work on something worthwhile. The rush to find meaning in life? There because we don't have enough time. The need to save for retirement and medical costs? The timer again, ticking away our health and ability to fend for ourselves.

When you cannot see even the first shape of what will be your life's work, and time is ticking away, the best thing you can do is to offer a helping hand to those who work on making more time - scientists, advocates, and others who support research and development of rejuvenation biotechnologies. You can do that at the same time as you search for the cause or idea that truly speaks to you, and it beats slumping back into the grey doldrums that seem to afflict so much of our society: people who never found that fire inside, and who have no time left in which to do so.

You have an option that the older folk of previous generations did not: you can help make more time for everyone, more health, more years, and time enough to find meaning in what you do.