More Video For SENS Science Underway

Via the Methuselah Foundation blog, it seems Foundation volunteers are digging in to expand the existing range of online video explaining the science of SENS: "Aubrey de Grey and I will be recording several short videos explaining the science of SENS, the Strategies for Engineered Negligible Senescence, for the benefit of the general public. These videos are intended to serve as an intermediate step between the brief text overviews at the SENS website and the scientific literature. This is a similar niche to that successfully occupied by Ending Aging, but intended to address a slightly different target demographic. The resulting videos will be hosted at the Foundation website, as well as being uploaded to YouTube and Google Video. We hope they do as wonderful a job of raising awareness that 'SENS makes sense' as the many existing presentations and interviews with Aubrey have done in past years. ... We would like this to be an ongoing process of engagement, reaching out to hit those points brought up by those people interested in SENS, and will be coming back to the studio many times in the months ahead. In order for this series to make as much impact as possible, please chip in with suggestions for slides, specific questions to tackle, or anything presentation-wise you feel we should bear in mind while we're recording."

Link: http://blog.methuselahfoundation.org/2007/11/videos_for_the_science_of_endi.html

Thoughts on the Prospects For Longevity

From an Independent op-ed on the continual upward revision of actuarial projections: "Researchers for the Cass have done a lot of sums and worked out that the current accepted figure for life expectancy - 76.6 years for men and 81 years for women - is probably too conservative as far as the younger generation go. ... The slightly odd thing about the Cass Business School was that it was widely reported not as a cause for universal rejoicing but as grounds for alarm. The vocabulary employed was of 'problems' and 'timebombs' and 'catastrophes'. Something similar has been true of recent television programmes about ageing - which generally follow up the good news (life is getting longer) with a furrowed anxiety about the consequences of this alteration to our biological destiny. ... Yes, there might be problems paying the bills, and yes, everything depends on the quality of those extra years. But anyone who really thinks an extra 10 years is a disaster can always volunteer to check out early and help the Treasury's figures. I won't be going a day earlier than I have to. There are too many books to read."

Link: http://comment.independent.co.uk/commentators/thomas_sutcliffe/article3198902.ece

Counting Time By Development Cycles

When will the future arrive? When does the nifty new science you read about in the popular press turn up in the clinic? When will the new medical technology be reliable and widespread in availability? I've found the best way to think about these sorts of things is to play a speculative game of counting development cycles.

It takes a certain amount of time to move from proof of concept to fundraising to development to commercialization of an actual product in fields dependent on scientific research. Much of this time has to do with human organization, communication and collaboration, rather than the actual work of progress. Even in the least regulated of such fields, a five year turn around is not unreasonable. Only after five years will the first widespread feedback, adaptation and planning begin for the next iteration of the broad, competitive development cycle.

It's important to realize that large differences in timing exist between what is theoretically possible, the expected dates on which a funded scientific community can deliver technology demonstrations, and availability of a commercial product. This is especially true when government regulation is involved in the process.

But on to the estimations. My view of the biotech and medical research field suggests that the development cycle for new products medians out at around a decade - a far cry from the rate of advance possible in less regulated industries, such as the development of computing devices. Calorie restriction mimetics look to come in under that median, while gene therapy is lagging far behind. Applications of autologous stem cell therapies look to fall somewhere in between. There are plenty of other examples if you care to go digging.

The conservative late adopter waits for the second business cycle for any product he can afford to wait for. The second round is always better than the first, more effective, cheaper and more widely available.

So to pick an example: I believe the estimates of the late 2010s for the first commercial organ generation via tissue engineering. That seems plausible, given progress to date; the first technology demonstrations are still a couple of years away, pending solution of the blood vessel problem. That suggests that the late 2020s would the time of routine, widely available organ replacement - a procedure analogous to preventative surgery today - at the completion of the second development cycle.

Another example: replacement of all damaged mitochondrial DNA through one or other of the vectors presently demonstrated. Should one of these research groups obtain sufficient funding, they will enter the ten year track - but it might take years more to arrive at that point. It can't hurt to assume that any promising, generally unfunded science is at least five years away from building critical mass. For that reason, I think the early 2020s are the earliest we are likely to see commercially developed mitochondrial DNA replacement technologies.

Following the two cycle rule again, that means the early 2030s will be age of routine mitochondrial DNA replacement starting in late middle age, an outpatient procedure that your physician will badger you into doing every couple of years. It'll be a pain to schedule, like the biopsies and exams, but skipping it will be like not checking for cancer - just dumb.

How Much Do We Care About Health and Life?

A survey of the world today would suggest we care about as much about health and life in the abstract as we care about anyone else's property - which is to say, not enough to do anything much about it. We'll grasp at the easy non-solutions, but putting in meaningful work? That's hard. I can't say I agree with more than half of what this Huffington Post columnist has to say, and his grasp of the science of longevity is miserable, but here's some of the half worth reading: "People who grasp whatever is at hand in the hope that it will slow or stop the rising water of mortality are not to be faulted or derided. But there are those who exploit this vulnerability to achieve or maintain power, or for financial gain, who exploit with twisted science and do great harm in the process. ... So far, what is possible now, is a longevity of 122.5 years, and I see no reason why a breakthrough cannot occur during this century to make it possible for many people to attain that age. Meanwhile, research on aging and longevity is underfunded, not overfunded. The cost to the U.S. taxpayers of one month of the Iraq war would fund a serious war against mortality for ten years." What do we really care about in life, enough to do something about it?

Link: http://www.huffingtonpost.com/dan-agin/methuselah-laughing-liar_b_74341.html

An Overblown Claim of Skin Aging Reversal

I can see this item from EurekAlert! getting much press, due to the nature of the claim: researchers "have reversed the effects of aging on the skin of mice, at least for a short period, by blocking the action of a single critical protein." That is greatly overstating the case. The researchers have identified a linked network of changes in gene expression that occur with age, and demonstrated that they can reverse those changes through a comparatively simple feat of engineering. The result looks positive at first, but what about the wear and tear and biochemical damage of age? What about the buildup of AGEs and other harmful compounds? What about damaged mitochondrial DNA and oxidized lipoproteins? What about the prospects for cancer when damaged skin cells are restored to full operation? This is a good technology demonstration, and a good investigation of the complex genetic mechanisms of a single organ - but it is not a general reversal of skin aging, as will no doubt be trumpeted in the general press.

Link: http://www.eurekalert.org/pub_releases/2007-11/sumc-srp112607.php

Developing Applications of Sirtuin Research

As Chris Patil notes, things have moved fast in the field of sirtuin research:

The work represents the culmination of a huge amount of progress in a relatively short time: in less than 15 years, the sirtuin story has evolved from basic biology in the simplest model organisms, through exhaustive (though essential) testing in larger animals, into a source of potential therapies for a major human disease.

Furthermore, for the first time we have a clearly defined path toward the regulatory approval and widespread use of a compound that could be used as a frank anti-aging drug.

It's a good model for modern biotechnology research - an example of the speed with which mechanisms can be traced and understood, once a starting point is made. The process is ongoing, for many other proteins and genes related to beneficial metabolic response to calorie restriction. Sirtuins are just the start.

I would not, however, agree that it is a good model for the application of such research. One can applaud the success of researchers in obtaining funding and carving out a viable, competitive, well-funded field from the first studies of genes and calorie restriction. But the path to applied longevity science is not to call triumph at finally pushing something (anything!) past the impossible hoops blocking applied aging research - it should be to destroy the regulatory nonsense rules preventing progress.

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.

The press is running another round of articles on Sirtris Pharmaceuticals at the present time, focusing on the next line of drugs that improve greatly upon the basic model of resveratrol - at least in terms of their effectiveness in stimulating sirtuin activity.

The potent new pills mimic resveratrol in mice by activating the SIRT-1 gene, which appears to trigger a process called caloric restriction. In many organisms, that process acts to slow down aging and ramp up cellular defenses in the face of a reduced diet during times of scarce food supplies. Sirtris's new compounds, however, act without the little critters having to reduce their diet.

As most of you probably know, I'm not convinced that this is all any more than a sideshow. For one, it is in no way an attempt to directly repair the damage of aging, and for two, for so long as the present regulatory structure forbids the development and commercialization of real, working anti-aging medicine, there is no financial incentive to develop real, working anti-aging medicine. Even if you have a promising start, of any sort, every venture-funded, competitive effort to turn science into medical technology will go towards turning that start into a patch, an after-the-fact and comparatively ineffective treatment for some age-related condition, rather than a treatment for aging itself.

Here is a simple rule for life: you won't accomplish task A by working on task B. That task A is cut off by regulatory fiat is the real problem here.

The Mouse AGEMAP

Via EurekAlert!, a hint of what the next generation of analysis and discovery in aging research will look like: "The study [uses] a newly available database called AGEMAP to document the process of aging in mice at the molecular level. ... Both changes in tissues and cellular damage lead to changes in gene expression, and thus probing which genes change expression in old age can lead to insights about the process of aging itself. ... some tissues (such as the thymus, eyes and lung) show large changes in which genes are active in old age whereas other tissues (such as liver and cerebrum) show little or none, suggesting that different tissues may degenerate to different degrees in old mice. ... there are three distinct patterns of aging, [and] tissues can be grouped according to which aging pathway they take. This result indicates that there are three different clocks for aging that may or may not change synchronously, and that an old animal may be a mixture of tissues affected by each of the different aging clocks. Finally, the report compares aging in mice to aging in humans. Several aging pathways were found to be the same, and these could be interesting because they are relevant to human aging and can also be scientifically studied in mice." To repair the machinery you must know the machinery.

Link: http://www.eurekalert.org/pub_releases/2007-11/plos-amm112807.php

Thoughts on Healthy Life Extension

From practicalethics: "One of the most important ideas in public health is that we can never really save lives: we just extend them. If a doctor 'saves the life' of a 60 year old patient who later dies at 90 years of age, then she hasn't actually stopped the patient dying, but has extended the patient's life by 30 years. ... People typically view [scientific] life extension projects very differently to how they view efforts to cure diseases, such as cancer. They see the former as interesting and somewhat exciting, whereas they see the latter as a moral imperative which deserves urgent government funding. These views are not consistent. All medicine is fundamentally about extending our lives and allowing us to be as healthy as possible while we live. Fighting aging pursues these objectives just as much as fighting a particular disease. If we could find some way of slowing aging so as to extend the human life span by 30% it would produce more benefit than curing any single disease. There is thus a moral imperative to significantly increase research into life extension." The field of "ethics", as usual, seems to have much to do with how to spend other people's money - but the points on the role of medicine stand whether or not we're discussing disposition of tax dollars.

Link: http://ethicsinthenews.typepad.com/practicalethics/2007/11/the-importance.html

Sunday Chat With S. Jay Olshansky at the Immortality Institute

Researcher S. Jay Olshansky will be the guest at the next Sunday chat hosted by the Immortality Institute:

I am happy to announce SJ Olshansky will be joining Imminst for the Sunday Night Chat this Sunday December 2nd at 6:30pm CST U.S. If you are not familiar with Professor Olshanksy...you should be. He was researching methods to slow aging while most Imminst members were still in diapers. He has seen all the hype, the successes, and failures. His latest endeavor is the The Longevity Dividend, which proposes to set aside 3 billion (that's billion with a B) dollars a year of NIH funding for the study of aging.

Chat Room: http://www.imminst.org/chat

Sun December 2nd
- 4:30 Pacific
- 5:30 Mountain
- 6:30 Central
- 7:30 Eastern

You can look back in the archives here for much more on the Longevity Dividend:

As far as I can see, Olshansky is in the camp of "metabolic re-engineering and slow but solid progress in slowing aging is the way ahead, but it'd be wonderful if things that worked far better were demonstrated to be plausible." Which is hopefully a transitionary stage on the way to "I always thought that the Strategies for Engineered Negligible Senescence was a great idea." We'll see.

Another Cancer Resistant Engineered Mouse

Via FierceBiotech, news of another gene-engineered mouse that doesn't get cancer: "researchers discovered that the Par-4 gene kills cancer cells, but not normal cells. There are very few molecules that specifically fight against cancer cells, giving it a potentially therapeutic application. ... mice born with this gene are not developing tumors. The mice grow normally and have no defects. In fact, the mice possessing Par-4 actually live a few months longer than the control animals, indicating that they have no toxic side effects. ... We originally discovered Par-4 in the prostate, but it's not limited to the prostate. The gene is expressed in every cell type that we've looked at and it induces the death of a broad range of cancer cells, including of course, cancer cells in the prostate. The interesting part of this study is that this killer gene is selective for killing cancer cells. It will not kill normal cells and there are very, very few selective molecules out there like this." You might recall the cancer-immune mice with immune systems capable of destroying tumors - work that was presented at SENS3 and is proceeding towards human trials.

Link: http://www.fiercebiotech.com/press-releases/press-release-cancer-resistant-mouse-discovered

On Searching For the Mechanisms of Longevity

Some interesting speculation on longevity genes across species: "The maximum longevity of different species can vary by 100-fold in mammals and by 1,000-fold or more from invertebrates to mammals. However, the life extension effect of single gene mutations or dietary restriction converges on a comparatively minute 1.3- to 1.6-fold difference with controls. It is proposed that this can be due to organization of genes affecting maximum life span in large clusters functionally linked by complex interactions ... A relatively small number of master genes would control the activity of the structural target genes of the whole cluster, strongly facilitating changes in longevity during species evolution. Experimentally manipulating the expression of those master genes would have the potential to increase maximum longevity to a much higher extent than the options available nowadays. ... Fortunately for gerontology, the first highly reliable completed genomes were those of the laboratory rodents and humans, mammals with strongly different maximum longevities, 3-4 years and 122 years, respectively. Comparing them focusing on longevity will help to discover the longevity gene cluster." Should things turn out to work that way, of course - looking for points of simplicity in biology has often proven to be wishful thinking.

Link: http://www.ncbi.nlm.nih.gov/pubmed/17972157

Biology: Always More Complicated Than First Thought

One of the constants of our present age of change and progress is that biology is always more complex than first thought. It's a given. Evolution is under no constraint to produce designs that fall within the bounds of complexity we feel comfortable taking in at one sitting.

The scientific community will still master our biology - reverse-engineer it, replicate it, and ultimately greatly improve on it - but we shouldn't be surprised when hoped-for simplicities in biological mechanisms fail to materialize. That's all the more reason for greater support and funding for efficient, goal-driven medical research.

MIT: Stem-cell therapies for brain more complicated than thought:

MIT scientists report that adult stem cells produced in the brain are pre-programmed to make only certain kinds of connections - making it impossible for a neural stem cell originating in the brain to be transplanted to the spinal cord, for instance, to take over functions for damaged cells.

...

"A stem cell that produces neurons that could be useful to replace neurons in the cerebral cortex (the type of neurons lost in Alzheimer's disease) will be most likely useless to replace neurons lost in the spinal cord. [Moreover], because there are many different types of neurons in the cerebral cortex, it is likely that we will have to figure out how to program stem cells to become many different types of neurons, each of them with a different set of pre-specified connections."

"In the stem cell field, it is generally thought that the main limitation to achieve brain repair is simply for the new neurons to reach a given brain region and to ensure their survival. Once there, it has been assumed that stem cells will ‘know what to do’ and will become the type of neuron that is missing. It seems that is not the case at all. Our experiments indicate that things are much more complicated."

Thinking About Ageless Animals

Anne C. takes a look at the very long-lived members of the animal kingdom: "rockfish, turtles, and whales [are] all documented to live 200 years or longer without showing signs of aging ... Of the long-lived animals presently known, some appear to have a built in 'negligible senescence' property. ... This is a very important observation because it clearly indicates that the life of an animal is not necessarily inextricable from a fixed 'expiration date' built into his or her deepest inner workings from the start. So while I do not deny the significance of the many human attempts over the years to garner meaning and poetic substance from reflecting upon the bodily breakdown that tends to eventually kill us all, it is well worth pointing out that some of this philosophizing is at least partially rooted in what appears to be a false belief -- that age-related decline of the sort experienced by humans is 'inevitable' in all members of the animal kingdom, and that our own decline somehow 'connects' us with everything else on Earth."

Link: http://www.existenceiswonderful.com/2007/11/menagerie-of-longevity.html

Meanwhile, Over at the Immortality Institute ...

The Immortality Institute volunteers are upgrading; always a painful process with a large forum and a content management system extensively customized over the years. If you haven't stopped by the Institute forum in a while, you should do so. Where else are likely to be able to participate in a discussion on the first recorded practitioner of calorie restriction - and noted author of the Renaissance - with researcher S. Jay Olshansky and other noteworthies?

A noble idea is a noble idea, and we shouldn't be surprised to find people from the past with constructive contributions to make on the topic of healthy longevity - taking into account the state of scientific knowledge in their time:

Sixteenth century Venetian Ambassador and Renaissance Christian Luigi Cornaro was celebrated in his time for his stance on dietary self-restraint, moderate living, and living to the age of 103. For these hundred of years his classic book has survived as a renowned text on longevity and an inspiring treatise on the path of temperance that the author believed could lead anyone out of a state of illness and into a healthy long life. The Art of Living Long contains Cornaros four discourses, respectively concerned with demonstrating his ideas through his own example, exploring the necessity of temperate habits, assuring a happy old age, and exhorting mankind to follow his rule. With introductions by Dr. Gerald Gruman and Joseph Addison, and additional essays by Lord Bacon and Sir William Temple.

To take a contrary point of view, however, is this really any different - important names of centuries past aside - from the standard mainstream media coverage of centenarians today? The form requires the journalist to ask for the centernarian's thoughts on longevity, but living for a long time doesn't make you an expert on how to live for a long time. Everyone has an opinion on how it is they've lived so long, but opinion isn't science.

When you're wandering through the vast libraries of writing on the topics of aging and longevity, remember that the scientific method is how progress is made. Opinions can be good, can be well-thought, can even be right as it later turns out, but opinions alone are not the foundation for a path forward.

An Interview With Dave Gobel

The Speculist interviews Dave Gobel for Fast Forward Radio: "Dave cofounded with Aubrey de Grey the Methuselah Foundation. This is the nonprofit charity that is behind the Methuselah Mouse Prize - a prize for proving life extension technologies in mice. This interview explains why developing life extension matters more, fundamentally, that almost anything else we can put our efforts into. It's also a fascinating glimpse into how the efforts of a few people can be leveraged to change the world. You'll want to hear this one for sure." The Methuselah Foundation is one of the most important efforts today in its influence on the funding and scientific infrastructure for longevity research. We stand at a crossroads, in this time of revolution and progress in bioscience, and few of the paths ahead will lead to rapid progress towards working rejuvenation technologies within our lifetime. It is just as important to steer research towards those paths as it is to convince the world that effective longevity research is possible, plausible and on our doorstep.

Link: http://www.blog.speculist.com/archives/001566.html

A Nice Turn of Phrase

This caught my eye while I was meandering my way through PubMed; a nice turn of phrase in this way of looking at the mechanisms of aging and the future of aging in a world shaped by human action.

Senescence Viewed through the Lens of Comparative Biology:

Although mortality and longevity are inherently biological phenomena, their study has historically been the purview of demography and the actuarial sciences. An infusion of biological thinking into these disciplines transforms demography into biodemography and provides expectations and coherency to observations on age-determined mortality that would not be explainable otherwise.

Comparative biology teaches us that reproduction is life's solution to the inevitability of death in the hostile environments of Earth. That solution, however, places a higher priority on investing physiological resources into reproduction that could otherwise have been used to maintain the soma (body) longer. As such, aging is an inescapable but inadvertent byproduct of imperfect maintenance and its attendant surveillance and repair. Biology also reveals that while bodies are not designed to fail, neither are they designed for extended operation. In other words, bodies are subject to biological warranty periods for normal operation. For sexually reproducing species, that warranty period includes the time from conception to sexual maturity, the production and nurturing of offspring, and a period of grand-parenting in some species.

Humans are the only species capable of exploiting the loophole in the biological contract of life (bodies that are not designed to fail). Human ingenuity (science, medicine, public health) has produced interventions that manufacture survival time by delaying death, and in so doing, has created a phenomenon never before seen in the history of life - population aging (and all the societal and health consequences that go with it).

Aging and individual death might well be the inevitable consequence of evolutionary pressure on cellular life, but it's far more noteworthy that we have the capacity to do something about it. Intelligence and technology are a loophole big enough to created physical immortality - given enough resources and time. The big question is whether the first stages on the road to the repair of aging and greatly increased healthy life spans happen rapidly enough to benefit you and I, or whether cryosuspension will be our only opportunity.

The choice is ours; how much do we want healthy longevity and how much are we prepared to work towards that goal?

On Thymic Regeneration

The aging immune system runs out of space, it's capacity taken up by memory T cells uselessly dedicated to cytomegalovirus. One approach is to remove all those errantly specialized memory cells (or eliminate cytomegalovirus early on). Another approach is to expand immune capacity by preventing or reversing involution of the thymus: "The immune system undergoes dramatic changes with age - the thymus involutes, particularly from puberty, with the gradual loss of newly produced naive T cells resulting in a restricted T cell receptor repertoire, skewed towards memory cells. Coupled with a similar, though less dramatic age-linked decline in bone marrow function, this translates to a reduction in immune responsiveness ... Given that long-term reconstitution of the immune system is dependent on the bi-directional interplay between primary lymphoid organ stromal cells and the progenitors whose downstream differentiation they direct, regeneration of the thymus is fundamental to developing new strategies for the clinical management of many major diseases of immunological origin."

Link: http://www.ncbi.nlm.nih.gov/pubmed/18024073

Desired and Useful Cell State Transitions

Randall Parker comments on the latest work in controlling cell state: "For several years I've been expecting clever scientists to figure out ways to basically program around the limitations on embryonic stem cell research. By finding ways to turn the knobs on genetic switches in the cell it was inevitable that scientists would figure out how to make cells change state into embryonic cells. They will next find more genetic knobs to turn in order to convert embryonic cells into precisely desired cell types and they will even find ways convert between various non-embryonic cell types while totally avoiding an intermediate state where the cells are like embryonic cells. Cells are just complex state machines. The next few decades of advance in biotechnology can be seen as a series of advances in techniques for causing desired and useful cell state transitions. ... These scientists basically figured out how to apply a software patch to human cells that made them express genes that make them act like embryonic cells. Scientists have already identified these genes as active in early stage embryonic stem cells and have experimented with activating them in mouse cells. ... It seems unlikely that these cells have been pushed into a state that is exactly like the state of an embryonic stem cell. That state might have very subtle aspects that are important in ways we have not yet discovered."

Link: http://www.futurepundit.com/archives/004807.html

AC5 Longevity Mutants

Mice lacking the gene to create the protein adenylyl cyclase 5 (AC5) live longer. This was accidentally discovered during research into potential heart therapies, and published earlier this year:

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.

Like many longevity mutations of this magnitude, this is thought to invoke the beneficial mechanisms of calorie restriction in some way. Researchers are still working on clarifying the action of the AC5 mutation, as illustrated by the latest paper on the topic:

Adenylyl Cyclase 5: A New Clue in the Search for the "Fountain of Youth"?

It is proposed that these beneficial effects may be the result of the increased activity of second messenger signaling proteins such as mitogen-activated or extracellular signal-regulated protein kinase kinase (MAPKK, also known as MEK) and extracellular signal-regulated kinase (ERK), or of enzymes such as manganese superoxide dismutase (MnSOD) that promote cell survival through protection against oxidative stress and apoptosis. These intriguing findings should stimulate additional research aimed at dissecting the complex cellular mechanisms regulated by AC isoforms and may lead to novel genetic and pharmacological approaches to delay aging-related conditions and to extend life span.

A fair number of bases covered there. "We don't really know yet, but have some places to start looking" would have been fine. Metabolism is complex; there's no end to the resouces we can productively sink into understanding the space of potential beneficial alterations to mammalian metabolic processes. Those same resouces, I feel, would be better directed to understanding how to repair the metabolism we have. After all, if you can repair age-related metabolic damage once, you can come back in ten years time and do it again - and again and again, for so long as you care to continue. If developing that possibility is on the table for the same sort of cost as developing a one-time manipulation that slows the accumulation of damage by 30%, I know which route I'd choose.

This is exactly the choice facing us today, and for some strange reason the mainstream of medical science is headed down the inferior, more costly, less effective path of metabolic manipulation. Comparatively little attention is given to the more effective strategies of repair. Changing this reality is one very good reason to support the work of the Methuselah Foundation.

More On Alzheimer's as Type 3 Diabetes

The Scientist looks at recent thinking on Alzheimer's: "accumulated evidence suggests that insulin and insulin-like growth factor signaling is impaired in patients with Alzheimer's disease. ... It looks like in Alzheimer's disease you end up having a defect in these kinds of pathways, which are similar to the pathways for insulin-resistant diabetes ... But, it's unknown as to which comes first, the disease or the insulin resistance, although de la Monte is confident that the signaling defects precede the disease. As for a decrease in insulin in the brain 'if that deficit is important, we don't know.' ... In July of this year, Morris White at Children's Hospital Boston found that insulin might actually be bad for the brain. He knocked out insulin signaling in mice and found that they live nearly 20% longer. Although he didn't conduct a cognitive assay, the animals appeared more resistant to oxidative stress, which should be protective against neurodegeneration. 'Attenuated insulin signaling in the brain is probably a good thing.' ... Excess insulin is also thought to compete with amyloid plaques for degradation, thereby contributing to their nefarious accumulation in the brains of Alzheimer's patients. White says that while these results appear to oppose de la Monte's findings that insulin deficiency is the problem, he agrees that approaching Alzheimer's as a diabetes-like disorder is a good direction to follow."

Link: http://www.the-scientist.com/article/home/53758/

Towards Reconstructed Immune Systems

EurekAlert! passes on news of more progress towards the safe reconstruction of an age-damaged or otherwise dangerously malfunctioning immune system: "researchers found a way to transplant new blood-forming stem cells into the bone marrow of mice, effectively replacing their immune systems. Many aspects of the technique would need to be adapted before it can be tested in humans ... When those barriers are surmounted, the benefits are potentially big. ... [researchers] mice with molecules that latch on to specific proteins on the surface of the blood-forming stem cells, effectively destroying the cells. That technique eliminated the blood-forming stem cells without otherwise harming the mice. ... It is essentially a surgical strike against the blood-forming stem cells ... When they transplanted new blood-forming stem cells into the mice, those cells took up residence in the bone marrow and established a new blood and immune system." This is one of a number of lines of research aimed at the goal of rebuilding the immune system. You might recall trials of another method aimed at curing type 1 diabetes, for example.

Link: http://www.eurekalert.org/pub_releases/2007-11/sumc-sct111907.php

Another Calorie Restriction Mimetic

Scientists are turning up calorie restriction mimetic compounds left, right and center now that there's serious money to be had for this branch of longevity research: "the antidepressant drug mianserin can extend the lifespan of the nematode Caenorhabditis elegans by about 30 percent. ... Our studies indicate that lifespan extension by mianserin involves mechanisms associated with lifespan extension by dietary restriction. We don't have an explanation for this. All we can say is that if we give the drug to caloric restricted animals, it doesn't increase their lifespan any further. That suggests the same mechanism may be involved ... In our studies, mianserin had a much greater inhibitory effect on the serotonin receptor than the octopamine receptor. One possibility is that there is a dynamic equilibrium between serotonin and octopamine signaling and the drug tips the balance in the direction of octopamine signaling, producing a perceived, though not real, state of starvation that activates aging mechanisms downstream of dietary restriction."

Link: http://www.eurekalert.org/pub_releases/2007-11/hhmi-aft112007.php

Strange Positions Held By Longevity Researchers

An interesting article from Esquire amply demonstrates the lengths some researchers go to convince themselves that it is fine to combat age-related degeneration, but not to lengthen life. "Should we change the aging program in humans? I can't make that decision. There has to be a regulatory body somewhere down the road that will make that decision. I have to believe that I'm doing this for age-related disease, and I have faith that there will be regulation later on. ... we will probably be able to show that the drug we have upregulates longevity, and that puts us on a slippery slope. ... To some degree, the future [is] already taking place right before his eyes ... In the past, the accumulation of a man's wealth was always offset by the accumulation of a man's years; now he sees men who are experiencing age as pure advantage [and] he finds the spectacle appalling. At the same time, he sees vigorous old scientists [still] doing crucial work, and he finds them inspiring. ... sure enough, striding energetically across the courtyard is some famous scientist or another, shod in sandals and wearing a towel, his white hair wet and his white teeth grinning. Dillin has no idea where he came from; but he does know where he's going - to his lab, and to science - and who is to say he shouldn't be able to go there forever?" No-one can judge how - or how long - you or I would like to live, and it is nothing less than cowardice to call for government to force your choices upon the rest of us.

Link: http://www.esquire.com/print-this/dillin1207

The Choroid Plexus, Revisited

You might recall research from last year suggesting age-related decline in the choroid plexus contributes to the buildup of amyloid characteristic to Alzheimer's disease.

the choroid plexus acts as a sort of 'fishnet' that captures the protein, called beta-amyloid, and prevents it from building up in the cerebrospinal fluid, which surrounds and bathes the brain and spinal cord. Moreover, tissue in the organ is able to soak up large amounts of the protein and may contain enzymes capable of digesting beta-amyloid.

I noticed a paper today that focuses on a quite different aspect of decline in the choroid plexus, but one that still leaves the brain the worse for it.

Aging reduces the neuroprotective capacity, VEGF secretion, and metabolic activity of rat choroid plexus epithelial cells:

Delivery of neurotrophic molecules to the brain has potential for preventing neuronal loss in neurodegenerative disorders. Choroid plexus (CP) epithelial cells secrete numerous neurotrophic factors, and encapsulated CP transplants are neuroprotective in models of stroke and Huntington's disease (HD).

...

In vitro, young CP epithelial cells secreted more VEGF and were metabolically more active than aged CP epithelial cells.

...

Implants of young CP were potently neuroprotective as rats receiving CP transplants were not significantly impaired when tested for motor function. In contrast, implants of CP from aged rats were only modestly effective and were much less potent than young CP transplants.

If (still a big if) Alzheimer's turns out to look a lot like Parkinson's at root, in that it stems from the failure of an important population of cells or narrow range of processes in the brain, the door is wide open for the next decade of regenerative therapies. There is so much we could do with the ability to grow fresh, healthy tissue to order - even in the brain.

The Answer Is Easy

As Ronald Bailey points out, the answer to the final question in this MSNBC op-ed by bioethicist Art Caplan is indeed easy and immediate. "Is it right to repair ourselves if it means that we live much longer than any human being has ever lived? ... The answer is easy: Yes. A long healthy life is a moral good. More life is better." As I've long pointed out, bioethicists are people who have put themselves into the position of requiring a constant stream of problems to justify their income. So of course, once they've exhausted debate over the limited range of actual problems - without helping in any way to overcome those problems - they drum up pseudo- and non-problems from nothing. There should be no debate over longevity; those who want to live longer, healthier lives will strive to do so, and those who do not will choose to suffer and die earlier than they might. But more life is good, for everything that is good in this world depends on someone being alive and well to make it happen. After that, all there is to argue over is why it is that some people feel they can force their choices of aging and longevity upon the rest of us.

Link: http://www.msnbc.msn.com/id/21885805/

Forging Ahead With Cellular Reprogramming

ScienceNOW reports on progress in turning ordinary cells into pluripotent stem cells by means other than somatic cell nuclear transfer. Competition in methodologies is always a good sign of progress: "Two groups report today that they have reprogrammed human skin cells into so-called induced pluripotent cells (iPCs). ... Yamanaka and his colleagues show that their mouse technique works with human cells as well. And [Thomson] and his colleagues report success in reprogramming human cells, again by inserting just four genes ... The crucial next step, everyone agrees, is to find a way to reprogram cells by switching on the genes rather than inserting new copies. The field is moving quickly toward that goal ... It is not hard to imagine a time when you could add small molecules that would tickle the same networks as these genes [and] produce reprogrammed cells without genetic alterations." Readily available, low-cost sources of tailored stem cells are fuel for the tissue engineering and regenerative medicine of the future.

Link: http://sciencenow.sciencemag.org/cgi/content/full/2007/1120/1

A Truly Astounding Opinion

I feel compelled to come back to a comment by Richard Sprott, director of the Ellison Medical Foundation, quoted in a recent article on investment in longevity research:

"We're all going to croak," says Richard Sprott, the Ellison Medical Foundation's director, who expects that humans may eventually live as much as 30 years longer, but only in the distant future.

The archives at SAGE Crossroads boast a debate between Sprott and Aubrey de Grey, each exemplifying a polar opposite of approach to aging research and its goals. From where I stand, Sprott is firmly in the full employment act for gerontologists camp, while de Grey is all goal all the time.

There are more people who think like de Grey out there, but I don't think they're talking loudly enough. There are certainly far too many scientists who coast, with no inspiring goals to their work. What is the purpose of research if not to get the damn job done? What is work without purpose? In the case of aging research it's not about making life easy for career scientists, it's about stopping a worldwide, horrendous, terrible, ongoing avalanche of death and suffering.

Even the most widely recognized greatest disasters in human history pale in comparison to natural death. For example, the typhoon that struck Bangladesh in 1970 washed away a million lives. In 1232 AD, Genghis Khan burned the Persian city of Herat to the ground. It took his Mongol horde an entire week to slaughter the 1.6 million inhabitants. The Plague took 15 million per year, World War II, 9 million per year, for half a decade each. The worldwide influenza pandemic of 1918 exterminated less than 22 million people – not even half the annual casualties from natural death. But natural death took 52 million lives last year. We can only conclude that natural death is measurably the greatest catastrophe humankind has ever faced.

It's about building a world in which we can create more of the most valuable commodity there is - time spent alive, healthy and ready to act.

So back to the quoted view of Richard Sprott above. How on earth does one manage to reconcile the belief that it's going to take an age to extend healthy human life by a mere 30 years with even a passing understanding of the present state of science, human knowledge and capabilities? Has he failed to notice the scorching pace of progress in understanding and controlling cells? That biotechnology is now firmly harnessed to exponential progress in computational capacity - and all the benefits that brings? That the laws of physics firmly allow nanoscale machinery capable of replacing and surpassing in every respect all organs and functions of the human body? That the tissue engineers predict a decade or two until we can grow and replace any damaged tissue aside from the brain? That the system biologists think tacking ten years onto healthy life over the next ten years is feasible? That even the tired, slow-moving, government cancer establishment is shooting for victory in a decade?

I want to point out just how outlandish it is to stand in the midst of outright revolution, of wild, foaming progress in bioscience, and say that things aren't going to change all that much. You're out there on your own, Sprott, with few others beside Hayflick for company. The position you hold is extreme and strange to me.

Better, Stronger, Longer Lived

From the Globe and Mail: "It's natural that our physical and mental abilities deteriorate in old age. Thus, all of the [everyday technologies aimed at changing that] could be described as 'unnatural.' They are unnatural but not, on that account, morally objectionable. It's fallacious to equate what's natural with what's good. ... Today, no one worries much about the ethics of analgesics or eyeglasses. Quite the opposite: You'd seem a complete idiot if you rejected all artificial aids to better living. So why is there so much fear and fretting about the present and future use of biotechnology to make ourselves healthier, stronger, smarter and longer-lived? John Harris, a leading British bioethicist, believes that the ethical controversy swirling around such new technologies as pre-implantation genetic diagnosis, embryonic stem cell cloning and regenerative medicine is mostly the product of ignorance, prejudice and bad reasoning." Good to see sense from the bioethics community for a change; would that it spreads.

Link: http://www.theglobeandmail.com/servlet/story/LAC.20071117.BKEVOL17/TPStory/Entertainment

Never Say Die - And Fund the Winners

Investment in longevity science is examined in Portfolio: "The longevity field is splintered between people like De Grey, who think a cure for aging is a realistic goal, and those like the researchers at Ellison, who argue that medical science will indeed be able to extend life, but not eternally. (Since 1970, the average U.S. life span has crept up by four years, to 77.9, not the kind of increment that the immortalists have in mind.) "We're all going to croak," says Richard Sprott, the Ellison Medical Foundation's director, who expects that humans may eventually live as much as 30 years longer, but only in the distant future. As for the rest of it, including cryonics, Sprott says, "I don't know how anybody takes some of this stuff seriously." Such skepticism explains why Peter Thiel, now head of Clarium Capital Management, a $2.7 billion hedge fund, has raised some eyebrows with his very public funding of De Grey's immortality work. ... In Thiel's view, "Aubrey is the rare combination of a first-rate scientist with an out-of-the-box thinker. In just the past five years, the notion of radical life extension has moved from the fringes to the mainstream, and he's been one of the central figures in bringing about that shift. Every myth on this planet tells people that the purpose of life is death. It's time for us to move beyond mythology and try to find a real cure for this universal disease." From where I stand, you fund the guys who are going to get the damn job done - which won't be the folk who say it's impossible before the attempt has been made.

Link: http://www.portfolio.com/executives/features/2007/11/19/Longevity-Industry

A Collection of Research of Interest

Sometimes there's just too much interesting research out there to link to one by one: inroads against age-related disease; uncovering new and important mechanisms of metabolism; progress in promising classes of future therapy. The list is endless. So sometimes, I throw together these roundups of diverse topics. Let's start with some promising gene therapy work for Parkinson's disease, and move on to Alzheimer's and cancer:

PET scans show gene therapy normalizes brain function in Parkinson's patients:

Brain scans used to track changes in a dozen patients who received an experimental gene therapy show that the treatment normalizes brain function - and the effects are still present a year later.

...

The patients only received the viral vector-carrying genes to the side of the brain that controls movement on the side of their body most affected by the disease. ... The gene makes an inhibitory chemical called GABA that turns down the activity in a key node of the Parkinson’s motor network. The investigators were not expecting to see changes in cognition, and the scans confirmed that this did not occur.

Position emission tomography (PET) scans were performed before the surgery and repeated six months later and then again one year after the surgery. The motor network on the untreated side of the body got worse, and the treated side got better. The level of improvements in the motor network correlated with increased clinical ratings of patient disability, added Dr. Feigin.

A novel way found to prevent protein plaques implicated in Alzheimer's:

Both studies used mice that were genetically engineered to produce human cystatin C as well as abundant amounts of amyloid beta plaques in their brains. The cystatin C bound to the soluble, non-pathological form of amyloid beta in these mice and inhibited the aggregation and deposition of amyloid beta plaques in the brain.

The research shows that cystatin C binds soluble amyloid beta also in the human brain, and suggests that this binding inhibits its aggregation into insoluble plaques in humans, says Dr. Levy. Cystatin C production and body fluid levels vary among healthy individuals and can be influenced by certain hormones, aging, and certain pathological conditions, she says. Furthermore, it was recently demonstrated that a genetic variation in the cystatin C gene in human populations is linked to a greater risk of developing Alzheimer’s disease during aging.

These findings suggest, says Dr .Levy, that even subtle modifications of cystatin C protein levels could affect amyloid beta accumulation and deposition in the brain, thereby modifying disease progression.

I seem to recall research indicating that the rate of turnover of amyloid is very fast, on the order of days. Alzheimer's is not a slow buildup of a compound that can just be removed, but rather a slow increase in the difference between generation and clearance rates. The best answer would be to determine where the fault lies and fix it; some work is aimed in that direction, but the majority aims to introduce new ways to clear amyloid without doing anything to repair the underlying issue. This is, alas, the dominant path in present day medical research.

But on to cancer:

Immune system can drive cancers into dormant state:

Like the older theory, cancer immunoediting suggests that conflict between cancers and the immune system naturally takes place but proposes that three very different outcomes can result. The immune system can eliminate cancer, destroying it; the immune system can establish equilibrium with cancer, checking its growth but not eradicating it; or the cancer can escape from the immune system, likely becoming more malignant in the process.

Until this latest study, evidence for the second outcome was lacking.

...

"We don't think the immune system has evolved to handle cancers," Schreiber notes. "Cancer is typically a disease of the elderly, who have moved beyond their reproductive years, so there probably was no evolutionary pressure for the immune system to find a way to fight cancer."

Schreiber, Smyth and Old speculate that from the immune system's point-of-view, a cancerous cell may look like a cell infected by an invading microorganism. To overcome the safeguards that prevent the immune system from attacking the body's own tissues, the tumor has to have a high level of immunogenicity, or ability to provoke an immune reaction. Cancer cells can reduce their immunogenicity by changing the materials they present to the immune system to more closely resemble those presented by normal tissue. This enables the third outcome of the immunoediting theory: escape.

Equilibrium sometimes may be a more common outcome of tumor-immune encounters than elimination. According to the researchers' theory, some of us may harbor dormant tumors that either developed spontaneously or from exposure to carcinogens. They propose that these quiescent tumors are unleashed only as we age or are exposed to environmental, infectious or physical stresses that cause a breakdown of the immune system.

Greater understanding of the tools already present in our body will be a real boost to fighting cancer, coming in the midst of a revolution in our capacity to alter and make use of those biochemical tools. Improving, retraining and redirecting the mechanisms of the immune system to attack specific cells is a very promising field of research. A good thing too, as we need effective, reliable cures for cancer if we're going to benefit from other strands of healthy life extension research.

Mitochondria In FIRKO Mice

An interesting paper on one of the many varieties of engineered longevity in mice draws our attention to the links between mitochondrial function and healthy longevity: "Caloric restriction, leanness and decreased activity of insulin/insulin-like growth factor 1 (IGF-1) receptor signaling are associated with increased longevity in a wide range of organisms from Caenorhabditis elegans to humans. Fat-specific insulin receptor knock-out (FIRKO) mice represent an interesting dichotomy, with leanness and increased lifespan, despite normal or increased food intake. ... At the whole body level, FIRKO mice demonstrated an increase in basal metabolic rate and respiratory exchange ratio. Analysis of gene expression [revealed] persistently high expression of the nuclear-encoded mitochondrial genes involved in [the process of energy generation] ... Together, these data suggest that maintenance of mitochondrial activity and metabolic rates in adipose tissue may be important contributors to the increased lifespan of the FIRKO mouse." More evidence that how the machine runs is a lot more important than how fast the machine runs.

Link: http://www.ncbi.nlm.nih.gov/pubmed/18001293

Keck Futures Initiative Conference on Healthspan

EurekAlert notes the latest Keck Futures Initiative conference: "This year's topic, 'The Future of the Human Healthspan: Demography, Evolution, Medicine and Bioengineering,' drew scientists, engineers, and medical researchers to discuss new interdisciplinary approaches in the fields of aging, longevity, and healthspan -- the period of a person's life during which they are generally healthy and free from serious or chronic illness. ... We have made great progress in extending the length of life and now must focus on the quality of those added years. We need to be bold and target innovative ways to help people sustain skills and abilities throughout extended lifetimes, assuring enhanced brain health as well as physical well-being." Which seems to be wrong thinking to me - we haven't made all that much of a foray into the realm of the possible when it comes to longevity through medicine, and we won't get much further if researchers stop thinking about pushing the boundaries in favor of patching up the results of aging as we see them today. If researchers instead focused on identifying and repairing the damage that causes aging, we'd never have to worry separately about healthspan - it'd sort itself out in the course of engineering longer, healthier lives.

Link: http://www.eurekalert.org/pub_releases/2007-11/tna-coh111607.php

The Significance of Primate Therapeutic Cloning

I, and no doubt you folk as well, noted the press on the first verified success for therapeutic cloning (also known as somatic cell nuclear transfer, or SCNT) in primates. The research group produced totipotent embryonic stem cells from a starting point of the skin cells of rhesus macaques.

Monkey embryo cloned in major breakthrough

Reproductive biologist Shoukhrat Mitalipov, of the Oregon Health & Science University, and his colleagues reported in the online version of the journal Nature that they have cloned rhesus macaque embryos using DNA from skin cells taken from the ear of a 9-year-old male. The resulting stem cells grew into viable heart and nerve cells, among others.

"This is a giant step toward showing that human therapeutic cloning is possible," said Dr. Robert Lanza, who is trying to produce human embryonic stem cells at Advanced Cell Technology in Worcester, Mass., and was not involved in the research. "It proves once and for all that primate cloning is not impossible ... as many people had thought."

Work has begun to use the new technique to clone human embryos, although the process remains very inefficient. Even so, Mitalipov said, "I am quite sure that it will work in humans."

What is the signficance of this? Well, one has to look at what a source of your own totipotent stem cells can be used for:

Over the past 25 years, mouse embryonic stem cells have been used to create models for scores of human diseases, including cancer, heart disease, obesity, and Alzheimer's. Research discoveries based on these models has led to new drug development and therefore touched countless lives. ... I believe it is only a matter of time before human embryonic stem cells are used in drug development research and become the basis for important new cell therapies.

Producing tissue in specific states to analyze and learn from is just the start. Totipotent cells on tap form an important resource for complex tissue engineering: totipotent stem cells generated from your own cells will be used to produce replacement parts for age-damaged organs and systems in your body in the next few decades.

The bottom line is that increasing control over our cells is a broad highway to increasing control over our healthy life spans. All progress is very welcome.

Overachievements in Worm Longevity

Merely doubling healthy life span is old hat, last decade work now. We can engineer far better nematode worms than that: "C. elegans strains bearing homozygous nonsense mutations in the age-1 gene [produce] progeny that were thought to undergo obligatory developmental arrest. We now find that, after prolonged developmental times at 15-20 degrees C, they mature into extremely long-lived adults with near-normal feeding rates and motility. They survive to a median of 145-190 days at 20 degrees C, with nearly 10-fold extension of both median and maximum adult lifespan relative to [a] long-lived wild-type stock into which the null mutant was outcrossed. PI3K-null adults, although a little less thermotolerant, are considerably more resistant to oxidative and electrophilic stresses than worms bearing normal or less long-lived alleles." This and similar work forms an impressive set of technology demonstrations - there is no necessarily direct relevance to extending healthy human life span, but it certainly gets people fired up and excited.

Link: http://www.ncbi.nlm.nih.gov/pubmed/17996009

Reminder: Video From SENS3

Anne C. reminds us that a wide range of presentations on longevity research and related areas of scientific enquiry from the SENS3 conference this year are freely available. What to know what the future of medicine looks like? Educate yourself: "These SENS talks are a great example of longevity medicine as healthcare that will hopefully come to benefit everyone at some point. I'm quite interested in learning more about things like: the efficacy of cancer vaccines to prevent cancer in the elderly; the potential for virus modulation of cell death pathways; Immunological approaches for amyloid beta clearance toward Alzheimer's disease treatment. As you can see...no mooning over mythological notions of 'fountains of youth' here. Just good, solid investigative science geared toward helping mitigate problems like cancer in the elderly, cell death leading to other health issues, and Alzheimer's. And you definitely don't need to be a biologist in order to appreciate media like this -- all you really need is to be interested in the subject matter. ... With all the 'anti-aging fluff' making the rounds these days, it's nice to know that some people at least realize how complex (and important) the task of helping expand truly effective medicine to the elderly is."

Link: http://www.existenceiswonderful.com/2007/11/sens-3-media-for-your-edification.html

The Insidious Urge to Control and Suppression

For some people, nothing should exist outside a state of complete regulation, every choice you could potentially make hemmed in by rules made and enforced by faceless others. It is somewhat strange that people are comforted by regulatory control: even when they obviously have no say in the results of that control, even when the consequences of that control are obviously terrible; even when such control is obviously more along the lines of suppression and destruction. That latter results when habitual and empowered controllers, unable to conceive of any other response to the new, are faced with something they do not understand.

Or perhaps this is all not so strange; many people would - and do - choose suffering over change, the familiar over the new, no matter how terrible the familiar might be at the moment. Human nature is, at heart, terribly flawed in many ways.

Community attitudes to the regulation of life extension:

Technologies purported to extend human life are already being marketed widely, and are being used by community members, despite a lack of evidence on their efficacy or safety: in fact, the use of some putative anti-aging technologies (e.g., human growth hormone) is illegal. Existing regulation is proving to be ineffective, especially in the face of Internet sales.

Further advances in the field of life extension are a distinct possibility, exacerbating the need for a policy response. This paper presents the preliminary results of a study of community attitudes to life extension, with a focus on attitudes to the control and availability of strong life-extending technologies.

Can't be having those advances, now, can we? I'm always deeply suspicious of people waving terms like "society" and "community." Invariably, those in fact mean something along the lines of "we who would like to think of ourselves as elites, but who prefer not to say so quite so openly."

It's rather sad that we live in an era of the downward spiral, right at the time at which there is so much progress in technology and human capabilities to be seized. Ever greater control and abrogation of personal responsibility leads to an irresponsible, demanding, passive-aggressive population, which leads to ever greater centralized control and destruction of freedom. We're overdue a revolution, a sea change in attitudes, or an unpleasant dip once more into comparative poverty of choice, vision and opportunity.

A Closer Look at the Age-Damaged Immune System

This paper at Aging & Immunity takes a look at just a few detailed biochemical changes in the aging immune system (and the full PDF format paper is freely available). It's another perspective on inflammaging, and you'll notice that calorie restriction emerges again as a beneficial practice: "The mechanism explaining the increased disease susceptibility in aging is not well understood. CD8+ T cells are crucial in anti-viral and anti-tumor responses. Although the chemokine system plays a critical role in CD8+ T cell function, very little is known about the relationship between aging and the T cell chemokine system. ... we have examined the effect of aging on murine CD8+ T cell chemokine receptor gene expression. Freshly isolated splenic CD8+ T cells from [old] mice were found to have higher CCR1, CCR2, CCR4, CCR5 and CXCR5, and lower CCR7 gene expression compared to their younger cohort. ... caloric restriction selectively prevents the loss of CD8+ T cell CCR7 gene expression in aging to the level that is seen in young CD8+ T cells. ... These findings are consistent with the notion that aging exists in a state of low grade pro-inflammatory environment." Receptors are a part of cellular biochemical programming, determining interaction and response. Change the balance of receptors and you change the capacity of the cell. Here, you're looking at the innermost workings of the grand machine we endeavor to understand, and then repair.

Link: http://dx.doi.org/10.1186/1742-4933-4-8

Mitochondrial Damage and Sarcopenia

Following up on work published last year, here's more on evidence for a link between accumulating damage to mitochondrial DNA and sarcopenia, age-related muscle loss: "Aging is associated with a progressive loss of skeletal muscle mass and strength and the mechanisms mediating these effects likely involve mitochondrial DNA (mtDNA) mutations, mitochondrial dysfunction and the activation of mitochondrial-mediated apoptosis. Because the mitochondrial genome is densely packed and close to the main generator of reactive oxygen species (ROS) in the cell, the electron transport chain (ETC), an important role for mtDNA mutations in aging has been proposed. Point mutations and deletions in mtDNA accumulate with age in a wide variety of tissues in mammals, including humans, and often coincide with significant tissue dysfunction. Here, we examine the evidence supporting a causative role for mtDNA mutations in aging and sarcopenia. We review experimental outcomes showing that mtDNA mutations, leading to mitochondrial dysfunction and possibly apoptosis, are causal to the process of sarcopenia."

Link: http://www.ncbi.nlm.nih.gov/pubmed/17997255

From the 2007 Hillblom Foundation Scientific Meeting

Researcher Chis Patil of Ouroboros has been blogging this year's scientific meeting of the Larry L. Hillblom Foundation, a gathering of scientists involved aging (and longevity) research and other medicine funded by the Foundation. Links and a few highlights:

2007 Hillblom Meeting: Morning session 1:

Getting down to brass tacks and emphasizing the real-world applications of the work, Kenyon described a brave new world in which the 40-year-old men of the future will find themselves unwittingly, but enthusiastically, hitting on 90-year-old hotties in singles bars.

2007 Hillblom meeting: Morning session 2:

Bill Mobley (Stanford) began with the bold claim that all neurodegenerative illnesses are ultimately breakdowns of neural circuitry - if not etiologically, then symptomologically. He went on to summarize and review the body of evidence supporting the view that axonal dysfunction contributes to Alzheimer’s Disease (AD) pathology, focusing especially on the idea that decreases in neurotrophic factor signaling and retrograde transport play a causative role in AD.

2007 Hillblom meeting: Afternoon session:

Lithgow begins from a simple premise: Given that genetic manipulations have revealed significant plasticity in the rate of aging, shouldn’t we be able to discover drugs that phenocopy, simulate or even outstrip the effects of longevity-extending mutations? Thus far, early screens for both stress resistance and lifespan extension per se have generated several lead compounds that delay aging in yeast, worms and flies (and in at least one case, both species). Studies from multiple labs are beginning to converge, with the ultimate goal of testing multi-species hits in mouse models of aging and age-related diseases. In closing, Lithgow acknowledged that understanding of the mechanism of action of these compounds is lagging behind their discovery, in part because some of the most promising molecules have mystifyingly large numbers of candidate targets.

Interesting stuff; that last quote is an excellent summation of the metabolic manipulation school of longevity science, the presently dominant view of that part of the aging research mainstream that supports initiatives to extend the healthy human life span.

Patil is off to the Keck Futures Initiative meeting on "The Future of Human Healthspan" next - more of what you get to do when you're one of the scientists actually working on aging and longevity research.

On Centenarian Characteristics

You might find this PDF-format paper interesting. Nothing we haven't seen before in various studies, but it is a good reminder as to the cost of being overweight - it damages you, and shortens your life expectancy: "A random representative sample of 240 men born in 1887 and survived to age 100 was selected from the US Social Security Administration database. ... This allowed us to validate 171 cases of exceptional longevity, and obtain information on vital characteristics of male centenarians when they were young adults. ... It was found that the 'stout' body build (being in the heaviest 15% of population) was negatively associated with survival to age 100 years. Both farming and having large number of children (4+) at age 30 significantly increased the chances of exceptional longevity by 100-200%. The effects of immigration status, marital status, and body height on longevity were less important, and they were statistically insignificant in the studied data set. This study provides the first estimates of height, body build and other vital characteristics for the future centenarians at their young adult ages, and shows that detrimental effects of obesity may have an exceptionally long time range, and that obesity at young adult age (30 years) is predictive for almost three times lower chances of survival to age 100 years."

Link: http://longevity-science.org/Centenarians-GSA-2007-paper.pdf

Expletive Deleted

Some very good points here, passed on by the Globe and Mail, whether or not it is 100% performance art: "Sipping Earl Grey tea at Ben Wicks, a lower-level Parliament Street hangout complete with paperback books and board games, they looked anything but nefarious as they described the Fuck Death Foundation, a non-profit charity they're launching over the next year to ultimately defeat mortality. Suspend your disbelief. Messieurs Wilkinson and Stewart are two of the city's most insightful people under 30 and their M.O. is not macabre, nor is it offensive ... Art can be so wishy-washy, so subjective. We wanted to have a quantifiable contribution to society ... An anonymous donor has covered initial administration and legal costs. In addition to assembling a board of directors, they hope to establish an operational model that will efficiently and effectively target parasitic and infectious disease, cardiovascular disease, cancer and AIDS. A Lightning Action Relief Fund will respond to global crisis situations. Over time, resources will be directed toward 'life extension sciences.' ... It's important to think about death. ... Unconsidered, life's not worth living." I'm all for covering all the memetic bases; best of luck to these fellows in creating more of the mindset whereby people are roused to shake their fists at aging and take action.

Link: http://www.theglobeandmail.com/servlet/story/LAC.20071110.COOL10/TPStory/TPEntertainment/Ontario/

The Value of Blood Vessels

Possibly the most crucial near-term technical hurdle on the way to sky's-the-limit regenerative medicine and organ regrowth is the matter of blood vessels. Unless you have a way of putting the blood vessels where they need to be, at every scale, or convincing blood vessels to grow according to plan, you simply can't engineer significantly sized pieces of tissue.

I noticed an article today that does a good job of illustrating why this is so, whilst loudly declaiming the significance of one particular research achievement:

Imagine being able to grow new tissue in a laboratory from cells that can later be used to repair damaged organs. This possibility is becoming a reality, as Cornell researchers make remarkable strides with the development of an artificial microvascular system.

This technology mimics the vascular system of the human body, carrying oxygen, sugar, proteins and growth factors to cells contained within a scaffold. The system is composed of microchannels embedded in a water-based gel, holding millions of living cells which can be formed to fit desired shapes.

“Whereas most microfabrication is done into silicon or glass, here we are microfabricating into a living tissue to put in these capillaries,” said Prof. Abraham Stroock, chemical and bio-molecular engineering, a co-author of the study, “and we can then use these capillaries as the microvascular system to keep the tissue alive and direct the tissue towards the desired structure and biological function.”

...

“One of the limitations of growing tissue outside the body is that they’re not hooked up to a vascular system that nourishes them in the body,” said Prof. Lawrence Bonassar, biomedical engineering, another co-author of the study. “We can create an artificial vascular system to keep these tissues alive for longer and potentially make larger tissues than can be made with other existing technology.”

...

“One of the main limitations of building tissue like liver or pancreas or kidney is the fact that they are vascularized inside the body,” said Bonassar. “Growing them outside the body or even taking them fully grown from outside the body and inserting them requires some connection to a vascular system. In many ways, this [microvascular system] could potentially be a very enabling technology for those kinds of efforts.”

...

“These microchannels are analogous to capillaries within tissues. Even though this is an improvement, the ultimate goal is to build something that not only has microchannels but where the microchannels can coalesce into a larger microvessel that we can attach to blood vessels already present in the body,” Spector said.

A lot of work is left to be done, but this is only one of a number of competing strategies aimed at solving the same problem. For example, the tissue printing community recently demonstrated a proof of concept that suggests blood vessels of any size can be fabricated as a part of new tissue using rapid prototyping techniques and a little reliance on the innate properties of cells:

As the tissue structure begins to form, the cells go through a natural process called 'sorting,' which is nature's way of determining where specific cells need to be. For example, an artery has three specific types of cells - endothelial cells, smooth muscle cells and fibroblast cells, each type needing to be in a specific location in the artery. As thousands and thousands of cells are added to the bio-paper under controlled conditions, the cells migrate automatically to their specific locations to make the structure form correctly.

Competition and the forging of multiple paths forward are always the most promising of signs.

Bad Reasons to Not Cure Aging

Methuselah Foundation volunteer Kevin Dewalt has penned a couple of good posts in the past week or two. You should head over and take a look:

Bad Reasons to NOT Cure Aging 1 - Foundation:

Ultimately we will figure out a way to undue this accumulated damage and prevent the diseases that will kill 90% of us. Whether we solve this problem in time to save the lives of our parents, us, our children, or our children’s children depends on how difficult these problems ultimately prove to be and how hard we work to solve them.

So with this foundation, it seems that we really don’t have to continue the debate unless you believe that solving this problem will create other problems that are both (a) Worse and (b) Unsolvable.

Although this reality can seem surprising at first, that’s basically it. If you strip away your emotional reactions to this issue - your cognitive dissonance - you’ll see that this discussions are rather silly. Reversing aging solves a huge, horrible problem, and it makes every sense to pursue it as fast as we can to make sure that we and the people we love will be able to take advantage of it.

Bad Reasons to NOT Cure Aging 2 - Overpopulation:

Ok, reversing aging may cause new problems. We just need to evaluate whether these problems are (1) worse than the horrible death of 100,000 people a day and (2) unsolvable.

I’ve been trained by our education system and media to worry about the dangers of human population explosion. I’ve been told that we will soon have billions more people than the Earth can support. Humanity is an inevitable time-bomb of exploding population that will outstrip our available resources.

Fortunately, like most doomsday predictions, the facts don’t support this conclusion. Human overpopulation may well be a total myth. Consider how we could choose to use the Earth differently, and I think you’ll conclude that how we use the available resources at our disposal is more influential than the total number of people using them.

I am absolutely of the school that overpopulation is a myth, a grave and unfortunately widespread misunderstanding of economic reality. Poverty certainly exists, thanks to human selfishness, bad governance and the inhumanity of man unto man. The Malthusians will call poverty a lack of resources per person, but it is always, always poverty in the midst of potential plenty - ample resources squandered, wasted through inefficiency, or left untapped.

More Work on an Alzheimer's Vaccine

A range of different approaches are being taken to develop Alzheimer's vaccines, aiming to incite the immune system to step in and block various known biochemical mechanisms of the disease. From ScienceDaily: "Tang and his colleagues at OMRF previously had identified the cutting enzyme (known as memapsin 2) that creates the protein fragments believed to be the culprit behind Alzheimer's. In the current study, researchers used mice that had been genetically engineered to develop symptoms of Alzheimer's, then immunized the animals with memapsin 2. ... What we saw is that the mice immunized with memapsin 2 developed 35 percent fewer plaques than their non-vaccinated counterparts. Those immunized mice also performed better than control mice in tests designed to assess their cognitive function. ... Tang's work with memapsin 2 also has led to the creation of an experimental drug to treat Alzheimer's disease. That drug, which works by inhibiting the cutting enzyme, began human clinical trials in the summer of 2007."

Link: http://www.sciencedaily.com/releases/2007/11/071112091855.htm

Ouroboros on Restricting Inflammaging

Ouroboros notes some joining of dots on the mechanisms of inflammaging: "High levels of inflammatory cytokines in aging tissues have been implicated in immunological dysfunctions and frailty in the very old. What causes this age-related upregulation of inflammation? From Kim et al., we learn of a connection between two 'usual suspects' that might help explain the phenomenon. They propose that NF-kappaB (the no-brainer go-to candidate transcription factor for inflammatory responses) is activated by phosphorylation of FOXO (a key transcription factor in an evolutionarily ancient longevity assurance pathway), which increases with age. Furthermore, calorie restriction (CR) may protect the animal by decreasing overall levels of insulin (and insulin-like growth factor) signaling: less insulin/IGF means less FOXO phosphorylation, leading to reduced oxidative stress. This in turn reduces nuclear translocation of NF-kappaB and a relative diminution of inflammatory cytokine production." The body is a collection of complex, interacting systems with many points of linkage - this is just as true when the systems begin to fail as when they are running according to plan.

Link: http://ouroboros.wordpress.com/2007/11/12/restricting-inflammaging/

On Intermittant Calorie Restriction

Here is more research supporting the benefits to be obtained from starting the practice of calorie restriction at any time in life. You'll benefit more if you practice longer, but there are always benefits to be gained by starting now: "Recent studies on the effects of dietary restriction (DR) in rodents and primates have shown that even late-onset short-term regimens can bring about comparable beneficial changes seen in animals subjected to life-long DR. We examined the effect of 3 months of DR on the expression of antioxidant enzymes and antioxidants, [and more] in 18-month-old middle-aged rats. The present study shows that DR initiated in late adulthood confers beneficial effects, such as attenuation of oxidative stress [and more]." The closer scientists look at the biology of calorie restriction, the more they find in the way of specific biochemical benefits, and a slowing of age-related decline in specific cellular processes. It's well worth your time to find out more about calorie restriction for humans if you haven't yet done so.

Link: http://dx.doi.org/10.1196/annals.1396.031

The Point of "Ending Aging"

The intent of Ending Aging is to achieve results like this, over and over again, expanding ever outward through the population of potential supporters of longevity research over the years ahead: "It's not light [but] I think it's a very important work. In fact, if I had friends who were in medical research, or undergrads interested in biology, I'd be buying them copies right now. This interview is a good introduction to de Grey and his quest to end aging. In short, he thinks we can stop aging, reverse at least some of it, and have healthy, vigorous lives for centuries. The book gets into the how. De Grey (and his assistant, Michael Rae) do a damn good job of explaining the intricacies of the metabolic problems behind aging. His proposal is to find ways to fix the damage done over time without bothering [to] explore all of its sources or the precise ways they can lead to death. ... He's taking an engineering approach, just wanting results without explanations of everything else in the tangle. ... Getting there is going to be tough. Right now the research is still at the level of animal experiments and there's not much funding. The Methuselah Mouse Prize is being offered for researchers who increase the lifespan of mice, funded by private donations. De Grey hopes a breakthrough in rejuvenating mice will create popular support for government funding of aging research. I'd settle for eliminating the government restrictions which prevent some of the research that could be done now. And I'm thinking about how much money I'm going to put into the Mouse Prize myself." Welcome aboard.

Link: http://selenite.livejournal.com/201085.html

Online Chat With Aubrey de Grey, Sunday November 11th

The Immortality Institute, a watering hole for many of the advocates and volunteers of the healthy life extension community, hosts a regular Sunday evening chat at 6:30 PM central time US. This coming Sunday November 11th the chat will be with biomedical gerontologist Aubrey de Grey:

I am happy to announce that the Immortality Institute Sunday evening chat has returned. The regularly scheduled time for the chat is 6:30 p.m. central time U.S. You can log into the Imminst chatroom by following the instructions found here:

http://www.imminst.org/chat/

This week, Sunday November 11th, the Institute proudly welcomes [biomedical gerontologist] and co-founder of the Methuselah Foundation - Aubrey De Grey.

Stop by, relax, and talk SENS!

It's a good opportunity to ask those questions about the Strategies for Engineered Negligible Senescence - and the plausible path to greatly extended healthy longevity - that you've been saving up for just such an occasion.

The Longevity Dividend in the Annals of the NYAS

The principle architects of the Longevity Dividend initiative make their case in the latest Annals of the New York Academy of Sciences: "The aging of humanity is about to experience a radical change as the demographic transformation to an older world is approaching its final stage. In recent decades, scientists have learned enough about the biological aging processes that many believe it will become possible to slow aging in humans. We contend that the social, economic, and health benefits that would result from such advances may be thought of as 'longevity dividends,' and that they should be aggressively pursued as the new approach to health promotion and disease prevention in the 21st century. The time has arrived for governments and national and international healthcare organizations to make research into healthy aging a major research priority." For my part, I don't think the record of government-funded aging research to date merits much more of its continuation - but the Longevity Dividend position still represents a major conceptual leap forward for the conservative mainstream of aging research.

Link: http://dx.doi.org/10.1196/annals.1396.050

The Value of Research Prizes

An op-ed at the New Scientist leaps halfway from the present doleful mainstream paradigm of medical research. Halfway because it imagines a world bettered by the absence of government-enforced intellectual property, but not without government at the hub of research, sadly. "We are conditioned to think that research into new medicines will come to a halt unless pharmaceutical companies continue to be allowed exclusive rights to sell the drugs they develop. But there is another way to stimulate research that would greatly enhance access to drugs, encourage companies to develop medicines that are more medically useful - and save money too. Rather than rewarding success with legal monopolies, governments could use large cash prizes. There has recently been a surge of prizes for particular research challenges, ranging from space travel and clean energy to video rental searches and yields from silver mining. Medical examples include the Prize4Life, which aims to advance research on amyotrophic lateral sclerosis; the Archon X prize for low-cost gene-sequencing techniques; the M prize to promote longevity research; and the Grainger Challenge to protect the world's poor from contaminated well water. Prizes are a potentially powerful tool whenever there is a sustainable way to finance them." The best way to turn any powerful tool into a rusty old mess is to let the government take charge.

Link: http://www.newscientist.com/channel/opinion/mg19626296.100-would-cash-prizes-promote-cheap-drugs.html

Proceedings of the Third International Conference on Healthy Ageing and Longevity

The latest Annals of the New York Academy of Sciences contains a range of interesting material from last year's third International Conference on Healthy Ageing and Longevity. I already pointed out the Longevity Dividend position paper over at the Longevity Meme, but there's much more to look into. For example:

Cytomegalovirus Infection: A Driving Force in Human T Cell Immunosenescence:

The human immune system evolved to defend the organism against pathogens, but is clearly less well able to do so in the elderly, resulting in greater morbidity and mortality due to infectious disease in old people, and higher healthcare costs. Many age-associated immune alterations have been reported over the years, of which probably the changes in T cell immunity, often manifested dramatically as large clonal expansions of cells of limited antigen specificity together with a marked shrinkage of the T cell antigen receptor repertoire, are the most notable. It has recently emerged that the common herpesvirus, cytomegalovirus (CMV), which establishes persistent, life-long infection, usually asymptomatically, may well be the driving force behind clonal expansions and altered phenotypes and functions of CD8 cells seen in most old people.

...

These virus-driven changes are less marked in "successfully aged" centenarians, but most marked in people whom longitudinal studies have shown to be at higher risk of death ... These findings support the hypothesis that persistent herpesviruses, especially CMV, act as chronic antigenic stressors and play a major causative role in immunosenescence and associated mortality.

You'll find a lot more on this topic back in the Fight Aging! archives. As for a couple of other near-future advances in longevity medicine, eliminating the influence of cytomegalovirus looks to be as much of a sure win as you're ever likely to see in the uncertain world of biotechnology research and development.

On Telomeres

A conservative view on the state of knowledge of telomeres and related biochemistry can be found in this paper: "Telomeres, the termini of linear chromosomes, consist of large but variable numbers of DNA oligomer repeats embedded in a nucleoprotein complex. In humans, telomere length (TL) is largely genetically determined but also featured by an age dependent attrition. TL has therefore been put forward as a marker for biological aging and was also reported to be associated with aging diseases such as cardiovascular disease. However it remains unclear whether the biomarker value in a particular disease depends on shorter TL at birth or rather if it's a mere reflection of an accelerated telomere attrition during lifetime, or else, if it is a combination of both. While the importance of telomere attrition is supported by cross-sectional evidence associating shorter telomeres with oxidative stress and inflammation, longitudinal studies are required to accurately assess telomere attrition and its presumed link with accelerated aging." A number of research groups and companies are working on safe ways to change telomere length, with the aim of impacting age-related disease or aging itself.

Link: http://www.ncbi.nlm.nih.gov/pubmed/17981769

Exercise and Progenitor Cell Activity

Another reason why exercise is good for healthy longevity is noted at EurekAlert!: "Exercise increased the growth of new muscle cells and blood vessels in the weakened muscles of people with heart failure ... researchers investigated whether exercise training could activate progenitor cells, a pool of immature cells in skeletal muscle that can divide into various mature cells as needed for muscle repair. Compared with healthy people, those with heart failure have about a 50 percent reduction in the number of progenitor cells in their muscles ... With exercise, the number of progenitor cells became almost normal, the cells started to divide again, and they began to differentiate into myocytes (muscle cells). And that's exactly what patients with heart failure need - replacement of muscle cells." The same mechanisms are at work in the rest of us as well. While we await the advent of medical technologies capable of reversing age-related degeneration, it makes sense to take good care of our long term health and longevity. Why reduce your chances of living into the age of rejuvenation medicine when there is so much you can do to move the odds?

Link: http://www.eurekalert.org/pub_releases/2007-11/aha-ehr102407.php

Aging and Oxidative Stress

Oxidative stress is the unassuming name for the state in which reactive oxygen species - the free radicals of the free radical theory of aging - are present in sufficient numbers to overwhelm the body's antioxidant defenses and thus cause potentially lasting damage and degredation by reacting with important molecules in cellular machinery.

If you care to head back in the archives a way, I explain some of the mechanisms in more detail in a post on the mitochondrial free radical theory of aging: where it is these reactive oxygen species come from, and how it is that they can do so much harm, leading to conditions such as atherosclerosis.

A paper on the rise of oxidative stress with aging caught my eye today:

Aging-Related Oxidative Stress in Healthy Humans:

Oxidative stress has been reported to increase with aging; however, the scientific evidence is controversial. We therefore aimed to analyze the relationship between aging and some markers of oxidative stress.

...

there was no age-related change in oxidative stress markers in subjects of < 60 years. These findings suggest that age of > 60 years may be associated with increased oxidative stress.

The full PDF version of that paper is freely available, if you are so inclined. As the evidence suggestions, age-related decline is far from a straight line; it seems to speed up greatly after 60, for example, becoming more dependent on the quirks of your biochemistry:

there was almost no genetic influence on age of death before 60

A number of age-related conditions start to emerge at 60, on average, once you start looking at that as a dividing line of sorts:

It may be that once you go beyond 60, which is the age when macular degeneration typically starts developing, the pigment is depleted for several reasons, including increased oxidative stress and a poor diet, both associated with an increase in age.

All the more reason to devote more resources to viable research initiatives aimed at removing sources of reactive oxygen species, or aimed at greatly reducing their impact on our biochemistry. There are groups out there working on the problem, and it's a tragedy in the making that very few of them are funded to the hilt.

Ageism As Economic Fear

Anne C. makes a case for ageism, in the sense of opposition to healthy life extension medicine, as irrational economic aversion. I'd call it common deathism, and it comes in varying shades of knowing or unknowing callousness. "It makes plenty of sense that a lot of what manifests as 'ageism' is actually a kind of economic phobia -- non-wealthy older people are considered (like disabled people, regardless of whether or not they would classify themselves as 'disabled') to be 'bad investments' with regard to employment, medical care, other forms of support, etc. This, combined with the independence myth can lead to particularly pernicious conditions for many. ... it's becoming more and more clear to me that, for instance, biogerontology is not likely to get much further unless great strides are made socially to affirm the value of older people and not push them to the corners, marginalize, or warehouse them by default." There are many explanations for this sort of thing; I favor fear of age-related degeneration as a contributing factor. Out of sight is out of mind, and no-one wants to think about what they believe to be inevitable suffering. But this behavior is now hindering progress that could plausibly lead to the repair of aging and radical life extension in our lifetime, if we all but put our shoulder to the wheel.

Link: http://www.existenceiswonderful.com/2007/11/rethinking-longevity-discourse-yes.html

Working Towards Printed Organs

Scientists continue to make steady progress towards the use of rapid prototyping technologies in tissue engineering. A little insight into progress from ScienceDaily: "For the past four years, [researchers have] been working to refine the process of 'printing' tissue structures of complex shape with the aim of eventually building human organs. In the latest study, a research team [determined] that the process of building such structures by printing does not harm the properties of the composing cells and the process mimics the naturally occurring biological assembly of living tissues. ... As the tissue structure begins to form, the cells go through a natural process called 'sorting,' which is nature's way of determining where specific cells need to be. For example, an artery has three specific types of cells - endothelial cells, smooth muscle cells and fibroblast cells, each type needing to be in a specific location in the artery. As thousands and thousands of cells are added to the bio-paper under controlled conditions, the cells migrate automatically to their specific locations to make the structure form correctly."

Link: http://www.sciencedaily.com/releases/2007/11/071106102650.htm

Regulation Destroys Progress, and Medicine is the Greatest Example

One subtle way in which increased regulation and other government intervention dampens progress - quite apart from raising costs, reducing competitive development, and making it harder for now technologies to be introduced - is by encouraging the formation of research communities with no accountability for progress, and no need to define and strike out for goals.

We humans are all backsliding apes at core; the only thing that keeps us honest and working hard is competition in the process of earning a living by building new and better things. Finding a niche where you don't have to stretch, work hard at ambitious goals, and make real progress - that's comfort for many.

You don't have to look too far in this world today to see just how pathetic progress in medical technology has been in comparison to other, much less regulated fields of endeavor. Over the decades, opportunity has been wasted on a grand scale. There are no excuses, no rationalizations. Medicine is just engineering, no special cases here. Other branches of engineering, just as technically challenging, have raced ahead while medical progress dawdled by comparison.

During the time Andrew S. Grovespent at Intel, the computer chip company he co-founded, the number of transistors on a chip went from about 1,000 to almost 10 billion. Over that same period, the standard treatment for Parkinson's disease went from L-dopa to . . . L-dopa.

...

Grove (who beat prostate cancer 12 years ago and now suffers from Parkinson's) thinks there is something deeply wrong with this picture, and he is letting the pharmaceutical industry, the National Institutes of Health and academic biomedicine have it. Like an increasing number of critics who are fed up with biomedical research that lets paralyzed rats (but not people) walk again, that cures mouse (but not human) cancer and that lifts the fog of the rodent version of Alzheimer's but not people's, he is taking aim at what more and more critics see as a broken system.

On Sunday afternoon, Grove is unleashing a scathing critique of the nation's biomedical establishment. In a speech at the annual meeting of the Society for Neuroscience, he challenges big pharma companies, many of which haven't had an important new compound approved in ages, and academic researchers who are content with getting NIH grants and publishing research papers with little regard to whether their work leads to something that can alleviate disease, to change their ways.

I noticed the symptoms of this malaise in a funding announcement not so long ago.

This might as well be language lifted from a mythical government release on the Full Employment Act for Gerontologists. It's all so grey and tired - rescue the scientists, pay the scientists, help the scientists. Note the utter absence of any sort of discussion of goals or results. What are these scientists actually doing? What is the value of it? Where are they going? When will they get there? What does it mean to me?

Does anyone really think that the computing industry would have achieved its growth if there was an FDA of computers, forcing every new development through billion dollar testing over a decade, stifling innovation under a weight of red tape and forbiddance?

The real obstacles to developing medical technologies to repair the cellular damage that is aging are not technical. No. They're all to do with the rules people make while trying to steer the lives of others. Government, representing centralized, forceful control over other people, has always led to broken systems; there is no substitute for freedom and competition if you want things done, done fast and done well.

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.

Granzyme B, Atherosclerosis, Longevity

From the newswires: researchers uncovered "new knowledge of granzyme B, an enzyme that plays an important role in the immune system. ... levels of granzyme B were significantly elevated in patients with atherosclerosis. ... this enzyme's expression was blocked, atherosclerosis could be reduced by over 70 per cent [in mouse models]. Atherosclerosis is the underlying cause of most heart attacks, strokes, aneurysms and complications arising from diabetes. It is the world's leading cause of death in those over 60. ... granzyme B may play a role in hair loss and aging. During experiments in which the expression of this enzyme was blocked in mice they did not appear to age, developed much denser fur and had a significantly longer lifespan. Granzyme B is released by many immune cells to target and destroy virus-infected cells. Until recently, it was thought that immune cells delivered granzyme B directly into cells targeted for destruction. ... in certain conditions it is also released by immune cells into the space around healthy cells and in the plasma. When this occurs, it destroys key structural proteins that surround the healthy cells, [like] termites eating away at the infrastructure of a home. This can lead, for example, to a loss of the structural integrity and elasticity of blood vessels and ultimately, atherosclerosis."

Link: http://www.newswire.ca/en/releases/archive/November2007/05/c4301.html

Aging Immune Systems and Macular Degeneration

From EurekAlert!: "age is key in determining whether damaging blood vessels will form beneath the retina and contribute to vision loss. The scientists discovered that specific immune cells called macrophages play a role in the disease process in older mice by failing to block the development of abnormal, leaky blood vessels behind the retina. But in younger mice, macrophages typically prevent abnormal blood vessel formation. The scientists believe better understanding of how macrophages work may provide potential targets for therapies to slow or even reverse vision loss. There are two basic types of macrophages - known as M1 and M2 - and in the older mice, there was a preponderance of cells with the M2 signature. These M2 cells promoted abnormal blood vessel growth in the eyes of older mice. In younger mice, most macrophages had the M1 signature, and those cells inhibited the development of defective blood vessels ... it appears the population of macrophages drifts from the M1 type to M2 cells because of an increase in the levels of an immune system molecule called interleukin-10 (IL-10) in the eye as the mice get older."

Link: http://www.eurekalert.org/pub_releases/2007-11/wuso-ica103107.php

Ouroboros on Hormesis

I thought I'd draw your attention to a couple of good posts on hormesis over at Ouroboros, a topic favored in that part of our community. It turns out that a little of a bad thing can improve the functioning of your biological systems over time:

Small doses of 'stressors' normally considered dangerous to health can actually boost the body's self-repair system, and as a side-effect preserve youth, experts believe.

Some like it hot: Resveratrol induces the heat shock response:

How might hormesis - the protective effect of low-dose or acute stress against higher-dose or chronic stress - work at the molecular level? One possibility is that the mild "priming" stress tones up the protective actions of stress responses: a hit of peroxide, for example, might accelerate expression of antioxidant enzymes like superoxide dismutase, protecting the cell against a future oxidative wallop. To the extent that chronic stresses can be risk factors for age-related decline in cellular function, hormetic stress might protect the cell against such long-term grinding damage, and ultimately against aging itself.

Compounds that protect against stress and aging might therefore function in a hormetic manner - either by literally stressing cells or by "simulating" stress, i.e., inducing protective stress responses without actually causing even short-term acute damage.

Hormesis in Aging:

Hormesis in aging is represented by mild stress-induced stimulation of protective mechanisms in cells and organisms resulting in biologically beneficial effects. Single or multiple exposure to low doses of otherwise harmful agents, such as irradiation, food limitation, heat stress, hypergravity, reactive oxygen species and other free radicals have a variety of anti-aging and longevity-extending hormetic effects. Detailed molecular mechanisms that bring about the hormetic effects are being increasingly understood, and comprise a cascade of stress response and other pathways of maintenance and repair.

As for so much of what we could do with our biology today, the plausible level of beneficial effects produced by a hypothetical program of evaluated, controlled hormesis are far outweighed by the plausible level of benefits from regenerative medicine or SENS-like biochemical repair technologies of the decades ahead.

It makes sense to take care of your health today, but we're going to age, suffer and and die on a similar time frame to our grandparents if we don't support and embrace radical advances in medical technology and aging research.

A Million Optimizations Without Forethought

Let us count the ways in which biochemical processes, optimized through evolution for youthful health and reproductive success, interact poorly as they change with age, and thus cause pain and suffering. Here is one example of many from EurekAlert!: "Jason Dyck and his research team at the University of Alberta have been studying the types of fuels used by the heart in young and aged mice. The young healthy heart normally used a balance of fat and sugar to generate energy to allow the heart to beat and pump blood efficiently. However, as the heart ages the ability to use fat as an energy source deteriorates. This compromises heart function in the elderly. Interestingly, at a time when the heart is using less fat for energy, Dyck has shown that a protein that is responsible for transporting fat into the contractile cells of the heart actually increases. Based on this finding, Dyck proposed that the mismatch between fat uptake and fat use in the heart could lead to an accumulation of fat in the heart resulting in an age-related decrease in heart function." This being the age of biotechnology, they go on to engineer a mouse that doesn't suffer from this specific problem - but you get the idea. Aging is damage and change that causes disarry; repair or prevent the changes sufficiently well and you don't have to patch up after the disarray.

Link: http://www.eurekalert.org/pub_releases/2007-11/uoa-sfo110207.php

Biomechanisms of Limb Regeneration

LiveScience reports on progress in understanding how salamander biochemistry regenerates entire lost body parts: scientists "ran experiments in which they chopped off red-spotted newts' limbs and the attached nerves. The nerves are needed to stimulate the production of the nAG protein, so the nerve-severing essentially removed the newts' source of nAG. Then they zapped the cells of the now-exposed body region with electrical pulses so they could deliver little bundles of DNA carrying genes for the protein nAG. Within 30 to 40 days, the newts had regenerated their lost limbs, digits and all. However, the new limbs had less muscle mass than the original ones. Further lab experiments revealed the nAG protein - a molecule - works directly on the blastema cells, causing them to grow and divide. ... It essentially tells us that one single molecule is able to support the proliferation of blastema cells right from the start of regeneration all the way through to the formation of the digits." As the researcher notes, it is a solid step but many more steps are required before we humans will be regrowing damaged organs.

Link: http://www.livescience.com/animals/071101-newt-limbs.html

Ending Aging Hits Amazon Top 100

Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime briefly spiked up above Amazon Rank 100 yesterday - and is floating just above 200 the last I checked - following wider distribution of the recent Washington Post article on biomedical gerontologist Aubrey de Grey and the Strategies for Engineered Negligible Senescence (SENS). Great news!

I am encouraged that a hard science book can still attract a lot of attention in the marketplace of ideas, and pleased that a grounding in the SENS view of how to defeat aging will spread further as a result. The spread and discussion of these ideas is a necessary foundation for the process of raising significant further funding for ongoing SENS research. Both MitoSENS and LysoSENS projects are funded at present by donations to the Methuselah Foundation, but a wide range of other SENS-like or SENS-applicable work takes place out there in the world. We would like to see those research groups grow and attain the funding they deserve.

FuturePundit on the Repair of Aging

Thoughts from Randall Parker: "Aubrey [de Grey] believes (and FuturePundit agrees) that we can develop biotechnologies that will allow us to reverse aging and make us young again. This goal will be achieved within the lifetimes of at least some of the people currently alive. The sooner the general public realizes this the faster this goal will be realized. ... Aubrey thinks people are heavily invested in believing that death from aging is inevitable. This position made sense back when death from aging really was inevitable. Best to rationalize that aging is a good thing if there's nothing you can do about it. Make your peace and find reasons to be happy with what you can't change. But the rate of advance of biotechnology is accelerating with DNA sequencers and microfluidic devices becoming more powerful in ways analogous to the rate of progress with computers. We can strive for goals that used to seem unattainable. We should start trying to conquer aging. It is a solvable problem." Exactly right - and we can all jump in and help. You don't have to be a researcher to help to researchers make faster progress towards the defeat of aging.

Link: http://www.futurepundit.com/archives/004744.html

Illustrative Progess In Stem Cell Research

A couple of releases culled from EurekAlert! in the past day or two are illustrative of the direction and progress of one major branch of stem cell based regenerative medicine at present. One the one hand is the exploration of how it is that transplanted stem cells can produce regeneration above and beyond what the body will accomplish on its own. On the other hand, there is a continual identification of new stem cell populations throughout the body, and the search for controlling signals and mechanisms that could be used to enhance their innate regenerative capacities.

Stem cells can improve memory after brain injury:

They found that only about 4 percent of [transplanted stem cells] turned into neurons, indicating the stem cells were not improving memory simply by replacing the dead brain cells. In the healthy mice, the stem cells migrated throughout the brain, but in the mice with neuronal loss, the cells congregated in the hippocampus, the area of the injury. Interestingly, mice that had been treated with stem cells had more neurons four months after the transplantation than mice that had not been treated.

“We know that very few of the cells are becoming neurons, so we think that the stem cells are instead enhancing the local brain microenvironment,” Blurton-Jones said. “We have evidence suggesting that the stem cells provide support to vulnerable and injured neurons, keeping them alive and functional by making beneficial proteins called neurotrophins.”

If supplemental neurotrophins are in fact at the root of memory enhancement, scientists could try to create a drug that enhances the release or production of these proteins. Scientists then could spend less time coaxing stem cells to turn into other types of cells, at least as it relates to memory research.

Jefferson researchers find stem cells in degenerating spinal discs, potential for repair:

Orthopedic researchers at Jefferson Medical College have for the first time found stem cells in the intervertebral discs of the human spine, suggesting that such cells might someday be used to help repair degenerating discs and remedy lower back and neck pain. ...

According to Dr. Shapiro, as the discs in the spine degenerate, cells are lost and the ability to produce water-binding molecules called proteoglycans is decreased. The water absorbs forces on the spine, essentially serving as shock absorbers. Losing proteoglycans can result in damage to the disc, and sometimes, pain.

...

Shapiro notes that other researchers have taken bone marrow stem cells and have made new bone, cartilage and fat tissue. “Our next step is to activate these disc stem cells and get them to repopulate the disc and make proteoglycans and restore the water-binding,

The scientists theorize that because the stem cells exist in the degenerate disk, there may be molecules that are blocking stem cell activity. “Something is inhibiting the disc repair process,” says Dr. Shapiro. Drs. Shapiro and Risbud agree that “new studies are needed to discover the nature of such inhibitory molecules” and to find ways to block their activities, promoting natural healing.

Regeneration is not rejuvenation - but it will be big improvement over the present capabilities of medical technology.

A Gentle Reminder About the Fat

Even moderate excess weight is not a good thing for health and longevity over the long term, as the BBC reminds us: "The World Cancer Research Fund carried out the largest ever inquiry into lifestyle and cancer, and issued several stark recommendations. ... People with a Body Mass Index (BMI), a calculation which takes into account height and weight, of between 18.5 and 25, are deemed to be within a 'healthy' weight range. But the study says their risk increases as they head towards the 25 mark, and that everyone should try to be as close to the lower end as possible. There is no new research involved in this document: the panel examined 7,000 existing studies over five years." BMI is not a one size fits all measurement, but the general conclusions fit regardless of where exactly a sensible lifestyle choice - such as practicing calorie restriction - places you. Cancer is just one of many age-related conditions whose risk is strongly correlated with excess body fat over the years. Maybe the technology of tomorrow will be available in time to save you from the neglect of today. Equally, maybe it won't; is that something you really want to gamble on?

Link: http://news.bbc.co.uk/2/hi/health/7069914.stm