As scientists learn more, all organs will become open to engineered replacements. From EurekAlert!: "urothelial cells [are] the specialised lining cells of the bladder that enable it to retain urine. The cells have a very low turnover rate, but scientists have found that if the bladder is damaged, the urothelial cells are able to rapidly re-grow to repair the wound. The researchers hope to harness this property to engineer new bladders. ... researchers have developed a series of models that mean they can study human urothelial cells in the laboratory. Of these models, the most important is their development of a urothelial cell sheet that functions as it would in the bladder. When the researchers create a wound in this model, the cells regenerate to repair the damage - just as they would in the body. Pharmaceutical companies should soon be able to use the research models to test therapies for the bladder, but the longer term aim for this research is to help patients who have lost bladder function or have had all or part of their bladder removed because of cancer. ... Our most exciting work moving forward is to develop natural and synthetic biomaterials that could be combined with regenerating urothelial cells. This has the potential to produce viable bladder tissue for transplant."
EurekAlert! reports on one line of work in regenerative medicine for the eye: "A special type of cell found in the eye has been found to be very important in regenerating the retina in zebrafish and restoring vision even after extensive damage. ... scientists believe they may be able to use these cells - known as Muller glial cells - to regenerate damaged retina in humans, according to a study published this month in the journal Stem Cells. ... researchers were able to develop the cells in vitro into all the types of neurons found in the retina. When tested in rat models with diseased retinas, the cells migrated into the retina and took on the characteristics of the surrounding neurons. The researchers are now looking at developing this approach for use in the human eye. In addition to growing the cells in the lab and transplanting them back into the eye, the researchers are looking at ways to stimulate growth and persuading the eye to repair itself using its own cells. ... Although Muller glial cells are present in the human eye, it is not clear whether they already automatically repair the retina in some people but not in others. It is possible that internal mechanisms exist in the normal adult retina that prevent these cells from dividing and replicating. ... Our next step is to identify which factor is responsible for blocking the regeneration."
An interesting paper on aging in bacteria illustrates some of the present thinking on the evolutionary roots of aging; in this case, that aging seems to be an inevitable consequence of the cellular model of life.
Aging refers to a decline in reproduction and survival with increasing age. According to evolutionary theory, aging evolves because selection late in life is weak and mutations exist whose deleterious effects manifest only late in life. Whether the assumptions behind this theory are fulfilled in all organisms, and whether all organisms age, has not been clear. We tested the generality of this theory by experimental evolution with Caulobacter crescentus, a bacterium whose asymmetric division allows mother and daughter to be distinguished.
Our results confirm that late-acting deleterious mutations do occur in bacteria and that they can invade populations when selection late in life is weak. They suggest that very few organisms - perhaps none - can avoid the accumulation of such mutations over evolutionary time, and thus that aging is probably a fundamental property of all cellular organisms.
You might recall that aging in bacteria was demonstrated back in 2005; previously it was thought that bacteria might be effectively immortal. This hypothesis of aging as an inevitable consequence of evolution in cellular life versus present studies of those forms of cellular life that might be immortal will make for good science in the decades ahead - but it is largely irrelevant as to how aging in humans proceeds from here on out. Evolution's days are all but over, and the invisible hand of the market will take over as technology enables individual humans to shape themselves rather than be shaped.
When people can choose between degenerative aging or no degenerative aging, I imagine there won't be a great deal of degenerative aging in the world - much the same as for the smallpox/no smallpox choice that became available in recent times, for example.
Via EurekAlert!, another look at the potential to use cellular senescence as a weapon against cancer: "Historically, most research involving genetic methods of battling cancer cells has focused on reactivating genes called tumor-suppressor genes, which are generally overcome by a proliferating cancer. No one had explored the idea that senescence might play a key role in diminishing tumors. ... senescence [acts] like a fail-safe mechanism to stop cancer. When a cell detects a deleterious mutation, it launches the senescence process, resulting in the permanent loss of the cell's ability to proliferate, thus halting any cancer. In order to become tumor cells, those cells have to overcome senescence ... the sudden diminishment they had observed in the tumors might be due to the reactivation of some latent remnant of the trigger for senescence. Through a series of experiments looking at enzymes associated with the senescence process, as well as some molecular markers, Wu confirmed her suspicion. And not only was senescence occurring in cells that had been thought to be incapable of it, the process was reactivated in all the different tumors they studied." The researchers have found a trigger mechanism to reenable cellular senescence in cancer in mice, but it remains to be seen how effective this strategy can be in humans.
Over at the Immortality Insitute, you'll find discussion and a YouTube embed of a recent healthy life extension community film "The Immortalists": the filmmaker "recently completed a short film/meditation on the will to become immortal. It features interviews with Ray Kurzweil, Michael West, Michael Fossel, and Dan Baker." It seems to be well-received by the Institute folk; healthy life extension advocacy can use more punchy to-the-point media of this sort. Most people wander through the corridors of life with focus or dazed, not seeing the possibilities just around the corner. We are at the very start of a curve of medical technology that will make healthy life spans indefinite some decades from now. Science will provide extra years more rapidly than aging takes those years away. There is a chance to be grasped here - that we can work together to bring that turning point closer, inside our lifetimes. What bigger prize could there be than to rid the world of all the suffering and death caused by aging?
As gleefully noted at the Methuselah Foundation blog, the latest award from the Glenn Foundation for Medical Research brings their support for the Strategies for Engineered Negligible Senescence (SENS) into the six figure range:
We here at the Methuselah Foundation are pleased to announce our receipt of a Glenn Award for Research in Biological Mechanisms of Aging: a further $50,000 towards the presently ongoing SENS research aimed at extending healthy human longevity, and funded by our generous donors.
As for all SENS research contributions, this award is matched by $25,000 from the $3 million fund set up by Peter Thiel in late 2006. It will help to extend Foundation research into bioremediation of damaging age-related byproducts in tissue, the protection of fragile mitochondrial DNA and future programs for other aspects of SENS, each tackling one form of age-related biochemical and cellular damage.
This latest award brings contributions from the Glenn Foundation for Medical Research to $120,000, more than $100,000 of that in the last year. Many thanks from all of us for this aid in our efforts to repair the damage that causes aging. We've set a fine pace of growth in the past twelve months, and we fully intend to keep it up!
We can all help the Foundation continue its growth and expand its success in raising funds for SENS research by continuing to donate. Even small amounts serve to illustrate the breadth of support for the scientific quest to reverse aging, and thereby make more large donations possible. Those folk who manage large sources of funding for research like to see just that sort of support from the public: it's an important validation, and that validation is exactly how the Methuselah Foundation obtained its first large donations just a few short years ago.
How things have grown - and no slowing the pace yet. You should all take a moment to think about those folk who are working hard to help you live a much longer, healthier life. What's that worth to you?
For those keeping track, Forbes notes recent events in the trend towards public funding of stem cell research by US states: "New Jersey voters will decide this November whether to approve borrowing $450 million to pay for stem cell research in the state for 10 years under legislation signed Thursday by Gov. Jon S. Corzine. ... The money would support research on adult and embryonic stem cells. ... The state has already approved spending $270 million to build stem cell research facilities. Several states are competing in stem cell research. California approved spending $3 billion on stem cell research, Connecticut has a $100 million program, Illinois spent $10 million and Maryland awarded $15 million in grants. New Jersey awarded $10 million for research grants earlier this year with money from the state budget." Politicians in other states are also moving forward with similar initiatives; some are larger, such as that put forward by in New York. Distributing public funds for political gain has always been a national pastime, but it seems to be a growth industry of late.
A nice confluence of processes in this research: the longevity difference between genders, the role of oxidative damage in aging, how mitochondria cause that oxidative damage, and how calorie restriction changes it all. "Caloric restriction (CR) without malnutrition has been shown to increase maximal life span and delay the rate of aging in a wide range of species. It has been proposed that reduction in energy expenditure and oxidative damage may explain the life-extending effect of CR. Gender also has been shown to influence longevity and energy expenditure in many mammalian species. The aim of the present study was to determine the gender-related differences in rat liver mitochondrial machinery, bioenergetics and oxidative balance in response to short-term CR. ... Female rats showed a higher oxidative capacity and GPx activity than males. This gender dimorphism was not modified by CR. Restricted rats showed slightly increased oxygen consumption, complex III activity and GPx antioxidant activity together with lower levels of oxidative damage. In conclusion, the gender dimorphism in liver mitochondrial oxidative capacity was unaffected by CR, with females showing higher mitochondrial functionality and ROS protection than males."
In addition to the first (with a focus on radical life extension) and second articles on Transvision 2007 from Ronald Bailey at Reason Online, a few other folk have stepped up to tell us how things went:
Too little biomedical funding (perhaps less than one percent) is going into reversing aging. Euphemisms for aging like "healthy aging" and "aging is not a disease" are being promoted. If it's not a disease, why fund fixing it? Aging is not less bad when postponed. We should admit that our goal is elimination of aging. How do we give this credibility?
Progress is being made in longevity science, both in lysosomal enhancement and in allotopic expression. Funding is increasing. The Mprize is at 4.5 million, which is starting to encourage some research for the purpose of the prize. SENS credibility improving.
Various groups, including theologians, are making documentaries and otherwise marketing the ideas. With enough money, the experts needed to develop therapies are ready to work on the problem. Funding is ramping up. Our action today can save many lives by accelerating the introduction of first therapies. Mealy-mouthed messaging has been tried, so now is time to be tougher. People were irrational about aging, but that is becoming decreasingly justifiable.
Rather than choosing to wax philosophical about the ethical imperatives in favour of life extension, the organizers of the IEET symposium specifically geared the event around the work of Jay Olshansky and his efforts to frame the discussion in more practical terms.
In other words, money.
Indeed, the case for a longevity dividend – the idea that prolonging life will save not just lives, but oodles of cash -- is beginning to take shape. As Reason science correspondent Ronald Bailey noted, “It's a way of rebranding the quest for extending human lives in a politically palatable way.”
That piece above is from George Dvorsky, who notes in another post the realities of being in the early stages of a growth movement of futurists:
Attendance, I am quite certain, was well below expectations. The number of empty seats was disturbing. ... Even more disturbing is how some of the most important ideas and thinkers of our time are largely being ignored by the general public. Watching Aubrey de Grey explain to a small audience how he’s going to conquer death created no small amount of cognitive dissonance in my brain; the room should have been packed. Hell, the room should have had people lined-up out front pounding at the door demanding to be let in.
It is true there are comparatively few people who spend time on transhumanist goals in a serious fashion - compared to, say, the number of people willing to form local sports clubs. The process of garnering attention even for demonstrably true concepts and meritous actions is slow and arduous. We'd all like to see more progress; we'd all like to see the healthy life extension movement match the spectacular growth of AIDS patient advocacy, for example, or generate a goliath research community the size of those working on Alzheimer's or cancer. That will take work and years, but compared to the state of affairs a decade ago, we've improved a hundredfold the level of funding raised and spread of awareness for directly attacking the aging process. We can and will keep that up.
Lastly, I should note Ronald Bailey's third and final report from the conference:
Kurzweil believes that humanity will accelerate itself to utopia (immortality, ubiquitous AI, nanotech abundance) in the next 20 to 30 years. For example, he noted that average life expectancy increases by about 3 months every year. Kurzweil then claimed that longevity trends are accelerating so fast that the life expectancy will increase more than one year for each year that passes in about 15 years. In other words, if you can hang on another 15 years, your life expectancy could be indefinitely long. He projects that by 2030, AI will be ubiquitous, and most humans will be physically melded to information and other technologies. Kurzweil argued that we must reject the fundamentalist desire to define humanity by its limitations. "We are the species that goes beyond our limitations," he declared.
Which is quite true, though as I've noted before, I think Kurzweil's timelines for the next couple of decades are too optimistic, for reasons relating to the incompressibility of human interactions in business cycles. One can of course conceive of technologies (like strong artificial intelligence) that get around that limitation, we being the species that treats limits like red flags, but you have to get them through the process of development first.
I would be very pleased to see us make the advances needed to achieve indefinite life expectancy - even in the laboratory, in mice - by 2022, but color me skeptical. I think it'll take a couple of decades more unless some very big players decide to jump into rejuvenation research money-first within the next few years.
Nature reports on a new longevity gene tweak: "Currently, the main focus of ageing research is on using calorie restriction as a way of activating a metabolic 'fountain of youth'. The new discovery, that knocking out a single cardiac gene could lengthen lifespan, was an unexpected byproduct of heart research. ... mutant mice lacking [the gene for protein] AC5 were more resistant to heart failure caused by pressure within the heart. But in the process, the research team also realised that the mutant mice lived longer than their normal counterparts. [Now] they report that the treated mice lived 30% longer and did not develop the heart stress and bone deterioration that often accompanies ageing. ... AC5 could boost longevity by reducing the trauma caused when chemically reactive forms of oxygen accumulate. The accrued damage from these molecules is thought to contribute to ageing. AC5 mutants make more of a protein called ERK2, which regulates oxidative-stress responses. When Vatner and his colleagues increased ERK2 levels in budding yeast, these yeast lived longer. There are several mysteries about the mice lacking AC5. Young mutants weigh the same as their normal counterparts, but elderly AC5 mutants weigh less - even though they eat more. That suggests a metabolic change [which] could be mimicking calorie restriction. It is also possible that mice without AC5 are more resistant to cancer."
Ronald Bailey brings us another report from Transvision 2007 at Reason Online: "The Tuesday evening session was devoted to another sort of speculative revival technology, cryonics. Presentations were made by three members of the Alcor Life Extension Foundation. ... Alcor currently has 850 members with 78 patients who are cryonically suspended. The first talk was by nanotechnologist Ralph Merkle who gave the standard line that cryonics is an experimental technology for life extension. The question is do you want to be in the experimental group or in the control group? ... Alcor has a team that flies to the bedsides of clients whose hearts are about to stop. Once they do stop, the team begins immediately to try to limit damage to their brains. To do that Alcor technicians pump patients' bodies up with cryoprotectants that prevent the formation of damaging ice crystals. ... Alcor is about to begin experiments with mice to see if they can be cooled and then revived. ... I'm still thinking about that, but it would be far more preferable if Aubrey de Grey and his colleagues succeeded in achieving Longevity Escape Velocity."
I would hope that regular readers are by now wary of chronic inflammation - the tentacles of causal relationships link inflammation with almost all well-known age-related conditions. Those conditions are the most visible end points of accumulated damage, as aging is nothing more than just that - damage at the cellular and molecular level. In this worldview, inflammation is a process acting as a source of damage. For example, we have this recent research on inflammation and age-related (type 2) diabetes:
It has long been known that type 1 diabetes is an autoimmune disease. The body attacks the islet cells in the pancreas that produce insulin. In recent years, the immune system has also been implicated in type 2 diabetes - in particular imbalances in cytokines, an immune system component that causes inflammation.
These imbalances become especially marked as people become obese. Dr. Jerry Nadler and his colleagues are investigating the role of a key gene - 12/15-LO (12/15-lipoxygenase ) - that has been implicated in the immune-system induced inflammatory effects linked to both forms of diabetes and their complications.
Macrophages appear in high concentrations in fatty tissue. With funding from the National Institutes of Health, Nadler has traced the mechanism by which the presence of large numbers of fat cells stimulate the macrophages to activate the 12/15-LO gene, and has documented the cascade of inflammatory reactions that results. He has found that the 12/15-LO gene produces two proteins that convert fatty acids into cytokines.
A nice demonstration of a plausible mechanism to link excess body fat with chronic inflammation, and then to diabetes and all the other conditions brought on by that inflammation. All the more reason to keep yourself in shape and take care of the health basics - if you don't let your body go to seed, then you'll accumulate cellular damage at a slower rate, and be better placed to benefit from the longevity medicine of the future.
We don't know how rapidly we'll be able to create medical technologies of rejuvenation and longer, healthier lives. It's foolish to think that advanced medicine will be developed fast enough to save you from neglect - why take the chance when there is so much at stake? Even the young adults amongst us should be concerned about missing the boat, and that's a wise position to take. We should all do our best to reach that future intact and healthy, and to help bring the development of real anti-aging technologies closer.
A new blog dedicated to longevity advocacy and healthy life extension science came to my attention just today:
To get people understanding and pushing for life extension technologies, its paramount that you become a good communicator.
If you ask people on a long enough time line, they will say life spans will extend but most people believe that at some point things will change, not in their lifetime. Part of this is due to there being are very few of the major diseases which have been eradicated, most are treated as ongoing concerns. I feel that this is a factor leading to people’s apathy towards aging.
The current perception of the general population is that aging is as constant as taxes. If you ask someone on the street they will say that not much can be done, or that it is natural. This state of mind has to be changed into accepting that something can be done and should be done, and finally energizing them to do something about it.
I'm always pleased to see more people putting their keyboards to good use and speaking their mind on the topic. Welcome aboard.
Think about the initiative and time it takes to put together the first few posts of a blog, and the value of that effort. If thousands or millions put in just that much effort to the broader effort to build an effective longevity research community - and the public awareness needed for such a venture - then imagine just how far we could advance on that wave of support.
The Methuselah Foundation came to where it is today through the actions of just a few thousand people, from the core volunteers and the few 6- and 7-figure donors to the generous donors and members of the 300, and out to the halo of bloggers, journalists, supporters, advocates. A near future of tens of thousands of volunteers and dozens of equally noteworthy and effective longevity research patient advocacy groups is not unreasonable. Look at the progression of cancer research advocacy and support for a model, for example.
It's just a matter of getting out there and putting your contribution into the ring. If we all do it, progress will result.
From the MIT Technology Review, an update on progress at Sirtris Pharmaceuticals. The company continues to push forward with the next compound based on their research into sirtuins and calorie restriction biochemistry: "the drug, SRT501, reduces glucose and improves insulin sensitivity in animal and in vitro studies of the drug's effect on type 2 diabetes. In people, the drug was tested for dose, safety, tolerability, and pharmacokinetics--that is, how well the drug was absorbed, distributed, metabolized, and removed from the body. Phase 1b trials are already under way to test safety and pharmacokinetics on patients with type 2 diabetes. Later-phase trials will test to see if the drug actually works in diabetics. SRT501 is a proprietary chemical developed by Sirtris that's based on the naturally occurring resveratrol that company cofounder David Sinclair of Harvard University has been studying for its effects in extending life span in a number of organisms, including yeast, flies, and mice." The regulatory pipeline is painfully slow and expensive, and forces incrementalism while preventing bold strokes. So we get drugs to gently tweak metabolism to slow aging a little rather than, say, attempts to replace damaged mitochondrial DNA in humans in order to repair an aspect of aging - and those drugs are relegated to patching up a disease rather than attacking the aging process.
A long piece at EureAlert! is illustrative of the present state of Alzheimer's research: moving forward, optimistic, but still mostly a product of the pills and drugs old school of medicine. "Imagine the day when a routine visit to the family doctor includes a simple blood test to predict the risk for developing Alzheimer's disease (AD). If the test returns a worrisome result - too many sticky brain proteins that might begin to gum up memory and thought in 10 to 15 years - a person could be offered an aspirin-like pill to keep those proteins in check. ... we are at the threshold of developing therapies that we hope will eventually impact Alzheimer's disease. We are not slogging through a fog anymore. We can see the top of the hill for the first time ... I think Alzheimer's is going to be much easier to treat if you can prevent accumulation of [amyloid beta] in your brain, than if you try to treat it once plaques form. We know that statins don't work very well if a heart artery is 99 percent blocked, but do if they are taken earlier. The same thing would go for a drug designed to prevent Alzheimer's ... in the process, they are attempting to answer the question that has stumped the Alzheimer's research world: to what degree is [amyloid beta] responsible for the neurodegeneration seen in the disease ... That is the biggest secret in Alzheimer's disease research. We'd like to know what role it plays."
Another view of the problem with the US regulation of research can be found in this review of futurist literature: "What really jumped out at me from both of these books is that much is possible, if we as a society (or the world) could just get past the 'monkeys with car keys' stage - we could achieve some truly great things. Maybe not absolute immortality, but maybe a much better and longer quality of life, for starters. Part of the stuff that needs to be discarded, IMHO, is dogma. That includes dogmatic religion, but also includes dogmatic ideologies that hold us back - this idea that man is meant to suffer is retarded and outright cruel, but it drives some of our laws. For instance, and this is the most glaring one (although I didn't corroborate this) is that a new drug cannot be brought into the U.S. market unless it's to treat a condition or disease. Read that again. So, if something is developed to extend life or extend your current capabilities, like vision or hearing, it will not be approved. It's the 21st century. How can this type of thinking still be with us?" It's quite true, and exactly why there are not dozens of companies in the US directly aiming at extending the healthy human life span. Those with the inclination are forced instead into disavowing any thought of treating the aging process. Their technological breakthroughs are relegated to patching up age-related diseases after the fact rather than reaching for rejuvenation and prevention of aging.
Damn straight it is - but some paths to that goal are better than others. Here, Ronald Bailey reports at Reason Online from the ongoing Transvision 2007 conference: "The room was packed with 50 or so people interested in the issue of securing the 'longevity dividend.' ... The audience [ranged] from doctors, professors, and economists to people who had lived in alternative communities and even a few high school students. One might think that longer, healthier lives should be an easy sell, but, in fact, there are people who believe that dramatically extending human lives would be a bad idea. ... What is the longevity dividend? It's a way of rebranding the quest for extending human lives in a politically palatable way. ... [Aubrey de Grey] is pessimistic about the idea that the way the campaigners for the longevity dividend want to pursue it will result in reduced medical costs. ... American life expectancy has already increased by about seven years since 1960 and medical costs have obviously not gone down. Inherent in the idea of the longevity dividend is the notion of compressed mortality, that is, the period of decrepitude at the end of life will be shortened. De Grey argues that this not biologically plausible. ... Instead of pursuing the longevity dividend research agenda, De Grey wants to focus [on] rejuvenation interventions would repair the damage that aging produces in a person enabling them to live another 30 years. Then further research would develop better interventions that would repair the damage that occurs during that 30 year period and so forth. This series of anti-aging interventions would push death off indefinitely."
Transvision 2007 is presently underway; there's already a good report online from the Longevity Dividend meeting held yesterday. So with that in mind, why not a look at the some of the first steps towards the medical technology of tomorrow:
There's kind of a revolution going on right now in the neurosciences and biomedical engineering. People are trying to take engineering approaches for directly interfacing with the brain.
"The hope is we can cure more immediately a variety of diseases."
Researchers have been able to decode brain activity for years using electroencephalography. Referred to commonly as an EEG, this technology involves placing a sensor-wired net over the head to measure brain activity through the scalp. But the technology wasn't quite sensitive enough to allow researchers to decode brain signals as precisely as needed, Sanchez said. Now researchers are focusing on decoding signals from electrodes placed directly into the brain tissue using wires the width of a strand of hair.
"(Scientists have) realized that by going inside the brain we can capture so much more information, we can have much more resolution," Sanchez said.
The chip UF researchers are seeking to develop would be implanted directly into the brain tissue, where it could gather data from signals, decode them and stimulate the brain in a self-contained package without wires. In the interim, UF researchers are studying implantable devices in rats and are evaluating an intermediate form of the technology - placing electrodes on the surface of the brain - in people.
The day may not be too far off when patients can control a prosthetic hand or leg just by thinking about it, Sanchez said.
"It's becoming a reality," Sanchez said. "We're designing electronics that we can interface with biological systems and we can use that to help people."
You might also recall a Popular Science article on more ambitious research along the same lines as well. Remember that a mere half century ago, computers were clumsy and the size of a room; consider where medical biotechnology will be another half century from now. Today's proto-interfaces to your biology will have shrunk from clunky electronics visible to the naked eye to devices the size of a cell - to devices made of assembled macromolecules, just like your cells, but better designed.
The eventual future of medicine is not perfect control over biology - although that is a step along the way - but rather an industry producing machinery to better serve and improve upon the purpose of biology. It will be just as complex as biology, but wholly designed by humans rather than evolution and happenstance. It will be far more reliable and cost-effective, in the same way that a plastic fork beats out a pointed stick. It will be built upon the very early work in nanotechnology and molecular manufacturing taking place today.
Your biology is the house you live in: why live in a cave over a wood cabin, and why live in a wood cabin when a modern house in the city is just as affordable? There is a lot to be said for the obvious future of nanomedicine and computation; we will have the choice of augmentation and ultimately replacement for the tissues of our body, with every step bringing greater capacity, reliability and life.
Why live in a body that can grow old and become cancerous when you don't have to? That will be a serious question not too many decades from now.
From PLoS Biology, a close look at what happens to stem cells with advancing age. Getting down to the nuts and bolts both raises more questions than are answered, and sheds light on a range of areas, from regeneration through to cancer: "The effect of age on the regenerative capacity of adult stem cells, which should rejuvenate tissues throughout life, is poorly understood. Bone marrow stem cells, also known as hematopoietic stem cells (HSCs), continuously regenerate the cells that comprise the blood, including the immune system, which fails with age. Here, we show that older HSCs were less able to regenerate the blood system than young HSCs. Paradoxically, the HSC number increased concomitantly, leading to no major difference in overall blood production, even though the immune system did exhibit some defects. ... evidence supports the idea that loss of overall gene regulation (epigenetic regulation) is a major event during aging. Whereas much of aging research is concentrated on accumulation of mutations in DNA rather than on global regulatory mechanisms, we speculate that these epigenetic changes could drive many of the manifestations of age. This view also may explain the increased incidence of cancer with age."
This review paper caught my eye: "The early observations on the rate-of-living theory by Max Rubner and the report by Gershman that oxygen free radicals exist in vivo culminated in the seminal proposal in the 1950s by Denham Harman that reactive oxygen species are a cause of aging (free radical theory of aging). ... Because the free radical theory of aging is not the only theorem proposed to explain the mechanism(s) involved in aging at the molecular level, we also discuss how this theory is related to other areas of research in biogerontology, specifically, telomere/cell senescence, genomic instability, and the mitochondrial hypothesis of aging. ... It is now possible to give at least a partial answer to the question whether oxidative stress determines life span as Harman posed so long ago. Based on studies to date, we argue that a tentative case for oxidative stress as a life-span determinant can be made in Drosophila melanogaster. Studies in mice argue for a role of oxidative stress in age-related disease, especially cancer; however, with regard to aging per se, the data either do not support or remain inconclusive on whether oxidative stress determines life span."
Anne C. attended the recent Future Salon debate between Aubrey de Grey (for more healthy life and the defeat of aging) and William Hurlburt (for the continuation of death on a massive scale) and wrote up an excellent account. A couple of high points from the report:
Aubrey de Grey began by noting two mutually exclusive positions (associated with science and ethics) that tend to come into play when people state opposition to longevity research:
Position 1: "I refuse to think seriously about whether defeating aging is feasible, because it is clearly not desirable."
Position 2: "I refuse to think seriously about whether defeating aging is desirable, because it is clearly not feasible."
Two argumentative frameworks tend to be associated with the above two positions, according to de Grey: the "Argument from Superficial Authority", and the "Argument from Personal Incredulity".
My impression is that people taking Position 1 most often tend to argue from superficial authority. I would imagine that this includes people who invoke "Nature", the words of conservative bioethicists, or possibly their deity of choice when attempting to explain why seeking to extend the healthy lifespan is a bad idea.
People taking Position 2, on the other hand, tend to argue from personal incredulity -- that is, they consider it a foregone conclusion that human lifespan is basically fixed at a particular point, and that our chance of moving this point outward is so small as to be functionally negligible.
I - and I'm sure any of you who take the time to talk to folk about healthy life extension - have seen a great deal of Position 2, the argument from personal incredulity. It's a real challenge to talk points with someone who has already fully vested their position in "no." In terms of making headway in the marketplace of ideas, I think Position 2 is a bigger problem than Position 1, the argument from superficial authority. Superficial authorities - pro-death advocates, bioconservatives and the like - seem to more readily understand that significant healthy life extension is, in fact, plausible for the near future. I'm not sure how much of that stems from the very human action of bolstering a threat in order to strengthen one's own position, but there you have it. Deathist bioethicists are often just as convincing as advocates for healthy life extension when it comes to the plausibility of and timeline for healthy life extension technologies.
Technorati tags: life extension
There's no shortage of interesting data and conclusions out there; here's a good example from researchers focused on stem cell biology: "The epidermal stem cells reside in the proliferative basal cell layer and are believed to persist for the lifetime of an individual. Acting through intermediaries known as transit amplifying cells, epidermal stem cells ensure that the enormous numbers of keratinocytes required for epidermal homeostasis to be maintained are generated. This continual demand for new cell production must be met over the entire lifetime of an individual. ... This leads us to question whether or not epidermal stem cells represent a unique population of cells which, by necessity, might be resistant to cellular aging. We hypothesized that the full physiologic functional capacity of epidermal stem cells is maintained over an entire lifetime. Using murine skin epidermis as our model system, we compared several properties of young and old adult epidermal stem cells. We found that, over an average mouse's lifetime, there was no measurable loss in the physiologic functional capacity of epidermal stem cells, leading us to conclude that murine epidermal stem cells resist cellular aging." Always a good starting point for "how," "why" and "what does this teach us?"
Many specific age-related degenerations have no name and remain uncategorized, poorly understood, even undiscovered. All likely stem from a small range of types of accumulated damage, but nonetheless it should serve as something of a wakeup call that scientists continue to uncover these sorts of things: "Multiple reports have documented an age-related loss, estimated at about 10% per decade, of the pigmented neurons in the substantia nigra. This is associated with motor dysfunction, including bradykinesia, stooped posture and gait disturbance. As microglia are activated by cell death and neuromelanin pigment, we hypothesized that there should be a significant microglial reaction in normal aging human substantia nigra. ... older subjects, the percentage of substantia nigra area occupied by microglial bodies and processes was significantly greater than for younger subjects ... The marked microglial reaction in normal aging human substantia nigra, together with the previously reported 35-80% pigmented neuron loss, indicates the presence of a powerful pathologic process that may be additive with specific age-related neurodegenerative diseases, including Parkinson's disease."
A short news piece on cancer stem cell work caught my eye today:
According to the "stem cell theory", only a minute number of cells within each tumour can multiply enough to keep the tumour growing and spreading. The vast majority of the cells cannot do this so were viewed as passengers. The Melbourne researchers, however, found that many tumours are fuelled to grow by a substantial portion of the tumour cells - sometimes even the majority. "(This) suggests that the proportion of cells that can propagate tumours was previously grossly underestimated," the institute said. Determining whether most cells in a tumour, or only a rare population, can maintain its growth has important implications for therapy, they say.
Very true: we'll all be very lucky indeed if it turns out that a majority of cancers are sustained by small, distinct, characteristic populations of cells. Scientists are becoming very good at safely destroying distinct populations of cells, and any research at the extremely well-funded intersection of cancer and stem cell research will move rapidly.
I chased the news above back to the scientific paper in question:
The cancer stem cell hypothesis postulates that tumor growth is driven by a rare subpopulation of tumor cells. Much of the supporting evidence for this intriguing idea is derived from xenotransplantation experiments in which human leukemia cells are grown in immunocompromised mice. We show that, when lymphomas and leukemias of mouse origin are transplanted into histocompatible mice, a very high frequency (at least 1 in 10) of the tumor cells can seed tumor growth. We suggest that the low frequency of tumor-sustaining cells observed in xenotransplantation studies may reflect the limited ability of human tumor cells to adapt to growth in a foreign (mouse) milieu.
Determining whether the growth of various tumors is sustained by most of the tumor cells or by a rare subpopulation has important ramifications for the design of novel therapies. Therefore, the cancer stem cell hypothesis merits more rigorous tests. For human tumors, ultimately this will require transfer of tumor cells into mice installed with all the requisite human support cells.
Unfortunately, we're likely to see more of this sort of thing in the next couple of years; there are good reasons to believe that the cancer stem cell hypothesis will not hold for more than a few types of cancer.
Cancers are characterised by extremely rapid mutation and adaptation as the result of their fast growth and aggressive cell replication. This is one of the reasons cancers are so hard to treat with more brute force techniques such as radiation and chemotherapy - cancer cell populations very quickly evolve resistance to most of what can (reasonably) safely be tried as a therapy in this arena. There is no reason per se that this rapid mutation cannot include the mutation of normal cells into stem cells or stem-like states sufficiently empowered to support the cancer. It is possible that many combinations of a small number of mutations exist to produce cells sufficiently stem-like to support a cancer - and are therefore likely to be created in a rapidly mutating cancer.
We can hope, however. Sometimes we get lucky, and an age-related condition really does have narrow, distinctive roots waiting to be discovered. At the present blistering pace of research, I don't see uncertainty surrounding cancer stem cells continuing for many more years.
From ScienceDaily, research that provides an interesting view of the insulin signaling mechanism, metabolism and its impact on life span: "The traditional prescriptions for a healthy life - sensible diet, exercise and weight control - extend life by reducing signaling through a specific pathway in the brain [activated] when insulin and insulin-like growth factor-1 switch on proteins inside the cell called insulin receptor substrates ... Diet, exercise and lower weight keep your peripheral tissues sensitive to insulin. That reduces the amount and duration of insulin secretion needed to keep your glucose under control when you eat. Therefore, the brain is exposed to less insulin. Since insulin turns on [an insulin receptor substrate] in the brain, that means lower [insulin receptor substrate] activity, which we've linked to longer lifespan in the mouse ... We are beginning to appreciate that obesity, insulin resistance, and high blood insulin levels are connected to Alzheimer's disease, Huntington's disease, and dementias in general. It might be that, in people who are genetically predisposed to these diseases, too much insulin overactivates [insulin receptor substrates] in the brain and accelerates disease progression. Thus, insulin resistance and higher insulin levels might be the environmental influences that promote these diseases."
Chris Patil notes a point I missed on recent research into human telomere lengths: "The paper's key finding (from my perspective, at least) didn't make it into the title: Telomere length is positively correlated with lifespan. While I'm aware of studies linking telomerase activity in animal species to lifespan, the growing consensus seems to be that this is a corollary of the relationship between telomerase and body mass, which in turn is correlated with lifespan; furthermore, the relationship is the opposite of the one here (larger, longer-lived animals tend to have lower telomerase activity than smaller, shorter-lived animals with a similar body plan; see our earlier article Telomerase correlates negatively with body mass). This is the first study I'm aware of in which human-to-human variation in telomere length (which occupies a concept space somewhere between the strictly genetic and the strictly epigenetic) has been shown to correlate with lifespan. The key issue now, of course: Where are the causal links, if any, between the telomeres a person inherits and their life expectancy?" This will no doubt boost the fundraising ability of companies presently building ways to manipulate telomere length.
The Methuselah Foundation is looking to the community with a contest to design the new Foundation logo:
Can you design a logo for the Methuselah Foundation? Would you like to see your work leading the charge in the fight to defeat age-related degeneration? We are upgrading our websites and outreach material, and as a part of this effort need a distinctive new logo that encapsulates and conveys the meaning of our mission and the essence of the Foundation.
The Methuselah Foundation has been built by the dedication of volunteers and donors of all stripes, and so we reach out to the same community in search of a new logo. Think you have good idea and a designer's hand? Fire up the scanner and send in your work!
Entries will be judged by Foundation chair Dr. de Grey with help from graphic design experts. The winner and two runners up will each receive an autographed copy of Dr. de Grey's book "Ending Aging: The Rejuvenation Biotechnologies That Could Reverse Human Aging in Our Lifetime", which is published by St. Martin's Press on September 4, 2007.
The closing date for this contest is August 15th, 2007. ... Best of luck, and tell your friends!
I don't think I can add much to that beyond repeating that it is the community of volunteers, supporters and generous donors who lead the Foundation to success in fundraising, education, research and advocacy. It is a real demonstration of the will to achieve far longer, healthier lives in the world today - and a measure of the potential for growth and greater goals in the years ahead.
The early registration deadline for the 7th Alcor Conference is the end of this month. A range of interesting presentations are lined up for this year: "Cryobiology is a small field, and cryonics is even smaller still. Finding answers to technical questions can be difficult. Common questions are: What can and cannot be cryopreserved today? How is freezing damage prevented? What lessons from cold tolerance in nature can be applied to cryopreservation? What is the difference between cryonics and suspended animation? When considering scientific fields that bring life processes to a complete stop, perhaps the most pervasive question of all is: What is the difference between life and death? This question and many others will be answered. ... For those interested in personal life extension, the news is complex. We all have busy lives and wish that effective life extension could be as easy as taking a vitamin pill, "One A Day for Longevity." Unfortunately, a quick fix is not an option today, but there is good news. Learn what you can do today to add healthy years to your life. This talk will review some of the more popular life extension approaches, beyond cryonics, because every year gained offers the benefit of yet another year of advances in longevity research."
Susceptibility to aging and susceptibility to cancer are viewed as a balance, centered around the disposition of multipurpose biochemical machinery like the p53 gene. You can tilt the mechanism one way or another - less cancer or slower aging - but not both at once. This Nature publication throws that out of the window - it seems it is possible to tinker p53 into providing slower aging and less cancer. "The conclusion seems to stand in direct contradiction to previous work, which showed that a boost in p53 kept mice cancer free but also caused them to age more quickly. But there's a key difference between these studies, the researchers say: in the new work, the normal regulatory mechanisms remain in place, so p53 is churned out only when needed. This seems to turn an ageing protein into a youth-preserving one. It's a very impressive effect. It's very hopeful because it says under some circumstances you can get the best of both worlds. ... These mice produce more p53 protein when prompted to by cellular stress, such as DNA damage or lack of oxygen. As expected, mice with the extra copy of p53 had fewer tumours than regular mice, and their cells were less likely to turn cancerous when grown in a Petri dish. On average, the transgenic mice lived 16% longer than normal mice."
Healthy life extension technology that can grant extra years or even reverse aging is on the horizon. Aging is no more than biochemical damage, and damage can be repaired. We can visualize the necessary science today, and directed work on the fundamentals is taking place at low levels of funding.
We are a fair way from the goal, standing on the ground where the ramp has yet to be built, the workers yet to be gathered, the crowds yet to arrive. Everything accomplished, every dollar given by those of us active today will snowball over the years ahead - now is the fulcrum time for growth in the research community and public support for serious longevity research. Every person to step forward catches the notice of more eager helpers, and success attracts success - witness the growth of the Methuselah Foundation from a gleam in Dave Gobel's eye to more than $8 million pledged, accomplished by the early volunteers here where the ramp is to be built.
Here is another slope, running in the opposite direction: the cost of biomedical research. Biotechnology is tied to advances in computational hardware - and what a slope that is! It is a slope that leads to sequencing genomes for a handful of dollars apiece, simulations of laboratory animals and biochemical interventions at a fraction of the cost of real world research, more data on our biochemistry than all the present stored data in the world combined, and much more. Everything of note in medicine will be faster, cheaper and better, riding on the engine of ever faster computers.
Switching back to growth trends, let's think about your net worth. If you're sensible and look ahead, live within your means and diversify your investments, then the passage of time will be kind to your wealth. Compounded gains are the path to riches - but only if you don't tap into your saved capital along the way.
Here's another trend: the decline in your remaining life expectancy and quality of life with advancing age. Aging is an ugly reality. Would you rather stick your head in the sand, or do something to help make the situation better?
The obvious action when it comes to making the situation better is to devote some of your resources to support plausible longevity research, or those groups working to encourage plausible longevity research through advocacy and engagement with the scientific community. But when and how much would you give? Look at all those crossing curves and trendlines:
- a dollar given today is not saved, and so cannot be two dollars given ten years from now
- a dollar given a decade from now will result in more research accomplished than a dollar given today
- a dollar given today will advance the cause today, rather than a decade from now
But on to the deliberately provocative question from the title: when would you donate 90% of your net worth to advance longevity and rejuvenation research? If you care more about posterity than your own survival, would you wait as late as possible? Or does this critical time for the present nascent longevity research community mean that 1% of that same "late as possible" investment in research and support would better serve the future if donated now? If you care deeply about your own survival, where do the curves and trends cross for greatest effect in your opinion?
There is no right answer in consideration of personal economic choices, but these are all questions we should ask ourselves. Wealth at any level is worthless to the dead, and being alive and healthy allows you to generate more wealth: logically we should all be willing to devote most of our net worth to longevity research at the most effective time. If we can buy time with money - and we can begin to now in earnest, for the first time in history, by supporting the research that will lead to the first healthy life extension medicine - then we should all be in that market.
That all said, and as I'm sure you're all aware, it's hard to be right and optimal in financial matters. Life is uncertainty, and risk is everywhere. What is the risk of being wrong in your estimations, and how can you hedge that risk? No-one wants to devote their wealth to a vital cause, only to see later that it was the wrong time for best effect. One way to reduce the risk is to spread out your support for research across time; you won't be absolutely efficient, but then it would probably require a great deal of luck or knowledge to be so. Another is to do the research necessary to satisfy your own economic calculations - that now, for the now that interests you, is the right time.
A final thought: if we all hold back for later, there won't be a longevity research community of any size and accomplishment later. People have to get the ball rolling if we're to see construction of the ramp underway.
(From the Times Online). Our cells are just complex protein machinery, which means there is no obstacle to one day building all the cells we need for any given medical usage from scratch, to order. For the near term, however, researchers are focusing on manipulating cells into desired states through signaling and growth: "It is hard to predict how the science will develop, but I think we could produce a basic prototype-induced stem cell made from a human adult cell within six months to a year. Within two to three years we may be able to create a stem cell that is indistinguishable from one taken from an embryo. What we cannot do, though, is to let the optimism over my science hold us back from conducting research on embryonic stem cells while we are waiting for the alternative ... The concept of artificially inducing adult cells to return to a stem-cell state raises [attractive] possibilities for organ transplantation. If, for example, a patient's skin cell could be reverted to stem-cell form and thence converted back into any other form of tissue - such as nerve, heart or other organs - it could then be transplanted without risk of rejection by the patient." Any advance that lowers the cost of regenerative research, such as by lowering the cost of creating suitable totipotent stem cells, will speed progress.
Here's something new to add to the list of interesting things calorie restriction (CR) does to your metabolism on the way to granting health and longevity benefits. Via Ouroboros: "Adipocytes (fat cells) are the site of much metabolic and endocrine activity; their physiology affects our energy balance, insulin sensitivity and a host of other processes throughout the body. And of course, as some of us know all too well, their behavior is dynamic not only from hour to hour but from year to year, over the course of aging. It's natural to ask questions about the impact of life-extending regimens like calorie restriction (CR) on the biology of adipocytes. A study of rat adipocytes reveals that CR influences the expression of a wide range of signaling molecules, and reverses or mitigates some of the age-related changes in gene expression observed in previous research." Wherever scientists look, the signs of CR affecting the biochemical symptoms of aging are there to be found - or so it seems, some days.
Thoughts from FuturePundit:
Some oppose the development of therapies to reverse aging because they argue that aging is a beautiful and dignified natural process. In this Panglossian view of aging the silver in one's hair is akin to a measure of accumulated wealth of wisdom and understanding. But the reality is a much uglier accumulation of losses - most notably including cognitive losses.
Aging is an accumulation of damage and loses. We should defeat aging. The breakdown and decay of our metabolisms is a bad thing. We need rejuvenation therapies. Such therapies are on the horizon but we should push harder to pull that prospect closer in our future.
Quite true. Aging is the unpleasant slope down into a real chamber of horrors: frailty, pain, the inability to care for yourself, and death. That the benefits of experience come with time is no reason to whitewash the ugly reality - that the systems that form you, the individual, are slowly breaking down as you read this.
But we live in the early years of a revolution in biotechnology and its inherent possibilities for regeneration and rejuvenation. Aging is merely biochemical damage, and the laws of physics show us nothing to say that we cannot learn to repair that damage - like all our technologies, the medicine that will put a halt to aging is just a matter of putting the molecules in the place you want them to be.
You do know that you can presently help to support and advance medical research that could plausibly put us on the way to halting aging within our lifetimes, right? The fight to cure aging is not a mythical beast - it's underway today.
As reported by Forbes, researchers continue to make progress in manipulating cell signaling to spur regeneration - a path that can be distinct from stem cell or gene therapy. This is a comparatively simple example of the type, and at an early stage in development, but still progress: "Normally, adult human hearts do not regenerate because the heart doesn't make more cardiomyocytes (heart muscle cells) after injury. It would be desirable to induce the heart to make new cardiomyocytes after injury. ... To that end, Kuhn's team created a patch that contains a compound called periostin, which helps cardiomyocytes divide and multiply ... Periostin is a natural component of tissue surrounding cells. It comes from the skin lying around bone and helps stimulate cells to divide. ... They placed the patches on the damaged heart muscle of rats in which they had induced a heart attack. After 12 weeks, the rats treated with the periostin patch experienced a 16 percent improvement in their heart's cardiac pumping ability. They also had less scarring of heart tissue, a reduction in the size of the damaged area of the heart, and more blood vessels feeding the area."
Anne C. on the practicalities and priorities of working towards healthy life extension technologies: "While the idea of saving lives in general is neither new nor remarkable, the idea of saving the lives of people 100, 110, 120, and even older is often considered to be radical at best. And while there are indeed various technical and practical challenges to achieving effective health care for people who are nearing (or in) the triple-digits, the existence of political challenges is somewhat confounding. What makes someone's impending death less of an emergency when they are ninety than when they are nine? If you were told that someone was dying and you didn't know how old they were, would it even occur to you to ask, with the intent of using their age to decide whether they were worth trying to save or not? Most likely, it wouldn't. If you can understand that age should not matter as a variable in terms of whether someone's life ought to be saved, you have grasped the philosophical underpinnings of life extension." Quite so.
A slow and presently irreversible process takes place inside your body, day in and day out: vital proteins are gummed and shackled into obstructive and sometimes toxic compounds by sugars and related chemicals from food. These byproducts of your metabolism are called advanced glycation end products, or AGEs, and are one root cause of aging. Year after year, this biochemical junk builds up; some forms accumulate faster than they can be broken down, and others your body is incapable of removing. Eventually, the levels of AGEs rise to the point of degrading the biological systems your life depends upon. Here is an informative review paper on how this all comes to pass:
Protein glycation is a slow natural process involving the chemical modification of the reactive amino and guanidine functions in amino acids by sugars and carbohydrates-derived reactive carbonyls. Its deleterious consequences are obvious in the case of long-lived proteins in aged people and are exacerbated by the high blood concentration of sugars in diabetic patients. The non-enzymatic glycation of proteins occurs through a wide range of concurrent processes comprising condensation, rearrangement, fragmentation, and oxidation reactions. Using a few well established intermediates such as Schiff base, Amadori product and reactive a-dicarbonyls as milestones and the results of in vitro glycation investigations, an overall detailed mechanistic analysis of protein glycation is presented for the first time. The pathways leading to several advanced glycation end products (AGEs) such as (carboxymethyl)lysine, pentosidine, and glucosepane are outlined, whereas other AGEs useful as potential biomarkers of glycation are only briefly mentioned. The current stage of the development of glycation inhibitors has been reviewed with an emphasis on their mechanism of action.
It is noteworthy that glycation in the body is comparatively well-understood at this time, and disappointing that so few initiatives are presently underway to develop the means of safely breaking down and removing AGEs before they rise to the level of causing damage.
The review above, for example, focuses on slowing the process of glycation; as for any therapy aimed only at slowing the processes of accumulated damage that cause aging, this will prove less valuable and effective than a therapy aimed at repair. Repair can be performed over and over again, and the underlying medical technology is not necessarily any harder to develop in the first place. This is a good specific example of a general problem in the approach taken by much of the mainstream at the present time.
I agree with this point made by Michael Anissimov. The technological Singularity - in its older, more useful definition relating to information and intelligence - has little to do with greatly extended longevity. "Radical life extension (people living to 100, 200, 300, and beyond) seems very plausible to me, and I believe that we are going to be experiencing this ourselves in our lifetimes, unless an existential disaster occurs. A Berkeley demographer found that maximum lifespan of human beings is increasing at an accelerating rate. However, life extension has very little, if anything, to do with the Singularity, other than that the Singularity is sometimes associated with technological progress and that technological progress may result in radically extended lifespans. This is somewhat like how house mice are somewhat associated with raccoons because both live in areas dense with human populations." This is a useful reminder that a future of greater healthy life extension is not a given: the future doesn't arrive on a conveyor belt, delivered deus ex machina. Desired futures are only achieved when we band together and help to make them real.
There is definitely a relationship between telomere length and human longevity; it remains to definitively and fully describe the mechanisms involved. Is this sufficiently close to the biochemical roots of aging - is it an independent form of accumulated damage - that the many research groups working to lengthen telomeres are onto something? This paper demonstrates the relationship once more: "Many studies have demonstrated the association between telomere length in mitotic cells and carcinogenesis and mortality, but little attention has been focused on post-mitotic cells and human life expectancy. We assessed the relationship between telomere length in cerebral gray and white matter and longevity in 72 autopsied Japanese patients aged 0-100 years ... the 90-100-year age group possessed significantly longer telomeres than the 70s ... Autopsy protocols showed a decrease in the rate of cancer death in individuals in their [80s and 90s] versus those in their 60s, and in their 80s the mean telomere length in the gray matter from cancer death patients was significantly shorter than that of patients who died of other diseases ... These data suggest that innate telomere lengths are maintained very well in the cerebrum, and are associated with longevity."
It is troublesome to live in a world in which evident truths are news - because they are not presently believed, acted on, nor in vogue. Buried in a recent op-ed on legislative control over which medicine is researched and which medicine you are allowed to use, you'll find the signs of common sense, positions far removed from what actually takes place. You didn't think you lived in a free country, in which you can choose the medicine you want to purchase and the research you want to support, did you?
To find out why this longevity "increase gap" exists, I examined several factors that researchers generally agree affect life expectancy, including medical innovation, obesity rates, smoking and HIV-AIDS infection rates. While each of these factors had an impact on longevity, the most important factor was medical innovation. In particular, I found that longevity increased the most in those states where access to newer drugs -- measured by their mean "vintage," or FDA approval year -- in Medicaid and Medicare programs has increased the most.
Congressional debate over the Prescription Drug User Fee Act is a microcosm of the national debate over the appropriate balance between safety and rapid access to new and sometimes very expensive medical innovations. While this debate is complex, my research indicates that the best way to achieve sustained improvements in health, longevity and productivity is by continuing to support policies that encourage medical innovation and the new medical goods and services it produces.
Newer medical technology is better - when you are permitted to use it by the rules churned out by unelected, unaccountable government employees more incentivized to prevent new medicine than to allow progress. Medical technology advances fastest when when innovation is greatest - which goes hand in hand with the greatest freedom of research and commercialization. This is not stunning new information, yet even modestly sane lines of thought like that in the quoted article - "let us make the present system less oppressively bad" - form the contrarian position these days.
The main obstacle to a future of far longer, healthier lives is not the technology. It's those people who are gleefully burning the boat that could get us there.
Michael Anissimov talks about the nature of technology: "We realize that the longer you look forward, the more uncertain the predictions get, but one thing is quite certain: if a [technology] is physically possible and obviously useful, human (or transhuman!) ingenuity will see to it that it gets built eventually. As we gain ever greater control over the atomic structure of matter, our technological goals become increasingly ambitious, and their payoffs more and more generous. ... Gene therapy replaces bad genes with good genes, and RNA interference can selectively knock out gene expression. Together, they give us an unprecedented ability to manipulate our own genetic code. By knocking out genes that code for certain metabolic proteins, scientists have been able to make mice that stay slim no matter how much junk food they eat. Lou Gehrig's disease has been cured in mice, and it could only be a few years before we develop a therapy that can cure it for humans too. Aubrey de Grey’s SENS (Strategies for Engineered Negligible Senescence) research program contains various prescriptions for the use of gene therapy. Within a couple decades or so, progress in anti-aging therapies will improve to the point where we are gaining more than an extra year of lifespan per year, reaching so-called 'longevity escape velocity' eventually culminating in indefinite lifespans. Like many transhumanist technologies, gene therapy is really exciting because it's just beginning."
The Scientist looks at return on investment for research - especially medical and biotechnology research - and misses the point. We're not in a gentle race to an ephemeral crown with other demographic groups overseas. Rather, we're in a nail-biting contest to defeat disease, degeneration and aging, amidst an ongoing tsunami of death that dwarfs any other cause of misery in the world. The sheer scale of economic devastation suffered daily, monthly and yearly due to aging is hard to visualize; as Robert Freitas notes, "the worldwide natural death toll of 52 million people in the Year 2001 represents an economic loss of about $100 trillion dollars. Every year. How big of an economic calamity is this? Taking Federal Reserve figures for the total tangible wealth of the United States, including all financial assets, all real estate, and all consumer durables, net of debt, and applying the ratio of U.S. to world GDP gives us an estimate of total global tangible net worth of $91 trillion dollars. So this means that every year, natural death robs us of human capital equivalent in value to the entire tangible wealth of the world." Nations have mobilized to oppose economic damage a fraction of this value. No practically attained level of resources directed towards the fight to defeat aging could ever be said to be sufficient.
Modern biotechnology can churn out much more raw information than the scientific community is presently equipped to analyze - the processing of terabytes of data on human biochemistry obtained and archived over the next decade will still be yielding important advances in the 2030s, I'll wager.
One of the important baseline projects - split across many independent research groups and initiatives - is obtaining data on the way in which gene expression and the resulting protein synthesis changes with age in various tissues in the body. These are maps of one very fundamental view of the way in which aging changes us for the worse, right down at the basement level of function in the cell.
Extended longevity is often accompanied by frailty and increased susceptibility to a variety of crippling disorders. One of the most striking features of human aging is sarcopenia, which is defined as the age-related decline in skeletal muscle mass and strength. Although various metabolic and functional defects in aging muscle fibres have been described over the last decade, it is not known whether a pathophysiological hierarchy exists within degenerative pathways leading to muscle wasting. Hence, in order to identify novel biomarkers of age-dependent skeletal muscle degeneration, we have here applied mass spectrometry-based proteomics for studying global muscle protein expression patterns.
These findings demonstrate a severely perturbed protein expression pattern in aged skeletal muscle, which reflects the underlying molecular alterations causing a drastic decline of muscle strength in the senescent organism. In the long-term, the systematic deduction of abnormal protein expression in aged muscle by proteomic profiling approaches may lead to the cataloguing of a cohort of novel therapeutic targets to treat muscular weakness in the aging population.
What more can be done with this knowledge? A good question, and here is an open question in return: what can you do with a map? Those choices, goals and initiatives are, as always, up to us. At the moment, little effort goes into using present knowledge to influence aging and human longevity - that will continue to be the case, even as knowledge grows tremendously, unless we choose to do something about it. New technologies don't invent themselves.
Chris Patil examines a contrarian viewpoint on antagonistic pleiotropy and the evolution of aging: "the idea is that genes which benefit an organism early in life but hurt fitness later on can nonetheless be selected, since extrinsic causes of mortality and the inexorable logic of exponential population growth cause the strength of selection to decrease with time ... The theory is an attractive one that has gained popularity among biogerontologists, as more and more findings are announced that appear consistent with its predictions. ... But every theory has detractors as well as adherents ... In a recent opinion in Biogerontology, Parsons launches a spirited attack on the generality of antagonistic pleiotropy ... The author’s main argument is that the requisite conditions for antagonistic pleiotropy are extremely rare in naturally occurring populations, and that environmental stress should be a major driving force in the evolution of longevity. Negative consequences of selectable traits should be less important at the levels of energy intake that actually occur in the wild, he argues; furthermore, he proposes that some of the data in favor of antagonistic pleiotropy are artifacts of the artificially benign environments we create in the lab."
Gerontologist Caleb Finch has a new book out this month, entitled "The Biology of Human Longevity: Inflammation, Nutrition, and Aging in the Evolution of Lifespans." Here, US News takes a gander: "In the last 200 years, one year of extra lifespan has been added for about every four years of historical time. Life expectancy has doubled since the industrial revolution, from about 40 years to near 80 years. ... Aging processes in humans are directly related to the nutritional and inflammatory aspects of the environment. One example is Alzheimer's disease: Research from our lab has shown that the senile plaques that build up in that disease are related to inflammatory processes in the brain. And we now know that inflammation intensifies atherosclerosis, the hardening of the arteries that can contribute to stroke and heart attack. Longer life spans have been a worldwide phenomenon associated with improvements in hygiene and medical care and reductions in infectious disease. Some have explained this through the reduction of infant mortality. But we're also living longer because we're staying healthier - kids have fewer infectious diseases to fight with. This reduction of inflammation and infection, along with the improvement of nutrition, has contributed to longevity by slowing many of the diseases of aging."
I thought I'd pass on a collection of interesting items that caught my eye in the past couple of days; none are really worth long commentary in and of themselves, but consider them to be signs of the times. Most of the amazing things researchers now know and can accomplish with modern biotechnology go largely unremarked in a field of similar acheivements - progress measured as a glazing of the eyes in the face of a sea of advances in medicine.
Telomere length (TL) is emerging as a biomarker for aging and survival. To evaluate factors influencing this trait, we measured TL in a large homogeneous population, estimated the heritability (h^2), and tested for parental effects on TL variation. Our sample included 356 men and 551 women, aged 18-92 years, from large Amish families.
As expected, TL was negatively correlated with age (r = -0.40; P < 0.001). There was no significant difference in TL between men and women, consistent with our previous findings that Amish men lived as long as Amish women. There was a stronger and positive correlation and association between TL in the offspring and paternal TL (r = 0.46, P < 0.001; = 0.22, P = 0.006) than offspring and maternal TL (r = 0.18, P = 0.04; = -0.02, P = 0.4). Furthermore, we observed a positive correlation and association between daughter's TL and paternal lifespan (r = 0.20, P < 0.001; = 0.21, P = 0.04), but not between daughter's TL and maternal lifespan (r = -0.01, = 0.04; both P = not significant).
King's College London scientists compared key ageing DNA with the number of moles in a study of 1,800 twins. They found the more moles a person had, the more likely their DNA was to have the properties to fight off ageing. The study, in the Cancer Epidemiology Biomarkers and Prevention journal, contrasts with the link between a high mole-count and high skin cancer risk.
In the study, researchers found those with more than 100 moles had longer telomeres than those with fewer than 25. The difference between the two mole groups was equivalent to six to seven years of ageing.
Lead researcher Dr Veronique Bataille said: "The results of this study are very exciting as they show, for the first time, that moley people who have a slightly increased risk of melanoma may, on the other hand, have the benefit of a reduced rate of ageing. This could imply susceptibility to fewer age-related diseases such as heart disease or osteoporosis, for example. Further studies are needed to confirm these findings."
This second article is another good example of the tradeoff between senescence and cancer seen in many aspects of human biology, but especially the mechanisms relating to telomere length:
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)."
A new project to partially sequence the genomes of 100 people age 100 or older could shed light on the genetic variations that allow some people to stay healthy decades beyond the average life expectancy. Dubbed the Methuselah Project, the endeavor will serve as a test bed for a new approach to sequencing
The project follows the highly publicized release of the genome of James Watson, codiscoverer of the structure of DNA. ... Carried out by 454 as a demonstration of its sequencing technology, the landmark project costs about an order of magnitude less than a human genome sequenced with traditional technologies.
But the Methuselah effort will use a new, streamlined way of analyzing the genome by isolating and sequencing only the so-called coding regions of DNA. By focusing on this small portion of the genome--about 1 percent--scientists can sequence 100 genomes for the same price as sequencing Watson's entire genome.
“The idea of using ES cells to make blood cells we can transplant, neurons that we can transplant . . . (with) all of the techniques and technologies, we thought that we had to target the stem cell,” Dr. Bhatia said. “Now we have a new target. We can also target the niche.”
“So we now have a completely new way of controlling differentiation toward regenerative medicine.... It really opens a whole new paradigm.”
Commenting on the paper Wednesday, the head of the Stem Cell Network of Canada said the work points scientists to new pathways for producing large quantities of embryonic stem cells in the lab, and brings the notion of regenerative medicine closer to reality.
Dr. Bhatia believes the work may also have implications for research into cancer stem cells, which appear to give rise to at least some tumour types and are resistant to chemotherapy, theoretically allowing malignancies that seemed to be cured to recur at a later time.
Conventional wisdom suggests that cancer stem cells - which have been identified in a number of malignancies, including blood and colon cancer - quietly hide in their niches for a period of time, then begin churning out daughter cells like some unstoppable Xerox machine, “which really is what a tumour is,” he said.
Dr. Bhatia suggested it may not be the cancer stem cell itself that goes awry, but the cells that make up the niche where it lives - particularly since the niche cells pump out proteins to feed their parent and may give it chemical directions for what to do.
“Maybe the niche lets go of its control. You can imagine that controlling the niche might be another target or way of controlling tumour growth.”
Matters are moving rapidly, and the cost of research is falling precipitously. Low cost research means more research, and at the same time it is increasingly the case that new discoveries in cell biology have implications for cancer, stem cell research and many other fields - a good sign of progress. Researchers are down at the basement level of biochemistry, tracing the wiring, with ever more helpers and ever better tools.
Technorati tags: medical research
When looking at the most impressive list of presentations set out for this year's Strategies for Engineered Negligible Senescence conference (SENS3), we should take a moment to acknowledge the generous donors who help to make it possible: "$25,000 from the Millard Foundation; $10,000 from the Glenn Foundation; $1,000 from HMX, Inc.; $1,000 from the Supercentenarian Research Foundation; $1,000 from Legendary Pharmaceuticals. Thank you all! Regular readers will recognize the Glenn Foundation as a major supporter of the Methuselah Foundation, as well as the force behind the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, and some of the other groups as long-time donors and associates. Gary Hudson of HMX, Inc. is well on his way through the six figure range - a true champion for healthy life extension science. For those of you with a mind for the history of computing - many, I know - you'll be interested to know that the Millard Foundation is the philanthropic face of William Millard, visionary pioneer of the PC industry and founder of Computerland. Pleased to have you on board!"
Researchers continue to move towards the use of stem cells to treat neurodegenerative conditions like Parkinson's. Via PhysOrg.com: "[The] study showed that only a small number of stem cells turned into dopamine-producing cells - not enough to improve the primates' function by replacing missing neurons. Instead, some stem cells turned into astrocytes, a supportive brain cell that produces neuron-nourishing chemicals. ... [we] have been arguing, for some time now, that stem cells are important for brain repair because they provide growth factors and because they send signals to the brain to help it repair itself. This study in primates showed the same effects that the stem cells are there to act as facilators of repair versus the original hypothesis that stem cells are transplanted to merely replace an injured cell ... We hear about new sources of stem cells monthly, but how we take those cells and treat disease is going to be a significant amount of translational work. This is one of the first studies that starts that process - looking at primates before going into people with Parkinson's disease ... Pending further preclinical studies, the results so far from the current study are supportive for developing a safe and effective stem cell treatment for Parkinson's disease."
I notice that researcher Stephen Spindler is soliciting the healthy life extension community of sci.life-extension for suggestions as to further compounds to test in his ongoing mouse longevity studies.
Does anyone have suggestions of single or groups of supplements, food additives or drugs to test in mouse lifespan studies?
I have funding for such studies. If you do, please forward your suggestions to me. Please include some information about the rationale for the suggestions.
I am already aware of and considering the following:
lipoic acid [We tested this at 600 mg/kilogram of the control diet alone and with n-acetyl-l-cysteine (2000) & vitamin E (585) & lycopene (300) and found no effect]
Tocopherol monoglucoside (TMG), a water soluble derivative of vitamin E
Ascorbyl palmitate (PROBABLY NOT SUITABLE)
Chenodiol (kee-noe-DYE-ole) (a.k.a. chenodeoxycholic acid)
synthetic beta-amino acid proteins
buckyball c60 antioxidants
EUK antioxidant compounds
pineal hormones. 5 in all.
cortagen, epithalon, vilon, livagen, prostamax other short synthetic peptides.
Januvia (Merck) (a.k.a. LAF237)
Exenatide (a.k.a. Exendin-4, marketed as Byetta) (Amylin Pharmaceuticals, Inc. and Eli Lilly and Company)
Imatinib (a.k.a. Gleevec, Imatinib Mesylate, STI571, CGP57148B)
Inhibitors of PDGF receptor
phenyl isopropyl adenosine
And the NIA interventions testing program is already testing:
Stephen R. Spindler, Ph.D.
Department of Biochemistry
University of California, Riverside
Riverside CA 92521
It has to be said, and I'm sure I've said it before, that I don't see this sort of thing as the path to the future. Consider that a decade or two from now, simulated mice on silicon will be cheap, and millions of compounds will be testable every year. Just how great a benefit can the study of a few thousand compounds between now and then gain versus, say, research aimed at advancing biomolecular repair technologies aimed at the known and suspected causes of aging?
That said, my suggestion is to pick a few of the class of compounds employed by Skulachev to target antioxidants to mitochondria without the need for gene therapy, and which were demonstrated to extend healthy life in mice - I'd like to see that replicated in a US laboratory.
Why, despite the great range of potential applicable biotechnology, do we not see hundreds of millions of dollars invested in startups attempting to address the aging process? The answer is buried in this New York Times article on Sirtris: "Dr. Westphal and Mr. Sinclair stress that they are not working to 'cure' aging, a condition that, so far at least, is common to all humanity and that most physicians do not consider a disease. 'Curing aging is not an endpoint the federal drug agency would recognize,' Dr. Westphal says dryly. Instead, both men say, they are working to ameliorate the diseases of aging." For so long as unelected government employees can declare, with no accountability and full force of law, what medicine is permitted and what is not, there will be no direct venture funded efforts to cure aging - or even to take the first steps by aiming to repair specific, identified age-related damage in order to intervene in the aging process. There is no lack of companies, research groups and billions of dollars ready to be directed to that end, as any brief survey of the biotechnology marketplace will show you - but the ignorant few who write policy continue to bury all that potential. The work that could have gone to advance the cause of healthy longevity is instead confined towards the backwaters of patching specific age-related conditions.
Effective gene therapies for cancer are becoming more plausible for the near future, as illustrated by this report from EurekAlert!: "A molecularly engineered therapy selectively embeds a gene in pancreatic cancer that shrinks or eradicates tumors, inhibits metastasis, and prolongs survival with virtually no toxicity ... The researchers call the system a versatile expression vector - nicknamed VISA. It includes a targeting agent, also called a promoter, two components that boost gene expression in the target tissue, and a payload - in this case a gene known to kill cancer cells. It's all packaged in a fatty ball called a liposome and delivered intravenously. ... In a test of the therapy against two aggressive lines of pancreatic cancer in two different types of mice, researchers loaded the VISA system with a mutant version of a gene named Bik, which expresses a protein that naturally forces cancer cells to kill themselves. The team created the more lethal mutant and named it BikDD. Untreated control mice in both experiments all died within 40 days. Mice treated with the mutant gene delivered via a less-targeted viral promoter driven expression system employing cytomegalovirus (CMV) all died within 90 days, most much earlier. In both trials, the VISA-BikDD mice lived longer, with at least half surviving for 14 months with no detectable sign of cancer recurrence."
I am reminded by Bruno Giussani that the release date for Aubrey de Grey and Michael Rae's "Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime" is another month closer - September is right around the corner. Giussani provides a short blog interview with de Grey:
How has your research progressed since your TEDGLOBAL05 and TED06 speeches?
The Methuselah Foundation has gone from strength to strength. The biggest development, among other donations, was the pledge of $3.5m from TEDster and PayPal co-founder Peter Thiel, which resulted from a dialogue that began at TED. Most of his pledge ($3m of it) is a 1:2 challenge, so out current goal is to obtain $6m from elsewhere to match that pledge in full.
OK, that's about the funding. But how's the research going?
It's been going really well too. We are currently sponsoring research by three teams (in Phoenix, Houston and Cambridge UK) on two of the most important SENS strands - LysoSENS, the identification and exploitation of microbial enzymes to break down molecules that we cannot naturally degrade, and MitoSENS, the incorporation of modified copies of the mitochondrial DNA into the chromosomal DNA so that mitochondrial mutations will have no effect. Both these projects are going really well, results coming out of the LysoSENS project have already been presented at two meetings and a paper has been submitted for publication in a prominent journal.
What should readers expect to learn from the book?
They will learn all about the detailed science of SENS. The book is written (largely by my splendid research assistant Michael Rae) very much for a non-scientist audience, but without dumbing down the science at all.
Having helped out with the editing a little here and there, I can attest to it being a very fine book indeed.
Aimed squarely at folk who want to know more about the science of repairing the molecular damage that causes aging, but find navigating the wild waterways of scientific publications too intimidating or time-consuming, this is a step by step, detailed explanation of how we could achieve radical life extension within our lifetimes, as best we understand from our present knowledge of our biochemistry.
If you're used to the "eat this, take supplements and exercise" longevity bookshelf, Ending Aging is a big step up - very much more "research this science to develop this specific therapy based upon that sound basis established over the past two decades." You'll be seeing more of that in the years ahead, and this exactly where your attention should be focused if you care about your own longevity.
A video presentation from the TED conference back in 2006 has been doing the rounds over the past couple of days; it's worth your time, for all of being dated. "Alan Russellis a professor of surgery -- and of chemical engineering. In crossing the two fields, he is expanding our palette of treatments for disease, injury and congenital defects. We can treat symptoms, he says, or we can replace our damaged parts with bioengineered tissue. As he puts it: 'If newts can regenerate a lost limb, why can't we?' ... [he] leads an ambitious biomedicine program that explores tissue engineering, stem cell research, biosurgery and artificial and biohybrid organs. [He] studies regenerative medicine, a breakthrough way of treating disease and injury by helping the body to rebuild itself. He shows how engineered tissue that 'speaks the body's language' has helped a man regrow his lost fingertip, how stem cells can rebuild damaged heart muscle, and how cell therapy can regenerate the skin of burned soldiers. This new medicine comes just in time, Russell says -- our aging population, with its steeply rising medical bills, will otherwise (and soon) cause a crisis in health care systems around the world." That crisis has far more to do with socialism than aging - only under a socialist system can a greater need and greater ability to meet that need be turned into a disaster - but advancing medicine brings great benefits for those free enough to research and use it.
Randall Parker notes one possible critique of WILT, Whole-body Interdiction of Lengthening of Telomeres as a strategy to eliminate cancer: "with a new report about telomerase enzyme [that] proposal seems problematic. According to this new result telomerase does not just lengthen the caps on the ends of chromosomes. ... If telomerase is keeping chromosomes stable then taking away telomerase could cause more things to go wrong sooner. I've never been enthusiastic about WILT because we need a cure for cancer for all our cells that do not already have telomerase knocked out in them. We have lots of cells all over our bodies that are getting older and at greater risk of becoming cancerous. Short of replacing our entire bodies WILT will not eliminate the risk of death from cancer. Fortunately, I expect cancers will become very curable. We'll develop immuno-therapies, gene therapies, cell therapies, and even nanobots that will seek out and selectively kill cancer cells." WILT is probably the least favorite part of present day SENS amongst those who support SENS; this is not an uncommon opinion. That is surprising in many ways, as WILT is no more ambitious than other SENS projects like allotopic expression of mitochondrial DNA.
It is with some interest that I watch the ongoing exploration of the biochemistry of exercise. Alongside calorie restriction, we all know that exercise is just about the most cost-effective thing you can presently do for your long term health - study after study demonstrates that fact. So how does this all work? Calorie restriction biochemistry gets all the press these days, with the high level of venture capital invested into developing drugs based on new knowledge, but the biochemistry of exercise is just as much under the microscope - and just as likely to produce meaningful results.
I bumped into one example today - research into the poorly understood link between exercise and reduced inflammation:
recent study by kinesiology and community health researchers at the University of Illinois provides new evidence that may help explain some of the underlying biological mechanisms that take place as the result of regular exercise. According to the researchers, that knowledge could potentially lead to a better understanding of the relationship between exercise and inflammation.
The objective of their research was to examine the independent effect of parasympathetic tone - in this case, determined by assessing heart-rate recovery after exercise - on circulating levels of C-reactive protein (CRP). Parasympathetic tone and its inverse function - sympathetic tone - are components of the autonomic nervous system. CRP, which is secreted by the liver, circulates in the bloodstream and is a biomarker for inflammation in the body.
“We’ve known that as people age, their CRP levels go up,” Vieira said. “That’s one of the reasons why older individuals are more prone to develop inflammation-related diseases such as diabetes and heart disease. So we just wanted to look at what’s predicting those levels of CRP in an average older population that is relatively healthy.”
Perhaps the most notable result of the study, according to the researchers, relates to heart-rate recovery following exercise.
“The quicker the individuals were able to get back to their resting heart rate after a strenuous exercise test was inversely related to their CRP,” Vieira said. “In other words, individuals who had better parasympathetic tone had lower levels of inflammation.
“And the reason we’re excited about this is that exercise is a great way to improve parasympathetic tone.
“We know inflammation is bad. We know it increases as we age, with stress and other things,” she said. “So if we can decrease that to protect ourselves somehow by just adopting a physically active lifestyle, that’s definitely an advantage.”
And while the study confirms the conclusions of previous research by others indicating that high body fat is related to high inflammation and high fitness to low inflammation, “the unique part of this paper is that controlling for those, we also show that high parasympathetic tone is related to low inflammation,” Woods said.
If you want a better chance of being alive and in good health to take advantage of breakthroughs in longevity science in the decades ahead, best to put reasonable effort into maintaining your health today. Don't expect medicine to rescue you from the consequences of negligence - maybe you'll get lucky, but why gamble away potential decades (or far more) of additional healthy life when it is so easy to take care of yourself?
From EurekAlert!: "In the vast majority of Parkinson's disease (PD) patients, the disorder arises not because of a genetic defect, but because some external insult triggers the death of dopamine-producing neurons. Now, researchers have reported progress in understanding the mechanism underlying that death ... a cellular switch called Cdk5 [regulates] yet another enzyme called Prx2. This enzyme [acts] to render harmless the chemically active reactive oxygen species that are produced inside mitochondria ... the loss of Prx2 activity also plays a role in human PD. They found reduced Prx2 activity in brain tissue from PD patients. ... our findings suggest that strategies to modulate Prx2 activity serve as beneficial targets for treatment of PD. This is of particular importance since Cdk5 is thought to have normal beneficial roles in neurons and modulating a relevant downstream target rather than Cdk5 directly may be a better therapeutic strategy with regard to this pathway." Interesting - recall that targeting antioxidants to the mitochondria extends life in mice, and recall the important role played by mitochondrial free radicals and reactive oxygen species in aging. More potential here than just a Parkinson's therapy, perhaps.
Scientists are striving to construct complex tissue from scratch, for use in transplants for damaged or age-worn organs: "The research demonstrates the potential for eventually growing tissue-engineered vessels out of stem cells harvested from the patients who need them, providing a desirable alternative to the venous grafts now routinely done in patients undergoing coronary bypass operations. ... Although not yet strong enough for coronary applications, the UB group's tissue-engineered vessels (TEVs) performed similarly to native tissue in critical ways, including their morphology, their expression of several smooth muscle cell proteins, the ability to proliferate and the ability to contract in response to vasoconstrictors, one of the most important properties of blood vessels. The TEVs also produced both collagen and elastin, which give connective tissue their strength and elasticity and are critical to the functioning of artificial blood vessels. ... The TEVs were implanted into sheep and functioned normally for five weeks."
Centenarians appear to be physically younger than many of their younger counterparts amongst the old. "Physically younger" is a term up for much discussion and definition, of course, but I'm thinking of specific measures of cellular and biochemical damage, or the functioning of important organs and systems in the body when I say this. Centenarians are, on average, less damaged - which is why they are, on average, still around long after their peers have aged to death.
In the present NONA immune longitudinal study, we investigate the previously identified Immune Risk Profile (IRP), defined by an inverted CD4/CD8 ratio and associated with persistent cytomegalovirus infection and increased numbers of CD8+CD28- cells, relative 6-year survival and age in NONA individuals. These subjects have now reached age 92, 96, and for the first time in this study, 100 years at follow-up. A 55 year old middle-aged group was used for comparison
The results confirmed the importance of the IRP as a major predictor of mortality in this population of very old. Moreover, the results suggested that survival to the age of 100 years is associated with selection of individuals with an "inverted" IRP that was stable across time, i.e., maintenance of a high CD4/CD8 ratio and low numbers of CD8+CD28- cells. The results underlines the importance of a longitudinal study design in dissecting immune parameters predictive of survival and show for the first time that centenarian status is associated with avoidance of the IRP over at least the previous 6 years and probably throughout life.
A damaged immune system leads into a spiral of further damage to your biochemistry and bodily systems. Those people with continually effective immune systems stand a greater chance of living longer, healthier lives. The best thing to take away from studies such as this is a target for new medicine and research: the goal of repairing and maintaining the human immune system in good condition for as long as needed. The various ways in which an immune system becomes damaged and poorly functional are becoming well known; researchers have enough to get started on doing something about this aspect of aging.
In response to a de Grey paper on aging, DNA damage and cancer I recently noted, Khrapko puts forward a different position: "In his pleasantly provocative opinion paper, Aubrey de Grey argues that (a) independent age-related deteriorative processes evolve to reach approximately equal importance for the aging process as a whole, but (b) this equality can be broken by 'protagonistic pleiotropies', i.e. when a process is contributing to more than one competing death causes. In particular, the fact that nDNA mutations are extremely efficient in killing by inducing cancer implies that these mutations should be irrelevant for non-cancer aging. In my opinion, (a) independent processes may not necessarily attain equal importance because of different inherent susceptibility of the corresponding genes or gene networks to evolutionary change. However, once this is taken in consideration, a refined evolutionary argument does imply that in protected environment, continuing lifespan extension will eventually make any age-progressive degenerative process a significant contributor to aging and (b) protagonistic pleiotropies may be ineffective in making degenerative processes."
An interesting paper here, proposing that changes in gene expression have as much or more to do with rising levels of free radical damage with age than simple damage to mitochondrial DNA (mtDNA): "The Mitochondrial Theory of Aging postulates that accumulation of mtDNA mutations and mitochondrial dysfunction are responsible for generating aging phenotypes and limiting lifespan. Although widely accepted, this theory remains unproven because the evidence supporting it, while substantial, is largely correlative. Furthermore, recent experimental results in mice with accelerated rates of mtDNA mutagenesis have challenged the traditional formulation of the Mitochondrial Theory, perhaps warranting a reevaluation of some of its core principles. In this perspective, we summarize recent work suggesting that both the quantity and the quality of mitochondrial gene expression play a much greater role in the aging process than previously appreciated. We speculate that this form of mitochondrial dysfunction may operate independently or in concert with mtDNA mutations to promote age-related pathology and limit lifespan." Non-functional gene expression has the same effective result as a damaged gene - the proteins produced from the blueprint of that gene, essential to cellular machinery, are no longer made inside that cell.
The fifth annual Calorie Restriction Society conference will be held later this year - another good chance to learn more about the science and practice of calorie restriction with the intent to extend healthy longevity and reduce risk of age-related disease. One of the highlights of the healthy life extension community, they illustrate the right way to develop ties to the scientific community and help to push forward and encourage research:
The fifth CR Society Conference (CR V) will be held in San Antonio Texas, November 7-11, 2007. The current roster of participating scientists includes Steven Austad, Rochelle Buffenstein, John Holloszy, Jim Nelson, Jay Phelan, Arlan Richardson, Walter Ward, and Bradley Willcox. We also will include presentations by members of the Society.
More information was forthcoming today via the CR Society mailing lists:
The Conference will open with a welcoming reception/registration on Wednesday evening November 7 starting at 6:30 pm. The presentations will start Thursday November 8 at 9:00 am and end Sunday Sunday November 11 at 11:00 am
The Conference webpage will be have more information and on-line registration available by Thursday.
Map of Sunset-Station and our hotels:
The current roster of participating scientists includes:
We also will include presentations by members of the Society.
We will have two banquet style meals. There will be one lunch on Thursday and one dinner on Saturday. The meals will be a salad bar buffet with a selection of vegetables, fruit, nuts and chicken breast (lunch) or Salmon (dinner). More details about the menu will be available soon.
Both Meals $50
CR Society Supporting Member Registration:
Early (before August 22) $275
After August 22 $325
Non-Member Registration (or the free Basic email list membership)
Early (before August 22) Non-member $325
After August 22 $375
Lifetime and Founding members receive an additional $50 discount and Spouses'/Significant Others registering together receive an additional $50 discount each. If you are not sure of your membership status contact Robert Cavanaugh, the Managing Director at email@example.com.
After registering for this conference, you are entitled to a discounted registration for the Glucose Control Workshop on August 10-12, 2007.
While Sunset Station does not operate a hotel, we have secured rooms at two nearby hotels from Wednesday through Sunday:
Staybridge Suites Sunset Station Downtown:
This is a new hotel opening in July 2007.
Studio Suites with 2 Double Beds $145 + tax (16.75%)
1 Bedroom Suite with King Bed $165 + tax (16.75)
Check in after 3:00pm, check out by 12 Noon (Additional charges may be assessed unless the hotels Rooms Division approves check out extensions)
To make your reservation, call the hotel at 210-444-2700 or the Central Reservation System 800-238-8000 and and tell the hotel's reservation agent you are with the Calorie Restriction Society Group to get our group rate. After our room block is filled or after our October 7 cut-off date, room rates will depend on availability. Rooms not guaranteed for late arrival will be held only until 6 PM. Rooms may be guaranteed by submitting one night's room and tax or through use of a major credit card. Guaranteed reservations (without occupancy) are held for one night and not for the entire length of stay.
Best Western Sunset Suites/Riverwalk:
Single King or Double Double $89 + tax (16.75%)
After our room block is filled or after our October 7 cut-off date, room rates will depend on availability. Your reservation will be guaranteed by either your credit card or an advanced first night's deposit. You will be held responsible for the first nights payment if not cancelled by 3 PM (CDT) of your arrival date.
To make your hotel reservations, call 877-775-0700 or 210-223-4400, and tell the hotel's reservation agent you are with the the CR Society Group.
We are very excited about having our fifth Conference in San Antonio. Set aside the dates, meet fellow CR Society members in person, participate in an enjoyable, interesting, and educational conference. We are looking forward to meeting you.
As for the last CR Society conference, it looks to be a worthy affair. If you'd like to find out more, a great many video presentations from the last conference are available online.
Via EurekAlert!, another demonstration of the use of existing cellular mechanisms as a part of cancer therapies: researchers "have been able to derive mesenchymal stem cells from human adipose, or fat, tissue and engineer them into 'suicide genes' that seek out and destroy tumors like tiny homing missiles. ... Mesenchymal stem cells help repair damaged tissue and organs by renewing injured cells. They are also found in the mass of normal cells that mix with cancer cells to make up a solid tumor. Researchers believe mesenchymal stem cells 'see' a tumor as a damaged organ and migrate to it, and so might be utilized as a 'vehicle' for treatment that can find both primary tumors and small metastases. ... the researchers worked to find a less toxic way to treat colon cancer than the standard-of-care chemotherapy agent, 5-fluorouracil (5-FU), which can produce toxic side effects in normal cells. They expanded the number of mesenchymal stem cells in the laboratory and then used a retrovirus vector to insert the gene cytosine deaminase into the cell. This gene can convert a less toxic drug, 5-fluorocytosine (5-FC), to 5-FU inside the stem cells, and the chemotherapy can then seep out into the tumor, producing a lethal by-stander effect. ... tumor growth was inhibited by up to 68.5 percent in the animals, and none of the mice exhibited any signs of toxic side effects."
The New York Times interviews Elizabeth Blackburn on the topic of telomere science: "Telomeres are the protective caps at the ends of chromosomes in cells. Chromosomes carry the genetic information. Telomeres are buffers. They are like the tips of shoelaces. If you lose the tips, the ends start fraying. Telomerase is an enzyme. In cells, it restores the length of the telomeres when they get worn. As the ends of the chromosomes wear down, the telomerase comes in and builds them back up. In humans, the thing is that as we mature, our telomeres slowly wear down. So the question has always been: did that matter? Well, more and more, it seems like it matters. ... In my lab, we're finding that psychological stress actually ages cells, which can be seen when you measure the wearing down of the tips of the chromosomes, those telomeres. ... we looked at two groups of mothers. One had normal, healthy children. The other group had a child with a chronic illness. Physiological and psychological measurements were done on everyone. With the stressed group, we found that the longer the mothers had been caring for their chronically ill child, the less their telomerase and the shorter their telomeres."
I've noted a couple of pieces in recent weeks that emphasised the common sense nature of transhumanism: helping to make life longer and better, one action at a time, is a core human ideal. There are no special cases, no magical transition point at which it's fine and dandy to write people off or justify their deaths. Healthy life extension flows quite naturally from the same mindset that helps neighbors and appreciates modern medicine. We all recognize that which is unpleasant in commonplace life, and it's only natural to work to remove that unpleasantness. Here's another example:
So is technology really such a great thing? Is researching it really one of our highest priorities, if it doesn't even make people happier?
In a word, yes. For there is a way out. Not every technology is meaningless - technology has indirectly made our societies more open-minded, helping members of different minorities feel more accepted. Happiness studies suggest that one's health is a major component to their happiness, so improvements in healthcare help as well. The key seems to be that technology needs to primarily modify, not our environment, but ourselves. If evolution has given us such a crappy deal, where we keep striving for externalities that don't make us any happier, let's beat evolution and modify the internalities.
That, of course, is what transhumanism is all about. In fact, since technology has such a great capability for making people happier, I would argue that anyone who cares about the happiness of others has a moral responsibility to be a transhumanist.
Currently, growing old is not a very enjoyable thing - your health begins to fail, your close ones start dying off, you become too tired to create new social circles when you lose the old ones. It is no wonder that there have been reports of disproportionally high suicide rates among the elderly. All of this could be avoided if we could eliminate aging and prevent all age-related decline, so people would stay healthy and physically young forever. This is a project many transhumanists are actively working on or supporting by donating to the Methusaleh Foundation - we already know what causes old age, so all that remains is fixing it.
All six categories - and others I have not mentioned - increase equality. People are not randomly condemned to be stupid. People are not condemned to be unhealthy simply because they're old. Like intelligence, some are naturally more talented at self-control than others: by increasing our control of our own brains, these inequalities diminish. Some people are not condemned to live in bodies they're unhappy with, while others get great ones. People are not condemned to be naturally less happy than others. People are not wiped out of existence when they'd still rather live. All of this increases people's happiness, and giving people control over these things gives them more choice. These are some of the core values that transhumanism's all about: Happiness, Equality and Choice.
Seeking equality of opportunity by helping people to overcome the limitations of their own personal human condition is a worthy goal today, and will be just as much so in a future of far greater opportunity. The foundation of opportunity is life - is being alive, and possessed of the vigor to take advantage of that fact. Without that, there is nothing. So I think we really have to start there, with aging, a great injustice blindly inflicted upon humanity by chance, physics and evolution. To not seek the cure for aging would be just as strange as to fail to seek a cure for cancer or Alzheimer's - it would be inhuman and unnatural for the species that helps its neighbors and appreciates the good things in life.
Ouroboros looks at the role of sirtuins in relation to age-related neurodegenerative conditions: "Where questions are asked about diseases of aging, the discussion will eventually turn toward the great scourge of age-related neurodegenerative disease. Given that sirtuins have already demonstrated potential to positively impact the aging process in a wide range of animals, it seems logical to ask whether they might also have therapeutic or prophylactic potential against neurodegeneration. The answer may end up being murky, and rely on the specific details of the specific illness and sirtuin family member in question. Two recent papers have studied the effect of sirtuin expression (and pharmaceutical modulation of sirtuin activity) on neurodegenerative disease - and come up with two diametrically opposing answers. Why the dramatic difference in results? The answer could lie either in differences between the diseases studied or in the functions of the sirtuin family members that were targeted." There is a great deal more to learn if scientists are to successfully manipulate metabolism to good effect. There are faster paths to a future of greatly enhanced longevity.
I'm seeing more press releases from Telomolecular of late. To me that suggests they are heading into the next round of funding. It never hurts to bang the drum: "Nanocircles (a nanotechnology developed at Stanford University) and vTert (Telomolecular's synthetic enzyme) are capable of repairing damaged and shortened telomeres. Researchers at Telomolecular believe they've found a way to deliver Nanocircles and vTert to chromosomes in living organisms, reversing diseases caused by that damage. The researchers envision the ability, eventually, to speed the healing process in humans, preventing or even curing cancer. ... In the laboratory, Telomolecular has regenerated aged tissues that remain permanently young and live thousands of times beyond their normal replicative life span. Duplicated in living animals, this process could cure a variety of diseases caused by critical telomere degradation." Longer lived tissues do not automatically translate to longevity of health - it's very specific to the situation at hand. I found the recent news relating to Telomolecular's licensing of mitochondrial repair technology to be much more interesting than these general interest releases, given research indicating links between mitochondrial damage and telomere shortening.
A couple of interesting, worthwhile articles drifted my way via the usual channels in the past couple of days. This first piece illustrates perfectly why Malthusianism, the inability to understand that present limits change through human action, is so much a part of opposition to healthy life extension - it's just as much a worship of death as the maunderings of Kass and others.
And yet, alongside the ethos of human rights and the development of heroic medicine, contemporary society appears estranged from its own humanity. To put it bluntly: it is difficult to celebrate human life in any meaningful way when people - or at least the growth of the number of people - are regarded as the source of the world’s problems. Alongside today’s respect for human life there is the increasingly popular idea that there is too much human life around, and that it is killing the planet.
today’s Malthusians share all the old prejudices and in addition they harbour a powerful sense of loathing against the human species itself. Is it any surprise, then, that some of them actually celebrate non-existence? The obsession with natural limits distracts society from the far more creative search for solutions to hunger or poverty or lack of resources.
Life - and by extension, the necessary means and medical technology to make that life worth living - is the goal of healthy life extension. Oblivion and poverty are the goals of the modern Malthusian. This is a reminder once more that the greatest obstacle to healthy life extension research is not the technological hurdles, but rather those amongst us who would see us all age and die to satisfy their errant beliefs.
On a more positive note, the second article sees Freeman Dyson reinforcing a bandwagon I jumped on a while back. Radical, competitive, inventive decentralization in any given field is a wonderful sign of progress; it tends to come about only when the costs of taking action have fallen past the point at which amateurs get involved, and when the old centralized priesthood has failed to use force to maintain their grip. At that point, a field of human endeavor can't help but be competitive and inventive - it's what humans do best. We are starting to see this transition in biotechnology, and can hope that the massive, interfering governments of this modern world are not turned to shut down the freedom to innovate by the sort-sighted and the foolish. Says Dyson:
Biology is now bigger than physics, as measured by the size of budgets, by the size of the workforce, or by the output of major discoveries; and biology is likely to remain the biggest part of science through the twenty-first century. Biology is also more important than physics, as measured by its economic consequences, by its ethical implications, or by its effects on human welfare.
I see a bright future for the biotechnology industry when it follows the path of the computer industry, the path that von Neumann failed to foresee, becoming small and domesticated rather than big and centralized.
Once a new generation of children has grown up, as familiar with biotech games as our grandchildren are now with computer games, biotechnology will no longer seem weird and alien. In the era of Open Source biology, the magic of genes will be available to anyone with the skill and imagination to use it. The way will be open for biotechnology to move into the mainstream of economic development, to help us solve some of our urgent social problems and ameliorate the human condition all over the earth.
The bounty of the future is in human freedom, decentralization, competition and collaboration, not in those monolithic institutions that strive to repress and control through use of government force.