Inducing Nerve, Blood Vessel Regrowth

Scientists are working on a variety of approches to stimulating specific tissue regrowth. Here, EurekAlert! brings news of another possible strategy: "The therapy involves netrins, a family of proteins that promotes nerve development. ... netrins not only accelerated blood vessel growth in ischemic mice (those with constricted blood flow) but they also restored blood vessel and nerve growth in diabetic mice. ... In the mice whose blood circulation was decreased by peripheral vascular disease, the researchers found netrins and [vascular endothelial growth factor (VEGF) delivered by gene therapy] promoted blood vessel growth equally well. But in the diabetic mice, netrins proved markedly better at promoting blood vessel and nerve growth than VEGF ... Gene therapy requires expertise that is available in only a few medical centers. The hope is that netrins could be more effective and may not have to be delivered as a gene therapy, making it available to a much larger group of patients."


More On Limb Regeneration Research

From EurekAlert!, a minor update on one of the higher profile efforts to develop limb regeneration technologies: the immediate goal "is to find ways to harness the body's natural regenerative abilities to heal limb wounds that involve bone, muscle, nerves, and soft tissue. For a model of tissue restoration, the scientists will look to the salamander, the only vertebrate that can regrow functional limbs as an adult. Adult salamanders are able to restore lost limbs by first making a blastema, a mass of undifferentiated cells much like stem cells. ... researchers will then attempt to recreate that regenerative ability in the mouse, giving this animal model the ability to develop a blastema and regenerate digits. ... if they are successful in achieving limb regrowth in a mammalian model, it will be the first step toward the long-term goal of regenerating digits, and perhaps whole limbs, in humans."


Bears, Osteoporosis and Data Mining the Living World

A great deal of biochemistry is going on out there in the world: odds are you'll learn something useful in relation to aging or age-related diseases - such as cancer - if you just know where and how to look. To pick one good example, a researcher has been investigating bear biochemistry for the past few years. This seems likely to provide some insight into methods to prevent osteoporosis - age-related deterioration of bone strength and density - in other mammals, such as we humans. A recent article at ScienCentral provides an update on progress since I last noted this research in 2004:

Most of today's drugs for this disease aim to prevent bone loss. But Donohue argues that it may be more effective to increase bone formation.

That's what hibernating black bears do. Donohue discovered this by analyzing the bending and breaking strength of a collection of black bear bones that was given to him by hunters. He found that while they do lose bone during hibernation, black bears grow new bone cells at an equal or faster rate. "And in fact their bending strength increases as a function of age, despite these annual periods of immobilization," Donohue says.


levels of a hormone known to promote bone growth, called parathyroid hormone or PTH, actually increase during hibernation. He points to one study in people that found that a synthetic version of PTH increased bone mineral density in postmenopausal women.

Donohue says that since the black bear version of the PTH gene is different from humans, understanding how it works could lead to better ways to treat or prevent osteoporosis in people. "We could develop those hormones or other growth factors synthetically, and then this could be used for drug treatments for osteoporosis in humans," he says.

Donahue has synthesized the hormone in his lab and his next step is to sprinkle it on bone cells and watch for bone-forming activity.

As the tools of biotechnology advance in capability and fall dramatically in cost, data mining the living world for existing solutions - or pointers to new solutions - to age-related medical conditions is ever more of an attractive proposition. In addition to those higher animals that avoid osteoporosis, others can regrow limbs, regrow damaged organs, or live healthily for centuries. In the grand scheme of things - a scheme that includes some truly strange and very different living creatures - the biochemistries of these overperformers aren't all that different from ours. Effective medical technologies will be built on this knowledge one day, and the cost-effectiveness equation for this research and development continues to tilt in our favor with each passing year of technological progress.

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Russian Cryonics

The St. Petersburg Times provides an interesting look at the culture and goals of cryonics seen through Russian eyes. "'We founded the company because human life is the most important thing there is. To lose a life without putting up a fight is a crime.' Potapov and his co-founders say they are Transhumanists, who believe technology can be used to transform human life and postpone death indefinitely. They founded Kriorus, the world's first cryonics company outside the United States, in 2005 so that they and their family members would have a place to stay until medicine found a way to bring them back to life. Now, for $9,000, anyone can spend eternity, or some portion of it, in cryonic stasis." This all sounds similar to the early history of cryonics in the US; a few people standing up to try and make a difference. More power to them. Cryonics remains the only option for people who will die before the coming era of working healthy life extension medicine: in a kinder world, this industry would be prospering.


A Brief Glance at Stem Cell Politics and Research Timelines

If you follow the machinations of those who spend their working lives striving to limit your access to new medical technologies, you'll no doubt know that a vote on stem cell research is coming up in the US Senate:

A controversial bill that would lift federal restrictions on embryonic stem cell research is headed to the Senate floor for a vote next month along with two related bills favored by social conservatives.

"We have been working a long time to bring this to the floor in an appropriate fashion," Senate Majority Leader Bill Frist, R-Tenn., said Thursday, nearly a year after his initial pledge to bring the bill to a vote.

Research would no doubt be far more effectively directed and well-funded without the intervention of a government that enforces taxation, debases the currency, tramples over freedoms, willfully damages economic growth, and wastefully gluts itself upon the resources it takes. Debating government restrictions on the disbursement of tax dollars is one of those line items I prefer not to touch.

A UPI article takes a broader view of the science and aspirations of researchers:

Deepak Srivastava, director of the University of California at San Francisco's Gladstone institute of cardiovascular disease, told United Press International embryonic stem cells hold the greatest promise for regenerating heart tissue and could be in the clinic in the next several years.

"There's a lot more that needs to be done in animal trials first before considering clinical trials ... but maybe within the next five years is a reasonable goal"


Robert Lanza, vice president of medical and scientific affairs at Advanced Cell Technology in Worcester, Mass., said his company plans to get embryonic stem cell-derived therapies for heart disease in the clinic even earlier.

"Optimistically, we plan to file an IND in 2008 for hemangioblasts derived from human embryonic stem cells," Lanza told UPI. "One of the lead applications would be cardiovascular disease," he added.

Lanza said his company's first IND for a therapy derived from embryonic stem cell therapy could be filed late next year, but that would be for macular degeneration.

To round off, Maclean's is running a profile of energetic researcher Hans Keirstead and his work on repairing spinal damage:

someday -- maybe someday soon -- his work will restore mobility for those who are paralyzed with spinal injuries or stricken with multiple sclerosis. He has already made partially paralyzed rats walk again, using derivatives of human embryonic stem cells. The next stop -- as early as next spring -- is trying the same therapy in human trials.


Critics have accused Keirstead of rushing ahead too fast, and of cozying up to biotech companies, but Keirstead is unapologetically entrepreneurial. If the purpose of the exercise is fixing spines, that means getting research out of the lab and into the market. With the cost of many human clinical trials for new therapies running about $500 million, that's not for the faint of heart. "Sorry if this sounds egotistical," he says, "but most scientists aren't as business savvy as I am."

There could never be too many people in possession of this sort of attitude to the repair of failing human bodies. Progress in medical science requires people to get out there, work hard and succeed. This is the essence of the future, not the posturing of stuffed shirts and other government employees in Washington DC.

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Delta G and Cancer Metabolism

A short article in Cambridge Evening News notes: "Two years ago Delta G, formed by William Bains, received £130,000 of funding to work on the ideas of Dr Aubrey de Grey, a Cambridge researcher. Dr de Grey's work concentrates on the metabolism of cells and what goes wrong as they age. ... Cancer cells use the energy they get from metabolism abnormally - a difference that many scientists have tried to fathom. Now, Delta G has discovered exactly what is wrong with cancer cells, allowing researchers to target them more effectively." A patent is on the way; Delta G's cancer science overview makes for interesting reading: "Delta G takes a new approach. It has been known for over 50 years that energy metabolism in cancer cells is abberant. ... Delta G is developing drugs that shoot at this target, attacking what cancer cells are rather than what they do."


From Cancer To Neural Regrowth

From Newswise, a report of a potentially positive outgrowth from cancer research: "Our finding suggests that the same process this protein uses for proliferating cancer could also potentially be used to regrow axons that are damaged in spinal cord injuries or neurological diseases ... The proteins - known as Id proteins - are abundant in the cells of many different types of cancer [and] were known to promote tumor growth and aid in the spread of cancer. ... Normally neurons cannot regenerate damaged axons because of the presence of myelin, a substance that surrounds the axons, but the degradation-resistant "super" Id protein was able to promote axon growth even in the presence of myelin. ... there is no chance that such a therapy would cause cancer in the brain or spinal cord. ... Neurons have completely lost the ability to create new cells so there's no danger of creating a tumor. The only growth they're capable of is regeneration of their axons."


Progeria and the Brittle Nucleus

(From EurekAlert!) Scientists continue to forge ahead in their understanding of the lamin biochemistry of progeria [HGPS], and the application of this knowledge to damage caused by "normal" aging. "The nucleus in all three trillion cells of the human body contains the DNA genome, which is wrapped with a stiff protein shell called the nuclear lamina. Children with HGPS have a mutation in one of the proteins of the lamina shell. ... the lamina shell in HGPS patients is stiffer than normal. However, stiffer isn't necessarily better. The stiffer lamina did protect the HGPS nucleus from some forces, but under excessive force the HGPS lamina was more brittle and eventually fractured. ... Once we understand what causes the lamina to stiffen, we can try to reverse or stop the problem. ... Our NIH collaborators have also found that the normal aged nuclei show the same structural changes as HGPS."


Towards Dental Regeneration

It's something of a historical accident that dentists stand in a somewhat separate cultural enclave of medicine; the forward edge of regenerative medicine for teeth is little different from that for other tissue these days.To pick one example, stem cells are a big deal in dental research:

research has demonstrated that mixed populations of cultured post-natal tooth bud cells can be used to generate bioengineered dental tissues.

Current research efforts focus on the identification and characterization of dental cell populations, scaffold materials, and design that can be most effectively used for tooth tissue engineering applications. Hoechst dye profiling and immuno-sorting methods were used to generate enriched clonal dental stem cell (DSC) lines. Expanded DSC and non-DSC lines are currently being examined, by both in vitro and in vivo methods, to define their potential to differentiate. Molecular and differentiation profiles will provide important characterizations of tooth bud cells, eventually to facilitate ongoing tooth tissue engineering efforts.

Efforts to tissue engineer replacement teeth, or repair damaged tooth tissue in situ, appear to be proceeding at much the same rate as other stem cell medicine. The next decade should prove to be very interesting indeed, as many threads of regenerative research come to fruition and commercially available therapies.

Meanwhile, intermediary technologies for regeneration are moving forward:

Using low-intensity pulsed ultrasound (LIPUS), Dr. Tarak El-Bialy from the Faculty of Medicine and Dentistry and Dr. Jie Chen and Dr. Ying Tsui from the Faculty of Engineering have created a miniaturized system-on-a-chip that offers a non-invasive and novel way to stimulate jaw growth and dental tissue healing.


"If the root is broken, it can now be fixed," said El-Bialy. "And because we can regrow the teeth root, a patient could have his own tooth rather than foreign objects in his mouth."


Dr. El-Bialy first discovered new dental tissue was being formed after using ultrasound on rabbits. In one study, published in the American Journal of Orthodontics and Dentofacial Orthopedics, El Bialy used ultrasound on one rabbit incisor and left the other incisor alone. After seeing the surprising positive results, he moved onto humans and found similar results.

There's no reason that effective stimulation of healing has to be achieved by the direct use of chemicals or biological cues, although that does seem to be the wave of the future. If mechanical or other forms of stimulation can be cost effective for the benefit they supply, then more power to those who are striving to understand the mechanisms and bring therapies to market.

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What People Want, What They Say They Want, and How You Ask

From a post on the practice of calorie restriction last week, pointed out to me just recently:

ABCNews reports a poll showing that 75% of women and 70% of men polled (lets not talk about the lack of information in "percentages" now...) are not interested in eating fewer calories to ensure living longer. In general, the poll respondents did not show overwhelming enthusiasm for an extremely long life; only 27% of women and 40% of men wanted to reach age 120. In that set of people, 44% said they'd be willing to eat one-third fewer calories in order to reach the goal. This means that 44% of 27% of 25% (or 2.97 of every 100) of women polled would consider giving up one-third of calories to live longer (and probably be thinner). Men were 1.5 times more interested. It seems that when offered a golden opportunity, we Americans prefer to pursue happiness in our bag of golden chips.

What people say they want is often quite at odds with their actions. Ask those poor folk pulling their hair out in any corporate marketing department - surveys are a tricky tool.

I'm inclined to think the apparent contradictions stem as much from the manner of asking as the nature of people to do say one thing and do another. Take that quoted poll above, for example. Given the widespread nature of the Tithonus error - the belief that living longer would mean being ever more frail and diseased - asking someone whether he would want to live to 120, providing no further context, is much the same as asking whether he would like to suffer for decades in increasing pain, frailty and disease. Not many takers there. Healthy life extension medicine will mean a longer healthy life; a postponement of disease and frailty by preventing or repairing the root causes of age-related degeneration. Tithonus is a mythical character, and will stay that way.

The success of the "anti-aging" marketplace illustrates that people really do want to be younger for longer. So much so that they are prepared to pull the wool over their own eyes rather than face up to the harsh reality of present day limits to medical technology. People want easy solutions and quick answers right now - but such things don't exist.

Calorie restriction is less popular than it might be because humans have a dreadfully short time preference - the lower regions of our brains value present food far more than the prospect of being alive and healthy decades from now. In effect, we've all evolved to screw the person we're going to be; good now, not so good when you have become that person.

You don't have to let the lower parts of your brain run your life, however. The part of you that is you can ponder much more sophisticated time preference calculations. Look to the future of radical life extension via actuarial escape velocity, and weigh the chances of living into an era in which biotechnology will allow a healthy life of centuries or millennia - an era in which you eat whatever you like, insulated by the same advanced biotechnology that sustains your longevity.

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The Limit of Good Genes

April Smith makes a succinct point: "Whenever the subject of life-extending, age-reversing biomedicine comes up, someone always has to say, 'Well, I'm not worried about aging because I have good genes.' To which I ask one question: 'Has anyone in your family ever died?' If anyone at any point in your family has died or is currently dead, then I suggest that your genes are not so great. ... The whole point of [Strategies for Engineered Negligible Senescence research] is to find therapies that actually reverse the aging process, making death, well, not absolutely unavoidable but a lot less likely to come as soon as it comes now." What you can do for your healthy longevity today is merely a stepping stone; best we recognize that truth and act to improve the situation. Without advocacy, without significant progress in real anti-aging science - progress that is neither funded nor taking place at this time - we will not live that much longer than our parents.


Notch Research Again

Nature reports on regenerative research centering on the Notch protein: "Researchers believe that many of the body's tissues harbour stem cells capable of dividing to make new tissue. But some of these are recalcitrant and do not naturally divide to repair damage wreaked by severe injuries such as stroke or spinal-cord damage. ... one protein, called Notch, can boost the survival of three different types of stem cell. ... researchers do not yet know whether this could be used to treat humans after a stroke, because stimulating Notch could have many other, perhaps unwanted, effects in the brain. But it does suggest that drugs that provoke Notch or a related protein might one day be used to persuade stem cells in the brain or other tissues to do what doctors want."


A Glance At Tissue Engineering Funding

Via a suitably exuberant press release at Yahoo! News, we learn that tissue engineering concern Tengion is doing well: "the company has raised $50 million in a recently completed Series B equity financing. ... Tengion plans to use the proceeds to fund human clinical trials to advance the development of its lead product, the autologous neo-bladder construct, for the treatment of neurogenic bladder associated with spina bifida and spinal cord injuries." This is representative of the funding pouring into regenerative medicine and tissue engineering these days. Development of a research infrastructure capable of building replacement organs from your cells is well under way. The next decade will be a kinder place for those with failing and age-damaged tissues, but there is still much more to be done in the fight to cure aging.


Getting Started on Garage Biotechnology

In the 70s, a handful of knowledgeable computer hobbyists gathered in the Homebrew Computer Club. A mere three decades later, hundreds of thousands of far more empowered individuals around the world collaborate on the production of hardware and software designs to the betterment of all. They are a cultural force and infrastructure for change unto themselves. What better future to look forward to that one in which many hands are joined in ever more beneficial trade and progress?

Today, the first biotechnology hobbyists are working their way through the same basics. As costs fall, the priesthood will dissolve and spread at the edges. Progress will accelerate - the long tail in any area of human endeavor has many hands and eyes, and a significant amount of funding power. More to the point, problems that traditional funds and organizations wouldn't touch will be open to new, less intensive, smarter approaches. This has all come to pass in the software world. It will also come to pass in biotechnology - which is simply a different form of programming in a wetter, much more complex operating system.

On a related topic, this piece caught my eye the other day:

A plan for a global database of all human gene mutations has been announced in Australia. The Human Variome Project could allow doctors to rapidly diagnose patients with rare genetic conditions and could ultimately lead to new treatments for diseases.

About 100,000 human gene mutations have been discovered, but this total represents only about 5% of the predicted total number of mutations.

I thought this interesting in light of recent research on the random nature of genetic mutations that accumulate with age. It won't be long now before complete genetic assays are a low-cost commercial product, something your doctor would order along with a blood test. What could one do for age-related genetic damage armed with the future technologies of genetic manipulation and replacement alongside a complete guide to the consequences of mutations?

There is no practical way to complete a list of mutations - not to mention epimutations and other important errors in cellular biochemistry - and their meaning in combination given today's technology. There was no practical way to complete the human genome project when it launched either - but, thankfully, we live in an age of breakneck technological progress. It is, I think, important that scientists embark upon these sorts of projects early rather than late: the early work is rendered quaint soon enough, but it is essential in informing and driving necessary advances in infrastructure technologies.

Soon enough, thousands, and then tens of thousands of biotech hackers will be joining in to assist efforts just like this one. Then it will all become most interesting - and we will all benefit greatly, just as we have from the blossoming of software development as a culture and infrastructure.

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More Nanog Research

More on Nanog and the creation of stem cells on demand through dedifferentiation via EurekAlert: in culture, embryonic stem [ES] cells tend "to lose stemness and evolve into muscle cell precursors, most likely goaded by a muscle differentiation factor known as BMP. ... When BMP turns ES cells into muscle it activates a protein called Smad1, a DNA-binding protein that, in opposition to Nanog, switches on genes responsible for muscle cell fate. Smad1 can only do this when assisted by generic factors known as co-activators, which stimulate gene expression. ... Nanog actually binds to Smad1 protein and interferes with its ability to recruit those obligatory coactivators, thereby rendering Smad1 powerless to initiate muscle gene expression. With Smad1 out of the game and Nanog in full control, cells revert to their forever-young state. ... in suitable conditions, differentiated cells are still capable of producing stem cells as descendants. The molecular mechanisms that we identified here might be used to regenerate stem cells from differentiated cells."


Penetrating the Philanthropist Demographic

Today, a brief reminder that great, world-changing wealth still exists in the hands of comparatively few folk - enough that the realignment of even a modest fraction of the total will cause great changes across the entire space of non-profit and grant-using research organizations.

"Brace yourself," Buffett warned with a grin. He then described a momentous change in his thinking. Within months, he said, he would begin to give away his Berkshire Hathaway fortune, then and now worth well over $40 billion.


Buffett has pledged to gradually give 85% of his Berkshire stock to five foundations. A dominant five-sixths of the shares will go to the world's largest philanthropic organization, the $30 billion Bill & Melinda Gates Foundation

Such dramatic realignments can only happen when effective control of wealth is very concentrated, and the purpose of wealth can be easily redefined. Such as, say, Berkshire Hathaway shares rather than an industrial conglomerate's manufacturing infrastructure. Large-scale wealth tends not to be fungible. Real wealth is tools, process and a cultural network of agreements with people actively engaged in the production of more wealth; everything else is a derivative of some sort.

While great (and purloined) wealth flows through government channels, controlled by comparatively few individuals, that does not amount to effective control. When was the last time a government applied a single billion dollars to successfully changing the world? You can see an example of this sort of failure in progress - waste, conflict and a commons on the way to tragedy rather than real progress - in the California Institute for Regenerative Medicine today. Yet we can point to stunning examples in private or philanthropic investment and endeavor many times over in each passing decade. True responsibility, ownership and accountability for results make all the difference in the world.

Back to the issue at hand: a reminder as to the scope of funds that are controlled by single or comparatively few individuals. Buffet may stand at the apex of wealth, but there are hundreds of billionaires in the world today. A decision by any one of them to enter the modern biotechnology arena with serious intent to defeat aging would change the landscape - just as those already in the pool have already accomplished. But today's progress is too slow, or too vested in conservative, limited-gain approaches, or undertaken with too few resources. If we are to live to see radical life extension, much more must be directed to this goal - as would be the case if more of the world's wealthy philanthropists found their way to our view of aging, biotechnology and the near future.

One very wealthy individual has already placed a first million-dollar vote of confidence with the approach advocated by the Methuselah Foundation and biomedical gerontologist Aubrey de Grey - and many thanks to you for that, whoever you are. What if the wealthy of the world were to repeat this vote of confidence a thousand times over in the course of a decade? A billion dollars could build the large-scale research infrastructure that develops robust rejuvenation in mice, the first step towards the the defeat of aging in humans. Ageless, healthy, biotech-repaired mice, living a life that could be brought to humans with further investment: there would be the world changed. And cheap at the price!

Resources for research must come from somewhere if we are to escape our fate of suffering and death by aging. We must explain our goal; educate the public; raise widespread support; motivate the scientific community. We have made good, strong progress in the past few years - but a long road lies ahead. As a community, we have yet to successfully engage and persuade the wealthiest and most conservative of philanthropists, seeking support for modern, aggressive bioengineering approaches to the problem of age-related degeneration.

We can do this. We must do this. Too many lives, too much suffering is at stake to fail.

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Presenting the Electric Hematon

(From A growing breadth of approaches are emerging within the field of tissue engineering. Scientists "have developed a new technique which uses electricity to engineer human tissue. They now believe it may have the potential to engineer bespoke bone marrow. ... The technique, which uses electric fields to build up layers of cells to form a tissue, is being used to create Hematons - aggregates of blood producing cells essential in the function of healthy bone marrow. ... If we can perfect this technique then it may one day be possible to create artificial bone marrow outside the body and produce any given blood type ... By varying the voltage and using different electrode shapes, cells can be positioned and stacked on top of each other in any pattern. Different electric fields can also be used to attract different types of cells. Most importantly, cells can be kept alive and active."


Answering an Amyloid Beta Question

Better science leads to better tools that allow for better science. EurekAlert provides a snapshot of this feedback loop in action in Alzheimer's research. Most of us have heard of the buildup of amyloid beta (Abeta) and its connection with this neurodegenerative disease, but it is still an open question as to whether the buildup is due to greater production or failure to break down amyloid. "Because Alzheimer's symptoms take many years to develop, some researchers had assumed that the creation and clearance rates for Abeta were very slow. But the initial test of the new technique [suggest] Abeta has the second-fastest production rate of any protein whose production rate has been measured so far. In a time span of about six or seven hours, you make half the amyloid beta found in your central nervous system." Many other basic questions remain unanswered - but the tools of modern biotechnology are becoming far more capable with each passing year.


A Certain Immortality

The work of Leonid Gavrilov and Natalia Gavrilova on the influence of birth order and mother's age on longevity is receiving press attention again. Earlier actuarial studies showing that birth order correlates with life expectancy is explained by the mother's age relationship - younger mothers seem to mean a greater life expectancy for the children.

The chances of living to the ripe old age of 100 -- and beyond -- nearly double for a child born to a woman before her 25th birthday, Drs. Leonid Gavrilov and Natalia Gavrilova reported. The father's age is less important to longevity, according to their research.

In a previous study, the husband and wife research team of Gavrilov and Gavrilova identified birth order as a possible predictor of an exceptionally long life. They observed that first-born children, especially daughters, are much more likely to live to age 100.

But their latest research suggests that it is the young age of the mother, rather than birth order, which is significant to longevity.

This can be tied in with the researchers' reliability theory of aging - younger mothers are producing children with a lower initial load of cellular or genetic damage. This is a conceptual framework for thinking about the processes and advance of degenerative aging; it poses many more questions than it answers, says nothing about the underlying biochemistry, and exists to guide future research.

The research serves as a reminder that a certain immortality runs through humanity and its biochemical components: for all that we suffer age-related degeneration - and frailty, pain and death as a result - we produce healthy, youthful children with each new generation. Our cellular biochemistry contains the potential to rejuvenate and repair itself: children are the demonstrable proof that decay and entropy are not inevitable. We must progress as fast as possible to understanding and developing the means by which our present decay as individuals can be arrested, and our healthy life spans greatly extended.

The threads of immortality that wend their way through humanity as a whole - and the ongoing daily demonstration of the effectiveness of our biochemistry to turn back time - form a romantic notion. But you can't enjoy romance when you're dead and buried, nor when you're suffering unto death. Via science, we are capable of better and more practical approaches to the toll of degenerative aging than hiding our heads in the sands of romantic appreciation.

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Reading Up On Sarcopenia

From the Journal of Endocrinology, a good preprint review paper (with full PDF available) on what scientists know about the biochemistry of sarcopenia: "This review describes the major hormonal factors that determine the balance between human skeletal muscle anabolism and catabolism in health and disease, with specific reference to age-related muscle loss (sarcopenia). The molecular mechanisms associated with muscle hypertrophy are described, and the central role of the satellite [stem] cell highlighted. ... The increasingly recognised role of myostatin, a negative regulator of muscle function, is described, as well as its potential as a therapeutic target. Strategies to counter age-related sarcopenia thus represent an exciting field of future investigation."


Stem Cells and the Immune System

Biochemistry is always more complex than you think. Via Medical News Today, we learn that our stem cells are very involved in the immune response: "marrow stem cells -- undifferentiated cells that eventually give rise to the blood cells that fight infection -- possess receptors that recognize bacteria and viruses. When activated, these receptors kick the stem cells and immature blood cells into action, enlisting them to help fight whatever pathogen is attacking the body." This opens the door to possible methods of controlling, enhancing or repairing the aging immune system. "It may be possible to boost immunity when necessary and also shut down inappropriate responses. That could provide a powerful tool to fight cancer, lupus and many other diseases."


Spreading Vitrification Research

No-one really wants to die and be vitrified to await a possible - plausible - future in which medical technology can repair damage and restore life. On the other hand, a sensible person will choose this over a future as worm food, forever dead and beyond the reach of any future science. Cryonics is an insurance policy against dying before the arrival of real anti-aging technologies, and as such we should pay attention to cryopreservation science: "the fact that in aqueous solution, the water component can be slowly supercooled to the glassy state and warmed back without the crystallization implies that, in principle, if the suitable cyroprotectant is created, cells in plants and living matter could withstand a large supercooling and survive." Vitrification science is already progressing well, but is not well known - as illustrated by the lack of awareness in this press release. Still, press releases and media attention are a part of spreading scientific knowledge nowadays; if it means more attention is given to the cryonics industry, all to the better.


Inducing Nerve Regrowth

Scientists are making progress in using existing biochemical signalling mechanisms to induce regeneration where none would normally have happened. Via, more on progress in nerve regrowth: "Scientists have used stem cells and a soup of nerve-friendly chemicals to not just bridge a damaged spinal cord but actually regrow the circuitry needed to move a muscle, helping partially paralyzed rats walk. ... This is an important first step, but it really is a first step, a proof of principle that you can rewire part of the nervous system ... the new research details a complex recipe of growth factors and other chemicals that entice the delicate cells to form correctly and make the right connections. Miss a single ingredient, and the cells wander aimlessly, unable to reach the muscle and make it move." These are the first steps on a very long and complex road - but progress has been very encouraging in recent years.


Methuselah Foundation: Illustration and Design Volunteers Wanted

Are you a skilled professional in the area of graphics, illustrations, prints or design work? Are you in a position to volunteer time over the next few months - enough time to get a good job done - to one or more projects aimed at advancing advocacy for healthy life extension research? If so, the Methuselah Foundation would like to hear from you.

A number of high-impact Foundation projects presently underway - and yet to be revealed on the Foundation website or to the wider public - would benefit greatly from the attention of professional, skilled artists, illustrators and graphic designers. If you would like to add your stamp to the developing future of longer, healthier lives and widespread public support for healthy life extension research, now is the time to speak up.

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Research Bans in Australia

Via The Scientist, a reminder that those despicable vermin known as "politicians" are never happier than when using force to take away your freedoms. In this case, the freedom of research, a subset of the vital freedom to own and do as you wish with property - and the only way forward to better our health and longevity. "Australian stem cell researchers got some bad news today when newspapers reported that senior ministers in the national government are going to ignore the advice of an independent review that had recommended somatic cell nuclear transfer be permitted for research." This is a very important baseline technology for the future of regenerative medicine and embryonic stem cell research to develop cures for age-related diseases. If your property rights only exist at the convenience of flawed, venal people in positions of power, then you are, in truth, a slave.


Two Old School Studies

A pair of studies presented at a recent neuroendocrinology conference have been doing the rounds of the science press: just the facts can be found at EurekAlert!, and an article with more commentary at the Post-Gazette. With no disrespect intended to the authors, both come across as something of a look back to the old school standard of progress prior to the bioinformatics boom: uncover a single relationship between a compound or molecule and health, then ponder on the possible significance. Nowadays, I think we're starting to expect somewhat more from research groups: metabolic pathways, complete understanding of relevant mechanisms, and the first steps towards a therapy all delivered in a nice package.

The first of the two studies investigates the use of a growth hormone stimulator to somewhat mitigate the consequences of muscle loss with aging; as for some previous work, it found benefits:

Aging is characterized by a progressive decline in muscle mass, strength and exercise capacity, often leading to frailty and the inability for living independently. Since growth hormone (GH) secretion also declines with age and many age-related changes resemble those seen in GH deficiency, the researchers are investigating the potential physical and endocrine effects of stimulating GH in older adults.

In this controlled trial involving 395 men and women aged 65 to 84 with mild limitations in their physical functioning, participants received either placebo or various oral doses of the growth hormone stimulator (GHS) capromorelin ... GHS at any dose prompted an acute GH peak and an increase in overnight GH secretion - increases that were sustained throughout a 12-month treatment period. The GHS treatment also was associated with a 1.4 Kg increase in lean body (muscle) mass and an improvement in tandem (heel-to-toe) walking at 6 months and in stair climbing at 12 months.

However, a weight of work still exists to show that there are potentially serious side effects; scientists do not yet fully understand the biochemistry and its variance between individuals. Growth hormone could have any number of unpleasant side-effects that are masked in the short term by the benefits of additional muscle, loss of fat and enabling increased exercise. Growth hormone for anti-aging use should not be illegal - for all the same reasons that taking any risk with your own body should not be illegal, providing it harms no-one else - but it's definitely a case for caveat emptor and careful research.

Compare this with the weight of evidence for the long-term, side-effect-free benefits of exercise, losing excess fat or calorie restriction, for example. As I've noted before, growth hormone seems very much like a drug for a few specific age-related conditions - the condition in this case being a frailty that prevents the use of the three methods mentioned above to maintain health as best as possible. Like many other drugs with wide-ranging effects on metabolism, growth hormone and growth hormone stimulators are poorly characterized, poorly understood, and the research is very much in flux.

Like calorie restriction, exercise, and losing excess fat, growth hormone therapies are short term, stop-gap measures that will not significantly extend your maximum life span - to 150 or beyond, say. No amount of tinkering with your metabolism at this level can achieve the goals of radical life extension or a defeat of aging. We must not lose sight of the fact that much more impressive technology will be needed - our primary effort should be to support the advance of suitable research to this end.

The second study illustrates a simple relationship:

A protein derived from fat tissue may be an important determinant of longevity, suggests a study of 133 women, including 25 aged 100 to 102, whom researchers found had notably higher levels of adiponectin circulating in their blood. Adiponectin is a peptide that has anti-inflammatory properties, helps keep vessels clear of fatty deposits and plays an important role in metabolism, particularly of lipids and glucose. Insufficient levels of adiponectin are thought to contribute to obesity, insulin resistance, diabetes or the formation of lipid deposits in the arteries, collectively known as symptoms of metabolic syndrome.

To restate my ealier point, this is one of those results that we would nowadays expect to be accompanied by much more "how," "why" and "what this means." Correlation is not causation, and so results like this are largely fuel for speculation and little else in the absence of further investigation into the underlying biochemistry. The obvious speculation would be the same as that for the ratios of LDL and HDL cholesterol in the blood of centenarians - the people who are lucky enough to have a metabolism with this characteristic tend to live longer. Which is no great advance in knowledge - just the first sight of a long road - without an accompanying explanation as to why this might be so.

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Progress For Parkinson's Research

Via HHMI News, a fairly detailed look at progress towards better therapies for Parkinson's disease: "researchers have pinpointed defects in a critical cellular pathway that can lead to the death of dopamine-producing nerve cells and ultimately symptoms of Parkinson's disease. They have also used several animal models of the disease to identify a new way to rescue dying neurons. ... the findings give important clues to why dopamine-producing neurons in the brain are the most vulnerable neurons ... We have found compounds that reverse [this cause of damage], and we plan to publish those results soon ... [researchers] have not by any means proven that this mechanism of pathology or the compounds that affect it are relevant to humans. However, given the fact that we've found the same results in yeast, flies, worms and rat neurons, I would be very surprised if we didn't find that they were relevant in humans."


Blood Vessels From Stem Cells

As a counterpart to recent work on dedifferentiating blood cells into stem cells, scientists are taking steps in the other direction: culturing blood vessels from stem cells. EurekAlert notes that researchers "have successfully differentiated the stem cells into myocytes, one of the building blocks of blood vessels ... scientists hope to be able to eventually grow whole blood vessels that can be transplanted back into mice. ... Tissue-engineered blood vessels have also seen some success when transplanted into animal models, but still face a variety of limitations, [key] among them rejection by the immune system. By creating a tissue-engineered blood vessel grown from a patient's own stem cells, this rejection could potentially be eliminated ... Our goal is to derive all the different cell types from the same, original cell. This would be new for an engineered tissue. We hope our work with mouse stem cells could eventually be translated to human autologous adult stem cells."


Dedifferentiation Progress

(From EurekAlert). A privately funded venture claims significant progress towards dedifferentiating blood cells into stem cells and then using them to build tissue. We've heard this before to no great result, but it'll be the real deal sooner rather than later: "The idea is to revert a patient's blood cells to the stem cell stage and then chemically nudge them to re-specialise into particular tissue types that can be implanted to heal damaged tissue. A huge advantage over using donated tissue is that the transplant would be 'autologous' - made of the patient's own cells, thus avoiding immune rejection ... [Pharmafrontiers] now claims to have refined a way to produce stem cells from white blood cells called monocytes and develop them into many different tissue types including, crucially, insulin-producing cells."


Random Genetic Mutations, Mishaps, Copy Errors and Other Oddities

A short walk throught the realm of DNA and genetic biochemistry today - never a dull moment here. You'll find an interesting letter at Nature on the growth of random changes (copy errors, oddities, mutations and other odds and ends) in your DNA. In science-speak, this accumulation of error is a stochastic process; somewhat random, somewhat determined by the state of your biochemistry today. The longer you live, the more genetic errors you will carry with you - and errors in your biological machinery inevitably mean that the machinery isn't working so well anymore.

The accumulation of somatic DNA damage has been implicated as a cause of ageing in [animals]. One possible mechanism by which increased DNA damage could lead to cellular degeneration and death is by stochastic deregulation of gene expression. Here we directly test for increased transcriptional noise in aged tissue by dissociating single cardiomyocytes from fresh heart samples of both young and old mice


Although gene expression levels already varied among cardiomyocytes from young heart, this [variance] was significantly elevated at old age. We had demonstrated previously an increased load of genome rearrangements and other mutations in the heart of aged mice.


These results underscore the stochastic nature of the ageing process, and could provide a mechanism for age-related cellular degeneration and death in tissues of multicellular organisms.

One of many mechanisms, sad to say. Researchers will need to significantly impact all of them to hit radical life extension or superlongevity - but incidental gains in fighting age-related disease along the way will not be negligible.

What we should be viewing with concern is the evidence of destruction of information: it's not unlike what happens to most magnetic storage media from the past two decades. Bits get flipped as time passes, and given long enough you lose the original data. In the case of your genome, the damage is less extensive but still worrisome.

Loss of data is much more expensive to understand and repair than other forms of damage; you're losing the very knowledge needed to guide you to the solution. It seems clear that gene therapies and related technologies are progressing rapidly towards safe, global changes and wholesale replacement of damaged portions of DNA. But what to replace in the case of pervasive, widespread random damage? It's by no means an impossible task, but it's a far more ambitious goal than curing a disease by changing a single gene.

Will it be easier if the aged patient thought to have a less damaged tissue sample cryogenically stored fifty years earlier? Maybe, or maybe bioinformatics will be at the point at which sorting out the loss of information safely will be trivial. Given the present (rapidly decreasing) cost of tissue storage, it seems almost sensible insurance against some of the possible future economics and science of healthy life extension medicine.

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Sirtuins and Acetate Metabolism

Those following the ongoing investigations of calorie restriction biochemistry, metabolism and potential gains in healthy longevity may find this interesting: "sirtuins directly controlled the two-member class of enzymes called AceCSs (for acetyl-CoA synthetases) ... This reversible process transformed the AceCSs into a form that allows the body to utilize the small fatty acid called acetate. ... Acetate can be very important in animals as an energy source ... In humans, acetate can be obtained from the diet and as a by product of other metabolic processes. However, it is believed that we don't generally rely on it heavily as an energy source. ... it's not clear what role acetate metabolism may play in the little-understood sirtuin molecular system that seems to confer so many advantages, but a connection to diabetes and aging does exist. Studies from the 1960s and early 1990s showed that diabetics and aged individuals exhibit a decreased ability to utilize acetate."


If My Cells Live Longer, I Live Longer ... Right?

There are any number of interesting studies and technology demonstrations that extend the life span of individual cells by one means or another. If your cells live longer, you live longer, right?

Well, no, sadly.

Consider this thought: if everyone in your city drove twice as fast, all the extra efficiency would make the local economy grow more rapidly. Right?

But wait - driving twice as fast only really works to save time and improve efficiency under some circumstances. What about residential areas and curvy roads? Can these cars even drive twice as fast all the time without falling apart and causing all sorts of other problems? Doesn't fast driving cause more noise and wear on the roads? Does it cost more to drive fast than the time saved adds to your income? Plus which there are always going to be people for whom driving fast is never going to translate into efficiency: they'll be at the beach or in the bar. I'm pretty sure that a large chunk of the economy has no relationship to how fast people are driving, in any case.

Your body is a complex system, and as such its properties - such as health and life span - are not necessarily directly related to the properties of its individual components. Like a city or an economy, your body is a process in motion, with more hidden depths than the mere sum of its parts might suggest. In many cases, tissue and organs have evolved to operate most effectively with a high turnover rate of individual cells, for example. Changing that is somewhat like trying to downgrade a precision engine. Damaged cells need to be removed from the system, and cancer is the ultimate expression of cellular longevity.

There are no doubt subsystems within your body that would benefit greatly from extended cellular longevity; specific tissues in which longer cell life spans would in some way put off the local advance of age-related degeneration. A number of groups are aiming at just this sort of goal in telomere research, attempting to produce therapies for specific, localized age-related conditions. For the most part, however, "extended cellular longevity" seems to mean "lots and lots of cancer." From the standpoint of the present scientific consensus, would take a challenging array of supporting biotechnologies to change this situation.

So, no, a focus on cellular longevity is not the way to be looking at present day research with an eye to applications in healthy life extension. Instead look at cellular damage and its repair: some classes of damage do indeed shorten the life span of individual cells, but that is not the reason why treating this damage is important. After all, some forms of age-related damage lead to cells lingering for too long, cluttering up the joint, or actively proliferating longer than is safe and damaging the body. Rather, we would benefit from medical technologies capable of repairing this damage because it has been demonstrated to contribute to the degeneration of biological systems within the body.

This is the way to go: identify the components, identify the damage, prevent or repair the damage. Whether it involves cellular life span along the way is somewhat irrelevant - we care about our healthy life spans.

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Turning Off Cellular Senescence

Chemical & Engineering News offers more insight into recent Korean research relating to the manipulation of cellular senescence: "Korean researchers have found a complex thiourea derivative that can extend the lifetime of mammalian cells and reverse cellular aging. ... CGK733 was discovered by screening a library of 20,000 synthetic molecules for their effects on aging cells ... CGK733 is an example of what many scientists hope will be a trend: the identification of small molecules to mimic more cumbersome genetic interventions to regulate cellular behavior." Cellular senescence has little to do with the common meaning of the term "senescence" in relation to degenerative aging. A longer examination of this research and its significance can be found at Fight Aging!


More Biopacemaker Research

A number of teams are presently working on ways to replace artificial pacemakers with biological solutions: researchers "have now taken preliminary steps toward using a patient's own cells instead of a pacemaker, marking the first time tissue-engineering methods have been used to create electrically conductive tissue for the heart. ... [scientists] obtained skeletal muscle from rats and isolated muscle precursor cells called myoblasts. They 'seeded' the myoblasts onto a flexible scaffolding material made of collagen, creating a 3-dimensional bit of living tissue that could be surgically implanted in the heart. ... When the engineered tissue was implanted into rats, between the right atrium and right ventricle, the implanted cells integrated with the surrounding heart tissue and electrically coupled to neighboring heart cells. ... The implants remained functional through the animals' lifespan (about 3 years)."


Kurzweil: Reprogramming Biology

At Scientific American, Ray Kurzweil opines on the prospects for reprogramming our biology for far greater healthy longevity: "We are now beginning to understand biology as a set of information processes, and we're developing realistic models and simulations of how the processes involved in disease and aging progress. Moreover, we are developing the tools to reprogram them. ... Human life expectancy was only 37 years in 1800. Such technologies as sanitation, antibiotics, and other medical advances have more than doubled it in 200 years. Our ability to reprogram the information processes of biology will dramatically increase it again, but this progression will be much faster because of the inherent acceleration of information technology. I expect that within 15 years, we'll be adding more than a year each year to remaining life expectancy. So my advice is: take care of yourself the old-fashioned way for a while longer and you may get to experience the remarkable century ahead."


Comments Requested on Superlongevity and Boredom

Mark Walker is requesting comments on an early draft of a paper on superlongevity and boredom. Take a look and see what you think:

As usual, comments welcome. Here is the abstract:

"Superlongevity" may be thought of as doubling (or more) the human lifespan through the use of technology. Critics have argued that superlongevity will inevitably lead to boredom, while proponents have denied this claim. Rather than attempting to resolve the debate through theoretical speculation, I argue that allowing persons to become superlongevitists can be construed as an experiment to decide this issue. Further, the moral benefits of conducting the experiment greatly outweigh the moral costs of not running the experiment.

A conclusion I wholeheartedly endorse. Run the experiment!

The idea that a far longer, healthier life somehow implies a doom comprised of boredom - and that this renders the whole exercise pointless from the outset - is one of those oddly widespread and utterly silly kneejerk objections to healthy life extension:

Even active, inventive, happy people often assume that longer healthy lives will bring boredom through repetition, however. Ask someone you know how long it would take them to run out of new things to do and become bored if they could live in good health forever. Your friend will give you an outrageously low number of years, I'll bet. If you stop to think about it - rather than just going on instinct - you'll soon realize that you are never going to be any more likely to become bored of life than you are right now. There is simply too much to do, too many different things to think, feel, do and accomplish. In fact, the advance of technology means there is always more to do with each new passing year. New possibilities, activities and enhancements to the quality and variety of life are constantly opening up.

If you enjoy healthy life, you'll most likely enjoy more healthy life - if you put in the effort to make it interesting. That's your responsibility; no-one else is going to help you make a life you like. So put in the effort! Don't let yourself be conned into accepting age-related suffering and death by those who haven't thought seriously about the issue. Or by those who couldn't care less about your welfare.

We live in a unique time: on the cusp of a biotechnology revolution that could deliver the keys to greatly extended healthy longevity and cures for age-related frailty and disease. But it won't happen in time for those of us reading this today if we all shrug our shoulders and fail to speed progress towards these worthy goals.

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A Lesson to Learn from Progress in Calorie Restriction Advocacy

Calorie restriction (CR) advocates have made great strides in the past few years - all the way from the fringe and mainstream media ignorance to a much higher profile, sensible, sympathetic articles in the popular press and a well-regarded yearly conference. These advocates are just as right today as they were back in 2000; the message hasn't changed, and neither has the extensive body of science demonstrating the health and longevity benefits of CR in almost all animals. So why success now rather than from, say, 1995 to 2000?

I think it's no coincidence that the rising profile for the practice of calorie restriction has come about at the same time as greater investment in research and the first mainstream scientific results for human CR studies. Mainstream science - the body of knowledge and culture built around sifting truth and understanding through the scientific method - is still the accepted arbiter of truth in most modern societies, for all the seemingly endless, ongoing attempts to change this state of affairs. Fads of ignorance come and go, but the scientific method is demonstrable, powerful, and quite simply right: all modern technology has mainstream science as its source, and people know it.

The lesson to take away here is that even an incremental advance in proven science makes advocacy far more effective. Suddenly your truth and correctness are corroborated by a source vastly more trusted in the public eye. The mass media become more engaged and easily accessed; people are less instinctively skeptical. This is a portion of a positive feedback loop: raising funding for research requires advocacy and the public support generated by advocacy. Further advocacy for further funding is made easier and more effective by tangible scientific results. Getting your cause and the associated research programs off the ground is the hardest thing that advocates will have to accomplish; after that, it's a matter of more and better of the same medicine.

None of this is rocket science. It's all been accomplished a hundred times over in the past decades for causes large and small; the methods are well established and time-tested. We advocates for serious anti-aging research should take note and learn from the calorie restriction experience: what are the near-term scientific advances we should put forward as confirmation of progress towards meaningful extension of the healthy human life span? How can we better leverage the ongoing incidental healthy life extension research presently taking place? Are there modest projects that can be effectively funded by private donations with a comparatively rapid payoff?

The more science behind us, the faster we go.

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First Embryonic Stem Cell Therapy

After good results in animal studies, researchers are aiming for human trials of an embryonic stem cell (ESC) therapy for spinal injuries. "Via the New Scientist: I'm confident that we will be in the clinic next year with the first human ESC-derived product ... Geron's plan is to treat people that have acute spinal injuries with oligodendrocyte progenitor cells grown from human ESCs. Oligodendrocyte cells support neurons in the brain and spine by sheathing them in myelin, a fat that helps neurons to transmit signals. Spinal 'crush' injuries often cause a loss of myelin, and so destroy the capacity of nerves to transmit signals. Previous experiments carried out by Geron in rats with damaged motor nerves suggested that oligodendrocyte progenitor cells injected into the spine can redress this, helping to restore movement." A thought for the day: if the FDA didn't exist, this therapy would already be in the clinic and at a far lower cost.


Update on Reliance Life Sciences

(From DNA India). The Indian group Reliance Life Sciences is a well-backed portion of a large conglomerate, and is forging ahead with stem cell research for regenerative medicine - Indian bureaucrats haven't developed anything as monumentally harmful to progress as the FDA in the US. "RLS also has plans to introduce therapies for cardiac and nerve-related diseases like Alzheimer's and Parkinson's. ... They are under pre-clinical stages and we are awaiting approval for human trials from the department of biotechnology (DBT) ... The efficacy of the therapies for neuro-degenerative diseases like Parkinson's and Alzheimer's has been successfully identified in pre-clinical trials ... The stem cell therapy developed by Reliance for the treatment of cartilage damage associated with osteoarthritis is under research studies and will soon enter the pre-clinical studies."


A (Very) Brief History of Tissue Engineering

The journal Tissue Engineering is taking a look back at 15 years of their field, at least by this definition of "tissue engineering":

Vacanti describes tissue engineering as, "a scientific discipline dedicated to the generation of new tissue using the principles of engineering in combination with an understanding and application of the biologic sciences."

The PDF of the article is freely available, and an interesting read for those of us who like to peer behind the curtain:

It is my intent in this paper to present a brief historical perspective of the emergence of tissue engineering as a multidisciplinary science and a new field in medicine.


To my knowledge, the first recorded use of the term tissue engineering, as it is currently understood, was in an article entitled, "Functional Organ Replacement: The New Technology of Tissue Engineering," published in Surgical Technology International in 1991.


Although the number of multidisciplinary technologies currently being studied in medicine and the biologic sciences appears to be overwhelming and unrelated, it is my belief that the accumulation of such knowledge will ultimately culminate in the clarification of one central process responsible for the development, repair, and regeneration of any organ system, as well as the mechanism and potential treatment for cancer.

I think this last is optimistic, but defer to the expert. It seems to me that there is no reason to necessarily suppose such a large commonality of function for biological systems within the body - at least at a level that helps to speed the engineering and manipulation of tissue. It would certainly be a very good thing if this were the case. Biochemistry is hugely complex, and the only way we are going to be able to manipulate and manage this complexity in the near future is through the use of algorithms (encoded biologically or otherwise) that map greater complexity to less complex systems that we can understand and manipulate. Examples include the use of stem cells to build tissue for us, or vastly improved bioinformatics technologies.

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On Growth Hormone Again

Via Yahoo! Sports, a fairly sensible article on growth hormone, the darling of the most disreputable, irresponsible end of the "anti-aging" marketplace. As I usually note when on this topic, growth hormone treatments appear to have legitimate uses for some conditions and injuries. It is certainly not the case that there is anywhere near a gold standard of evidence for general anti-aging use, however - compare the wide-ranging disagreements between possible results, benefits and damage to health resulting from growth hormone studies with the strong agreement and far more impressive results for the practice of calorie restriction, for example. Many organizations have a great deal of money vested in convincing you to buy growth hormone products, whether or not the science is there to back up their claims, and regardless of whether it will help or harm your health. It should always be your choice to try or not, but be appropriately skeptical.


More On Lamin A and "Normal" Aging

More on what researchers have learned from studying the biochemistry of progeria can be found at the Journal of Cell Biology: "Aging looks and feels like it is multifactorial: everything falls apart independently. ... [but] multiple hallmarks of cellular aging can be reversed by eliminating one aberrant splicing product of lamin A. The lamins form a structural cage on the interior surface of the nucleus. Lamin A has a long tail that is first farnesylated and then chopped off. In [progeria] an aberrant splicing event creates a lamin A that gets farnesylated but not cleaved. ... normal cells also have a small amount of this aberrant splice product. Although neither the splice product nor its protein product accumulate to higher levels with age, their effects do. As in [progeria] cells, older cells have decreased heterochromatin and other nuclear markers, and increased markers of unrepaired DNA damage. Many of these changes were reversed by an oligonucleotide that eliminated the aberrant splice product."


Towards Liver Regeneration

(From the Seattle Times). Researchers are making progress towards regenerative medicine capable of repairing the liver: "the scientists were able to both isolate the liver stem cells and grow them into basic liver and bile-duct cells. ... It's so far the best work on the characterization of stem cells in the human liver. ... UW researchers then maintained the cells in special lab cultures for up to six months, and at various times infused them into mice with about half of their livers destroyed. The immune systems of the mice were suppressed to prevent rejection of the human cells. ... It was a delight when we saw these cells were capable of [partially] repopulating the damaged liver ... we gained tremendous understanding of human embryology, cell origins and how the liver is put together. That kind of knowledge is absolutely crucial for future research." Researchers are making similar progress for many other types of tissue in the body, setting the stage for a blossoming of regenerative medicine for age-related tissue damage in the years ahead.


Pointing Out Sierra Sciences

Via a post to Betterhumans, a pointer to Sierra Sciences, another of the small, privately funded companies (such as Telomolecular and Phoenix Biomolecular) that aim to use telomere-based medical technologies to tackle aspects of degenerative aging.

Check it out! Looks like they are really growing. I know Reason and a few others here don't really subscribe to the "Telomere theory" of aging, however, any attack on the process is a good one. I for one believe that the cosmetic applications alone will be enough to [propel] anti-aging into a serious spotlight and be able to attract more attention to the science as a whole.

I can't say I agree with that last sentence - the vast and unhelpful cosmetic "anti-aging" industry is, well, unhelpful. Counterproductive, even. For better or worse, however, for this research community to lean in that direction would seem to be a natural outgrowth of the research between five and eight years ago on telomere length, telomerase and aging physiology in skin. Such leanings are well in evidence over at Phoenix Biomolecular. Not so at Sierra, but more power to either company if they can raise money for more constructive research by going down that path - hopefully without ending up like the Life Extension Foundation, wherein the lion's share of effort goes towards maintaining a business based on old school technologies that will not significantly extend life spans rather than pushing the frontiers forward.

The past few years have not been kind to the telomere theory of aging as it originally stood - that telomere shortening alone causes aging. The contribution of shortened telomeres to the plot is more complex and not yet well understood; a great deal is yet to be learned about the underlying biochemistry and genetics. Scientists are still obtaining apparently contradictory results in telomere and telomerase research, which indicates that the fundamentals are not yet clear.

Successful application of new knowledge of telomere biochemistry to the treatment or prevention of specific age-related conditions seems plausible at this stage, but you don't know until you try. These scientists and company founders have raised the money, so let them get out there and make progress.

As a final note to the biologists in the audience, Sierra Sciences is hiring.

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Making Your Stem Cells Work Harder

Research noted at EurekAlert suggests that stem cells could be manipulated into working much harder to produce replacements for damaged tissue. Scientists "have identified an important mechanism that regulates how many new cells are produced by each intestinal stem cell. ... As many serious disorders cause a reduction in the production of new cells, scientists are keen to develop drugs that stimulate the process, which in turn could help the body to cure itself. ... Understanding how cell production is regulated increases our chances of producing drugs able to stimulate the endogenous production of new cells ... He hopes that the new findings can be used to develop drugs that stimulate, for example, the formation of new nerve cells to treat conditions such as stroke and Parkinson's and skin cells to facilitate the healing of wounds."


Better Calorie Restriction Press

From NBC11, another reminder that more scientific investigation of the practice of calorie restriction and its health benefits is turning skeptical, ignorant press attention into more educated, supportive press attention. "Studies prove that in animals, calorie restriction works. Monkeys, rodents, even fish sometimes live up to twice as long when they're forced to eat less. The initial human research suggests that even exercise can't compete with cutting calories when it comes to living longer. The calorie cutters in the studies had almost zero heart-attack risk. They had the blood pressure and cholestorol levels of a teenager, even when they were in their 50s." Scientists are still the arbiters of truth in our culture - and rightfully so. We should remember this in our efforts to advocate greater funding for directed anti-aging research: the more science that is funded, the more ammunition flows back to advocates to aid in advancing the debate.


Slow Progress on Nanog, Pluripotency

Researchers are making slow but steady progress towards creating pluripotent cells from adult cells - to recapture the regenerative utility of embryonic stem cells on demand. Via Forbes: "Nanog was first identified in 2003. It is a protein that acts in embryonic stem cells [and in the early embryo] to keep cells pluripotent. ... At the moment, it is not yet feasible to turn an adult cell into an embryonic stem cell simply by introducing Nanog ... Many other molecular players are likely to be involved and [there] is still much more work to be done to unravel the whole process of reprogramming [cells] ... Stem cell research is arguably one of the most exciting fields of biomedical research today, but, as with all scientific endeavors, it advances step by step, at times apparently gently, but always surely."


Rejuvenation Research Journal Now Officially a Success

Via the Gerontology Research Group mailing list, news from the scientific publishing side of the house: Rejuvenation Research is now officially a success. As if there was any doubt, what with the attention publisher Mary Ann Liebert has started to lavish upon the journal. Here's the scoop from the GRG:

The 2005 impact factors were announced yesterday, including the inaugural impact factor for Rejuvenation Research. I'm pleased to tell you that we obtained the very agreeable ranking of 8.571. This puts us at No. 1 in the "Gerontology and Geriatrics" category by a large margin, even including Aging Cell at 6.013 (which, for whatever reason, is not listed in that category). For a wider comparison, we would be No. 20 in Biochemistry and Molecular Biology and No. 17 in Cell Biology, ahead of such prominent titles as Human Mol Genet, NAR, FASEB J, MCB, MBC, JCS, and Oncogene. (BTW, I'm working with our Publisher Mary-Ann Liebert of New York to try to get us listed in those two categories.) Moreover, a rough calculation based on available data suggests that this is not a fluke arising from our conveniently small denominator this year -- we will be around the same level next year.

In contrast to the journal from which RR sprang ("Journal of Anti-Aging Medicine" edited by Michael Fossel, M.D., Ph.D.), Rejuvenation Research is primarily a research journal. Though reports of a more clinical nature are also considered, the overall remit of RR is a broad definition of aging-related regenerative medicine -- in other words, any research that can be viewed as having potential relevance to eventual aging-related regenerative medicine, even if only in the longer term. Please bear this in mind both when considering submitting articles and when you recommend RR to colleagues (as I trust you often do!).

Acting as the editor of a growing scientific journal is something akin to herding cats - if cats had wings. Congratulations are due to editor-in-chief Aubrey de Grey for successfully relaunching a noted research journal as a glowing success in the field - at the same time as flying around the world to present at more or less every conference of interest to healthy life extension science and its funding, guiding the growth of the Methuselah Foundation and MPrize hand-in-hand with Dave Gobel, Kevin Perrott and the other volunteers, sitting on the boards of half a dozen active organizations and keeping up a book's worth of email and forum correspondence with the healthy life extension community. Impressive stuff.

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New Approach to Gene Therapy

An interesting new approach to gene therapy is outlined at the New Scientist: "Take an artificial chromosome containing the gene to correct a serious disease, put it in a stem cell, and transplant into the body. That is the future of gene therapy, according to Mitsuo Oshimura of Tottori University in Japan. Oshimura's team has now proved that the concept works by correcting a genetic defect in mouse stem cells." A diversity of approaches to engineering our DNA is a good thing: greater diversity leads to faster, greater success. The road that starts with correcting single gene defects leads to technologies capable of repairing all the random age-related damage to our DNA - restoring our genomes to pristine condition and turning back the clock on one of the root causes of degenerative aging.


Dig Dirt From Around the World to Advance Anti-Aging Research

When was the last time you really looked down at the ground you walk upon? The soil from your backyard - or the next street over, or a nearby graveyard, or the park across the way - could contain the key to advancing real anti-aging science: bacterial enzymes capable of repairing biochemical damage that accumulates with time and leads to age-related disease.

The Methuselah Foundation, which administers the $3.5 million MPrize for anti-aging research, commenced funding the search for these bacterial enzymes last year. The research program is called LysoSENS, the name stemming from the Strategies for Engineered Negligible Senescence, or SENS. The object of this research is to break down and render harmless the age-related buildup of lysosomal toxins your body cannot handle by itself.

Cells have a lot of reasons to break down big molecules and structures into their component parts, and a lot of ways to do so. Unfortunately, one of the main reasons to break things down is because they have been chemically modified so that they no longer work, and sometimes these chemical modifications create structures that are so weird that none of the cell's degradation machinery works on them. This is very rare, but in the long run it adds up. The place where it adds up is called the lysosome, a special vessel that contains the most powerful degradation machinery in the cell; if something can't even be broken down there, it just stays there forever. This doesn't matter in cells that divide regularly, because division dilutes the junk away, but non-dividing cells gradually fill up with this stuff -- different types of stuff in different types of cell. The heart, the back of the eye, some nerve cells (especially motor neurons) and, most of all, white blood cells trapped within the artery wall all suffer from this. Eventually these cells can't take any more and they stop working right. This is the sole cause of atherosclerosis (the formation of lumps, called plaques, in the artery wall, which eventually burst and cause heart attacks and strokes). It is also important in several types of neurodegeneration and in macular degeneration (the main cause of blindness in the old). So it's very important to fix it.

In the search for suitable enzymes, as wide a range of samples as possible from around the world is vital. John Schloendorn, one of the LysoSENS researchers, is asking for your help to extend the range of this work! By digging a little dirt from your neighborhood, you can help to bring on the era of real, working anti-aging medicine:

I am pleased to announce that thanks to recent progress, the need for soil donations has arisen once more.


Whatever you contribute now will become the foundation of a growing DNA library that will probably accompany us until the three LysoSENS targets (intracellular junk, extracellular junk, xlinks) are out of the way. In this first public offensive in the war on aging, the online life-extension community can truly make all the difference, by contributing their local microbial diversity. Show the scientific community how much you want to see aging defeated, by helping us make the most remarkable DNA library on this planet!

All types of environmental samples are suitable. Try to avoid sending whole plant and animal parts, since we are interested only in microbes. Otherwise, there is just one rule: Biodiversity is key.


If you choose to send us samples, please do so immediately after you obtain them. Do not store them unnecessarily. For packaging we would recommend to wrap solid samples in plastic, liquid samples in some sort of screwcap bottle and put them in a suitably sized parcel. 100-200 grams ("a handful") will be a plentiful amount. Cooling or sterile handling will not be necessary. Please also add a brief description of where and when you took the sample. Please send your sample(s) to:

By regular mail:

John Schloendorn
The Biodesign Institute
PO Box 875701
Tempe, AZ 85287-5701

(The above address cannot receive FedEx / UPS shipments)

By FedEx / UPS:

K. Anderson / Schloendorn
The Biodesign Institute
1001 South McAllister Ave
Tempe, AZ 85287-5701

(Apparently, the above address cannot receive regular mail -- sorry about the trouble).

UPDATE: Schloendorn has put up a web page with more details, including a small contest for the most interesting soil sample.

Biomedical gerontologist Aubrey de Grey, chairman of the Methuselah Foundation, added this:

I want to emphasise the importance of John's push for diversity in soil samples. Don't do anything dangerous to get them, but bear in mind that any environment with an abundance of unusual organic compounds is likely to harbour microbes that can break those compounds down, and thus can probably also break down a variety of similar compounds. Since we have quite a few target compounds (things that accumulate in different tissues), the chances of striking lucky will not reach diminishing returns for a long while yet. John and Jacques are set up to test a wide range of samples in parallel and we're working hard to secure more funding to bring more manpower onto the project, so there is no danger of your sample being discarded because the researchers are swamped!

The funding for serious, directed anti-aging science is starting to roll in - by helping to support LysoSENS, you help to build the scientific community and infrastructure that will provide additional healthy years for all of us. So get out there and get digging!

For further discussion on this topic, and to meet like-minded diggers of dirt for healthy life extension research, visit the Immortality Institute forum to read and contribute to the main LysoSENS thread.

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Alzheimer's and Calorie Restriction

(Via Newswise). Most research funding is tied to repairing specific diseases or the end-stage results of accumulated cellular damage that we call disease. There's money - and greater effectiveness - in prevention, but inefficiency is the way that the present over-regulated medical system leans. So we see a lot of "forest for the trees" research, such as this study. It is clearly a step on the way to pushing calorie restriction (CR) mimetics as a therapy for end stage Alzheimer's disease (AD) - rather than, say, the practice of CR as one of the best preventative measures you could be employing to avoid Alzheimer's. From the article: "caloric restriction through promotion of SIRT1 (a molecule associated with brain longevity) may initiate a cascade of events like the activation of alpha-secretase which can prevent AD amyloid neuropathology. ... the study demonstrates a mechanism by which dietary caloric restriction might benefit AD."


More on Long Term CR in Monkeys

A long-running study on calorie restriction and healthy longevity in rhesus monkeys has been funded out to 2011: "The idea that fewer calories can extend lifespan and improve health has a long experimental history. ... rhesus macaques in the Wisconsin study [offer] perhaps the best window into a phenomenon that is the only proven dietary way to extend lifespan. ... The animals on a restricted diet exhibit 70 percent less body fat, and the fat tissue itself [is] very different from the fat tissue in the control animals, those allowed to eat freely. His group has also observed that the animals that eat less have less insulin in their bloodstreams and less insulin resistance ... So far, we've had complete protection from type 2 diabetes. Normally, 30 percent of the animals in a research colony will exhibit type 2 diabetes. ... 90 percent of the animals who began the study on a reduced diet are still alive, while only 70 percent of the animals allowed to eat freely have survived to this stage."


Discussing Telomerase and Cellular Senescence

It think it's something of a given that, somewhere, a scientific study exists to apparently disproves any given consensus view of human biological processes. Half are wrong, of course, but that still leaves the uncomfortable truth that a complex, incompletely understood biological system can be accidentally coaxed into confounding almost any reasonable expectation. This is one reason why looking at a single study is never all that useful, and why it usually takes a great deal longer to change a scientific paradigm than to run any given study. No one ever said science was an easy or clear-cut business.

With that in mind, I'll direct your attention to a discussion on telomerase and cellular senescence - in the context of building better regenerative medicine for the replacement of age-damaged tissue in the elderly - over at the Immortality Institute forums:

Utilising cells from the older patient with which to engineer tissues to replace dysfunctional ones poses a special problem: the replicative lifespan of cells from such patients is severly limited and thus cannot be used to synthesize replacement tissues. One way around this is to utilize cells donated from a younger person but then we encounter the problem of histocompatibility. There is another way involving the use of telomerase to increase the replicative potential of cells derived from very old patients. A recent study reported that by inserting a genetic construct that encoded the telomerase gene, cells from 85 year old patients that would normally only be able to undergo 15 population doublings before entering senescence were able to slingshot to 100 population doublings! In comparison similar cells from 17 year old patients untreated with telomerase could only achieve 41 population doublings before entering senescence. Most exciting of all, was that in this study the cells which were made to express telomerase for increased replicative lifespan the incidence of carcinogenicity did not increase over the control cells. In fact, is some cases the incidence of carcinogenicity decreased as compared to the controls.

This is, for me at least, an entirely unexpected result. Take a look at the original paper and see what you think. Many other studies seem to confirm that increasing the number of cell divisions by altering telomere shortening rates - through the use of telomerase - and thus pushing back cellular senescence will give you cancer, and lots of it:

Without the enzyme [called telomerase] that 'regenerates' telomeres (the ends of DNA), stem cells lose functionality and the organism rapidly ages, while it acquires cancer resistance. ... the lack of telomerase causes a severe defect in the fundamental functions of stem cells. ... in genetically modified mice that did not express telomerase, stem cells lost their functionality and became unable to regenerate the damaged epithelial tissue. On the whole, these mice aged more rapidly than normal mice. But, there was a very interesting side effect: without telomerase, mice showed a marked cancer resistance. ... Further experiments on telomeres structure showed that every time the shortening process is altered, the result is either 'early aging and cancer resistance' (if shortening is boosted), or 'aging inhibition and more cancer occurrence' (if shortening is reduced)."

Cellular senescence or cancer - pick one, it seems. Senescence serves as a cancer suppressing mechanism by removing older, more damaged cells from operation. These accumulating senescent cells still cause harm and contribute to age-related degeneration, but that's presently the lesser evil when compared to the level of cancer that would exist without cellular senescence.

So what is going on in this study? It seems to show that pushing off cellular senescence leads to less cancer, even though it was accomplished in much the same way as leads to more cancer in other studies. If I had to hazard a guess (as opposed to pointing out that you can't go far wrong with more research), I'd suggest looking into in vitro versus in vivo differences in cellular biochemistry. We know that a number of cellular processes can run quite differently in culture rather than in an organism; perhaps this is one of them. That is a pity, given the possibilities, but there you have it - there is no free lunch.

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On DNA Repair Mechanisms

PLoS Biology has published an introduction to DNA repair mechanisms and some of their implications. A portion of degenerative aging - not to mention cancer - is caused by a buildup of DNA damage. This is a problem that must be solved along the way to working healthy life extension medicine: "You probably weren't thinking about your body's DNA repair systems the last time you sat on the beach in the bright sunshine. Fortunately, however, while you were subjecting your DNA to the harmful effects of ultraviolet (UV) light, your cells were busy repairing the damage. The idea that our genetic material could be damaged by the sun was not appreciated in the early days of molecular biology ... it was assumed that DNA is fundamentally stable since it carries the blueprint of life. However, more than 50 years of research have revealed that our DNA is under constant assault by sunlight, oxygen, radiation, various chemicals, and even our own cellular processes."


The Long Life Family Study

The LEF News reprints a piece on the Long Life Family Study, soon to start and seeking participants: "Over the next several years, hundreds of families from Pittsburgh, Boston, New York and Denmark with multiple members alive and functioning in their 80s, 90s or beyond will be interviewed and have blood samples drawn. Researchers say it may be the most extensive aging study yet, with hopes of uncovering not a fountain of youth, but a sea of information on what contributes to healthy aging. ... Given that these individuals pan out to be models of successful aging and have abilities to escape or delay age-related disease, or escape or delay disabilities, we want to find out how they do that. And we don't believe it's because of any one single factor." Successful aging is something of a contradiction in terms, but these studies serve a useful purpose: it is still more efficient to find starting points for biochemical investigations into longevity and metabolism this way.


Towards Controlled Stem Cells

From Scientific American, news of another step towards the control - and possibly creation - of embryonic stem cells: scientists used short hairpin RNA (shRNA) "to sequentially turn on and off various genes within embryonic stem cells from a mouse. The shRNA, delivered by a virus, allowed the researchers to determine whether a given gene helped control stem cell differentiation. ... the scientists found 10 likely candidates [and] engineered versions of these genes that could be turned on and off by the presence of the drug doxycycline to uncover their specific effects. Seven of the identified genes proved to be potent regulators of a stem cell's ability to split and then renew itself. Without them, the cell rapidly became specialized, losing its unique pluripotent status."


"Anti-Aging Molecule" and the Need to Read Behind the News

You just can't follow science through the mainstream media alone; the Korea Times provides an excellent demonstration today as to why this is the case:

"All cells face an inevitable death as they age. On this path, cells became lethargic and in the end stop dividing but we witnessed that CGK733 can block the process," Kim said.

"We also found the synthetic compound can reverse aging, by revitalizing already-lethargic cells. Theoretically, this can give youth to the elderly via rejuvenating cells," the 41-year-old said.

Kim expected that the CGK733-empowered drugs that keep cells youthful far beyond their normal life span would be commercialized in less than 10 years.

Where to start on this? My suspicion is that a reporter was entirely caught up a confusion between cellular senescence and degenerative aging in people. These are two very different things, but terms like senescence and aging - meaning "degenerative aging" in common usage - have a range of more precise meanings in scientific circles:

Cellular senescence is the phenomenon where cells lose the ability to divide. In response to DNA damage (including shortened telomeres) cells either senesce or self-destruct (apoptosis) if the damage cannot be repaired. Organismal senescence is the aging of whole organisms. The term aging has become so commonly equated with senescence that the terms will be used interchangeably in this article.

It might not even be the reporter who slipped up, but rather a translator; the article makes much more sense and is far less sensational if you replace "aging" with "cellular senescence" throughout.

If you backtrack to the actual scientific paper, you'll find some interesting work on uncovering and manipulating the cellular mechanisms of senescence:

Most somatic cells encounter an inevitable destiny, senescence. Little progress has been made in identifying small molecules that extend the finite lifespan of normal human cells. Here we show that the intrinsic 'senescence clock' can be reset in a reversible manner by selective modulation of the ataxia telangiectasia-mutated (ATM) protein and ATM- and Rad3-related (ATR) protein with a small molecule, CGK733.

This is a proof of the capabilities of a fairly new system that allows far more effective and efficient insight into the workings of a cell than was possible even just a few years ago:

Kim basked in global recognition last June when he and his associates developed a technology dubbed MAGIC, short for magnetism-based interactive capture.

MAGIC uses fluorescent materials to check whether any drug can mix with targeted proteins inside the cell. The results were globally recognized by being printed by the U.S.-based journal Science at the time.

"MAGIC is kind of a source technology to see inside cells. Based on the method, we also found a pair of promising substances that can deal with cancers," Kim said.

Biotechnology marches ever onwards! By any standards, this is good science and very useful technology - but I don't see it as an immediate, direct step towards extended healthy life spans. Let me explain: an accumulation of senescence cells is a part of the aging process, and is quite possibly directly harmful in addition to cluttering up the body with inactive or oddly active tissue.

The second type of supernumerary cells, senescent cells, accumulate in quite large numbers in one tissue, the cartilage in our joints. They also accumulate elsewhere, but in much smaller numbers; however, these may still be important by being actively toxic. They aren't able to divide when they should, and they also secrete abnormally large amounts of some proteins.

However, cellular senescence serves at least one essential purpose in the body: it protects against cancer that results from age-damaged cells.

"Cellular senescence is considered an essential contributor to the aging process and has been shown to be an important tumor suppression mechanism. In addition, emerging evidence suggests that senescence may also be involved in the pathogenesis of stem cell dysfunction and chronic human diseases. Under these circumstances cells undergo stress-induced premature senescence, which has several specific features." As this review paper points out, developing a technology to turn off programmed senescence would simply result in much more cancer - the process serves an important purpose in shutting down potentially dangerous cells. The problem needs a better solution, more likely focused on convincing the body to recycle these cells rather than leaving them to degrade the performance of tissue.

Simply turning off or reversing cellular senescence is an impressive technology demonstration and teaches us more about cellular biochemistry, but it doesn't appear to me to the foundation for a viable anti-aging therapy.

As a last note, and while we're on the subject, I should point out this timely item from Medical News Today:

"Unless journalists are careful to provide basic study facts and highlight limitations the public may be misled about the meaning, importance and validity of the research", said Woloshin. For their study, the team analyzed newspaper, TV and radio stories that appeared in the US for research reports from five major scientific meetings in 2002 and 2003 to see if basic study facts (eg., size, design) were reported; whether cautions about inherent study weaknesses were noted; and if the news stories were clear about the preliminary stage of the research.

The researchers found that basic study facts were often missing. For example, a third of reports failed to mention study size; 40% did not quantify the main result at all.

Important study limitations were often missing. For example, only 6% (1/17) of the news stories about animal studies noted that results might not apply to humans. And only 2 of 175 stories about unpublished studies noted that the study was unpublished. Schwartz and Woloshin, who frequently present to the media on how to understand and accurately report research results, say that while reporters can and should do better, another reason for misinterpreted or "over-hyped" research is its early release at professional meetings that reporters are encouraged to attend.

Food for thought, no? In this day and age of a searchable internet, there's no excuse for not getting out there to verify that a reporter knows what they're talking about. A simple internet connection gives you more power than the entire research department of a 1970s major news organization - make use of it!

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Another View of What Underlies the Reliability Theory of Aging

Around the same time that the reliability theory of aging and longevity was proposed - an extension of existing tools used to determine failure rates in complex financial, electrical and mechanical systems - another paper on the interconnectivity of genes and biochemical processes, insofar as they apply to aging, was published. This was drawn to my attention by the folk at the Immortality Institute forums; I think it provides useful insight-by-comparison into the processes and connections that underly the mathematical models of reliability theory in biological organisms. Being an older paper, the full text is readily available:

The topology of genetic and metabolic networks is organized according to a scale-free distribution, in which hubs with large numbers of links are present. We have developed a computational model of aging genes as the hubs of biological networks. The computational model shows that, after generalized damage, the function of a network with scale-free topology can be significantly restored by a limited intervention on the hubs. Analyses of data on aging genes and biological networks support the applicability of the model to biological aging. The model also might explain several of the properties of aging genes, including the high degree of conservation across different species. The model suggests that aging genes tend to have a higher number of connections and therefore supports a strategy, based on connectivity, for prioritizing what might otherwise be a random search for aging genes.


The decline in physiological function observed during aging differs from that associated with disease: Taffet lists 147 major physiological parameters that decline with age in 22 body systems. Furthermore, the decline is progressive and gradual, initially affecting only physiological reserves. There is no disease that has such a widespread effect on the biological function of an organism. In diseases, some organs and functions are usually affected to a major extent and others only secondarily and in a minor way. Aging-related dysfunction has therefore special properties: it is global (because of the large number of physiological functions declining), generalized (no specific function predominates) and gradual (distributed over a considerable portion of life span). No disease possesses these properties to the same extent. We suggest that aging is the biological dysfunction where network level properties of the genes have the greatest importance. In contrast, disease-related dysfunctions are likely to preferentially involve specific portions of a biological network.


We have tried to address the following questions: Should a view of aging as a generalized process of degradation lead us to be skeptical of recent reports claiming substantial benefits after interventions aimed at single genes? Conversely, do these reports imply that aging is caused by specific genetic programs? How can we reconcile the observed conservation of aging genes among evolutionary very distant species with the prevailing non-adaptive view of aging? Can we propose a model that explains these facts and also makes testable predictions? Can we find initial evidence supporting these predictions? And, finally, can we use this model to devise a more efficient strategy for the search of aging genes?

Network analysis and reliability theory are ways of thinking about the complexities of the aging human body; tools to allow us to interact with levels of complexity that would otherwise be beyond us. Models and tools of this sort don't lead us directly to the hows and whys of aging in terms of precise biochemical mechanisms and explanations. Rather, they steer our thinking towards more effective research, consideration and debate. How important is random genetic and cellular damage to aging? Is it really random? How much more important is any one specific mode of damage over all the rest? How do we best go about enhancing our understanding of the details and importance of line items within known categories of age-related damage?

One important bottom line question relates to whether there are a small number of therapies that will have a comparatively large effect on degenerative aging at a comparatively small cost. The Strategies for Engineered Negligible Senescence (SENS) form a higher level look at this sort of efficiency concern: repair causative damage and put in place preventative measures rather than patch up the resulting problems after the fact. Within the categories of SENS science, however, lie many unanswered questions relating to efficiency: reliability theory, network analysis and similar tools are guides to the future of research and development in this field. We don't have the luxury of time - we need every efficiency we can obtain if we are to see the steps towards radical life extension take place within our lifetimes.

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Aubrey de Grey Interview Podcast

Methuselah Foundation volunteer Mark Patterson has been stepping up to the plate and getting radio show interviews with biomedical gerontologist Aubrey de Grey organized in his area. This is exactly the sort of thing I like to see - people like you or I making an effort, moving forward with advocacy and education for healthy life extension research. Via the modern miracle of podcasting, any local radio show of interest can make it into wider circulation - so go and listen to this one: "Is it possible to stop people from growing old? Dr. Aubrey de Grey of the Methuselah Foundation is one of the world's leading experts on biogerontology, the study of anti-aging. At least that's what Mark Patterson says. He and de Grey are the guests on the June 11 Wake-Up Call." You might also be interested in another podcast radio show from the same series of interviews.


Better Delivery Means Better Therapies

Via AzoNano, a glance at the proliferation of clever new technologies for targeting therapies - most notably anti-cancer therapies - to a particular location in the body. Killing cancer cells is easy, but doing it without harming healthy tissue is extraordinarily hard; one might say that this is the main hurdle to be overcome by present day research. Nanoscale manufacturing and the automation made possible by advancing information technology is leading to up to a leap in effectiveness for a wide range of present and possible therapies: "The nanomedicine work [has] far-reaching implications for a variety of disease areas, including neurological disease and cardiac disease ... Because the nanocarriers proved to be significantly stable and because they retained the PDT drugs, we are optimistic that they will be able to deliver a wide range of therapies to tumors or other disease sites in the body without any significant loss in the circulatory system or in normal tissues."


Aubrey de Grey Podcast, More on the SENS Challenge

Biomedical gerontologist Aubrey de Grey was interviewed recently for a Boston area radio show, Tech Talk With Craig Peterson. Via the miracles of modern technology, the podcast is ready and waiting for your attention:

Aubrey De Grey, a biogerontologist from University of Cambridge in the United Kingdom joins Craig to discuss the technology of regeneration and what advancements are currently taking place.

While we're here, I thought I'd also point your attention to a couple more items from the blogosphere and healthy life extension community on the SENS Challenge and related matters.

Color me confused:

So some people are going to use learned debate to prove something is unworthy thereof? Sounds a bit self-defeating to me.

What does Aubrey de Grey need to have a shot at achieving his goals?

If I understand correctly, de Grey wants one billion dollars for a decade long research program that he would spearhead in an attempt to make major progress in the war against aging. Is this correct? And I'm curious to know if list members think this is enough money and/or time to achieve his goals. Finally, what do you think the odds are that any government agency or very wealthy private individual will put forward the money so he can try to make his ideas a reality?

A good conversation is underway in the comments to this last post - you can find the answer to the first question at least at the SENS website, within the outline for the Institute for Biomedical Gerontology. This, more than the science, is the struggle we face: to raise the large-scale funding needed, and to bring into being a growing, self-perpetuating research culture and infrastructure to best make use of those funds. It is not rocket science, and has been accomplished a number of times within the past few decades for specific research goals: AIDS, cancer, Alzheimer's, for example. But it is not easy. It will require a great deal of work from a great many people - but we must achieve this goal, and soon, if we are to see radical life extension within our lifetimes.

Transhumanism: The SENS Challenge:

Three people have responded to the $20k prize for critiques of Aubrey de Grey's SENS proposal. They need to show that it is "unworthy of learned debate", which is obviously an extremely high barrier, since the very act of submitting a critique is a type of "learned debate" (i.e. the challenge is almost self-denying, in a sense). Nevertheless, it's extremely important to get critiques of the SENS plan out into the open, both so that we can learn if there are real problems with the plan, and so we can learn from those real problems. Maybe a SENS+ plan will work better?


To go to an even bigger big picture, I wish these guys would sit down with Aubrey and actually work on some kind of "SENS+" thing that they can agree is a good plan for addressing the causes of aging. Their own research is already doing this in a piecemeal way, from a roundabout disease-based direction, and you'd think that a "big picture" of the field that they can all agree on would have a beneficial effect in terms of optimizing the distribution of research efforts on a global scale. Their resistance to SENS as given should be inspiring them to make a better SENS, not to go on a pseudoscience witch hunt. I think that the general term 'anti-aging' scares them because of it's power, and that's why the field has shied away from it in the past. They need to get over their fears and accept their proper role as heroes in pursuit of an ancient human dream.

A lot of interesting opinions in there; it's a long piece, so read the whole thing. As with a number of other people, the poster doesn't think any of these challenge submissions will merit the pot - but that's very much in the hands of the judges now. Hopefully they'll be thinking along the same lines.

UPDATE 06/15/2006: I just missed another good, long set of thoughts from Anne C.

What I've read and managed to process so far of the challenge submissions, rebuttals, and counter-arguments seems to indicate that even in the scientific community (except for a noted few), the very notion of drastically extending human lives is considered to be so unfathomable as to be unworthy of true scientific consideration. One thing that struck me about the challenge submissions was the space taken up by offering definitions of pseudoscience and quackery -- definitions that are most likely understood quite readily by the average skeptically-minded armchair philosopher, and that any serious scientist would most likely have to understand in order to become and work as a scientist in the first place.

In general, this SENS Challenge exercise is proving to be very illuminating in terms of drawing out the wide range of views from folk within and without the healthy life extension community. This, I think, is a very good thing. More discussion means more support means more progress.

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Air Quality, Correlation and Causation

"Correlation does not imply causation" - repeat three times before looking at the results of any study of data. Via the LEF News, reports of a correlation between air quality and life expectancy in the US: "The findings were based on research in metropolitan areas in six states ... participants, ages 25 to 74 when the study began, were followed for a period of 24 years. Air quality improvements were matched by a proportional drop in death rates from cardiovascular disease, respiratory illness and lung cancer, the study found." I would be willing to wager that the correlation has more to do with the relative wealth of these areas and those who make the economic choice to live there, as well as access to medical technology and lifestyle choices. Things are rarely as simple as a two-parameter study casts them to be.


Continuing Growth in Life Expectancy

(From the Telegraph). Life expectancy is continuing to rise, just as one would expect from the Reliability Theory of aging and across the board improvements in medical technology: "Life expectancy in Britain has been increasing at a rate of five hours every day ... Previous forecasts of life expectancy had predicted that the rapid increase seen in recent decades would begin to level off steeply, and bump up against a ceiling, but the ageing process seems much more malleable than this. ... Biological research over the last 20 years has shown us that actually there is no strict biological programme for ageing and no set upper limit for the length of human life. It is about time people woke up to this. ... At the moment we have an extraordinarily ageist society. It is about time we recognised that people are living longer and longer." Those extra years are extra healthy years - and we could be doing far better to provide more of them.


More Oxidative Stress Research

Scientists are making progress in unraveling the complex biochemistry of oxidative stress: how it originates, how it damages our cells, how it contributes to age-related conditions. Via RxPG News, a look at recent research: "Just as humans undergo daily stress, so do our individual cells. The cellular variety, called oxidative stress, is caused by the build-up of free radicals, which over time inflict damage linked to aging and age related diseases such as Alzheimer's. [Researchers] have now defined a molecular signaling pathway by which oxidative stress triggers cell death, a finding that could pave the way for new drug targets and diagnostic strategies for age-related diseases. ... Once stimulated by oxidative stress, MST acts in its capacity as an enzyme to modify and thereby activate the FOXO proteins, instructing the FOXO proteins to move from the periphery of the cell into the nucleus of neurons. Once in the nucleus, the FOXO proteins were found to turn on genes that commit neurons to programmed death."


Embryonic Stem Cell Research Picking Up

The International Herald-Tribune notes one manifestation of a return by funding organizations and scientists to building an embryonic stem cell research infrastructure. "Scientists at two universities - the University of California at San Francisco and Harvard - will try to develop embryonic stem cells from the adult cells of patients suffering from certain diseases. Their purpose in creating the cell lines, which require making an early human embryo, is to study how the diseases develop, and to see if replacement cells can be generated to repair the patient's own degenerating tissues." Five or more years of damage have been done by anti-research politics and the unfortunate consequences of a centralized, powerful, meddling system of governance - the benefits of this research to those suffering and dying from age-related diseases will be similarly postponed. This is what happens when freedom of research is blocked and curtailed: the suffering and death continues unabated.


George Dvorsky, Glenn Reynolds on the SENS Challenge

George Dvorksy ran up a long, sensible post on the topic of the SENS Challenge today - well worth a look. He brackets some of the items I've meandered over in the past, albeit from a more skeptical perspective on the science, and perhaps a little more neatly than I managed:

First, regardless of the outcome, it is extremely important that both de Grey and SENS be put under this kind of scrutiny -- even if the contest is a tad sensationalistic. If de Grey is guilty of propagandizing pseudoscientific beliefs and establishing a cultish personality around himself - and I am not suggesting that he is - it is important that this be considered and brought to the public's attention. More importantly, however, the ad hominem that has in no small way characterized this contest has similarly got to be fleshed out and exposed; as Reason aptly pointed out in his Fight Aging review, "SENS is not de Grey." This heated debate has brought out the worst in all parties as far as I'm concerned.


To all you de Grey groupies on the edge of your seats in anticipation of The Big Decision, it's time to take a chill pill and a deep breath. The outcome of this contest will have no bearing on the work to come against the ravages of aging. A ruling by the judges against de Grey would have no bearing on anti-aging research, and would at worst cause de Grey to have to revise his strategy (or his approach). But he needs to do this anyway as SENS should at no time be considered a static document. Twenty years from now we may laugh at the naivete of SENS, but I highly doubt we'll laugh at the maturation of real anti-aging interventions that will have sprung from this seed of an idea.

When all is said and done (whatever that means), it may be that de Grey will have had very little to contribute to bona fide anti-aging advances (although I doubt that). De Grey will not cure aging by himself and any assertion that he will is patently ridiculous. The war against aging will be a concerted and protracted effort that will in all likelihood take many decades, numerous researchers and vast resources. Further, the efforts to halt the aging process will be the result of converging therapeutic interventions that will address aging related pathologies on an individualized basis. While an all-reaching overview like SENS is laudable and even practical, it will still come down to the specialists working on their focused aging related problems.

Glenn Reynolds is somewhat more concise, as usual:

They've gotten some submissions, and judges will announce their opinion next month. I predict that no prize will be awarded.

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SENS Challenge Submissions Unveiled

The next step in the $20,000 SENS Challenge is now online at the MIT Technology Review. Three critiques of the Strategies for Engineered Negligible Senescence (SENS) - the start of a roadmap to effective therapies to prevent and repair degenerative aging - and biomedical gerontologist Aubrey de Grey's rebuttals are available for consideration by the recently formed panel of judges. Good to see progress towards greater engagement and debate by the scientific community! Science is not advanced when the old guard refuses to debate new ideas and paradigms on the merits - constant, robust examination is a pillar of the scientific method. Only by widening the debate within and surrounding the scientific community can the SENS proposals be made more robust, and formed into the best possible course towards radical life extension within our lifetimes. You'll find more thoughts over at Fight Aging!


Judge the SENS Challengers For Yourself

Three qualifying submissions for the $20,000 SENS Challenge have been posted at the MIT Technology Review, along with Aubrey de Grey's rebuttals and author counter responses - a lot of reading for those interested in healthy life extension science and the progression of the Strategies for Engineered Negligible Senescence (SENS):

Last year, Technology Review offered a $20,000 prize to any molecular biologist who could prove that SENS (Strategies for Engineered Negligible Senescence), self-taught biogerontologist Aubrey de Grey's much publicized prescription for defeating aging, is so wrong as to be unworthy of learned debate. Here are the three submissions that qualified for consideration according to the terms of the Challenge. The results of the judges' deliberations (with their reasoning) will be announced on this website on July 11, 2006 and published in the July/August issue of Technology Review magazine.

It has indeed been nearly a year since the Challenge was launched; much of that time has been spent in gathering judges sufficiently noteworthy to make their judgement worth everyone's time and effort. I think that editor Jason Pontin succeeded in that respect:

Rodney Brooks, PhD, director of MIT's Computer Science and Artificial Intelligence Laboratory, and chief technical officer of iRobot Corp. IRobot is one of the most successful makers of robots in the world. Anita Goel, MD and PhD, founder and chief executive of Nanobiosym. Vikram Kumar, MD, cofounder and chief executive of Dimagi, and a pathologist at the Brigham and Women's Hospital in Boston. Nathan Myhrvold, PhD, cofounder and chief executive of Intellectual Ventures, and former chief technologist at Microsoft. J. Craig Venter, PhD, founder of the Venter Institute. Venter developed the process called whole-genome shotgun sequencing, which sped up the human genome project.

The healthy life extension community will be kept in suspense for the next month while the judges come to their conclusion and issue a response, it seems - but that should be quite long enough for us to act as our own judges on the submissions. Worthy or not? Interesting new criticisms or same old, same old? There is a great deal of debate and interpretation to be done, I can see; the regulars at the Immortality Institute forums will be getting off to an early start on that front, as usual.

As I've said before, constant criticism, reexamination and debate on the merits is vital to the scientific method. You don't advance science by indulging in the all too human folly of building your castle for keeps, and refusing to accept shifts in paradigm and knowledge that render your ideas obsolete - science moves too fast for that. If you're not tearing down as much as you're creating, you're holding up the train.

Until very recently, all too many gerontologists and other scientists - and funding organizations, and people like you and I - have been holding up the train. They've been hanging on to the old paradigms, they've been refusing to open up to new ideas that might require work and thought; that aging is not actually a medical condition; that aging cannot be addressed; that we shouldn't repair aging because it is natural; that we do not know enough to get started; that intervening in the aging process is not worthy of scientific research; that extending life would extend frailty; that overpopulation would result; that more life would be boring. All wrong, all nonsense! But even obviously erroneous consensus views change painfully slowly, even with the hard work of advocates within and without the scientific community.

The $20,000 SENS Challenge is one of many efforts to bring on an era of large-scale, effective, scientific anti-aging research by raising awareness, educating scientists and the public, and widening the debate. With more support and more scientists engaged with the concepts of SENS, the prospects for funding and progress rise. With more funding, more work is accomplished and more attention gathered - the process will snowball into a research infrastructure and community to rival the size and dedication of cancer research. If we keep at it.

But back to the submissions; I'll do no more that give a summary of my impressions at this point. There will be plenty of time for more later, and de Grey's rebuttals comprise a far more effective point by point that I could muster in any case.

Firstly the longest, from Preston Estep and collaborators. He and de Grey have exchanged views in public before, but this group submission is more in the way of a personal attack than a scientific criticism, I think. A pity, because Estep is clearly capable of better. He has become quite virulantly opposed to SENS over the years; I suspect this has to do with the characteristic suspicion of any form of publicity within the scientific community. In any case, Estep attempts to cast SENS as pseudoscience, un-science, or a cult of personality, thereby setting himself a very high bar at the outset. SENS is not de Grey; as noted here at Fight Aging!, SENS science is taking place in an incidental fashion - in the service of seeking cures for specific age-related conditions - in laboratories around the world. The last SENS conference attracted intelligent, aware, A-list researchers in many related fields. I think it's clear that Estep can't make this case:

Estep et al.'s Challenge tactics centre on repeating the word "unscientific" as often as possible in the apparent hope that this will render the judges oblivious to the complete absence of substance in their submission. Particularly incongruous is their accusation that I use the media to skirt expert criticism, when the SENS Challenge itself is my most conspicuous effort to do just the reverse, exposing the public reticence of SENS's off-the-record detractors and thereby forcing them to make their supposed case in print. Their summary consists entirely of claims of their own scientific infallibility, aspersions on my methods and credentials, and blurrings of the distinctions between the methods of science and of technology.

Weinstein's submission is a much more constructive attempt, but varies between a reliance on niche theories to errors of logic and understanding, insofar as I understand it. Again, you will see the very characteristic suspicion of publicity - an engrained and time proven defense mechanism within the scientific community. In this case, as de Grey has made clear on numerous occasions, publicity is the tool by which the community can be convinced or compelled to debate new paradigms they are choosing to ignore. Irrespective of this, the errors of understanding rather doom the attempt, I think:

Weinstein's challenge to SENS rests on three main assumptions, each extremely speculative or simply inconsistent with current knowledge. Moreover, all he attempts to infer from those assumptions is that SENS will fail in its ultimate goal, namely to defeat aging completely. This conclusion clearly fails the test demanded by the SENS Challenge, which is to argue that SENS is so laughable that it should not even be discussed: if SENS could realistically confer, say, a few decades of additional healthy life on those already in middle age before treatment begins, then it would indisputably merit intense discussion and research, since that degree of postponement of aging far exceeds the efficacy of anything else currently in prospect.

The submission by Charles Mobbs is, I think, the most useful of the set, as it illustrates a fundamental misunderstanding that might be more widespread than I would have imagined. From early on:

treating symptoms, rather than causes, is about the most brain-dead therapeutic approach imaginable. Should a patient [develop] a web based campaign to promote treating symptoms rather than causes of disease, physicians would not likely take time away from treating patients to publish a detailed critique of the joke. Unless, of course, the patient develops a following large enough to land him in the pages of Technology Review. Then attention must be paid.

So it is with SENS. The SENS strategy to treat symptoms rather than causes of aging has obvious and numerous flaws, any one of which would doom the strategy to failure

I think we're all in agreement that intervening in causes is a good deal more efficient and effective than patching up the end results. But SENS is precisely a plan aimed at causes, is it not? From the rebuttal:

the symptoms of aging (age-related diseases and debility) are not targets of SENS: rather, SENS targets their accumulating and initially inert precursors ("damage"), including indigestible molecules, mutations and changes of cell number. Those are in turn caused by metabolism itself, but that does not mean metabolism should be our sole target: just like a car, the human body needs maintenance (repair of ongoing damage) as well as a robust design (to resist such damage), and improving the design after manufacture is far harder than maintenance.

It would never have occurred to me that folk would take SENS as a collection of approaches for symptoms; I suppose this might arise from the strong bias in the mainstream towards approaches to slow aging by manipulating metabolic processes and thereby reduce the rate at which cellular damage accumulates. Engineering a more robust design, in other words. But without the capability to repair damage, better designs for metabolism will be largely ineffective in the grand scheme of things - we'll still be suffering and dead all too soon - and certainly far more inefficient. A thought experiment: in the absence of a toolkit and repair shop, how long can you keep a Model T Ford running versus something right off the assembly line in Japan today? It's the repair capabilities that will determine our healthy life spans; repair is not treating symptoms, it's the more important form of prevention.

But enough for the moment; I've barely scratched the surface, and there will be other folk to weigh in with opinions and novel ideas. It think it's telling to see the scientific community building a fort for dearly-held but dramatically wrong ideas from the twin strategies of refusal to engage and personal attacks on those who try to draw them out. Human nature is human nature - some things never change.

Until they do, that is. We're changing the way in which the world looks at serious, scientific anti-aging research. You are too, by reading this and talking on the topic with your friends and colleagues. Here's to a better world, with better medicine and longer, healthier lives!

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More Possible Eye Regeneration

(From EurekAlert). Researchers are consistently finding that tissues thought not to regenerate do, in fact, have some capacity for regrowth. Modern biotechnology can then be turned to make "some" into "a lot": "scientists conducting experiments with mice have found evidence that the body naturally replenishes small amounts of cells in the eye essential for healthy vision. The finding may shatter the belief that a cell layer vital for eyesight called the retinal pigment epithelium, or RPE, is a nonrenewable resource ... What this tells us is for problems such as age-related macular degeneration, we should be able to harvest stem cells to help repair the damage ... In people, retinal pigment epithelium can become damaged with age. ... The problem is without these cells, the rods and cones - our primary cells for vision - die. If we can regenerate the retinal pigment epithelium, it could make a big difference in our visual health."


A Glance at the Roots of Biotech Progress

The cost and speed of of DNA sequencing and synthesis is a baseline metric for progress in biotechnology. An article in the latest Scientific American illustrates a good point: these fundamental technologies are to bioscience as laying out circuitry was to computing - and as ripe for a revolution in standardization, effectiveness and efficiency.

As ever less money and time is required to experiment with DNA, we'll see ever more good science accomplished. We are not far from an era of garage biotechnology, of a million eyes looking at compelling problems in medicine - such as the root causes of aging and how to prevent them - and startups by the thousands.

Some calibration points for continuing progress can be found in a recent article at the MIT Technology Review:

It's about reducing cost at a reasonable accuracy. Right now the cost of synthesizing a base [using conventional technology] is about 10 cents. That's the current street price for raw oligonucleotides. For synthesizing simple genes, it's more like $1.30 a base. [Our method] can manufacture oligonucleotides at .01 cent per base.


The implications are that we are getting closer to being able to arbitrarily "program" the millions of base pairs in microbes or billions of base pairs in plants and animal genomes similar to the way that we program computers.


I think what is affordable -- and remember, this is a lifetime expense; your personal genome will hopefully last you 80 years or more -- is $10,000. If I can save $100 on average a year, it is a no-brainer. That's the cost of a couple days of missed work, or one diagnostic test that can be put off due to low risk, or avoiding bad choices on a year's worth of drugs. Then the question is, how much of a person's genome can we sequence for $10,000? Seven thousand dollars will buy you a million base pairs of DNA [using conventional technology], which is one-6,000th of your diploid genome. Not very much.

Polony sequencing [a method developed by Church and colleagues] is about a hundred times less expensive. So you can sequence about 1 percent of the genome [for $10,000]. That's not bad. You could focus on likely places you're going to have problems.We got a factor-of-ten improvement in the last six months, so if we could get another 10 percent improvement in the next year, that would give us 10 percent of the genome. If we could pick 10 percent of the genome for which we have lifestyle, nutritional, or synthetic solutions, that would be a good deliverable for a $10,000 investment. And it will just get better from there.

Interesting stuff. We're heading for a real influx of information; vast, ever-growing databases that will dwarf everything known today about human biochemistry and systems. How will the scientific community - soon to extend out to everyone with $10,000 in the bank, a good idea, and the will to research - and its tools develop to manage and make sense of this vast complexity?

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Interesting Fly Longevity Research

EurekAlert brings us interesting research in flies: scientists "showed in 2003 that boosting the amount of a molecular signal known as JNK in a fruit fly allows the fly to live 85 days instead of 60, by spurring the fly to defend itself more aggressively against the oxidative stress that accelerates with aging. ... While scientists knew that JNK in a fly cranks up the anti-oxidants, helping to keep the integrity of genes and proteins [intact], few had considered that simply boosting the amount of JNK could have such a broad impact on life span. ... JNK targets the same protein as the widely studied insulin receptor, central to human health and to the disease process that underlies diabetes ... We're learning that an organism's life span may not be limited by design. It was once thought that people and other organisms could simply live only a certain number of years and that's it. Instead, our genes play a crucial role in determining and adjusting how long we live. Can we control this process more fully?"


Tissue Engineering Heart Tissue

Via ABC Online, a look at one strategy to build three-dimensional tissue structures: "It involves combining the expertise of biologists and chemical engineers, particularly where we mix cells and scaffolds together and implant them in the body where they grow and mature and develop into specific tissues. ... this essentially is an empty box into which we implant a blood vessel using microsurgery techniques. ... we use microsurgery to create this environment and we mix cells inside this chamber and we let them grow according to the specific environment that we can create. Now, currently we have been able to make breast tissue, fat, muscle, pancreas tissue that secretes insulin and we have also created thymus tissue, which may have an application in immunology. ... There is an artery in it that keeps this alive, but the heart cells are actually beating at their own rhythm."


Primary Aging Versus Secondary Aging

It was with some pleasure that I noticed the phrases "primary aging" and "secondary aging" have lately worked their way into the wider science press. I think this demonstrates that the public conversation about anti-aging, longevity research and strategies such as calorie restriction has advanced to the point at which more precise and careful language is needed - which means more people are talking, thinking about the topic, and asking sensible, intelligent questions.

Primary aging is the gradual - and presently inevitable - process of bodily deterioration that takes place throughout life: the accumulation of biochemical damage that leads to slowed movements, fading vision, impaired hearing, reduced ability to adapt to stress, decreased resistance to infections, and so forth. Secondary aging processes result from disease and poor health practices (e.g. no exercise, smoking, excess fat and other forms of self-damage) and are often preventable, whether through lifestyle choice or modern medicine. The two categories are somewhat fuzzy at the borders by these definitions; we hope that advancing medical and biotechnology will move the known and understood aspects of primary aging into the secondary aging category as rapidly as possible.

A paper from back in 2000 - an eternity ago in biotechnology development - still provides a good indication as to the present day position within mainstream generontology:

Nothing has been demonstrated to slow or reverse the primary aging process in humans; instead, the factors that are known to affect longevity do so by their influence on disease development, which is part of secondary aging. Preventive strategies against secondary aging are aimed at maintaining health and functional capacity and rectangularizing, rather than extending, the survival curve.

The main development in recent years is the growing acceptance amongst the mainstream that primary aging can be tackled, effectively and soon, and the start of a cultural transformation that will see longevity research no longer the instant death third rail of grantsmanship.

If you look at my Longevity Meme piece on anti-aging science and medicine, you'll see that a confusion - deliberate or otherwise - between primary and secondary aging is at the root of much of the conflict between business and science (and between reputable businesses and shysters). One can hope that the reputable end of the anti-aging marketplace takes the opportunity offered by a more sophisticated cultural conversation on longevity and aging to more accurately position their products ... but I'm not holding my breath there.

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John Holloszy on Calorie Restriction

The MIT Technology Review recently interviewed researcher John Holloszy: practitioners of calorie restriction [CR] are "are powerfully protected against the diseases of old age, such as heart disease. They have low levels of cholesterol and triglycerides and extremely low blood pressure - similar to a young child, around 100/60. As a result of the low blood pressure, they have less strain on the arteries, which are much more elastic than usual for people of their age. Their hearts resemble the heart of a person 17 years younger. They also have very good insulin sensitivity, so they are not going to get Type 2 diabetes. ... As we get older, we get an increasing amount of inflammation, which is probably a very important part of the aging process. [CR practitioners] have very low levels of inflammation. C reactive protein, for example, is a marker and cause of inflammation. An average value for a middle-age person is about 2.5; but [CR practitioners] have levels of 0.2. It's just amazing."


Engineering Bone Growth

Researchers at HHMI are working on another way to stimulate bone growth - a potential strategy to treat osteoporosis: "slightly increasing the activity of a protein called NFATc1 causes massive bone accumulation ... Mice with the hyperactive NFATc in their osteoblasts had an immense increase in bone mass compared to normal mice, suggesting that the balance between bone formation and breakdown had tipped. ... The results were dramatic, yet the molecular alteration is very, very minimal ... NFATc1 in the mice that developed extra bone mass was only 10 percent more active than it is in normal mice. ... If you could find a small molecule that would flip 10 percent of the existing NFATc into the active form, you could favor the formation of osteoblasts and make stronger bones."



"Shortgevity." It's an interesting coinage; with no outside reference, I'd take it to mean what people are attaining for themselves by a) failing to take care of their health in the here and now and b) failing to support and nurture the future of anti-aging research. The coiner has something a little more geopolitical in mind, however:

"Health and longevity create wealth," according to Butler, who recently keynoted the University of Indianapolis Center for Aging and Community's (CAC) annual conference on Managing the 21st Century Workplace. Nations characterized by "shortgevity" - nations with low life-expectancy rates - are impoverished, unproductive, and unstable. They drain the world economy. Nations characterized by high life expectancies, however, are wealthy, highly productive, and stable. They fuel the world economy.

I think the implication here is precisely backwards. In fact wealth - in the broadest sense of the term - fuels longevity. Only with wealth can sufficient resources be directed to luxuries such as research and medical infrastructure to extend healthy life spans. There is likely an element of negative feedback in this picture; once you're in a position of shorter longevity, it is harder to get out. But it can't be that hard, because cultures through the world and history have managed it time and time again, and in a very short span of years.

The roots of wealth and prosperity are deceptively simple: strong property rights, the rule of law and as little government as humanly possible. Lives are short in the poorest nations precisely because the inhabitants are poor, and they are poor not for lack of trying to be otherwise, but because their politicians, despots and political culture are even more destructive, ignorant and rotten to the core than our own.

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On Parkinson's As Faster Aging

A slightly different take on recent research into Parkinson's disease and mitochondria can be found at the Daily Progress: "In one sense, the disease may represent a premature aging of the nervous system ... In aging, what happens over time is the rate at which you produce oxygen free radicals exceeds the rate at which you can detoxify them ... for some reason, he said, people with Parkinson's have more damage from free radicals ... Bennett hopes that as he learns more [he] can begin to test a drug that would absorb the free radicals in the neuronal mitochondria and stop the damage they cause. He also hopes to develop a way to test mitochondrial damage in other tissues or cells, such as in blood platelets, to come up with an earlier way to test for Parkinson’s. The disease can only be diagnosed currently when symptoms begin to appear, which Elliott said occurs after 70 percent to 80 percent of the dopamine cells have already been lost."


Back to Aging by Gender

A Newswise release delves back into the whys and wherefores of gender differences in life span and aging: "It has been widely assumed that men age earlier than women, as evidenced by their higher mortality rates and shorter average life spans. But [researchers] contend that the opposite is true. ... theory and data suggest that females begin to exhibit signs of physiological decline earlier than males, and that higher mortality figures are not necessarily correlated with the rate at which we age. ... There is also the physiological cost of testosterone, which suppresses the immune system and results in higher death rates among males due to infectious diseases and cancer. During the evolutionary history of our species, few individuals lived long enough to express genes that cause physiological deterioration late in life, so those genes had little effect on fitness and there was little natural selection to remove them. ... Getting old, falling apart and dying is not an adaptive trait. It evolves because of a lack of natural selection."


MPrize for Anti-Aging Research Passes $3.5M in Cash and Pledges

Good news from the Methuselah Foundation: Ali-Reza Anghaie, the newest - and 92nd - philanthropic supporter of anti-aging research to join The Three Hundred, has pushed the MPrize fund total of cash and pledges past $3.5 million. Congratulations to all the past and present donors for another impressive goal reached!

If you're a science journalist or researcher working with mice and potential longevity science, the MPrize for anti-aging research is becoming increasingly reputable and increasingly hard to ignore. That will only continue as the funds roll in.

I should note that the $3.5 million in the prize fund is in addition to more than half a million dollars in expense and LysoSENS research contributions from generous donors worldwide. People want to see progress in serious, mainstream, scientific efforts to to produce effective therapies for age-related degeneration - and here is the proof of that.

At this rate it isn't going to be too much longer before I start reminding folk that The Three Hundred really is limited to 300 donors - the first 300 visionaries of ordinary means with the courage to change the world for the better. By taking a stand and placing your name squarely in favor of longer, healthier lives and better medical science, you lay the foundations for more five and six figure donations to the cause. Somewhere out there, another million dollar donor is pondering whether or not to take the plunge! You can help make this happen - and all for the cost of a coffee a day.

Remember: the future of your health and longevity is what you make it to be. The only viable way forward is to lend your support to research that will lead to longer, healthy lives for all.

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Update on Myostatin Gene Therapy

It wasn't all that long ago that scientists linked myostatin to muscle growth, and started to think about therapies for age-related muscle loss and injuries. Here, more news on that research via EurekAlert: "researchers injected mice with a gene therapy vector containing myostatin propeptide - a protein that blocks the activity of the muscle-growth inhibitor myostatin - three weeks prior to experimentally damaging the mice's skeletal muscles. Four weeks after skeletal muscle injury, the investigators observed an enhancement of muscle regeneration in the gene-therapy treated mice compared to the non-gene-therapy treated control mice. There also was significantly less fibrous scar tissue in the skeletal muscle of the gene-therapy treated mice compared to the control mice. ... we expect that gene-therapy treated cells will continue to overproduce myostatin propeptide for at least two years."


On Premature Cellular Senescence

How much of degenerative aging is due to the acculumation of senescent, no longer functioning cells? More in some tissues than others, such as skin, it seems. "Cellular senescence is considered an essential contributor to the aging process and has been shown to be an important tumor suppression mechanism. In addition, emerging evidence suggests that senescence may also be involved in the pathogenesis of stem cell dysfunction and chronic human diseases. Under these circumstances cells undergo stress-induced premature senescence, which has several specific features." As this review paper points out, developing a technology to turn off programmed senescence would simply result in much more cancer - the process serves an important purpose in shutting down potentially dangerous cells. The problem needs a better solution, more likely focused on convincing the body to recycle these cells rather than leaving them to degrade the performance of tissue.


More on Arguments for Anti-Aging Research

Of late, the healthy life extension community seems to be spending a fair amount of time and ink discussing biomedical gerontologist Aubrey de Grey's persuasions and ethical or moral arguments for all-out, fast as possible, large-scale anti-aging research. I'm all for that - the more people thinking about healthy life extension and what we have to do in order to develop meaningful anti-aging technologies in our lifetimes the better. It all adds to the background level of education by osmosis and support for progress in extending the healthy human life span ... and we certainly have a long way to go yet in raising that level.

Still, it's reassuring that I see ever more common sense and educated awareness on healthy life extension in the blogosphere as time moves on, such as this one on last year's unfavorable (and widely attacked) Nuland article:

The author, Sherwin Nuland, is pretty down on de Grey's philosophy of life extension. He seems to view it as unnatural and socially disruptive. However, Sherwin himself is a medical doctor, in fact a surgeon who has "cared for around 10,000 patients" according to the article. He never explains why his own contributions to "life extension" are so much more virtuous than de Grey's.

All of Nuland's arguments against de Grey can be used as arguments against modern medicine. If extending the maximum life of one man from 100 years to 1000 is a crime against nature, surely handing out penicilin makes you the equivalent of an eco-hitler. Or vaccinating people's kids against smallpox. The list goes on and on.


As for myself, I would be happy to live to be 1000, given a certain minimum quality of life. I'm not sure if I'm up for eternity, but I certainly want more than just a century.

But back to the discussion of moral and ethical arguments for healthy life extension. If you found Russell Blackford's thoughts on the matter interesting, you'll probably also want to read Anne C.'s long, long post that uses Aubrey de Grey's presentation at the IEET Human Enhancement Technologies and Human Rights conference as a starting point:

There is a considerable degree of cognitive dissonance required to maintain a respect for life and at the same time, an opinion that death and frailty should be forced upon people when there might be a means to prevent these things


Dr. de Grey makes the case that by not acting with vigilance and haste toward medically addressing human sensescence, we are committing a moral transgression rooted in inaction. In short, Dr. de Grey applies the "bystander effect" hypothesis to issues associated with aging treatments; if it is possible to act, and people die due to the fact that those who could act refuse to do so, then these people are in a sense accountable for the deaths that occur.

Now, I think it is quite possible to take this "bystander effect" observation to a ridiculous and paralyzing extent; I actually have a bit of a problem with this "inaction is negative action" line of reasoning unless one assumes that the circumstance requiring action is the most important circumstance in observable reality. This, of course, is impossible to determine. As far as I am concerned, all involuntary deaths are tragic, regardless of whether these deaths occur when a person is 9 or 90 (or 900)! Even the fact of potential overpopulation doesn't make involuntary death any less horrible -- while I do not deny that overpopulation is a practical issue in need of being seriously and rationally addressed, I think that humans as supposedly rational beings ought to be able to come up with a better solution than condoning the deaths of scores of innocent people.

I should say that I view these sorts of events somewhat warily; you might want to read Ronald Bailey's comments on the conference for some of the reasons why. On the one hand, there is a strong subcultural bias towards talking rather than doing - a worldview in which making rules and inventing reasons to slow down progress in medical science is valued more highly than the hard work of creating a cure. On the other hand, you have the willful embrace of socialism and centralized control, the use of force to enact policy, and other strategies that destroy freedom, choice and the ability to create wealth and progress. As usual, this all drags along the sad array of attendant memes, such as opposition to free markets and property rights, a liking for large, meddlesome government, and the economic ignorance necessary to hold the other ideas in mind without cognitive dissonance. A pro-progress socialist is a runner with one leg shackled to the starting line - the terrible fates and utter poverty of those trapped within the Soviet Union should more than adequately demonstrate this fact.

But I digress. Most people in the Western world are pro-socialism; we'll hear more of these views as the healthy life extension community grows. I think it's unfortunate that so much effort is spent propping up and fighting for the reigns of a societal order that is so clearly corrupt, unethical, dangerous and wasteful.

This morass is why I largely prefer to focus on getting things done rather than sinking into the swamp of ethics discussions. The future is not going to make itself - we need to step up and make sure tomorrow is the sort of day we'd like to see.

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The Life Lost to Excess Fat

The Life Extension Foundation News quantifies the life - and health - lost to even a modest amount of excess fat: "Simply put, overweight people die younger. On average, they lose as many years to their excess weight as smokers lose to their cigarettes. It stands to reason, doesn't it? With all the health problems that we know are caused or worsened by excess weight, it is to be expected that those who carry an excess would die sooner than those who don't. ... Dutch researchers studying Americans found that there's a lot to lose for those who don't lose their extra pounds. ... Among those subjects who were overweight but not actually obese, the study showed that 40-year-old female nonsmokers lost 3.3 years of life due to their excess weight. In this weight class, the 40- year-old male nonsmokers lost 3.1 years of life expectancy." This is in addition to the life lost because you are not practicing calorie restriction, and the costs of suffering age-related disease - it all adds up, and could be avoided.


Viral Gene Therapy Squashes Cancer

Impressive progress is being made with gene therapies in the laboratory, as demonstrated by this item from EurekAlert: "researchers have used gene therapy to either completely abolish or significantly inhibit tumor progression in a mouse model of ovarian cancer ... They treated some of the mice immediately with a genetically engineered vaccinia virus containing a gene coding cytosine deaminase, a suicide gene, and delayed treatment of other mice for 30 or 60 days. ... The researchers found complete inhibition of tumor growth in the mice that were treated immediately with gene therapy and significant tumor inhibition in the 30- and 60-day delayed treatment mice." Scientists can now target abnormal cells with great specificity based on their biochemistry, but the real economic barrier for this sort of treatment is the enormous variety in that biochemistry for cancer cells.


Never Too Late For Exercise

EurekAlert delivers another pointed reminder of the necessity of exercise for healthy longevity. Calorie restriction may be strictly better, but you're only hurting yourself by not keeping up with the exercise: "Continuing to lead an inactive lifestyle leads to a gradual decline in many important markers for cardiovascular health. ... The good news is that a small amount of physical activity can make a big difference in reducing the risks for developing such conditions as heart disease, stroke or diabetes. Our findings demonstrate that while the cost of choosing a sedentary lifestyle can be high, switching to an active way of life can be beneficial at any time." You only have the one shot at living healthily into the era of meaningful anti-aging medicine - why risk missing out on a long, exciting future by failing to keep up with the health basics today?


On Hormesis and Healthy Longevity

Via the Life Extension Foundation News, a short article on hormesis and its effects on our health and longevity. As for so many complex aspects of our environment and biochemistry, researchers presently know too little to offer specific recommendations: "Small doses of 'stressors' normally considered dangerous to health can actually boost the body's self-repair system, and as a side-effect preserve youth, experts believe. ... In recent years, it has been shown to extend lifespan in yeast, fruit flies, worms and rodents. If the results of such studies also apply to people, it means hormesis could extend average human lifespan to 90. Average lifespans in the UK are now around 75 for men and 80 for women. Stressors seem to kick-start natural repair mechanisms, including the enzymes that patch up damaged DNA. As the repair systems fix damage normally caused by ageing, the body is rejuvenated. ... Exercise and calorie restriction may both promote longevity partly through the stress they cause."


Returning to the Moral Imperative to Develop Working Anti-Aging Medicine

Do we have a moral imperative to step up to the plate and help develop medical technologies to prevent and reverse the root causes of age-related degeneration? Russell Blackford has been considering this of late; I jumped straight to the (libertarian) answer to the question in a post two weeks ago. Blackford took the much longer, more scenic route in a series of later posts, but I think the destination is much the same, albeit with a different take on the meaning of the journey.

Anti-aging, again:

I do not intend to deny that contributing to anti-aging research is morally praiseworthy, or even that it may turn out to be morally obligatory in current circumstances when all facts are known and all things finally considered. It's just that the nature of any moral obligation has not been demonstrated to be of the same high (if less than absolute) order as the obligation to avoid murdering other human beings. Thus, the force of any such obligation might need to be weighed against other claims on resources, possible unwanted side effects, and so on. Anti-aging research may still be worth paying for through the tax system, but a quite different sort of argument will have to be made as to why this is good policy in the whole range of circumstances that now confront us.

Apart from the sheer intellectual stimulus involved, it gives me no great pleasure to criticise particular arguments in support of funding for anti-aging research, because I am actually in favour of such funding. However, it looks to me right now as if arguments that attempt to establish an overwhelming moral obligation, similar to the obligation not to murder, are doomed to failure. The problems I've identified above will probably affect all arguments of that kind.

If I'm right about that, advocates of anti-aging research may have a more arduous and less palatable task than is immediately apparent. It will involve facing questions about whether human desires to resist aging, and preserve youthful health and robustness, are rational, and whether they are worthy of being satisfied for their own sake. My claim is that these desires can, indeed, survive scrutiny, and that it takes an unattractive, if not uncommon, kind of puritanism to want to deny them. Bioconservative moralists of the left and right, who typically dismiss such desires as narcissistic or hubristic, are on shaky ground. However, making out this case will require a different style of argument.

Of course, we libertarians can simply skip over the "justify your existence" stage of using our own resources in ways that cause no harm to others. The only justification you should need is the one you use to convince yourself. The biggest problem with modern society is all those folk who have come to think that an opinion is in fact a veto...

But onwards: you should read all of these posts from Blackford, since the excerpts really don't do justice to the breadth and length.

More thoughts on killing and life extension

Assume for the sake of argument that failing to provide the general population with an immortality drug, if one became available, could be considered equivalent in some sense to killing the individuals who are so deprived. Even if we get to that point, it is not clear that this sort of killing would be morally wrong. It depends on what would be the actual effect of having a population of people who use an immortality drug. If the outcome would be some kind of disastrous conflict for resources, or some kind of widespread, catastrophic unhappiness, withholding the drug might be justified. Bioconservatives such as Francis Fukuyama who evidently expect dreadful outcomes are being rational, in their fashion, in claiming that society and the state are morally entitled to tell us how long we may live.

Of course, it is a shocking kind of rationality. I immediately want to add that the last thing I want to do is join Fukuyama in handing such a power to the state - any state, no matter how democratically accountable. To be clear, I am suggesting that there is no absolute right to an immortality drug, even if we had one, or for some more plausible "cure for aging". But at the same time, I want to stress what kind of argument has to be run if there is to be an intellectually credible case against technologies that would extend human life.

What do I get out of this?

As I've been writing about life extension, a cure for aging, etc., over the last few weeks I've been struck (again) by the fact that I personally am now too old to have much prospect of benefiting from any truly radical technological breakthroughs that would greatly extend human capacities or the maximum human life span.

It's good to be realistic - many people in the healthy life extension community are too damn optimistic about their prospects, leading to a lack of activity and support. But I think Blackford swings too far in the opposite direction here, underestimating what could be accomplished and made economically feasible for you and I over the course of the next three to four decades. We are indeed at the beginning of a biotechnology revolution to match the information technology revolution of the past 30 years - but it is up to us to ensure that this revolution delivers the goods.

Watching from the sidelines isn't good enough - all that will get us is the privilege of being the last generation to live and die on an old-school timescale. If you want a better future, then get up and do something about it!

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Exploring the Cancer-Aging Link

EurekAlert shows one of many ongoing investigations into the biochemical roots of the relationship between aging and cancer: "Proteins which prevent cancer in humans by ensuring that cells don't divide if they have chromosomal damage have been shown to determine lifespan in the nematode worm C. elegans. ... checkpoint proteins, traditionally thought only to be functional in cells that divide, are also active in cells that no longer divide. The fact that the proteins appear to have dual functions opens a new way to study the connection between aging and cancer.
... variations in checkpoint proteins in humans may place some individuals at risk for cancer, but protect them against other age-associated diseases; or conversely, set a genetic course for a shorter life which would be free from cancer. ... We think there are many more checkpoint proteins - in worms, in complex animals, in humans. Some may be more attractive than others for developing therapies for cancer and aging."


Longevity Meme Folding@Home Group Hits Rank 300

The growing Longevity Meme Folding@Home team have worked their way up past rank 300 - congratulations all round!

Running the Folding@Home software in the background on your PC is one of the easiest, most effortless way you can make a lasting contribution to medical research - alongside donating to the MPrize for anti-aging research, of course. The study of protein folding via distributed computation helps to advance Alzheimer's and Parkinson's research, amongst others:

Alzheimer's disease (AD) is caused by the aggregation of relatively small (42 amino acid) proteins, called Abeta peptides. These proteins form aggregates which even in small clumps appear to be toxic to neurons and cause neuronal cell death involved in Alzheimer's Disease and the horrible neurodegenerative consequences.

We have many calculations being performed on AD. Our primary goals are the prediction of AD aggregate structure for rational drug design approaches as well as further insight into how AD aggregates form kinetically (hopefully paving the way for a method to stop the AD aggregate formation).

As you may recall, I sent around some momentos when the team hit rank 500 last year. I'll do it again at rank 200, so consider that an incentive and challenge - sign up for the team and get folding for better biotechnology and medical science!

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35th AGE Annual Meeting Starts

As Kevin Perrott notes, the 35th American Aging Association (AGE) annual meeting gets underway tomorrow. "The broad theme selected for the AGE 2006 meeting is Interventions in Aging and Age-related Diseases: The Present and the Future. ... The first day is comparison of caloric restriction (CR) in model organisms which I think will be a very helpful in integrating what is known about CR into a more coherent picture of what it might mean for its effectiveness in humans. There are more than a couple of Mprize researchers making presentations so it should be particularly interesting. Day two is focusing on the role of mitochondria in aging and the mechanisms behind sarcopenia and osteoporosis. Day three continues in the same fashion of discussing the physiological basis for aging syndromes of the skin and immune system. ... All in all another busy weekend of information sharing and some great opportunities to talk with some of the major players in aging research today."