Fight Aging!

As a technology platform, the manipulation of stem cells is very broad indeed. Once the fundamental methodologies and infrastructural technologies involved in sourcing and altering stem cells are made reliable and cheap - a process that is still very much underway - then the sky will be the limit. Any part of the human body will be up for at least some benefit and quite possible outright replacement: mature stem cell medicine will provide the closest thing yet to a general repair kit for human beings.

Much like a general repair kit for cars, stem cell medicine cannot be used to evade the end results of aging - you can slow down the consequences, but there are aspects of aging that cannot be tackled using these tools. Cell replacement and manipulation is only one of a number of different technology platforms required to restore age-damaged biochemistry to a youthful state. But it is a step in the right direction.

Here are a couple of articles on recent work at opposite ends of the stem cell research field - reversing degenerative blindness and muscle loss. They are representative of stem cell science at present: a fast pace of discovery, new technology demonstrations every week, and a lot of promise when it comes to near-future applications in medicine.

Stem cells give sight to blind mice, raising hope for aging humans:

Using stem cells salvaged from the retinas of human cadavers, researchers with the University of Toronto have restored sight to the eyes of, well, three blind mice. The feat, aside from indicating a quirky sense of humour, has been repeated several times over the last year and marks an important step toward the goal of restoring sight in people. ... All the basic biology of the human eye and retina is the same as it is in the mouse. If we can get enough of the cells to grow and integrate, I think we’d go right into [trials with] humans.

Stem Cells in Injured Mice Give Them Huge Muscles for Life:

A happy accident may hold the key to healing muscle diseases and granting humans incredible physiques. Researchers at the University of Colorado at Boulder and the University of Washington discovered that stem cells injected into mouse muscles led to increased growth for the rest of the mouse’s life. Young mice with injured legs were given donor muscle stem cells from other young mice. Those injuries not only healed, but muscle mass increased 50% and muscle volume increased by an incredible 170%! Performance tests show the muscles were twice as strong as normal, and still above average when you control for size. Two years later, about the lifetime of a mouse, the legs were still bigger and stronger than normal, much to the scientists surprise.

The paper for that second article is entitled "Prevention of Muscle Aging by Myofiber-Associated Satellite Cell Transplantation". You might look back into the Fight Aging! archives for more on satellite cells in muscle and aging - decline of function and/or numbers in this stem cell population has been a hot topic in the research community for a few years now:

• Rejuvenating Aging Stem Cells ... Or Not
• Myostatin, Muscle Loss, and Patching the Symptoms
• More On Myostatin and Satellite Cells in the Aging Body
• Another Run at Making Old Stem Cell Act As Though Young

A promising study in mice: researchers "have discovered a new strategy to prevent memory deficits in a mouse model of Alzheimer's disease (AD). Humans with AD and mice genetically engineered to simulate the disease have abnormally low levels of an enzyme called EphB2 in memory centers of the brain. Improving EphB2 levels in such mice by gene therapy completely fixed their memory problems. ... EphB2 [acts] as both a receptor and an enzyme. We thought it might be involved in memory problems of AD because it is a master regulator of neurotransmission and its brain levels are decreased in the disease. ... To determine if low EphB2 levels actually contribute to the development of memory problems, the investigators used gene therapy to experimentally alter EphB2 levels in memory centers of mice. Reducing EphB2 levels in normal healthy mice disrupted neurotransmission and gave them memory problems similar to those seen in AD. ... Increasing EphB2 levels in neurons of mice engineered to produce high levels of human amyloid proteins in the brain prevented their neurotransmission deficits, memory problems and behavioral abnormalities. The scientists also discovered that amyloid proteins directly bind to EphB2 and cause its degradation, which helps explain why EphB2 levels are reduced in AD and related mouse models. ... Based on our results, we think that blocking amyloid proteins from binding to EphB2 and enhancing EphB2 levels or functions with drugs might be of benefit in AD."

Link: http://www.eurekalert.org/pub_releases/2010-11/gi-gtp112210.php

From Maria Konovalenko: "I'd like to draw your attention to Jan Vijg's words: 'People are a little afraid to confess that they want to cure aging. I think it would be a good thing to make it very clear that that is exactly what we want to do, we want to try to get rid of aging.' Dr. Vijg discerned one of the major problems in biogerontology - the fear and pretence of the scientists, who want the grant money, but don't want to sound 'inappropriate.' I have to say this approach of not saying what you have in mind is lethal. For everybody. Why is so much money being spent on cancer research? Because cancer researchers cry out loud that cancer is a very dangerous disease that needs to be cured. They clearly state their goal. Biogerontologists, on the other hand, would never say their goal is to cure aging. This is why they don't get the money. This is why the whole field rather survives, not lives. I believe this attitude has to change. Researchers have to state their noble goal - to defeat aging. They should be neither afraid, nor embarrased to say this explicitly. This is the only right way to get public attention and needed grant money for studying the fundamental mechnisms of our worst disease - aging."

Link: http://mariakonovalenko.wordpress.com/2010/11/29/major-problem-in-biogerontology/

The social media communities and mainstream media have been abuzz over a recently released study on telomerase and aging in mice. For my part, I think that this is nothing more than a good example of the random and at times self-defeating way in which research is publicized and then catches the public eye. A short summary of the study is as follows:

At Harvard, they bred genetically manipulated mice that lacked an enzyme called telomerase that stops telomeres getting shorter. Without the enzyme, the mice aged prematurely and suffered ailments, including a poor sense of smell, smaller brain size, infertility and damaged intestines and spleens. But when DePinho gave the mice injections to reactivate the enzyme, it repaired the damaged tissues and reversed the signs of ageing.

You might look back into the Fight Aging! archives for a primer on the intersection of telomeres, telomerase, and aging. It's interesting stuff, but unfortunately this present research is being headlined as "scientists reverse aging in mice" - which is absolutely not what was accomplished. Reversing an artificially created accelerating aging condition by removing its cause is not the same thing as intervening in normal aging, and it will rarely have any relevance to normal aging. The study results are teaching us something about the way in which telomerase works in mouse metabolism, but I - and other, more qualified folk - are dubious as to the relevance to human aging:

The goal for human tissue 'rejuvenation' would be to remove senescent cells, or else compensate for the deleterious effects they have on tissues and organs. Although this is a fascinating study, it must be remembered that mice are not little men, particularly with regard to their telomeres, and it remains unclear whether a similar telomerase reactivation in adult humans would lead to the removal of senescent cells.

The bottom line is that it is really only worth getting excited over a study that shows extension of life rather than an un-shortening of life. It's all too easy to create short-lived mice and then make them less short-lived - hundreds of studies have achieved this result in one way or another. Also bear in mind that the media and public at large don't tend to seize upon one specific research result above another for any rational reasons. When it comes to what is shouted from the loudspeakers on a given day, it's all a matter of accident and marketing rather than facts and understanding. For example, you might recall that telomerase and p53 were used to extend normal mouse life span by 50% a few years ago - far more important and interesting than this present study, yet it received next to no attention.

The Harvard researchers responsible for the accelerated aging and telomerase study in mice we're discussing today will go on to look at extended longevity:

The team is now investigating whether it extends the lifespan of mice or enables them to live healthier lives into old age.

If they find some way to boost the normal life span of mice, then we might pay more attention. But for now the circus treatment is unwarranted.

Another demonstration of the potential utility of autologous stem cell therapies: "A spray solution of a patient's own stem cells is healing their severe burns. So far, early experiments under a University of Utah pilot project are showing some remarkable results. What was once a serious burn on Kaye Adkins foot is healing nicely now because of a topical spray. With diabetes as a complication, the small but open wound had not healed after weeks of failed treatments. ... With a wound that is open for several months, as this patient suffered prior to seeing us in our burn clinic, we worry about a pretty heavy bacterial load there. ... But enter the evolutionary world of regenerative medicine, using almost a bedside stem cell technique that takes only about 15 minutes. With red cells removed, a concentrate of platelets and progenitor cells is combined with calcium and thrombin. The final mixture looks almost like Jello. Though her own skin graft had failed before, the topical spray was used during a second graft. It 'took' and healed. ... Adkins burn is healing and so is her heart. Coincidentally, stem cells were used during her bypass surgery five weeks ago to hasten healing for that procedure as well. While hundreds of heart patients have had stem cell treatments, burn patients are still few in numbers. Cardiothoracic surgeon Amit Patel and burn care surgeon Amalia Cochran are experimenting on small burns for now. But down the road, both are hoping for large scale clinical trials on patients with much larger burns."

Link: http://www.ksl.com/?nid=148&sid=13424065

This interview with Aubrey de Grey and David Brin encapsulates the divide in longevity science. On the one side, people who see repair-based methodologies like SENS and the reversal of aging as the best way forward, and who foresee great progress within a few decades after major funding is achieved. On the other, people who look towards changing metabolism to slow aging, and who foresee little progress over the next few decades because the challenge of building a new, viable human metabolism is very, very hard. From de Grey's side of the article: "I think we have a 50% chance of achieving medicine capable of getting people to 200 in the decade 2030-2040. Presuming we do indeed do that, the actual achievement of 200 will probably be in the decade 2140-2150 - it will be someone who was about 85-90 at the time that the relevant therapies were developed. There will be no one technological breakthrough that achieves this. It will be achieved by a combination of regenerative therapies that repair all the different molecular and cellular degenerative components of aging." As a counterpoint, from Brin's side of the article: "I do not expect this any time soon. There are way too many obstacles. First, there is no low-hanging fruit. Simple switches, like the ones that are flipped in many animals, by caloric restriction or celibacy, are there to give creatures a delayed chance at reproduction, if it cannot happen earlier. These switches have already been thrown in humans. All of them! Because we had genuine darwinistic reasons to evolve longest possible lifespans. When the lore held by grandparents helped grandchildren to survive, we evolved a pattern where the tribe would always have a few grandparents around, who remembered stuff."

Link: http://www.ilookforwardto.com/2010/11/when-will-life-expectancy-reach-200-years-aubrey-de-grey-and-david-brin-disagree-in-interview.html

When people say "DNA" they usually mean nuclear DNA. Our nuclear DNA resides, as you might guess, in the nucleus of cells. It is the packaged blueprint for the proteins and biochemical processes that give rise to our physical structure, protected, repaired, and manipulated by a dazzlingly complex array of attendant biological machinery. Our cells are constantly assaulted by reactive molecules created as a byproduct of metabolic processes, and despite the very efficient DNA repair mechanisms we have evolved, damage to nuclear DNA accumulates slowly over time and results in mutations - changes to the information coded in the DNA strands - or other forms of outright impairment of cellular operations.

It is well settled that the level of nuclear DNA damage and mutation exhibited by an organism rises over time. It is also well settled that higher levels of nuclear DNA damage and mutation mean a greater cancer risk - this is one of the reasons why cancer is predominantly a disease of the old. The more cells that suffer DNA damage, the more likely it is that one or more cells experience exactly the type of damage needed to run amok as the self-replicating seeds to a cancer. But is nuclear DNA damage and mutation a cause of aging?

That increasing instability of the genome contributes to age-related degeneration is the present working assumption for much of the aging research community, but this hypothesis is not unchallenged. The lack of a definitive proof is one problem: there is no good experiment to show that reduction in nuclear DNA damage levels - and only nuclear DNA damage levels - extends life. We can point to, for example, the fact that calorie restriction results in lower nuclear DNA damage levels, but this is only correlation. Calorie restriction slows the progression of every measure of biological aging, and produces significant changes in all of the master controls of metabolism and their subsystems, which makes it very hard to tease out any one dominant first cause. (And where work is proceeding on that front, boosted autophagy is the leading candidate in any case).

Biomedical gerontologist Aubrey de Grey has argued for the irrelevance of nuclear DNA damage to aging - beyond the issues of cancer risk, and over the present human life span, that is:

Since Szilard's seminal 1959 article, the role of accumulating nuclear DNA (nDNA) damage - whether as mutations, i.e. changes to sequence, or as epimutations, i.e. adventitious but persistent alterations to methylation and other decorations of nDNA and histones - has been widely touted as likely to contribute substantially to the aging process throughout the animal kingdom. Such damage certainly accumulates with age and is central to one of the most prevalent age-related causes of death in mammals, namely cancer. However, its role in contributing to the rates of other aspects of aging is less clear. Here I argue that, in animals prone to cancer, evolutionary pressure to postpone cancer will drive the fidelity of nDNA maintenance and repair to a level greatly exceeding that needed to prevent nDNA damage from reaching levels during a normal lifetime that are pathogenic other than via cancer or, possibly, apoptosis resistance.

The high level goal of de Grey's SENS program is to develop the biotechnologies needed to repair and reverse all of the identified biochemical differences between a young person and an old person. That remit obviously includes nuclear DNA damage and mutation, but de Gray's position above is essentially an efficiency argument - other forms of difference are far more important, so the research community should deal with those first.

This is far from the last word in the ongoing debate over aging and nuclear DNA damage, of course, and until someone designs an experiment to show extended life in mice achieved through nothing more than better DNA repair, it will remain a debate. If you look back into the Fight Aging! archives, you'll find more on this topic:

• Arguing for Nuclear DNA Damage as a Cause of Aging
• Another Way to Look at DNA Damage and Aging
• Fuel for the Debate Over DNA Damage and Aging
• More DNA Damage Research, In Mice This Time

There are good arguments and supporting evidence on either side; sometimes in the life sciences you have to accept that a good answer beyond mere hypothesis remains elusive, and more work must be done in order to change that fact.

A recent open access review paper looks at the evidence for accumulated senescent cells as one of the causes of aging: "Epidemiological studies have shown that age is the chief risk factor for lifestyle-related diseases such as cardiovascular disease and diabetes, but the molecular mechanisms that underlie the increase in the risk of such diseases conferred by aging remain unclear. ... Interestingly, most of the molecules that influence the phenotypic changes of aging also regulate cellular senescence, suggesting a causative link between cellular senescence and aging. ... Cell division is essential for the survival of multicellular organisms that contain renewable tissues, but places the organism at risk of developing cancer. Thus, complex organisms have evolved at least two cellular mechanisms to prevent [cancer]: apoptosis and cellular senescence. In this regard, aging and age-associated diseases can be viewed as byproducts of the tumor suppressor mechanism known as cellular senescence. Consistent with this idea, the number of senescent fibroblasts increases exponentially in the skin of aging primates. Conversely, extension of the lifespan by calorie restriction decreases biomarkers of cellular senescence."

Link: http://dx.doi.org/10.1253/circj.CJ-10-0916

From Maria Konovalenko: "There are many studies that involve extending the lives of laboratory animals - through gene manipulation, pharmaceutical intervention, and dietary restriction. But according to Steven Austad, a biologist at the Barshop Institute for Longevity and Aging Studies, these manipulations 'pale in comparison to the remarkable diversity of lifespan produced by evolution.' He points out that maximum life span across the animal kingdom varies 40,000-fold. For example, some adult flies live less than an hour; some shellfish for centuries. Among mammals alone, longevity varies 1,000-fold. The average fruit fly lives a little more than a month, so scientists' ability to double its lifespan is a remarkable achievement but Austad says we may be missing something by focusing so much of our longevity research on animals - flies, worms, mice - that are 'demonstrably unsuccessful at combating basic aging processes.' He suggests we put more effort into understanding molecular solutions nature has devised to help long-living creatures evade their deaths. ... Aging affects all of us. People are going to continue to live longer because of medical advances. We want them to live healthier as well as live longer. The best way to achieve longer health is to figure out ways to medically slow aging. That's a different sort of approach than figuring out how to cure cancer or heart disease. If you can cure aging, or if you can slow it, then you can really delay or prevent a whole host of disabilities and diseases."

Link: http://mariakonovalenko.wordpress.com/2010/11/21/what-old-animals-can-teach-us-about-aging/

Manipulating the immune system to destroy specific targets in the body is an approach that shows great promise. Targets involved in aging include senescent cells, cancerous cells, and aggregates such as amyloids that become harmful as they build up over time. An added bonus to the increasing importance of immune therapies in the research community is that it will force researchers to spend more time on establishing ways to reverse the decline of the immune system with age. The people who will most benefit from immune therapies are the old - but their immune systems need to be functioning well in order to obtain the best results.

Here is an example of present work on training the immune system to destroy cancer. These are still the opening years of this field of research, but the benefits are evident even now, while the therapies are comparatively crude and unrefined.

A new process for creating a personalized vaccine may become a crucial tool in helping patients with colorectal cancer develop an immune response against their own tumors. ... Basically, we've worked out a way to use dendritic cells, which initiate immune responses, to induce an antitumor response. ... The new research grew dendritic cells from a sample of a patient's blood, mixed them with proteins from the patient's tumor, and then injected the mixture into the patient as a vaccine. The vaccine then stimulated an anti-tumor response from T-cells, a kind of white blood cell that protects the body from disease.

...

In the study, Barth first operated on 26 patients to remove tumors that had spread from the colon to the liver. While some of these patients would be expected to be cured with surgery alone, most of them would eventually die from tiny metastases that were undetectable at the time the tumors were removed from the liver. The DC vaccine treatment was given one month after surgery. The results were that T-cell immune responses were induced against the patient's own tumor in more than 60% of the patients. The patients were followed for a minimum of 5.5 years.; Five years after their vaccine treatment, 63% of the patients who developed an immune response against their own tumor were alive and tumor-free. In contrast, just 18% of the patients who did not develop an immune response against their own tumor were alive and tumor-free.

It'll be a couple of decades before people of my generation reach the prime years for developing cancer. Progress of this sort today, when we are still at the very start of the age of biotechnology, is one of the reasons why I'm not overly concerned about the cancer in my future. The impact on my personal finances will no doubt be painful at the time - but that can be planned for, and I'll take it over the other options.

From the Huffington Post: "There is no question that social equity issues such as poverty and access to medical treatment affect life expectancy. The same is true with our life style choices (e.g., eating, exercise). Yet the precise benefit often is elusive as is the case for alcohol where epidemiological studies find surprisingly contradictory results. So, what happens when we throw [the] FDA into the brew? We have a system of FDA approval that requires a pharmaceutical company show three things: (1) a mechanism of action (i.e., identify why a drug works), (2) safety and (3) efficacy in managing a measurable biologic end point associated with a disease. This last condition is a problem. Look at the conundrum: You're a researcher and you walk into FDA one day and say: 'I have in this bottle an elixir that if taken every day of your life will add on average 4 years to how long you can expect to live.' FDA says: 'What disease will it cure?' The researcher says: 'It won't cure disease, it will postpone or mitigate the lethality of some diseases, but as you get older you will get other diseases.' FDA then hopefully says: 'We get it. While we do not now nor have we ever thought about age as a disease metric, we accept the concept. All we need to do is test your drug on a sufficiently large population and for a long enough period of time to prove to us it works.' That is the problem." For so long as the FDA and its more similar foreign counterparts exist, progress in turning science into applied longevity-enhancing therapies will be greatly slowed.

Link: http://www.huffingtonpost.com/gary-liberson/does-fda-need-to-rethink_b_787383.html

Good news for the cryonics community: "Alcor has received seven million dollars following final settlement of the estate of a confidential member who was cryopreserved several years ago. The bequest will be divided equally between Alcor's Patient Care Trust and a new Endowment Fund to be created with a maximum legally allowed annual distribution of 2% per year. This will double the value of the Patient Care Trust to approximately $7 million, increasing the security of all 100 patients in Alcor's care. The Patient Care Trust is devoted solely to funding the ongoing biostasis of Alcor's patients and their eventual revival and reintegration into society when the medical technology to restore them to full health is developed. ... This is a marked departure from past Alcor practice, which has been to place windfalls into either the Alcor general or reserve fund accounts. The funds would then be gradually depleted to cover operating deficits, with the hope that an additional windfall would arrive prior to the depletion of funds. Alcor is instead now seeking to eliminate structural operating deficits so that it is no longer dependent upon these unpredictable events. Consequently, this bequest will not make a large difference in Alcor's budget next year: it will only contribute an extra $70,000. While $70,000 will help close next year's deficit, it must be combined with other difficult measures. In the longer term, however, this financial discipline will make Alcor a healthier and more robust organization."

Link: http://www.alcor.org/blog/?p=1432

Moderate regular exercise, much like calorie restriction, is demonstrated to slow down almost all measures of aging investigated to date. It's fair to say that exercise modestly slows aging - or perhaps more accurately we would say that a lack of exercise accelerates the accumulation of biological damage and resulting decline in health that occurs with the passing of years. Being a sedentary couch potato cuts short the life you would otherwise have lived, and makes its later years much more unpleasant to boot.

We can talk about some of the ways in which exercise impacts long term health and the state of your biochemistry. Given that aging is nothing more than the accumulation of damage, it is probably important that exercise has a hormetic effect: it puts a little stress on the system, which activates heat shock proteins and thereby boosts cellular repair and recycling mechanisms - such as autophagy - to greater efforts, producing a net benefit. This may explain why exercise is shown to produce lower levels of mitochondrial DNA damage, and hopefully you all know by now that mitochondrial DNA damage is one of the important contributions to age-related degeneration.

Today I noticed another speculative mechanism by which exercise can modestly improve your lot in life. You might recall that one of the primary issues with our immune systems is that necessary cells become crowded out over time - the body supports only so many immune cells, and the naive T cells needed to fight new invaders become depleted in favor of memory cells uselessly devoted to persistent viruses that the body cannot clear. In essence, the adaptive immune system is evolved to hit the ground running and fight the battles of a young life - and that front-loading of its effectiveness leaves us high and dry later on, once too many battles have been fought.

One of the strategies that medical researchers could use to solve this problem is to destroy the unwanted specialist cells, freeing up room for more useful T cells and restoring immune response to a more youthful level. The targeted cell-hunting and cell-killing technologies under development in the cancer research community would be ideal for this use.

Now consider that even though the vast majority of people are infected with persistent viruses like cytomegalovirus, the quality of their immune systems in later life varies widely. Some people have comparatively good immunity when they are old - nowhere near as good as when young, but certainly better than their fellows. It could be argued that exercise goes some way towards establishing this difference - and in this paper, the argument is that exercise lures out decrepit T cells so that they can be destroyed by the body's maintenance systems:

Overcrowding the "immune space" with excess clones of viral-specific T-cells causes the naive T-cell repertoire to shrink, increasing infection susceptibility to novel pathogens. Physical exercise preferentially mobilizes senescent T-cells from the peripheral tissues into the blood, which might facilitate their subsequent apoptosis and create "vacant space" for newly functional T-cells to occupy and expand the naive T-cell repertoire.

Bear in mind that exercise is no substitute for the biotechnology of the next two decades - people who regularly exercise become frail and age-damaged in the end as well, they just tend to have a longer span of healthy years and a longer overall life expectancy. You can't exercise your way into rejuvenation, no matter what the fools in the "anti-aging" marketplace might say on the topic. But if you want to make the best of your chance to live to see the age of true rejuvenation medicine, you should take good care of your long-term health in the obvious and straightforward ways that are known to work.

Early efforts to simply transplant stem cells and let them do their work continue to show promise. First generation cell transplants are not a miracle cure, but they are an improvement over any other options available for some patients: "researchers are [utilizing] patients' own stem cells to regenerate heart and vascular tissue [in] a study examining stem cell transplantation as treatment for critical limb ischemia. ... Traditionally, cardiovascular medicine has focused on repairing damaged tissues with medication or surgery. For some patients, their cardiovascular disease is advanced to the point that standard treatment options are not effective. Regenerative cardiovascular medicine strives to redevelop cardiac and vascular tissue and stimulate new blood supply to areas like the heart and legs by using stem cells already present in the patient's body. ... [the] study examined the effectiveness of stem cell therapy in limb preservation for patients with critical limb ischemia (CLI). CLI develops in patients with severe obstruction of the arteries which limits blood flow to the extremities. CLI results in more than 100,000 amputations annually in the United States. The trial tested the ability of CD34+ cells to stimulate new blood vessel formation in ischemic limbs, which can improve perfusion and salvage function. ... The patients enrolled in this study were [in] the later stages of peripheral artery disease and at heightened risk for amputation. Patients in the randomized group had CD34 injected at eight locations in the ischemic limb and were followed for 12 months. ... Stem cell treatment was associated with a significant reduction in amputation rate. Treatment was associated with a 50 percent reduction in the total amputation rate compared to control."

Link: http://www.eurekalert.org/pub_releases/2010-11/nmh-rsc111610.php

The Longevity prize offered by La Fondation IPSEN is a modest cash award and recognition given to leading researchers in the field of aging and longevity science: "The 15th annual Longevity Prize has been awarded to Judith Campisi (Buck Institute for Age Research, Novato, USA) in recognition of the work she has been carrying in the domain of Longevity, Senescence and Cancer, by an international jury ... Founded in 1996, the Longevity Prize of La Fondation Ipsen has been awarded to renowned specialists ... Judith Campisi received a PhD in Biochemistry from the State University of New York at Stony Brook, and postdoctoral training in the area of cell cycle regulation and cancer at the Dana-Farber Cancer Institute and Harvard Medical School. As an Assistant Professor at the Boston University Medical School, she became interested in the control of cellular senescence and its role in tumor suppression and aging. She left Boston to accept a Senior Scientist position at the Lawrence Berkeley National Laboratory in 1991; in 2002, established a second laboratory at the Buck Institute for Age Research, where she is a Professor. At both institutions, she established a broad program to understand various aspects of aging, with an emphasis on the interface between cancer and aging. Campisi’s laboratory has made several pioneering discoveries in these areas, and her research continues to challenge and alter existing paradigms."

Link: http://www.businesswire.com/news/home/20101123006256/en/15th-Longevity-Prize-La-Fondation-Ipsen-Professor

As a companion to yesterday's post on insulin metabolism and human longevity, here is an open access paper that looks at stem cells, insulin signaling processes, and aging. In short, the activity of stem cells is vital to your long-term health, but this activity declines with age - and this decline is linked to other age-related changes, such as in insulin metabolism:

Tissue and organ rejuvenation and senescence/aging are closely related to the function of stem cells. Recently, we demonstrated that a population of [pluripotent] very small embryonic-like stem cells (VSELs) resides in the adult murine bone marrow (BM) and other murine tissues. We hypothesize that these pluripotent stem cells play an important role in tissue/organ rejuvenation, and have demonstrated that their proliferation and potentially premature depletion is negatively controlled by epigenetic changes of some imprinted genes that regulate insulin factor signaling.

...

Since the attenuation of insulin/insulin growth factor (Ins/Igf) signaling positively correlates with longevity, we propose, based on our experimental data, that gradual decrease in the number of VSELs deposited in adult tissues, which occurs throughout life in an Ins/Igf signaling-dependent manner, is an important mechanism of aging. In contrast, a decrease in Ins/Igf stimulation of VSELs that extends the half life of these cells in adult organs would have a beneficial effect on life span. Our preliminary data in long-living Igf-1-signaling-deficient mice show that these animals possess a 3-4 times higher number of VSELs deposited in adult BM, lending support to this novel hypothesis.

The big picture here is that mammals have evolved a balance of mechanisms to (a) repair themselves, and (b) suppress cancer. Crudely, we might think of cancer as being caused by damaged repair mechanisms run amok. The loss of repair capacity with age - which involves stem cell populations being reduced in number or becoming inactive due to changes in signaling processes - is a way to reduce the risk of cancer. This loss of stem cell capacity is coordinated by changes in the controlling systems of our biology: responses to accumulated damage and dysfunction, for example.

Thus, we should not be surprised to find that longer-lived animals of a given species have a greater regenerative capacity: more stem cells, or more active stem cells, or both. Nor should we be surprised to find out that known biochemical changes associated with longevity are a part of the controlling systems for stem cell behavior.

It is clearly the case that the evolved present state of many species is not optimized for longevity, but individuals have the capacity for longer lives if their metabolism ran slightly differently. Life spans are more plastic than was thought even a few decades ago: members of a smaller mammalian species like mice can live 30% longer if calorie restricted, and a change to their insulin metabolism can achieve the same end. There are survival advantages for a species that can more easily evolve into different lengths of life, better allowing it to prosper even if the environment changes dramatically.

Maria Konovalenko considers the present day mainstream of medical science: "Considering the success of the moon race, why isn’t there a comparable race against aging and its terrible diseases? Why is there so much opposition to promising developments such as therapeutic cloning or stem cell research? Why is modern medicine, and society at large, investing so much in trying to extend the last years of life (often spent in a nursing home) instead of trying to extend the period of youthful vigor? Mainstream medicine [operates] from the mortalist paradigm: it assumes that aging is 'normal' and nothing can be done about it. Weight gain, hearing and vision loss, a rise in blood pressure, a decline in muscle mass - all these are regarded as normal manifestations of aging. Since aging is not regarded as a disease, much less the most important disease, it is acceptable to treat only the symptoms of this universal, underlying degenerative syndrome. It is OK to treat heart disease or Alzheimer's, but not OK to try to slow the aging process itself, much less aim at physiological rejuvenation - even though this would be the most cost-effective solution to the catastrophic rise in medical costs as the population ages. We think medicine badly needs a paradigm shift."

Link: http://mariakonovalenko.wordpress.com/2010/11/18/paradigm-shift-needed/

From the Technology Review: "Researchers have repaired large muscle wounds in mice by growing and implanting 'microthreads' coated with human muscle cells. The microthreads - made out of the same material that triggers the formation of blood clots - seem to help the cells grow in the proper orientation, which is vital for rebuilding working muscle tissue. ... We hypothesize that cells migrate along these scaffolds, which act like a conduit. The cells grow into the space where muscle used to be, but they grow in a guided way. Currently, there's not much doctors can do when someone suffers massive injury to a muscle, such as in a car crash or an explosion. Thick bands of scar tissue can form in the wound, leaving the muscle severely and permanently impaired. Scientists are developing numerous approaches to creating replacement muscle, including growing patches of cells in a dish, injecting stem cells into damaged muscle, and implanting cell-seeded scaffolds designed to mimic native tissue. While all of these efforts show promise for certain applications, one of the major challenges has been growing enough cells in the correct structure to heal large muscle wounds. ... Muscle alignment is very important. You want the sarcomeres [the basic functional unit of muscle] to be aligned, that's how you get muscle contractions."

Link: http://www.technologyreview.com/printer_friendly_article.aspx?id=26709

It is an unfortunate fact of life that some people are dealt a better hand by chance and happenstance. This includes the biology we are born with, and its contributions to our life expectancy: for example, some people have better mitochondrial DNA than others, which does seem to be correlated with inherited longevity.

By way of a different example, let me point out recent research that shows a correlation between better insulin metabolism and inherited longevity. You might look back into the Fight Aging! archives for an introduction to insulin and its relationship with aging. It's a much-studied area:

Mainstream research on the biochemistry of aging and longevity - with an eye to slowing down aging rather than repairing it - is at this time primarily focused on a small number of areas. One is the cluster of mechanisms and signaling pathways associated with insulin and insulin-like growth factor 1 (IGF-1). You might recall that a tenfold increase in nematode life span was engineered via manipulation of IGF-1, for example.

Here is the research paper that caught my eye. The authors look at insulin sensitivity in long-lived families - how well the body's glucose metabolism operates, and whether that correlates well with longevity.

Familial longevity is marked by enhanced insulin sensitivity:

Insulin resistance is a risk factor for various age related diseases. In the Leiden Longevity study, we recruited long-lived siblings and their offspring. Previously we showed that, compared to controls, the offspring of long-lived siblings had a better glucose tolerance. Here, we compared groups of offspring from long-lived siblings and controls for the relation between insulin and glucose ... After adjustment for sex, age and fat mass, the insulin-mediated glucose disposal rate was higher in offspring than controls ... Furthermore, glucose disposal rate was significantly correlated with the mean age of death of the parents. In conclusion, offspring from long-lived siblings are marked by enhanced peripheral glucose disposal. Future research will focus on identifying the underlying biomolecular mechanisms, with the aim to promote health in old age.

Folk like you and I do in fact have a great deal of control over the course of our own insulin and glucose metabolisms. We can laze around and grow fat, or we can exercise and eat a diet that keeps us thin - type 2 diabetes, and the unseen biochemical damage that precedes it, is largely a choice. The Leiden offspring have a helping hand in this game in comparison to the rest of us, but it is only a helping hand, not a get out of jail free card. They can still damage themselves and become diabetic if they choose to take poor care of their health.

To me, it has long seemed that one of the more noble goals of longevity science is to make all the human variability in DNA and metabolism irrelevant when it comes to our life spans. Medicine of the near future will add far more healthy years to life - and far greater resistance to age-related disease - than even the best natural human metabolism. Longevity-enhancing therapies will make it possible for even the most genetically disadvantaged people to live in youthful vigor for far, far longer than we presently can.

From EurekAlert!: "A potent anti-tumor gene introduced into mice with metastatic melanoma has resulted in permanent immune reconfiguration and produced a complete remission of their cancer. ... researchers used a modified lentivirus to introduce a potent anti-melanoma T cell receptor gene into the hematopoietic stem cells of mice. Hematopoietic stem cells are the bone marrow cells that produce all blood and immune system cells. The T cell gene, which recognizes a specific protein found on the surface of melanoma, was isolated and cloned from a patient with melanoma. The gene-modified stems cells were then transplanted back into hosts and found to eradicate metastatic melanoma for the lifetime of the mice. ... We found that the transplantation of gene-modified hematopoietic stem cells results in a new host immune system and the complete elimination of tumor. To date, cancer immunotherapies have been hampered by limited and diminishing immune responses over time. We believe this type of translational model opens new doors for patients with melanoma and potentially other cancers by taking advantage of the potent regenerative capacity of hematopoietic stem cells and new advances in gene therapy."

Link: http://www.eurekalert.org/pub_releases/2010-11/iuso-gtf111810.php

The practice of calorie restriction slows almost all aspects of aging examined to date: "researchers described experiments with mice showing that a 25% reduction in calories activated a single enzyme, Sirt3, that helped preserve hearing. Although small numbers of people practice strict caloric restriction - consuming just 1,000 to 1,500 calories a day - scientists concede that such a diet is exceedingly difficult. But there may be other ways to achieve the same benefits. ... If we can find compounds that activate Sirt3, we may be able to obtain some of the benefits of caloric restriction without having to restrict our calories. ... [researchers] carried out experiments with normal mice and mice without the Sirt3 enzyme. In one experiment both groups were fed the 25% reduced calorie diet for 10 months. The diet had the same weight loss effect on both groups. Although the diet delayed hearing loss at various frequencies in the normal mice, it did not work at all in the mice lacking Sirt3. ... What seems to happen that drives caloric restriction is that the organism senses it is under stress. There are then metabolic changes that favor self-preservation. ... Under normal conditions, he said, levels of Sirt3 are low. Caloric restriction appears to boost levels of Sirt3 and the boost helps the cells' energy factories, called mitochondria. The mitochondria make not only the energy, but also atoms called free radicals, which damage cells and advance the effects of aging. When Sirt3 levels rise, however, they reduce production of the harmful free radicals. One result is less damage to cells, including the cells of the inner ear."

Link: http://www.jsonline.com/features/health/108972779.html

In the fantasy land where you have control over a large sum of money, millions or tens of millions of dollars, how would you spend it to best advance the state of longevity science - to bring forward the age of greatly extended healthy human lives? You can't take it with you, after all. In this life, the only rational use for large sums of money is longevity science; all else is fleeting and soon enough dust and ashes.

A hundred years ago, additional time was a limited commodity. You could spend resources to have a little more of it - doctors, a good life, the learning needed to take advantage of these items - but after a certain point there was no amount you could spend that would let you live for even one additional day. This is no longer the case. A sufficiently massive directed research program could, for example, realize the SENS program for rejuvenation within a couple of decades, to produce the planned and presently understood methods for repairing the biochemical and cellular damage that causes aging.

So what would you spend your fantasy millions on? How would you invest in research? This question is something of a litmus test: you can't answer it without sharing your opinions on what is important and what is not in present day aging science, related biotechnologies, and strategies for application or commercialization.

I see that Maria Konovalenko has thoughts on this topic:

4. Research in increasing cryoprotectors efficacy - $3 million
5. Creation and realization of a program 'Regulation of epigenome' - $5 million
6. Creation, promotion and lobbying of the program on research and fighting aging - $2 million
7. Educational programs in the fields of biogerontology, neuromodelling, regenerative medicine, engineered organs - $1.5 million
8. 'Artificial blood' project - $2 million
9. Grants for authors, script writers, and art representatives for creation of pieces promoting transhumanism - $0.5 million
10. SENS Foundation project of removing senescent cells - $2 million

Now for my part I think what is most needed today is a demonstrated success in the application of SENS research. Something that works to extend life in mice by repairing one of the forms of biochemical damage catalogued by Aubrey de Grey, and that we can all point to as an example of how longevity science should be done - a magnet for future fundraising, and validation for repair-based approaches to human longevity in the eyes of people yet to be convinced.

So, given that, I wouldn't spread my non-existent large sum of money around between many different classes of project. I put it all into one of the SENS research themes most likely to achieve a good result soon. For $30 million, I'd probably go for biomedical remediation of the unwanted biochemicals that build up and degrade our metabolism. A great deal of this work is discovery: sifting soil for microbes that can digest the gunk that our bodies cannot break down, and then performing many, many low-cost chemical tests in parallel to find useful bacterial enzymes. $30 million will buy you coverage of a large swath of the possible search space, followed by tests in aged mice to demonstrate improvement in measurable biomarkers of health following treatment with the most promising candidates.

A working method of biomedical remediation that improved measures of mouse health by eliminating the build-up of otherwise persistent metabolic byproducts would be exactly a form of limited rejuvenation. That would be big news.

From the Technology Review: "Growing living tissue and organs in the lab would be a life-saving trick. But replicating the complexity of an organ, by growing different types of cells in precisely the right arrangement - muscle held together with connective tissue and threaded with blood vessels, for example - is currently impossible. Researchers at MIT have taken a step toward this goal by coming up with a way to make 'building blocks' containing different kinds of tissue that can be put together. ... The MIT group [put] embryonic stem cells into 'building blocks' containing gel that encouraged the cells to turn into certain types of cell. These building blocks can then be put together [to] make more complex structures. The gel degrades and disappears as the tissue grows. Eventually, the group hopes to make cardiac tissue by stacking blocks containing cells that have turned into muscle next to blocks containing blood vessels, and so forth. ... The researchers expose clusters of stem cells called embryoid bodies to a physical environment that mimics some of the cues the cells experience during embryonic development. ... The result is a hydrogel block, half gelatin, half polyethylene glycol, with a sphere of embryonic stem cells inside. ... within an individual embryoid body, cells on the squishier, gelatin side took a different path from cells on the polyethylene glycol side. The gelatin is easier for the cells to push into, and this affects how they grow, directing them to become blood vessels." This sort of technology is a potential path to replicating the complexity of the extracellular matrix from the bottom up, necessary to the goal of producing highly structured tissue from scratch while ensuring it is laced with the required tiny blood vessels to support the cells.

Link: http://www.technologyreview.com/printer_friendly_article.aspx?id=26749

From MIT News: researchers "have had some striking successes treating melanoma with T-cell therapy, but so far it has been much less effective against other cancers. ... [An] obstacle is keeping the T cells alive once they are returned to the patient. Most T cells have a short lifespan, so after weeks of manipulation in the lab, they may die soon after they enter the patient. Furthermore, the tumor itself creates an environment very hostile to T cells. ... Giving patients large doses of growth factors called cytokines [helps], but those can have severe side effects, including heart and lung failure, when given in large doses. ... [researchers] recently developed a new approach that could avoid those side effects. They engineered T cells with tiny pouches that can carry cytokines, which are gradually released from the pouches, enhancing the longevity of the T cells that carry them. ... [they] used their modified T cells to treat mice with lung and bone marrow tumors. Within 16 days, all of the tumors in the mice treated with T cells carrying the drugs disappeared. Those mice survived until the end of the 100-day experiment, while mice that received no treatment died within 25 days, and mice that received either T cells alone or T cells with injections of cytokines died within 75 days. They are now working on ways to more easily synthesize the pouches at a large scale, so they can be tested in humans, using materials that would be more likely to get FDA approval."

Link: http://web.mit.edu/newsoffice/2010/targeting-cancer3-1117.html

Some thoughts stood out for me from a couple of recent Depressed Metabolism posts. People believe a great many things, individually and as groups, and beliefs shape actions - or lack of action, as the case may be.

Historical Death Meme

Historically, there has been a powerfully optimized meme regarding the topic known as death. If you lost vital signs, you were irrevocably lost. There was nothing that could be done. The belief evolved that there is a mysterious point termed 'death' which is in principle irreversible. ... Now, bring cryonics into the picture. The cessation of vital signs is no longer a sign of irreversibility-in-principle. ... In other words, the perfect conditions for cognitive dissonance have been established.

As the author points out, traditions regarding what can be done and should be done with the bodies of the dead are powerful things, and cryonics - like so much of medicine has done at one time or another - breaks those traditions. So we see a certain level of hostility, something that is true of longevity science in general, and for the same broad reasons. There is an ongoing collision between hidebound cultural traditions and the moving boundary of what is possible in medical science.

Over the decades ahead, the research community may, with sufficient directed funding, slow and reverse the course of aging, ultimately eliminate aging entirely (as well as the frailty and age-related disease it brings), and even provide a way to prevent other forms of death from being permanent under optimal circumstances. A substantial proportion of the population does not see these as desirable goals, however. That is a problem, our problem, and a challenge we have to surmount.

The diminishing returns of reactive medicine

So what is the reason why vast amounts of money are spent on research to treat age-associated diseases but so little on eliminating or mitigating aging as such? Why is this "one-disease-at-a-time model" so dominant? One reason might be that most people believe that overcoming one specific manifestation of aging is easier to do than overcoming aging itself. Not surprisingly, most academic and commercial research is shaped by short term ambitions or short-term financial interests.

The argument can be made that in fact it is cheaper to try to repair (or even just slow down) aging than to fix a particular disease - because to truly eliminate an age-related condition such as Alzheimer's or heart disease, you would in effect need to remove all of the contributions of aging. You need to fix the damage or replace the damaged parts in other words. So you might as well start there, rather than finishing there - but this isn't happening yet. Research communities hold different beliefs, and so work as they have done, one disease at a time.

Exercise is more powerful for the healthy than any presently available medical technology when it comes to maintaining health and establishing a good life expectancy: "Regular exercise can reduce around two dozen physical and mental health conditions and slow down how quickly the body ages, according to a research review summarising the key findings of 40 papers published between 2006 and 2010. .... Health conditions covered by the review include: cancer, heart disease, dementia, stroke, type 2 diabetes, depression, obesity and high blood pressure. ... The literature reviewed shows that how long people live and how healthy they are depends on a complex mix of factors, including their lifestyle, where they live and even luck. Individuals have an element of control over some of these factors, including obesity, diet, smoking and physical activity. ... Ideally, to gain maximum health benefits people should exercise, not smoke, eat a healthy diet and have a body mass index of less than 25. The more of these healthy traits an individual has, the less likely they are to develop a range of chronic disorders. Even if people can't give up smoking and maintain a healthy weight, they can still gain health benefits from increasing the amount of regular exercise they take. Physical inactivity results in widespread pathophysiological changes to our bodies. It appears that our bodies have evolved to function optimally on a certain level of physically activity that many of us simply do not achieve in our modern, sedentary lifestyles. ... What is clear from the research is that men and women of all ages should be encouraged to be more physically active for the sake of their long-term health."

Link: http://www.sciencedaily.com/releases/2010/11/101115074040.htm

From ScienceDaily: "A new vaccine protects against memory problems associated with Alzheimer's disease, but without potentially dangerous side effects, a new animal study reports. ... Vaccines against amyloid-beta accumulation in the brain, one of the hallmarks of Alzheimer's disease, have long been considered a promising approach to developing a treatment. But finding a vaccine that is both safe and effective has been challenging. Previous research in mice showed that a vaccine that targets the human version of amyloid-beta reduces learning and memory loss associated with the disease. However, the vaccine caused dangerous autoimmune inflammation of the brain during human clinical trials. ... In the current study, researchers [tested] a vaccine developed against a non-human protein that had the same shape as amyloid-beta, but a different sequence of amino acid building blocks. The Alzheimer's mice that received the vaccine showed improved performance on memory and other cognitive tests. The vaccine also reduced the clumps of amyloid-beta and tau protein that may be toxic to brain cells. ... This finding is important because it shows that you don't need a human protein to get an immune response that will neutralize the toxic amyloid oligomers associated with Alzheimer's disease ... Because the protein was not human, [researchers] believe it is unlikely to cause the dangerous autoimmune response."

Link: http://www.sciencedaily.com/releases/2010/11/101116204730.htm

As you might know, there is some concern that stem cells in the old will not produce the desired results when used in autologous therapies. They may be damaged in ways that will decrease their ability to spur regeneration, or make it impossible to use them to build a new organ - which would be problematic, as old people are exactly the population who most need the potential benefits of regenerative medicine and tissue engineering.

I noticed good news on this front today:

Scientists surgically removed tissue from the muscular wall of the heart’s chambers in 21 patients. They then isolated and multiplied the cardiac stem cells (CSCs) found there. Most of the patients had ischemic cardiomyopathy (enlarged and weakened muscle due to coronary artery disease). Eleven also had diabetes. The average age of patients was about 65.

"Regardless of the gender or age of the patient, or of diabetes, we were able to isolate in all of them a pool of functional cardiac stem cells that we can potentially use to rescue the decompensated human heart."

The status of the stem cells is only one part of the problems caused by an age-damaged biochemistry, however. Even if the cells are pristine, the environment they will be returned to is not - and that environment generates chemical signals that steer the behavior of stem cells. If the signals are dysfunctional, then the cells will behave in a similarly dysfunctional fashion, and this is no doubt a factor in the present struggle to make first generation stem cell transplant therapies a going concern.

You can look back into the Fight Aging! archives for an overview of some of the issues and related research:

• The Importance of the Stem Cell Niche
• Stem Cell Decline and Aging Niches
• Rejuvenating Aging Stem Cells ... Or Not
• Another Run at Making Old Stem Cells Act as Though Young
• More Ways For Aging Stem Cells To Go Awry
• Inserting Repair of Aging Into Tissue Engineering

From the BBC: "Doctors in Glasgow have injected stem cells into the brain of a stroke patient in an effort to find a new treatment for the condition. The elderly man is the first person in the world to receive this treatment - the start of a regulated trial at Southern General Hospital. He was given very low doses over the weekend and has since been discharged - and his doctors say he is doing well. Critics object as brain cells from foetuses were used to create the cells. The patient received a very low dose of stem cells in an initial trial to assess the safety of the procedure. Over the next year, up to 12 more patients will be given progressively higher doses - again primarily to assess safety - but doctors will be looking closely to see if the stem cells have begun to repair their brains and if their condition has improved. ... The first group of patients to receive the treatment will be men over 60 who have shown little or no improvement in their condition over a number of years. It is an ideal group to assess the safety of the procedure - doctors will be keen to know first of all that the treatment makes them no worse. But having such a precisely defined group will enable doctors and scientists to compare like with like if they notice any improvement - even in these early stages. If these trials show promise, doctors plan larger trials on a more varied group of patients. The earliest this could begin is in two years' time."

Link: http://www.bbc.co.uk/news/health-11763681

SFGate looks at ongoing work in replicating the function of a kidney: "The artificial kidney is still at least five years away from being tested in a human patient. Researchers have built a large model of the kidney - so big that it filled a hospital room - and used it on human patients to show that the theories behind it will work. And parts of the small kidney have been successfully tested in animals. If [the] team is successful, the kidney will be about the size of a large cup of coffee, and it would last for years, maybe decades, and require no pumps or batteries. Patients wouldn't need anti-rejection drugs either, because there would be no exposed natural tissues for the immune system to attack. ... The artificial kidney will be made of two parts - a filter side and a cellular side. On the filter side, silicone membranes with microscopic pores will separate toxins from the blood, much as dialysis machines do. The body's own blood pressure will force blood through the filter, so no pumps will be needed. The key to the filtration side is the silicone membrane, which can be made fairly inexpensively and precisely, much as computer chips are. ... On the cellular side, the filtered blood will be pumped over a bed of cells taken from either the patient's own failing kidneys or from a donor. The cells will sense the chemical makeup of the filtered blood and trigger the body to maintain appropriate levels of salt, sugar and water. ... It mimics more of a kidney function than just dialysis. When we think of kidneys, we think of waste removal. And dialysis just does that. Dialysis doesn't make you healthy - it just keeps you alive."

Link: http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2010/11/16/MNKF1GBCRJ.DTL

The Future Tense event on engineering human longevity was held today:

This week, Slate, the New American Foundation, and Arizona State University are sponsoring a conference on the future of life extension and its global ramifications: economic, social, and political. ... Will 250 be the new 100 in the foreseeable future? Human life expectancy has made steady gains over the last two centuries, and anti-aging scientists seeking to spare human cells and DNA from the corrosion once deemed inevitable are eager to trigger a radical extension in our life spans. How likely is such a spike? And how desirable is it to live to be a quarter of a millennium? Will life-extending scientific breakthroughs translate into an interminable twilight for many, or will they also postpone aging?

If you were alert and awake, you might have caught the live streaming video, which included a presentation by biomedical gerontologist Aubrey de Grey, as well as panel discussions between other scientists in the field of aging research. There is video up at the site for latecomers.

There's a post up at Futurisms that gives a general outline of events for the first half of the conference, though as usual you'll have to filter for the opposing viewpoint - despite the name, Futurisms is really more of a despairing grip upon the safely known and cataloged past than any sort of view ahead. One has to wonder when those folk will tire of playing the sour Canute facing down a rising tide of technological progress. Perhaps just in time for the next generation to take up the refrain, one step further up the ladder: grumbling about change is scarcely a novel activity, nor one I see ending any time soon.

You'll also find an outline at the IEET blog:

Dan Perry, from the Alliance for Aging Research, asks when the political tipping point is coming when the public and policy makers catch up with the growing conviction among biogerontologists that radical life extension therapies are possible. Stephen Johnston makes the Longevity Dividend point: policy makers will wake up and fund anti-aging research when they are convinced it is the solution to health care cost containment. When he argued for a more applied focus for NIH research funding he really got Cynthia Kenyon’s back up. She leaped to defend basic research, and Johnston dismissively noted that that was the typcal NIH response.

As you might gather, everything is politics when the government controls so much of the flow of money through research fields. Amongst other consequences - such as tremendous waste, an open door for ever-increasing regulation of medicine, and much funding of work that has little value - it drives a wedge between real world goals, real world results, and funding outcomes. If it is possible to gain funding to perform work that has little application, then you will see a great deal of work that has little application.

Another Slate article, this time S. Jay Olshansky on the Longevity Dividend: "Aging bodies with chronic diseases are not the same as young bodies with independently acquired infectious diseases. Yet medicine continues to act as if the diseases of aging are separate from the consequences of aging itself. ... While we can extend life in aging bodies through behavioral improvements and medical treatments, the time has arrived to acknowledge that our current model of reactive medicine, of trying to treat each separate disease of old age as it occurs, is reaching a point of diminishing returns. ... Many scientists and geriatric physicians now suggest that the primary goal of medical technology should not exclusively be life extension but, rather, lengthening the period of youthful vigor. Although efforts to combat disease should continue, one way to protect against the unwanted prolongation of old age while simultaneously extending the period of healthy life is to pursue the means to modify the key risk factor that underlies almost everything that goes wrong with us as we grow older - aging itself. Those of us working toward this goal have referred to this shift in approach to public health as the 'Pursuit of the Longevity Dividend.' ... Medical institutes and public health professionals across the globe are dedicated to combating the causes and consequences of heart disease, cancer, stroke, and a myriad of other fatal and disabling conditions that plague humanity, and many people are alive today because of their heroic efforts. These battles need to continue. But so too should we fight on a new front: aging itself."

Link: http://www.slate.com/id/2274468/pagenum/all/

From the Huffington Post, an example of ill-thought opposition to working to defeat the suffering and death caused by aging: "Rapid turnover is nature's way of making sure that a species can keep up with changing circumstances and survive the long haul. But since humans have gone beyond basic biology, why not re-engineer ourselves for a lifetime without an end point? Or at least for one where we outlast the Roman Empire? Well, it turns out there are problems... even beyond the tedium of boorish men. Let me first state that if we can pull this off - cure death - it's self-evident that we'll also obliterate the debilities of aging. You'll be healthy to the end. Nonetheless, there are countless gotchas for any descendants that have made themselves as indestructible as zombies. First off, they'll need to engineer a major societal revamp. You can't have kids every two years forever: we don't have the real estate. And of course, marriages would have an expiration date. A myriad of other social structures would also have to be rejiggered: Imagine the frustration of waiting for a tenure slot at the local college which, even after millennia, is still stuffed with its original faculty. Other difficulties are neither obvious nor tractable. For example, today more than 30,000 Americans die annually on the roads. That means you have a 50 percent chance of being taken out in an auto accident if you live for 3,600 years. So if we extend our lifetimes to thirty or forty centuries, using a car becomes an existential threat. You won't do it."

Link: http://www.huffingtonpost.com/seth-shostak/living-forever-not-a-good_b_783958.html

The end of 2010 approaches - blink and it'll be the winter solstice already. Time flies. It seems somewhat traditional here on the American side of the watery divide for people to make their charitable donations near the year-end, and so here are three suggestions for those of us interested in advancing the cause of engineered human longevity.

1) SENS Foundation

The SENS Foundation funds research into rejuvenation biotechnology, and aims to encourage greater adoption of the repair-based engineering viewpoint espoused by biomedical gerontologist Aubrey de Grey. Repair the known forms of biochemical damage that cause aging, in other words, and thereby reverse and prevent the diseases and frailty of aging. This is sadly a minority position in the aging research community, and few researches have the defeat of aging as their goal. By donating to the Foundation, you help to fund present work into repair biotechnologies, and encourage more researchers to take up the fight against aging.

2) Methuselah Foundation

The Methuselah Foundation encourages science that will extend healthy human lives through research prizes and targeted investment in key companies. Most of you will hopefully be familiar with the Mprize for longevity science by now, and the Foundation recently launched the NewOrgan Prize aimed at speeding the new science of tissue engineering. Amongst the Foundation's investments are the noted organ printing startup company Organovo. Research prizes have a demonstrated multiple effect on donations - for each $1 in the pot, historical prizes have spurred between $15 and $50 in funds raised by competing teams. Long-term donors to the Foundation can join the 300, and will see their names inscribed on a monument designed to last for thousands of years.

3) Immortality Institute Research Project 2010b - Microglia Stem Cells

You might recall that the Immortality Institute regularly raises funds for small research projects in aging and longevity science, the last of which was a mitochondrial uncoupling experiment to take place in Singapore. The second project for 2010 is presently open, and the Institute is seeking a few thousand dollars in funding to get it started:

Cognitive functions of the brain decline with age. On of the protective cell types in the brain are called microglia cells. However, these microglia cells also loose function with age. Our aim is to replace non-functional microglia with new and young microglia cells derived from adult stem cells. We will inject these young microglia cells into 'Alzheimer mice' - a model for Alzheimers disease. After giving the cells some time to work, we will sacrifice the mice and measure microglia activity, neurogenesis, proliferation of neuroprogenitors and plaque density in the brain. A reduction in plaque density of Alzheimer mice would be a first proof that the transplanted microglia are performing their expected function.

This sort of transparent microfunding of research projects is the wave of the future - encourage it, because it will help longevity science move more rapidly into the era of garage biotechnology, distributed projects, and far broader progress.

Infrastructure is important in stem cell research and development. When sourcing stem cells for experiments or therapies is hard and expensive, progress will be slow. Building the tools to enable reliable, uniform, and low-cost culturing of stem cells is a necessary step, and here is one example: "Growing human embryonic stem cells in the lab is no small feat. Culturing the finicky, shape-shifting cells is labor intensive and, in some ways, more art than exact science. Now, however, a team of researchers [reports] the development of a fully defined culture system that promises a more uniform and, for cells destined for therapy, safer product. ... It's a technology that anyone can use. It's very simple. ... At present, human embryonic stem cells are cultured mostly for use in research settings. And while culture systems have improved over time, scientists still use surfaces that contain mouse cells or mouse proteins to grow batches of human cells ... The new culture system utilizes a synthetic, chemically made substrate of protein fragments, peptides, which have an affinity for binding with stem cells. ... The system, according to the new report, also works for induced pluripotent stem cells, the adult cells genetically reprogrammed to behave like embryonic stem cells. ... The disadvantages of the culture systems commonly used now are that they are undefined - you don't really know what your cells are in contact with - and there is no uniformity, which means there is batch-to-batch variability. The system we've developed is fully defined and inexpensive."

Link: http://www.sciencedaily.com/releases/2010/11/101114161838.htm

From Slate, an example of Aubrey de Grey expanding the definition of regenerative medicine to include SENS: "Aging is bad for you. Whether you call it a disease, not a disease, a set of disease precursors, or some other variation on the theme, it is a medical condition, and thus a legitimate target - in principle - for medical intervention. But is it a practical target? Medicine generally targets individual problems - a particular strain of virus, for example, or damage to a particular area of flesh. Aging seems like a huge number of progressive, chronic diseases all interacting with one another. Might such complexity be beyond the power of medicine - even medicine decades hence - to address? Once these progressive, chronic diseases have become debilitating, piecemeal targeting of them is far less effective than medicine generally is against other, aging-independent diseases. The complexity is bad enough, but what's worse is that the diseases are progressive - they get harder to treat as time goes on, because they are simply the later stages of intrinsic, lifelong processes of accumulation of molecular and cellular damage. Is there a way out? ... in the past decade a new approach to medical intervention in aging has been explored: regenerative medicine. The attraction of this approach is that it acknowledges the irreducible complexity of aging but attacks the problem more pre-emptively than contemporary geriatric medicine does. Regenerative medicine can be defined as the restoration of structure to any damaged tissue or organ. As such, it encompasses molecular, cellular, and organ-level repair. As applied to aging, it amounts to preventative maintenance: periodic partial elimination of the accumulating damage of aging before that damage reaches a pathogenic level, thus postponing, maybe indefinitely, the age at which the ill-health of old age emerges."

Link: http://www.slate.com/id/2274582/pagenum/all/

We are somewhere in the middle of the ten year period in which researchers establish practical methodologies for growing three-dimensional, complex, structured tissue from a patient's own stem cells. The difficulty of moving from the two dimensions of the petri dish cell culture to fully functioning three-dimensional tissue should not be understated: how to build the right sort of supporting scaffolding with features at the nanoscale, how to incorporate the required capillary network to supply the cells with oxygen and nutrients, how to ensure that different cell types are arranged as they would be in natural tissue, and so on. This is the sort of many-faceted problem that requires a large scientific community and a great deal of investment to solve in any reasonable amount of time - fortunately both exist in this case. Other areas of life science research and medical development should be so lucky.

So far decellularization shows great promise, and has been used in a number of human transplant surgeries, but still requires a donor organ to supply the complex scaffolding of the extracellular matrix. Research groups have also demonstrated the ability to build a few structures that are much simpler than natural organs, but which can still perform some of the required tasks adequately - such as the tissue engineered bladders produced by Tengion.

There is a way to go yet, however. Here is a popular science article from Cosmos Magazine that examines the third dimension of tissue engineering - still novel, exploratory, and new:

Since the 1950s, scientists have probed the molecular secrets of cells plucked from the body and grown in the laboratory on flat plates or Petri dishes. These standard cultures have taught us about normal cell biology, cancer and other diseases.From a cell's point of view, however, these 2-D habitats - dubbed 'plastic palaces' by one researcher - are a poor substitute for real life. Scientists have come to realise that a cell's surrounding microenvironment plays a much larger role in directing its growth and shaping its behaviour than anyone understood 10 or 20 years ago.

In the body, cells are accustomed to living large, in three dimensions, embedded within an extracellular matrix (ECM). Through the pores of the fibrous ECM, a cell is bathed in nutrients and signalling molecules. A thin basement membrane anchors the cell to surrounding connective tissues and emits chemical signals that regulate some cell processes. In addition, physical forces push and pull the cell from all directions.

Without this extracellular community, cells grown in single layers on standard flat cultures will proliferate, but they usually don't differentiate into specialised cells forming structures such as capillaries. They can be inadequate models yielding misleading results.

It's easy to take for granted the less lauded hurdles overcome by researchers along the way to building replacement human organs on demand - moving from two-dimensional cell cultures to three-dimensional structures was one of them. Easy to say, far harder to accomplish.

Vladimir Anisimov of the Science for Life Extension Foundation here discusses some of the differences in aging between individuals, and what might be learned from primate studies: "it is well known [that] heterogeneity is crucial feature of the aging process. There are individual peculiarities in vulnerability and resistance to stresses and stress-related pathologies among different persons due to the heterogeneity of the ageing process. It is of great importance to elucidate the individual specificity of age-related changes of the [hypothalamic-pituitary-adrenal (HPA) axis] in the context of aging of the organism as a whole and the stress-dependent age pathologies. ... [The aim of recent research] was see in which way the differences in the HPA axis function in young (6-8 years) and old (20-27 years) female rhesus monkeys depends on various behavioral types, under basal conditions, as well as under conditions of acute psycho-emotional stress. It has been found that the monkeys with depression-like behavior demonstrate age-related changes in the HPA axis function. ... taken together these results suggest that age-related dysfunctions of the HPA axis are individual features associated with peculiarities of adaptive behavior of animals. This approach seems very fruitful for future studies. Indeed, nonhuman primates and humans are [similar] in physiology of HPA: both species have cortisol as a main glucocorticoid hormone, similar circadian rhythm of HPA activity, age-related decline in DNEA sulfate secretion. Furthermore, unlike rodents, nonhuman primates feature the psycho-emotional reactions and adaptive behavior more similar to those in humans."

Link: http://www.impactaging.com/papers/v2/n11/full/100228.html

From Maria Konovalenko: "A recent study from researchers in Canada and Sweden has shown that biosynthetic corneas can help regenerate and repair damaged eye tissue and improve vision in humans. ... This study is important because it's the first to show that an artificially fabricated cornea can integrate with the human eye and stimulate regeneration. With further research, this approach could help restore sight to millions of people who are waiting for a donated human cornea for transplantation. ... Eye surgeons currently use cadaver corneas for transplants, but that requires the use of anti-rejection drugs and presents a risk of infection. Plastic corneas can also be used, but they present other problems and are generally tried only when tissue transplants have failed. To fabricate the biosynthetic cornea, human genes were inserted into yeast cells to generate recombinant human collagen. The collagen was then chemically cross-linked and molded into a scaffold in the shapes and sizes of normal human corneas. ... The implant acts like a scaffold to attract cell and nerve ingrowth, the end result is a cornea that looks and functions like a healthy cornea. ... The clinical trial consisted of 10 patients who underwent surgery on one eye to remove damaged corneal tissue and replace it with a biosynthetic cornea. Over two years of follow-up, the researchers observed that cells and nerves from the patients' own corneas had actually grown into the implant, resulting in a 'regenerated' cornea that resembled normal, healthy tissue."

Link: http://mariakonovalenko.wordpress.com/2010/11/11/biosynthetic-cornea-stimulates-regeneration-in-damaged-eye-tissue/

Life science researchers are very interested in establishing biomarkers that are fairly reliable measures of physical age, mortality risk, and remaining life expectancy. Without quantifiable biomarkers, how do you determine whether a potential rejuvenation technology is actually working? The only other way is to wait and see how long it takes your subjects to die: impractical in humans and costly in laboratory mice. The field of longevity science is very much in need of ways to rapidly determine the effectiveness of a given therapy - because otherwise you're stuck testing for three years in mice to even qualify an approach as potentially useful. Which few will be, of course, but it'll take those three years and a pile of money to find out in each case.

Related to this issue, I noticed an open access paper that explores how well the rate of change in common measures of health can predict mortality. As it turns out, quite well - better than considering snapshots in time. This makes good sense: aging is exactly the accumulation of damage and failure of systems. People who are failing faster will see their health measures change more rapidly in the crucial years between age 40 and age 60, when biochemical damage starts to seriously impact metabolism and health.

It is well known from epidemiology that values of indices describing physiological state in a given age may influence human morbidity and mortality risks. Studies of connection between aging and life span suggest a possibility that dynamic properties of age trajectories of the physiological indices could also be important contributors to morbidity and mortality risks. In this paper we use data on longitudinal changes in body mass index, diastolic blood pressure, pulse pressure, pulse rate, blood glucose, hematocrit, and serum cholesterol in the Framingham Heart Study participants, to investigate this possibility in depth.

We found that some of the variables describing individual dynamics of the age-associated changes in physiological indices influence human longevity and exceptional health more substantially than the variables describing physiological state. ... We showed that the rate of changes in physiological state at the age interval between 40 and 60 years may serve as a good predictor of morbidity and mortality risks later in life. For nonmonotonically changing indices, the rates of decline after reaching the maximum, the maximal values, and the age at the maximum are important predictors of morbidity and mortality risks.

It's worth reading the whole thing (or skipping to the last quarter at least, if statistical discussion makes you queasy) for a sense of which changing values were shown to be more important than others. The take away here is that actively maintained stasis is important: the longer you can keep your measurable health parameters looking like they did when you were 40, the better your chances. Making a serious go at this will of course require a sane diet and good exercise regimen at the very least - and this is likely why those people whose measurements changed to a lesser degree were better off.

No presently available medical technology does as much good for the healthy as exercise and calorie restriction. Which is a state of affairs we'd all very much like to change - longevity medicine that can provide additional decades of healthy life is very possible, very plausible, and not too many decades away if the funding is forthcoming for strategies like SENS.

Understanding the mechanisms of regeneration implies the ability to improve it greatly: "scientists have shown that a previously overlooked group of cells - the endothelial layer of blood vessels - is essential in helping adult stem cells multiply and revitalize damaged tissue. ... In healthy adult tissues, including bone marrow, small populations of stem cells lie dormant. The trick has been to figure out what prompts them to emerge from this hibernation-like state and start proliferating to heal damaged tissue. ... The endothelium is the innermost layer of blood vessels, made up of cells that had largely been assumed to function primarily as delivery vehicles for oxygen and nutrients. But earlier this year, [researchers] figured out that these endothelial cells also release growth factors that direct bone marrow stem cells to multiply and differentiate into different types of blood cells. Now, the researchers have shown that such ability is not limited to bone marrow but exists in the endothelium of the liver, and that it can be activated to initiate and sustain liver regeneration in adult mice. [Researchers] show that by altering the activation state of the endothelium in liver and bone marrow, they could induce adult hepatocytes and blood stem cells to divide and regenerate lost tissue. ... For the last decade, physician-scientists have been trying to transplant hepatocytes to regenerate the liver. But they grow for a few months then the majority die off. Based on our data, one could argue that just transplanting hepatocytes is not going to work. To regenerate long-lasting liver, we may need to transplant hepatocytes with the properly activated endothelium, which produces the right growth factors for the hepatocytes to attach, grow, and connect with other parts of the liver."

Link: http://www.hhmi.org/news/rafii20101110.html

Researchers demonstrate an approach to tackling sarcopenia, the loss of muscle strength and mass with aging: "Skeletal muscle is dynamic, adapting to environmental needs, continuously maintained, and capable of extensive regeneration. These hallmarks diminish with age, resulting in a loss of muscle mass, reduced regenerative capacity, and decreased functionality. Although the mechanisms responsible for this decline are unclear, complex changes within the local and systemic environment that lead to a reduction in regenerative capacity of skeletal muscle stem cells, termed satellite cells, are believed to be responsible. We demonstrate that engraftment of myofiber-associated satellite cells, coupled with an induced muscle injury, markedly alters the environment of young adult host muscle, eliciting a near-lifelong enhancement in muscle mass, stem cell number, and force generation. The abrogation of age-related atrophy appears to arise from an increased regenerative capacity of the donor stem cells, which expand to occupy both myonuclei in myofibers and the satellite cell niche. Further, these cells have extensive self-renewal capabilities, as demonstrated by serial transplantation. These near-lifelong, physiological changes suggest an approach for the amelioration of muscle atrophy and diminished function that arise with aging through myofiber-associated satellite cell transplantation."

Link: http://dx.doi.org/10.1126/scitranslmed.3001081

Immune system degeneration is one of the more important consequences of the accumulating biochemical damage that causes aging. The immune system performs many vital tasks: not just keeping out invading pathogens, but also destroying senescent cells and cancerous cells, amongst other duties. As the immune system grows weak and ineffective, disease becomes a far greater threat, cancer risk rises, and the number of senescent cells increases dramatically.

So-called 'senescent' cells are those that have lost the ability to reproduce themselves. They appear to accumulate in quite large numbers in just one tissue (the cartilage in our joints), but even in these small numbers they appear to pose a disproportionate threat to the surrounding, healthy tissues, because of their abnormal metabolic state. Senescent cells secrete abnormally large amounts of some proteins that are harmful to their neighbours, stimulating excessive growth and degrading normal tissue architecture. These changes appear to promote the progression of cancer.

While the big picture of immune system aging is fairly well defined, many of the details are hazy. As is true for all aspects of human metabolism, researchers are still far from a complete and definitive understanding of the changes that take place over time. Today I'll point you to a very readable open access paper that discusses the present state of knowledge:

In humans, the relationship between aging and the immune response is a complicated one. Aging is characterized by an overall decline in immune function termed immunosenescence, which affects both the innate and adaptive immune systems.

With age, cells of the innate immune system exhibit decreased function; for example, macrophages and neutrophils exhibit a weaker phagocytic response and a weaker oxidative burst. Dendritic cells from older individuals have a decreased ability to stimulate T cells. Cells of the adaptive immune system are also affected by age. T cells in older individuals display decreased T cell memory. There is also a decrease in the naive T cell population in the thymus and decreased B cell production present in the elderly.

Although older individuals have a weaker immune response, conversely, they also display a chronic inflammatory state termed inflammaging, characterized by an increase in inflammatory cytokines present in the serum and an increase in the total NK cell count. Immunosenescence leads to a decreased vaccine response and an increased risk of infection; inflamm-aging could contribute to a host of inflammatory diseases such as atherosclerosis.

Thus, aging can have dramatic effects on the immune response, and conversely, the immune system can affect the risk of many age associated diseases and can therefore affect lifespan. Thus, understanding the relationship between aging and immune system function is of critical importance to human health, particularly as the average human lifespan lengthens, increasing the impact of age-related diseases.

What can be done about the failing immune system? It could - and I think should - be argued that more than enough is known to make inroads into immune system repair for the aged. This is an area with much more fuzziness in the state of knowledge than, say, mitochondrial dysfunction, but clear roads ahead still exist. Some of these are outlined in past posts here at Fight Aging! For example:

In essence, the [adaptive] immune system fails because the thymus, source of immune cells, ceases production and withers away. At the same time, the population of immune cells becomes ever more biased towards memory cells and away from cells capable of fighting new infections - and this is largely due to persistent viruses like cytomegalovirus. Eventually the immune system becomes so focused on the viruses it cannot clear from the body that it has no resources left to perform its other functions.

These problems suggest their own solutions: replace or rejuvenate the thymus, for example, or apply new targeted cell-killing methods developed for cancer therapies to destroy unwanted memory cells. On that note it's worth recalling that thymus transplants have been shown to extend life in mice, but there is plenty of other evidence to support these and similar attempts to restore the aging immune system to youthful levels of activity.

Deterioration in blood vessels in the brain is connected to the onset of neurodegeneration - which is an ongoing process, starting long before someone is diagnosed with dementia. It is one of the mechanisms by which brain health is connected to general health. Here, researchers shine a light on failing blood vessels in the brain: "A small amount of bleeding in the brain seems to be common among older individuals ... cerebral microbleeds are highly prevalent in the aging brain - and not primarily products of stroke-related injury, hypertension or neurodegenerative diseases such as Alzheimer's, as had been thought. ... Prior work relied on brain imaging to show cerebral microbleeds. But in this study, deep regions of the brain were closely examined under a microscope, and nearly all subjects had evidence of small areas of bleeding. ... [Researchers] studied postmortem brain specimens from 33 individuals, ranging in age from 71 to 105, with no history of stroke. Cerebral microbleeds were identified in 22 cases - all occurring in capillaries, the small blood vessels of the brain. This is a substantially higher rate of incidence than that reported in MRI studies, which have shown microbleeds in 18 percent of people between 60 and 69 and in 38 percent of those over 80. ... Results from [the] study also indicate that leakiness of brain blood vessels increases with age, [despite] the fact that a specific barrier (known as the blood-brain barrier) exists to prevent leakiness."

Link: http://www.sciencedaily.com/releases/2010/11/101108151340.htm

Enforced retirement by regulatory decree is a great injustice, one of the many perpetrated by government employees around the world. It must go - and retirement as an institution is clearly unsustainable in a world of increasing healthy longevity. But most people think about this issue within the box: change government regulations on retirement, don't remove regulation and let it be the choice of the individual. Sad. Here is an example from Maria Konovalenko: "schools of thought on this from biogerontologists and longevity experts including myself believe that the focus should be about making the elderly population less of a burden on the healthcare system and more productive in the workforce for longer periods of time through a global initiative on combating aging. To truly combat this crisis, a mass-scale collaborative effort similar in size to the Manhattan Project or the Apollo Project is needed so that the mechanisms that cause us to age can be identified and better understood. ... The other way to tackle this problem could be through initiating a change in retirement policies where retirement would be dependant upon biological causes as opposed to chronological age. Insurance companies could pay for appropriate medical testing to determine health status, which would be an important measure in itself. Under this scenario, individuals would be more motivated to keep their health optimized because good health would be more valuable in terms of earning potential as compared to a small monthly pension."

Link: http://mariakonovalenko.wordpress.com/2010/11/08/retirement-should-depend-upon-biological-causes-as-opposed-to-chronological-age/

Biomedical gerontologist and advocate for engineered human longevity Aubrey de Grey appeared on Southern California Public Radio today:

How old is too old? Some scientists think the body has a metabolic stop-sign at about age 122; others think that through new technologies, genetics, and robotics we can expand our longevity to a quarter millennium. And one man thinks immortality is possible - that the first human who will reach 1000 years of age has already been born. But with great age our assumptions of life, family, work, taxes, government, health, sex… our humanness…would change. Are you ready for the long life?

You can listen to the program and leave comments at the SCPR website. I am interested to note the overwhelmingly negative nature of the comments - people pretty much lining up to declare their intent to die on schedule. I think that indicates an audience unfamiliar with the concepts of radical life extension, the great enhancement of health and life span that could be realized through rejuvenation biotechnology in the decades ahead. Presently sympathetic audiences, such as the readers of technology magazines and tech-news sites, were originally just as hostile before they began reading about longevity science more often and in greater detail.

In the comments to this radio program, I see the bitter fruits of Malthusian environmentalism: people convinced that the world is dying, that division and development of resources is a zero-sum game, that humanity is fundamentally evil and should be removed from the world. It is an essentially religious impulse, immune to logic, immune to facts, immune to the history of Malthusian predictions proven wrong over and over again.

By far and away the most common reason I see given these days in opposition to engineered longevity is fear of overpopulation. Environmentalism has become almost a religion in its own right now, and many strands of that religion are essentially death cults: loose networks of like-thinking people who fervently believe, for whatever reasons, that the world is dying, that humans already live too long, and that people should be forced to relinquish technology and return to a simpler era. Extreme fringe variants of the environmentalist death cult really do stand for the complete destruction of humanity, but even supposedly reasonable, middle of the road people are influenced by deathist environmentalism to the point at which it is seen as reasonable to say that (a) too many people exist, and therefore (b) the unending horror, pain, and suffering of death by aging is necessary.

Death cult environmentalism of the "too many people" variety is, fundamentally, a failure of understanding. It is to look at the undeniably bad situations and unpleasant regions of the world and say "this is because too many people are using too many resources," rather than to see that in fact it's all due to misallocation of existing resources and the failure to develop new resources - a grand procession of waste, corruption, and the inhumanity with which human beings treat one another. These situations are problems that can be solved through development and tearing down corrupt systems of rulership - they are not immutable facts of life that must lead to the deaths of millions.

So you see these strange online gatherings and discussions in which people strive to outdo one another in declaring just how eager they are to age, suffer, and die on the same schedule as their parents and their fellows. Yet when longevity science is in the clinic, they will be just as accepting of engineered longevity and longer healthy lives as they are opposed to it now - they will follow whatever the crowd follows, and it is the great shame of our age that the crowd, in its ignorance of basic economic knowledge, cries out for self-destruction, suffering, and death.

Smart Planet interviews one of the Wake Forest Institute for Regenerative Medicine researchers: "The miniature livers are a step toward achieving a transplant-able size liver. That's our goal. We need to start small in order to understand all the technical issues we will encounter as we scale up. These miniature livers can be used for drug screening. Drug screening and toxicity screening are being done on liver cells grown in the laboratory or on laboratory animals. These miniature livers will provide the closest individual system to test drugs in the laboratory. ... We have extended that functional phase [of the miniature livers] to three weeks. That's in the laboratory. We would now put these livers in rodents and see how they function. Our goal is to create a model in a rodent of a liver disease. These livers will rescue the rodents from the liver disease. ... [Because of media attention], the public starts developing hope and hype around these discoveries. It's not that we don't want people to develop hope. But with that comes caution. How long will it take us to develop the technology of getting enough cells [and] the technology of repopulating larger organs with those cells? And once we do that, how safe will these organs be for human use? Even after we confirm they pose no harm to the patient, how functional will they be and for how long? We need to consider all of that as we develop this technology for clinical use. Only once we accomplish all of these tests of toxicity, safety [and] functionality can we say we have succeeded."

Link: http://www.smartplanet.com/people/blog/pure-genius/from-miniature-livers-in-the-lab-to-human-transplantation/4867/

Our cells are capable of greater feats of healing than normally take place - if they are correctly instructed to take action. One present branch of stem cell research involves discovering how to deliver those instructions: "It is well known that oral infection progressively destroys periodontal tissues and is the leading cause of tooth loss in adults. A major goal of periodontal treatment is regeneration of the tissues lost to periodontitis. Unfortunately, most current therapies cannot predictably promote repair of tooth-supporting defects. A variety of regenerative approaches have been used clinically using bone grafts and guiding tissue membranes with limited success. ... a team of researchers conducted a human clinical trial to determine the safety and effectiveness of fibroblast growth factor-2 (FGF-2) for clinical application. This is the largest study to date in the field of periodontal regenerative therapy. A randomized, double-masked, placebo-controlled clinical trial was conducted in 253 adults afflicted with periodontitis. Periodontal surgery was performed, during which one of three different doses of FGF-2 was randomly administered to localized bone defects. Each dose of FGF-2 showed significant superiority over the standard of care [for] the percentage of bone fill at 36 wks after administration, and the percentage peaked in the mid-dose FGF-2 group. These results strongly support the topical application of FGF-2 can be efficacious in the regeneration of human periodontal tissue that has been destroyed by periodontitis."

Link: http://www.eurekalert.org/pub_releases/2010-11/iaa-gfr110810.php

Any prospective longevity therapy will have to be studied in mice: numerous experiments for testing and replication throughout the scientific community, with each experiment potentially requiring three or more years to produce results. Mouse studies are very expensive in both time and money, which is one reason why matters are not advancing as rapidly as they might in the field of applied aging research.

Can this bottleneck be removed by speeding up the studies or reducing their cost? Obviously in the long run the answer is yes: real mice will be replaced by very detailed simulations of mouse biology, and processing power will be so cheap that experiments involving thousands of sim-mice will run for sim-years in a matter of real world days. Everyone will be happy to see the back of racks of lab mice, the costs associated with their maintenance, and the whole industry of running animal studies in real time.

This future is a way away, however - ten to twenty years, give or take. With an eye to the here and now, here is a paper that looks at what might be done today to make the work move faster:

Many rodent experiments have assessed effects of diets, drugs, genes, and other factors on life span. A challenge with such experiments is their long duration, typically over 3.5 years given rodent life spans, thus requiring significant time costs until answers are obtained. We collected longevity data from 15 rodent studies and artificially truncated them at 2 years to assess the extent to which one will obtain the same answer regarding mortality effects. When truncated, the point estimates were not significantly different in any study, implying that in most cases, truncated studies yield similar estimates. The median ratio of variances of coefficients for truncated to full-length studies was 3.4, implying that truncated studies with roughly 3.4 times as many rodents will often have equivalent or greater power. Cost calculations suggest that shorter studies will be more expensive but perhaps not so much to not be worth the reduced time.

Shorter but not cheaper is possible, or so it seems. This isn't too surprising; researchers have the same incentives as everyone else, and will aim to maximize the publishable output of their scientific work given a set budget. If there was a way to use statistics and truncation to cut down on mouse study costs, I'm sure it would have made its way into common usage at some point over the past century.

Another potential disadvantage of truncation: if you cut short your study, you take yourself out of the running for establishing a new mouse life span record. If you have what looks like an impressive advance, you'll want to keep the study going. Building a better mouse is a ticket to the big leagues in the present day biotechnology community.

Aging is biochemical and cellular damage: if you are more damaged than someone of the same chronological age, then you are physically older. This implies a shorter remaining life expectancy, but it doesn't necessarily imply that you will look older. For the purpose of close comparisons between people of a similar age, exterior appearance doesn't correlate well with the health of vital organs: "Even though most adults want to avoid looking older than their actual age, research [shows] that looking older does not necessarily point to poor health. The study found that a person needed to look at least 10 years older than their actual age before assumptions about their health could be made. ... Few people are aware that when physicians describe their patients to other physicians, they often include an assessment of whether the patient looks older than his or her actual age. This long standing medical practice assumes that people who look older than their actual age are likely to be in poor health, but our study shows this isn't always true. ... We were really surprised to find that people have to look a decade older than their actual age before it's a reliable sign that they're in poor health. It was also very interesting to discover that many people who look their age are in poor health. Doctors need to remember that even if patients look their age, we shouldn't assume that their health is fine."

Link: http://www.sciencedaily.com/releases/2010/11/101105124239.htm

From the Vancouver Sun: "Canadian scientists have transformed pinches of human skin into petri dishes of human blood - a major medical breakthrough that could yield new sources of blood for transfusions after cancer treatments or surgery ... The discovery [could] one day potentially allow anyone needing blood after multiple rounds of surgery or chemotherapy, or for blood disorders such as anemia, to have a backup supply of blood created from a tiny patch of their own skin - eliminating the risk of their body's immune system rejecting blood from a donor. Researchers predict the lab-grown blood could be ready for testing in humans within two years. ... The procedure is also relatively simple. It involves taking a small piece of skin just centimetres in size, which would require only a stitch to close, extracting fibroblasts - abundant cells in the skin that make up the connective tissue and give skin its flexibility - and bathing them in growth factors in a petri dish. Next, by adding a single protein that binds to DNA and acts as an on/off switch, the researchers turned on or off some 2,000 genes and reprogrammed the skin cells to differentiate or morph into millions of blood progenitors - the cells the produce blood."

Link: http://www.vancouversun.com/health/health/3791337/story.html

What is your proteome? In short, it is the list of all the proteins built within your body and their abundance - a parts catalog for your biological machinery. Analysis of even modest fractions of the proteome has only recently become practical, but it is potentially a good way to measure the complexity of repairing and reversing aging, or gain insight into which contributing mechanisms of aging are the most important. Aging is no more than change: damaged proteins, unwanted molecules, things in the wrong place at the molecular level - which leads to malfunction and failure in the large-scale organs and processes of the body.

The good news for today is that a comparison of young and old proteomes in mice shows that there is little change with aging. This is a positive result for the future of longevity science, because it means researchers can rapidly follow up on the few changes that were identified. The opposite result - many changes, as is the case for gene expression - would have been rather discouraging: a sign that matters are very complex in yet another area of the biology of aging, and that much work would have to take place in order to understand the relevance of the data.

From the open access paper (for the full paper, you'll want the PDF version):

The biological process of aging is believed to be the result of an accumulation of cellular damage to biomolecules. While there are numerous studies addressing mutation frequencies, morphological or transcriptional changes in aging mammalian tissues, few have measured global changes at the protein level. Here, we present an in depth proteomic analysis of three brain regions as well as heart and kidney in mice aged 5 or 26 months.

...

In frontal cortex and hippocampal regions of the brain, more than 4,200 proteins were quantitatively compared between age groups. Proteome differences between individual mice were observable within and between age groups. However, mean protein abundance changes of more than two-fold between young and old mice were detected in less than 1% of all proteins and very few of these were statistically significant. Similar outcomes were obtained when comparing cerebellum, heart and kidney between age groups. Thus, unexpectedly, our results indicate that aging-related effects on the tissue proteome composition at the bulk level are only minor and that protein homeostasis remains functional up to a relatively high age.

It is unexpected, given the gene expression findings to date - but welcome. I look forward to seeing the results from human studies. Given the free-falling cost of bioinformatics, and commensurate improvement in the technology, comparing proteomes in young and old people will be a graduate student project within a handful of years.

From Singularity Hub: "Wake Forest's Institute for Regenerative Medicine (WFIRM) and the Armed Forces Institute for Regenerative Medicine (AFIRM) have developed a skin printer that can deposit cells directly onto a wound to help it heal faster. They recently presented the results of their latest experiments at the American College of Surgeons Clinical Congress (ACSCC) in Washington DC. Mice given topical wounds were able to heal in just three weeks when a new skin was printed onto the damaged area (compared to 5-6 with control groups). WFIRM and AFIRM also stated that the skin printer had been tested to see if it could print human cells, but that the next step forward would be experiments on pigs. If ultimately successful, skin printers could revolutionize the way we treat injuries - making serious wounds less fatal and rapidly speeding the healing of other injuries. ... the recent conference [gives] some valuable insights into how the skin printer actually works. Two different printing heads are used - one with skin cells, a coagulant, and collagen; the other with a different kind of coagulant. Keeping these substances separate allows them to be deposited easily (like ink) but then quickly bond together and form a solid skin covering with fibrin."

Link: http://singularityhub.com/2010/11/04/wake-forest-could-print-you-some-new-skin/

Peripheral artery disease is one of a number of conditions shown to benefit from even early, crude efforts at stem cell transplantation: "Peripheral artery disease (PAD) affects 8 million Americans. It's when arteries in the legs narrow. The most common symptoms of PAD are cramping, pain or tiredness when walking. It can so bad that some can't walk at all. Now an experimental stem-cell therapy may offer hope to people with severe pad. Ronald Davis can move again after seven long years. 'Pain 24 hours a day, seven days a week,' said Davis. Plaque clogged the artery carrying blood to his leg, which cut off oxygen flow. ... Left alone, it can cause ulcers, gangrene and even lead to amputation. ... Davis began a last-ditch stem-cell therapy at Duke University. His leg was marked for 30 injections, totaling millions of stem cells. For him, there was no other choice. ... Cells are taken from the placentas of Israeli women who've given birth. Once injected, they secrete proteins, which boost additional cell growth. Then, it's believed those cells may contribute to the growth of additional vessels around the plaque, circumventing the blockage. ... Three days after injections, Davis was walking, and doctors say the oxygen level in his leg tissue jumped from 43 percent to 67 percent. ... This specific type of stem-cell therapy is currently involved in a Phase 1 clinical trial."

Link: http://abclocal.go.com/kabc/story?id=7765921

I posted not so long ago on the topic of foundational work in artificial sight:

The present mainstream approach involves building a grid of electrodes in place of the retinal cells lost to forms of degenerative blindness; images captured by a worn camera are analyzed and the electrodes stimulated appropriately. ... Progress in this model is at present a matter of making implantation safer and more reliable, greatly increasing the density of electrodes, and improving the ability to translate a camera's view into a helpful picture - a combination of medicine, electrical engineering, and computer vision research. The end result of this form of technology will never produce anything more than a detailed, glowing sketch of dots and lines for the patient: it is not true vision as experienced by those of us fortune enough to retain our sight. Nonetheless it works - already providing a great improvement for patients over being blind - and it will serve as a foundation for later forms of artificial sight technology.

Today, let me point your attention to a refinement of this technology under development by a German company:

researchers based in Germany have developed a retinal implant that has allowed three blind people to see shapes and objects within days of the implant being installed. ... The device - known as a subretinal implant - sits underneath the retina, directly replacing light receptors lost in retinal degeneration. As such, it uses the eyes' natural image processing capabilities beyond the light detection stage to produce a visual perception in the patient that is stable and follows their eye movements. Other types of retinal implants - known as epiretinal implants - sit outside the retina and because they bypass the intact light-sensitive structures in the eyes they require the user to wear an external camera and processor unit.

...

"The present study...presents proof-of-concept that such devices can restore useful vision in blind human subjects, even though the ultimate goal of broad clinical application will take time to develop."

This seems like a natural evolution if it can be made to work in a practical fashion - cut out the aspects of the system that were awkward to manage in favor of an implant that can stand alone. The obvious path for incremental improvement is still to increase the number and density of electrodes, and thus the resolution of the glowing grids and images seen by the patient. Work on that area will likely benefit numerous similar lines of development in the artificial sight community.

There remains a big difference between "vision" and "useful vision" - but I imagine that the gap will close as this technology evolves further. An implant that replaces one part of an eye is an invitation to build a second implant that attaches to it and replaces a neighboring feature...and so forth. This research and development community will give the tissue engineers a run for their money.

Some of what the body does in response to injury, especially in the nerves and brain, is in fact counterproductive in the long term: "Stroke is the leading cause of adult disability, due to the brain's limited capacity for recovery. ... Researchers interested in how the brain repairs itself already know that when the brain suffers a stroke, it becomes excitable, firing off an excessive amount of brain cells, which die off. The UCLA researchers found that a rise in a chemical system known as 'tonic inhibition' immediately after a stroke causes a reduction in this level of excitability. But while this 'damping down' initially helps limit the spread of stroke damage, the increased tonic inhibition level and reduced brain excitability persists for weeks, eventually becoming detrimental to the brain's recovery. ... It was surprising to find that the level of tonic inhibition was increased for so long after stroke and that there was an inflection point where the increased level eventually hindered the brain from recovering. It was also surprising that we could easily manipulate tonic inhibition in the brain after stroke to restore it back to a normal, 'non-stroke' level and, in doing this, enhance behavioral recovery. ... They found that by applying specific blockers of this inhibitory brain chemical, they could then 'turn off the switch.' The resulting enhanced brain excitability immediately improved behavioral recovery after stroke."

Link: http://www.eurekalert.org/pub_releases/2010-11/uoc--srw110110.php

Some studies on the genetics of human longevity have looked at small, homogeneous populations - this makes the task easier for a number of reasons. Here is another example: "The advantage of working with a homogeneous population is, you're reducing the variances that can be associated with the environment. [Mennonites and Amish] don't drink, don't smoke. Most do some sort of physical activity. They don't sit around working on a computer all day. ... 5 percent of healthy Amish octogenarians have 'haplogroup X,' a genetic pattern within the mitochondria, which are the regions of cells that generate energy and help guard against deterioration. Haplogroup X is generally found in only 2 percent of Europeans, from whom the Amish descended. In the University of Miami study, only 3 percent of the control group - Amish people who had made it to 80 but suffered from significant disease or disability - had the genetic variant. ... Mitochondria have their own DNA, which is passed down from the mother only. This unique chromosome has variations, called haplogroups. Nine such haplogroups have been well characterized in people of European descent ... But only haplogroup X was found to be prevalent among healthy aged people in the University of Miami study." As we know, some people have better mitochondria; a side-effect of technologies that allow us to replace damaged mitochondrial DNA throughout the body would be the ability to upgrade to a better haplotype. That benefit is tiny, however, compared to the benefit of removing the damage that contributes to degenerative aging.

Link: http://www.technologyreview.com/biomedicine/26669/

We're all vaguely familiar with what a kidney looks like, where it resides, and what it does. It's a blob of specialized tissue that sits somewhere in the lower torso and works to filter blood and maintain fluid balance - that sort of thing. It performs a function. But the evolved form of the kidney is far from the only way to achieve this goal, and a kidney is also far removed from the best conceivable ways of performing the its function.

Consider dialysis as a crude example that shows the function of the kidney doesn't have to be performed by a kidney, and nor does it have to be performed in the present location of the kidneys in the body. As this age of biotechnology advances, more and more people are going to purchase and make use of artificial kidneys. At the one end of the scale, you might imagine that kidney 2.0 will be a tissue engineered copy of your failing kidney 1.0 - researchers can almost build them, we know they work, and the only downside is the invasive surgery required to install a new model. But I think we will see a very wide range of kidney 2.0 products that bear as little resemblance to kidney 1.0 as does a dialysis machine.

A pocket calculator does not look like a slide rule, for all it has the same function. Similarly there is no reason to expect the next generation of technology that performs the function of a kidney to resemble either an actual kidney or a present day dialysis machine.

For example, researchers are presently developing bioartificial devices comprised of kidney cells and machinery. It doesn't take too much of a leap of imagination to see that 20 years from now, tiny permeable encapsulations of kidney cells could manufactured by the billion extremely cheaply - and injected once a week to clean the bloodstream from the inside. Alternately, a person might have a dozen implanted bioartificial dialysis machines each the size of a thumbnail sitting beside major arteries. Or kidney function could be incorporated into an implanted artificial heart while the diseased kidneys are removed entirely, and the heart machine itself is a break with the past because doesn't beat, but rather pumps blood continuously.

I've used the kidney as an example, but every organ has it's own set of potential variations, and the present shape and location of each is far from the only way of achieving their different functions. As time moves on, biotechnology developers who think outside the box will hit on new ways of maintaining the functionality of the human body. Many of their results will be very different to the organs we're equipped with today, and some will be far superior.

The technique of stripping cells from a donor organ and repopulating the extracellular matrix with a patient's own cells is moving ahead, as illustrated by this article: "Spain, a world leader in human organ transplants, is now also a pioneer in the creation of bioartificial organs with stem cells implanted into patients after the opening on Tuesday in Madrid of the first laboratory in the world dedicated to the growth of artificial organs for human transplant. The laboratory will 'empty' human hearts or other human organs unsuitable for transplantation and recolonize their cell content with the patient's stem cells, allowing the organs to grow anew, ready for tranplant back into the new body ... Transplantation of such organs could a daily reality in 'between five and ten years' ... So far, the cardiology unit of the Gregorio Maranon has 'applied the elimination of cells' to eight hearts that have succesfully become viable organs using the patient's stem cells. And by late 2010 they want to install a heart from a donor using regenerated cells. Moreover, 'as it advances, [we could also use] animal organs.'" The downside of decellularization as a technology is that it does still require a donor organ - it is essentially a way of working around the present inability to build a suitably structured framework for an artificial organ. Since replacing all of the cells largely eliminates immune rejection issues in a transplant procedure, there is no reason not to use animal organs, however. They should be just as effective.

Link: http://thereader.es/en/spain-news-stories/4907-spain-opens-worlds-first-organ-growing-laboratory-for-human-transplants.html

Nrf2 has shown up in past research as a part of the mechanisms of hormesis induced longevity, and here researchers make a pitch for its importance: "Although aging is a ubiquitous process that prevails in all organisms, the mechanisms governing both the rate of decline in functionality and the age of onset remain elusive. A profound constitutively upregulated cytoprotective response is commonly observed in naturally long-lived species and experimental models of extensions to lifespan (e.g., genetically-altered and/or experimentally manipulated organisms), as indicated by enhanced resistance to stress and upregulated downstream components of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2)-signaling pathway. The transcription factor Nrf2 is constitutively expressed in all tissues, although levels may vary among organs, with the key detoxification organs (kidney and liver) exhibiting highest levels. Nrf2 may be further induced by cellular stressors ... The Nrf2-signaling pathway mediates multiple avenues of cytoprotection by activating the transcription of more than 200 genes that are crucial in the metabolism of drugs and toxins, protection against oxidative stress and inflammation, as well as playing an integral role in stability of proteins and in the removal of damaged proteins via proteasomal degradation or autophagy. Nrf2 interacts with other important cell regulators such as tumor suppressor protein 53 (p53) and nuclear factor-kappa beta (NF-kappaB) and through their combined interactions is the guardian of healthspan, protecting against many age-related diseases including cancer and neurodegeneration. We hypothesize that this signaling pathway plays a critical role in the determination of species longevity and that this pathway may indeed be the master regulator of the aging process."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21031035

A recently published open access paper provides a good short overview of the current state of development for stem cell transplants - essentially the first generation of therapies to follow right on the heels of the ability to identify and culture stem cells. It covers the high points:

• A great deal of work is presently taking place in the field and progress is rapid.
• Results to date have been encouraging: the benefits are more than enough to make continuing research and development worthwhile.
• Evidence suggests that transplanted stem cells trigger healing largely through release of signalling biochemicals that spur native cells to greater efforts - rather than any other method, such as cell division to reestablish cell population.
• The state of the local cellular environment is a big concern - and potentially a big influence on the success of a therapy. In the old, the dysfunctional cellular environment may cause a therapy to fail because its damaged signals outweigh those of the transplanted cells.

• Infrastructure technologies need a great deal more work: sourcing stem cells for transplant needs to be much easier, cheaper, and more reliable.

From the paper:

Preclinical and clinical trials of stem cell therapy have been carried out for treating a broad spectrum of diseases using several types of adult stem cells. While encouraging therapeutic results have been obtained, much remains to be investigated regarding the best cell type to use, cell dosage, delivery route, long-term safety, clinical feasibility, and ultimately treatment cost. Logistic aspects of stem cell therapeutics remain an area that requires urgent attention from the medical community.

Recent cardiovascular trial studies have demonstrated that growth factors and cytokines derived from the injected stem cells and host tissue appear to contribute largely to the observed therapeutic benefits, indicating that trophic actions rather than the multilineage potential (or stemness) of the administered stem cells may provide the underlying tissue healing power.

...

However, aging and disease can adversely affect the host tissue into which stem cells are injected. A better understanding of the host tissue response in stem cell therapy is necessary to advance the field and bridge the gap between preclinical and clinical findings.

One intriguing view of the future is that stem cell therapies will prove to be a short-lived intermediary technology. If it is the signals that are triggering healing, then cell transplants could be done away with entirely - we only need them now because researchers do not yet understand how to reproduce the same chemical signalling that the cells deliver. This evolution might well happen over the next decade, and researchers who work with stem cells will focus instead on producing organs grown from a patient's own cells and other feats of tissue engineering.

Maria Konovalenko looks at research into salamander biochemistry: "By tracking individual cells in genetically modified salamanders, researchers have found an unexpected explanation for their seemingly magical ability to regrow lost limbs. Rather than having their cellular clocks fully reset and reverting to an embryonic state, cells in the salamanders' stumps became slightly less mature versions of the cells they'd been before. The findings could inspire research into human tissue regeneration. ... The cells don't have to step as far back as we thought they had to, in order to regenerate a complicated thing like a limb. There's a higher chance that human or mammalian cells can be induced into doing the same thing. ... People working on stem cells are trying to de-differentiate cells in an artificial fashion. It will be very important for the regenerative-medicine community to take stock of what's going on in the salamander, because they've been doing it for 360 million years, and found a natural way to de-differentiate their tissues."

Link: http://mariakonovalenko.wordpress.com/2010/11/01/discovery-in-salamanders-could-lead-to-human-limb-regeneration/

Thoughts on aging from Hybrid Reality: "In the 2050 family picture, there will be many siblings in their 60s with graying hair, a handful of adult children with their spouses, and just two or three grandchildren. It's a strange picture: a family with more older people than younger people. Everything we've grown up seeing in our families and neighborhoods is contrary to this picture. Yet this is exactly the kind of family that will dominate the middle and late half of the 21st century. We're moving to a world of old people, and unless science can radically stop the aging process, that family will be yours in 2050. ... Old age brings maladies like diabetes, Parkinson's, Alzheimer's; it makes one tired easily, unable to sleep well, or run and have sex easily; it makes one's metabolism slow, one's bones brittle, and one's skin wrinkled. In other words, old age is not fun. Frankly, it is hard to argue with the fact that old age is generally more unpleasant than youth. [Aubrey de] Grey believes that science is capable of stopping the aging mechanisms of our bodies. If he receives the funding he needs, he is convinced that we can decouple chronological age from biological age, i.e. even if we're chronologically 70 years old, for instance, our bodies can biologically look and feel as if they're 50, 30 or even 20 years old. ... Which world do you want to live in: the gray world or the youthful world? If you support the young world, you need to push the FDA to treat aging like a disease so that anti-aging research can be funded, and perhaps even write a check to the SENS Foundation started by Aubrey de Grey. ... You need to act today: your future family portrait depends on it."

Link: http://bigthink.com/ideas/24760

A recent post by Sarah Marr of the SENS Foundation should really be read as a companion piece to Aubrey de Grey's interview with Wired last month. Taken together they go a way towards explaining the present thinking of the SENS Foundation principals on how to position engineered human longevity to best raise funds and obtain broader support. The lynchpin:

This is the basis of our core message: SENS Foundation works to advance research on rejuvenation biotechnologies. We exist because no-one else is working to deliver on the promise of rejuvenation biotechnologies, to steer academia and industry towards the adoption of a damage-repair paradigm which is currently neglected.

The mission statement also describes these rejuvenation biotechnologies as being applied to the disabilities and diseases of aging, not simply, aging. Our approach will create a comprehensive set of interventions (on which, more later), but each of the individual interventions in that set will address one or more specific diseases, and those interventions will develop over time, not all at once. It would be wrong, therefore, to frame our mission in a way which suggested the 'all or nothing' proposition implied by our using the word aging alone. Each individual success - each new application of rejuvenation biotechnologies - will solve very real medical problems.

The Foundation is moving to establish "rejuvenation biotechnology" as an alternative to SENS (the Strategies for Engineered Negligible Senescence) - as a brand for raising funds and educating people - for the simple reason that you don't have to work as hard to explain it. (A situation I am not unsympathetic towards given my own sites and efforts). There are other benefits, but as the common wisdom runs:

if your business is a mix of information provision and persuasion then it's probably not a good thing that you have to explain the meaning of your name to everyone.

A second important point in Marr's post concerns moving beyond one's origins. It's no great secret that the transhumanist and futurist community did more than their share in helping to make the Methuselah Foundation and SENS viable and ongoing concerns. But it is traditional in every movement's growth to marginalize the smaller groups and subcultures that helped it to get off the ground - we should look on it as a sign of progress when it happens. Changes start at the fringe, and as they move inward their rebellious origins are buried, one by one, and everyone pretends that they never existed.

The bottom line is that you (as a supporter) want us to succeed, and that means you want us to be a organization which does things, which nurtures rejuvenation biotechnology in its early stages, and then helps it to grow into a coordinated, global enterprise. For those reasons, there are some things you don’t want us to be. As an example (or two, or three), you don’t want us to be a ‘transhumanist’ organization: there’s no need for the distraction of couching what we do in terms other than curing disease and ending the suffering of humans. You don’t want us to be a ‘futurist’ organization: what we do is no more ‘futurist’ than any other medico-scientific research organization, and there’s no value in artificially separating ourselves from those organizations. You don’t want us to be seen as immortalists: immortality (in the sense sometimes associated with our work) is easily dismissed, both metaphorically and literally, often by an unseen bus, or - less frequently - falling piano. The list of ‘things you don’t want us to be’ goes on, but what it comes down to is that you do want us to be what we were founded to be: a mature, mainstream, biomedical charity. Anything else would be setting ourselves up for failure.

The very same process of burying the origins will happen to SENS itself - and when it does, we should all celebrate, because the movement that will bury SENS as its rebellious origin will be a large, mainstream research community that is working to reverse degenerative aging through repair biotechnologies. This is the way of the world; while some people might feel like getting up in arms about the marginalization of their contributions back in the day, it really isn't worth it. As Aubrey de Grey put it:

And there will be abundant people who are better than me at all the things I have to do at the moment, and I will no longer be necessary. And I shall fade away into glorious obscurity.

As shall we all - and if things work out well, we'll be alive and healthy for a good long time to enjoy it.

Researcher Thomas Kirkwood revisits the well known difference in life expectancy between the genders: "It turns out that the females of most species live longer than the males. This phenomenon suggests that the explanation for the difference within humans might lie deep in our biology. ... Many scientists believe that the aging process is caused by the gradual buildup of a huge number of individually tiny faults - some damage to a DNA strand here, a deranged protein molecule there, and so on. ... We might well ask why our bodies do not repair themselves better. Actually we probably could fix damage better than we do already. In theory at least, we might even do it well enough to live forever. The reason we do not, I believe, is because it would have cost more energy than it was worth when our aging process evolved long ago, when our hunter-gatherer ancestors faced a constant struggle against hunger. ... If you can avoid the hazards of the environment for a bit longer by flying away from danger or being cleverer or bigger, then the body is correspondingly a bit less disposable, and it pays to spend more energy on repair. Could it be that women live longer because they are less disposable than men? This notion, in fact, makes excellent biological sense. In humans, as in most animal species, the state of the female body is very important for the success of reproduction. The fetus needs to grow inside the mother's womb, and the infant needs to suckle at her breast. So if the female animal's body is too much weakened by damage, there is a real threat to her chances of making healthy offspring. The man's reproductive role, on the other hand, is less directly dependent on his continued good health."

Link: http://www.scientificamerican.com/article.cfm?id=why-women-live-longer&print=true

Decellularization is a recently developed technique that allows researchers to work around the present inability to create the complex three dimensional framework that supports the cells of an organ. Here it is demonstrated in a liver: scientists "have reached an early, but important, milestone in the quest to grow replacement livers in the lab. They are the first to use human liver cells to successfully engineer miniature livers that function - at least in a laboratory setting - like human livers. The next step is to see if the livers will continue to function after transplantation in an animal model. ... To engineer the organs, the scientists used animal livers that were treated with a mild detergent to remove all cells (a process called decellularization), leaving only the collagen 'skeleton' or support structure. They then replaced the original cells with two types of human cells: immature liver cells known as progenitors, and endothelial cells that line blood vessels. The cells were introduced into the liver skeleton through a large vessel that feeds a system of smaller vessels in the liver. This network of vessels remains intact after the decellularization process. The liver was next placed in a bioreactor, special equipment that provides a constant flow of nutrients and oxygen throughout the organ. After a week in the bioreactor system, the scientists documented the progressive formation of human liver tissue, as well as liver-associated function."

Link: http://www.eurekalert.org/pub_releases/2010-10/wfub-rem102710.php