$36,000
$24,120

Life Extension and Glycation in Nematodes

A most interesting report drifted into my sphere of notice today; a way of boosting life span in nematode worms. We are complex machines, built from a constantly recycling pool of component proteins built into intricate structures and systems; when proteins become damaged, that is wear and tear - grit in the works, the onset of aging, loss of function and the degenerations that lead to death.

Protein degradation and malfunction is a major cause of ageing and can be the result of attacks on proteins by other molecules. One of these processes, called glycation, involves the spontaneous attack by sugars on proteins. If glycation gets out of hand many proteins are degraded or destroyed – proteins which are important for the proper functioning of the body. Protection against glycation declines with age leading to increasing glycation damage with increasing age. A critical enzyme involved in protection against glycation is "Glyoxalase 1". Using a model nematode system, Professor Paul Thornalley (University of Warwick) and his collaborators at the University of Heidelburg have shown for the first time that by enhancing levels of glyoxalase I the glycation process can be diminished and life can be extended by up to 40%. Similarly, by decreasing amounts of the enzyme they have shortened the lifespan of the nematodes. Professor Thornalley will present the results at the Society for Experimental Biology's Annual Main Meeting on Sunday 1st April.

"This work shows for the first time that this enzyme also protects proteins against damage by oxidation and nitration", says Professor Thornalley. The enzyme works by converting the damaging reactive products of glycation derived from glucose into harmless compounds. "This implies that glycation promotes multiple types of protein damage in ageing"

You might be familiar with "advanced glycation endproduct" or AGEs, a class of damaging compounds that build up in the body over the years and that lead to some forms of progressive loss of function. As one might espect, the process of formation for these compounds starts with glycation - more glycation, more AGEs. In effect, AGEs are one portion of the root cause of aging. Scientists have shown promising results in animals with anti-AGE drug candidates (such as ALT-711) over recent years, but humans have very different types and proportions of AGEs than even other, shorter-lived mammals.

One can hope that the result quoted above will be repeated up the chain of animal models in the years ahead, and glyoxalase (or something similar, derived from this branch of research) will prove beneficial to humans. The odds are it'll end up in the same bucket as ALT-711 and a range of other compounds, however - a lot of different compounds are tested and fail for every one that even makes it to the "promising but near miss" category. It doesn't pay to get too excited about studies in nematode worms. Wait until the mice at least.

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Support For Immunotherapy Versus Alzheimer's

Via ScienceDaily, more evidence that your immune system fights the onset of Alzheimer's - which lends further support to those working on vaccines and other immunotherapies: "Our results provide in vivo evidence that the brain's immune system plays a protective role in early Alzheimer's disease by mediating the clearance of amyloid-beta ... While it has been known that the immune system reacts against amyloid-beta in the brain, the relation of that response to the pathology of Alzheimer's disease has not been clear. ... The current study was designed to clarify the role of microglia in Alzheimer's and identify factors involved in the immune cells' accumulation at amyloid plaques. ... lack of a protein required for recruitment of the brain's primary immune cell led to increased amyloid-beta deposits and earlier death in a mouse model of Alzheimer's disease. ... By showing that microglia have a protective role in helping remove amyloid-beta from the brain, our findings suggest that enhancing the accumulation of these cells may be beneficial to patients with early-stage Alzheimer's disease."

Link: http://www.sciencedaily.com/releases/2007/03/070327113731.htm

Supercentenarian Research Foundation In Edmonton

(From Canada.com). A representative of the Supercentenarian Research Foundation was amongst the attendees at Edmonton Aging Symposium: "What the supercentenarians have in common is that they do not have diseases such as Alzheimer's, Parkinson's or cancer, which kill the majority of the population. The supercentenarians' longevity is a 'side-effect' of not dying from these common diseases ... So, the question then is: why do they die? Autopsies have shown that some supercentenarians have a buildup of a 'gunky protein' in their bodies, although there is not enough evidence to prove this is a significant cause of death amongst the very elderly ... He hopes that by raising money for research, his foundation can better understand how to keep supercentenarians alive and how to achieve longer, healthier lives for others. ... the anecdotal evidence seems to confirm what many have-long suspected: living a long life probably has more to do with genetics than lifestyle. ... One of the biggest predictors of living for a long time is having grandparents and parents who lived for a long time."

Link: http://www.canada.com/components/print.aspx?id=97931bf4-135d-4bd0-ad1e-cf8f1fb868ff

Intermittent Fasting, Sir2 and p53

A number of researchers have investigated intermittant fasting as a method of calorie restriction (CR) to obtain health and longevity benefits - no weighty conclusions yet as to whether it's better or worse for the average fellow (or mouse) than simple CR. This paper notes that fasting, as one might expect, causes alterations in sirtuin expression, just like straightforward calorie restriction: "The aim of the present study was to study the role of intermittent fasting (IF) on [diabetic nephropathy (DN)] and studying the expression of Sir2 and p53. At biochemical level, we found that IF causes significant improvement in blood urea nitrogen (BUN), creatinine, albumin and HDL cholesterol, parameters that are associated with the development of DN. Diabetic rats on IF also show significant improvement in onset of hypertension. Interestingly, the expression of Sir2, a NAD dependent histone deacetylase, decreases in diabetic rat kidney and this decrease is overcome by IF." You should already be aware that a better (i.e. smaller) diet can work wonders for type 2 diabetes and related issues - why damage yourself more than you have to?

Link: http://www.ncbi.nlm.nih.gov/pubmed/17316625

Towards Salamander-Like Regeneration

Much drumming of publicity is taking place for those research groups investigating the mechanisms of regeneration in lower animals, as illustrated here by ScienceDaily: "Fueled by about $6 million in private donations, university support and state matching funds, 'The Regeneration Project' will connect scientists who work with adult human stem cells - the building blocks of self-renewal that exist within our brain, bone marrow and blood - with scientists who study how tissues and limbs develop in a variety of organisms. ... A salamander can be injured to the point that it loses its limbs or part of its spinal column, yet a few weeks later you'll see it scurrying across your lanai. The Regeneration Project will focus on unlocking the mysteries in living, simple organisms that sustain successful tissue and organ regeneration following injury and disease, and then applying this knowledge toward encouraging repair in the more complex human, where regeneration is not so simple. ... We are bringing together the best of the developmental biology world with the best of the stem cell world and starting the conversation, with the focus on how to get regeneration to work in a mammal."

Link: http://www.sciencedaily.com/releases/2007/03/070330111307.htm

The Edmonton Aging Symposium Is Underway

The Edmonton Aging Symposium is underway; congratulations are due to the hardworking volunteers who organized the event.

The degeneration which occurs with age was once thought to be the result of causes too complicated to ever understand and ultimately not amenable to medical treatment. However, new discoveries reveal common mechanisms involving the accumulation of damage are shared by most age-related diseases and that new technologies have the potential to repair that damage, restoring health and function to the aging body.

If you missed your chance to register and view the symposium presentations via streaming video, I'm sure it'll be available for purchase or download later. Given the attendees, I'm also sure we'll be seeing reports from the symposium soon enough, but here are a couple of articles from the mainstream Canadian press that surfaced today:

Conference hears of ways to repair aging bodies, restore health

International doctors and scientists met in Edmonton Friday to discuss how to repair the damage of aging.

The aging symposium looks at the types of damage that accumulate with age, what can be done to slow or repair it, as well as future therapies. Other sessions look at the economic costs to society of aging.

As millions of baby boomers worldwide approach their senior years, there is no better time to get the word out about new ways to live longer, said Kevin Perrott, a biomechanical engineer who is organizing the meeting.

Scientists try to answer age-old query: Should people live longer?

"If we all live to be 150, the hospitals would all be full and everyone would still say it certainly went by fast," says Daniel Callahan, from the Hastings Center, a bioethics research institute in Garrison, N.Y. "The only case for extending lifespans is that some people want it and that doesn't seem to be good enough."

At the symposium, Callahan will debate the ethics of "life extension" -- he has long attacked as "utopian" the arguments of those who say that science will find ways to keep elderly populations healthy. More importantly, he says, an older population will do nothing to solve today's social ills and could cause more problems. "I don't see it making any contributions at all to society beyond satisfying the wish of some individuals to live a long life. It's often said that the elderly have a wisdom to contribute. Well, I'm 76 and I don't notice that among people my age that we have any special wisdom," he says.

For proponents of life extension, the idea of keeping people alive without keeping them healthy is irresponsible. However, they think funding research that might help people live longer, healthier lives is vital to stave off the rising costs associated with caring for aging populations. Many also believe that extending lifespans is in line with society's core values.

"If you judge by what people do to improve their health, they value their lives highly," says Gregory Stock, director of UCLA's medicine, technology and society program. "So adding to your period of vitality is something that most people would certainly do. If there was a pill that would do that, it's clear that everyone would take it."

Stock will face off against Callahan in a debate over public funding for life extension. He argues that scientists must take risks, even if the ultimate outcome of their research is still unknown.

It has long struck me that some of the more vocal opponents of healthy life extension simply don't enjoy being alive all that much. Couple that to the strange delusion that people like you and I must wait for the elite to approve our actions and intents, and there you go. Rather sad, really.

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At the Interface Between Aging and Cancer

An interesting conference report from a new contributer to Ouroboros: "The idea is this: some cells in the body proliferate too much or get too much DNA damage and undergo cell senescence. These cells cause aging, not because we run out of cells, but because these cells stick around indefinitely and poison the environment with nasty factors that they secrete into the extracellular space. [Judith Campisi's] group has now identified many of these factors and analyzed the phenotype and underlying pathways to a great extent. The secreted proteins fall into two main categories: Inflammatory cytokines and proteases. Inflammation has been popular in recent years (with good reason), because it is involved in all kinds of bad stuff ranging from heart disease to arthritis to Alzheimer's. Dr. Campisi now believes that the primary culprit in the inflammatory response is IL-6. ... Here's the shortest talk summary ever: Massimiliano Bonafe reported that IL-6 activates Notch, which in turn promotes breast cancer malignancy. (Are you starting to see a trend here? IL-6 sucks!)"

Link: http://ouroboros.wordpress.com/2007/03/29/conference-report-translational-research-at-the-aging-and-cancer-interface/

Alzheimer's Vaccine Effective For Mice

From MSNBC, news that another potential Alzheimer's vaccine has passed the animal model test: "Japanese scientists have developed an oral vaccine for Alzheimer's disease that has proven effective and safe in mice ... The team is preparing to move to small-scale clinical trials in humans, possibly this year ... We hope the Phase I trials go well. Animals are able to recover their functions after developing symptoms, but humans are less able to do so. It may be that this only works in the early stages of the disease, when symptoms are light ... The vaccine is made by inserting amyloid-producing genes into a non-harmful virus. When taken orally, the virus stimulates the immune system to attack and break down the amyloid proteins in the brain ... The treatment was tested on 28 mice genetically modified to develop Alzheimer's disease. Half the animals were given a dose of the vaccine at the age of 10 months, while the control group were not treated. Three months later, tests showed mental function in the treated mice had returned to levels close to those before they developed Alzheimer's symptoms."

Link: http://www.msnbc.msn.com/id/17853445/

Charlie Rose On the Science of Longevity

The latest Charlie Rose show, which can be watched online at Google Video, takes a look at the modern mainstream of longevity research. By the guest list - including Cynthia Kenyon, Richard Weindruch, Robert Butler and Jay Olshansky - you might correctly guess that the focus will be in Longevity Dividend territory: modest gains, modest ambitions, the history of the past decade of genetic manipulation of longevity, calorie restriction research of the sort performed by Sirtris Pharmaceuticals, and the manipulation of metabolism to slow aging.

If you wander over to the Immortality Institute, you'll find an ongoing discussion on the show:

Well I thought it was very informative.

They talked about a lot of the research going on into longevity and aging. It was a round table discussion and they had a lot of experts sitting around (and one by satellite). They covered a lot of ground throughout the hour, but some of the things that they hit on were Caloric Restriction (and the results of study in worms, mice, monkeys, and humans so far), Resveratrol (and why it works, plus a word of warning to be cautious about the stuff you buy because of not knowing the quality of what you are buying, which could cause other problems), the effects of lengthened lifespans on society (which they all felt would be a net positive), genetic research and the results that have been shown in animals, plus a lot of other things I am probably forgetting.

I found it very interesting, and would urge all ImmInst members to watch the program if and when they get a chance. They were all very standard researchers that appeared, so there were no claims of immortality or indefinite lifespans or anything like that, but it was very interesting to see and hear what some of the top scientists in aging related fields are working on and think about some aging related issues.

...

The worst quotes of the show award goes to (starting at about the 45 minute mark):

Charlie Rose: "Nobody is arguing we could have a way to become immortal are they?"
One of the panel: "No, No, No. Nobody here is making that argument."
Charlie Rose: "Although there are some people that talk about it."
One of the panel: "There is a school out there that does."
Charlie Rose: "What is that school called?"
*everyone laughing*
One of the panel: "The radical school."
*laughing some more*
Charlie Rose: "Yeah...right"

...

I'm glad there are two "schools" as it's going to take a lot of funding and there will be many possible solutions to the problems of aging. I see it boiling down to :

School A: Metabolic Tinkerers. Focus is to slow aging and maximize qaulity - Sinclair, Olshansky, et al.

School B: Radical Engineering via Damage Repair, Gene & Stem Cell Therapy, etc (SENS). Focus is to rejuvenate and maximize both quality and quantity - de Grey, SENS et al.

If you don't stretch for the greater goals, you won't attain them. if you're not working towards the best possible result, you certainly won't get there. If we want to see significant progress towards true rejuvenation within our lifetimes - enabled by the march of science towards methods of repairing the cellular damage of aging - then we'd better step up and help to support the growth of SENS-like research programs.

Repairing aging is better than slowing aging, and doesn't look like it will take much longer, or be any harder. So why take the obviously worse route? Sadly, the obviously worse route is the dominant path for that part of the modern gerontology community willing to work towards healthy life extension. This must change in the years ahead.

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Enhancing Liver Regeneration

From EurekAlert!: "researchers have used adult bone marrow stem cells to regenerate healthy human liver tissue ... When large, fast-growing cancers invade the liver, some patients are unable to undergo surgery, because removing the cancerous tissue would leave too little liver to support the body. Researchers [used] adult bone marrow stem cells to help quickly regenerate healthy liver tissue, enabling patients to eventually undergo a surgical resection. ... Our study suggests that liver stem cells harvested from the patient's own bone marrow can further augment and accelerate the liver's natural capacity to regenerate itself ... researchers compared the results of portal vein embolization (PVE), a technique currently used to help regenerate liver tissue, to a combination of PVE and an injection of bone marrow stem cells into the liver. ... Patients who received the combination of PVE and stem cell injection had double the liver growth rate and gain in liver volume, compared with those who underwent PVE alone."

Link: http://www.eurekalert.org/pub_releases/2007-03/rson-scs032107.php

Stem Cells Slow Degenerating Vision

EurekAlert! notes an accidental discovery: "In a study in rats, neural progenitor cells derived from human fetal stem cells have been shown to protect the vision of animals with degenerative eye disease similar to the kinds of diseases that afflict humans ... The finding that the brain cells protected the cells in the eye was a surprise ... The neural progenitor cells, which arise from stem cells and further differentiate into different types of cells found in the central nervous system, were being tested for their ability to deliver another agent, a growth factor that has been shown to be effective in treating some types of degenerative disease. ... On their own, they were able to support retinal cells and keep them alive. We didn't expect that at all. We've used a number of different cell types from different sources and these have given us the best results we've ever got. ... How the cells act to preserve the deteriorating eye cells remains unknown ... Like all cells, neural progenitor cells do many things and secrete many different types of chemicals that may influence the cells around them."

Link: http://www.eurekalert.org/pub_releases/2007-03/uow-sct032607.php

On the Perceived Value of Research

In response to the last Longevity Meme Newsletter, Ian Clements emailed:

Thanks for another newsletter.

But why are you so down on small improvements? Re: Patching, Regulation, Trial and Error (March 24 2007)

I say: thank goodness for the trial-and-error brigade, a foundation of human progress over the ages.

...

Incidentally, I fail to see why you enthuse over the also relatively small improvement to teeth yet are scathing about possibility of reducing Parkinson's. Because even tho' the former falls within a regeneration/rejuvenation paradigm, it is further from implementation than the latter.

The answer to this question is, at root, that I am far less impressed by old-style drug development based on search-and-trial methodology than I am by work that is an exploration of a new space, builds upon new knowledge of biochemical mechanisms, and as a result returns more knowledge to the general pool for others to use. Modest gains with no follow-on, to my eyes, forms a worse deal than modest gains with ramifications.

The resources poured into the above mentioned studies of the Parkinson's drug that may bring only a modest improvement lead to a dead end - you have the drug, for whatever incremental benefit it brings, and nothing else. It does not enable any wider parallel or following work in a meaningful way. I see this as an example of everything that is wrong with the present mainstream of drug research and regulation - the entire setup leads to mediocrity, a suppression of more ambitious approaches.

Researchers are for the first time testing to see if creatine, a nutritional supplement popular with weightlifters, might hold Parkinson's at bay. ... Creatine is one of several over-the-counter supplements being investigated as a Parkinson's treatment.

There is no real attempt to understand mechanisms - only to test on the basis of screening and see how the results turn out. This black box science, all too recently all that could practically be done, is now positively archaic and wasteful in this age of biotechnology. We can do better, and by virtue of being able to better, we should do better. To progress just a little is just as much a failure in this environment as the absence of progress.

The tooth enamel research, on the other hand, for all that it is just as small a step in and of itself, is everything that the creatine study is not.

Now that dental epithelial cells can be propagated in culture, the next step will be to achieve the same success with their partners in tooth formation, the dental mesenchymal cells. Further development of this technique will be aimed toward production of tissue to replace damaged or missing enamel, and ultimately, regeneration of whole teeth

It builds upon known mechanisms, returns new knowledge to the fold, and will help a wide range of other projects in regenerative medicine by the fact of its existence. It is an example, as Ian Clements points out, of research taking place within a more effective paradigm.

That, at least, is my view of matters. Your mileage may vary - and we still live in a society in which you can direct your resources to support the research you value the most. Discussion is good, but setting forth to help make a difference is better.

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Engineering the Heart, Piece By Piece

EurekAlert! look at tissue engineering and the heart: "Some day, heart attack survivors might have a patch of laboratory-grown muscle placed in their heart, to replace areas that died during their attack. Children born with defective heart valves might get new ones that can grow in place, rather than being replaced every few years. And people with clogged or weak blood vessels might get a new 'natural' replacement, instead of a factory-made one. These possibilities are all within reach, and could transform the way heart care is delivered ... Technology has advanced so much in recent years [that] scientists are closer than ever to 'bioengineering' entire areas of the heart, as well as heart valves and major blood vessels. ... Although there remain tremendous technological challenges, we are now at a point where we can engineer first-generation prototypes of all cardiovascular structures: heart muscle, tri-leaflet valves, blood vessels, cell-based cardiac pumps and tissue engineered ventricles." It won't be too many years now until the simpler organs can be rebuilt from your own stem cells.

Link: http://www.eurekalert.org/pub_releases/2007-03/uomh-eth032707.php

Calorie Restriction Society Conference DVDs Available

The Calorie Restriction Society is making available DVDs of the last three Society conferences, held in 2003, 2004 and 2006.

There are two DVDs for each conference (Volume 1 and Volume 2). Each stores about 7 hours of video, for a total of about 14 hours of video for each conference. This allows essentially all the talks at each conference to fit onto the two DVD set. The DVDs are packaged in a slim plastic case, which takes up very little space. They use the DVD-R media type and the VCD encoding format which play on most (more than 90%) of DVD players, and essentially all computers with a working DVD ROM drive.

You can find a list of the contents by following the links below:

There is a strong emphasis on the science of calorie restriction and its effects on health and longevity throughout; the members of the CR Society have always fostered strong ties with the research community. The 2006 conference features presentations from Luigi Fontana, Aubrey de Grey, Edward J. Masoro, Caleb Finch, Steven Austad and Steven Spindler, for example - quite the array of researchers with interests in aging, longevity and calorie restriction.

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On the Edmonton Aging Symposium

The Edmonton Aging Symposium starts this Friday 30th, and those of us scattered about the world can listen in over the internet. Here's a little press on the event from the ExpressNews: "When we're born, we're given these bodies, and it's like being given the most extraordinarily complex car and not being given an instruction manual. We can't change the oil. We don't even know where the dipstick is. Imagine how much more mileage we could get out of our bodies if we knew how to do the proper maintenance. ... Once the science world started talking about the Human Genome Project, I realized that we were being given that manual to our bodies. It's in a language we're only just beginning to understand, but at least we have it now ... Up until 10 or 20 years ago, no one looked at it, because people just accepted aging as a fait accompli, that we couldn't do anything about it. That's changing now. If we have the knowledge and technology to actually address the causes and symptoms of aging and we don't do anything about it, it's like watching someone drown and not throwing out the rope that's in your hand."

Link: http://www.expressnews.ualberta.ca/article.cfm?id=8325

Xenotransplantation: Why Aren't We There Yet?

From PLoS Medicine: "Organ transplantation across a species barrier - xenotransplantation - has been attempted for over a century. Given the rapidly increasing gap between the organs required and those available for transplantation, over the last 20 years xenotransplantation has been aggressively pursued ... It is evident from the progress to date that there are several mechanisms of xenograft rejection which still must be overcome and which will require extensive investigations ... With diminishing industry support and limited funding from granting agencies, it has become more evident that finding a solution to xenograft rejection is not within the scope of one investigator or laboratory. ... I believe that the research in this field is progressing in the right direction and, in the course of seeking to solve xenograft rejection, has significantly advanced our understanding of several important immunological mechanisms ... There is a fair amount of optimism that with careful planning and a coordinated effort, the dream of clinical xenotransplantation can be achieved." However, funding drains away as tissue engineering appears an ever brighter prospect with each passing year as a source of replacement tissue for age-damaged organs.

Link: http://dx.doi.org/10.1371/journal.pmed.0040075

State Stem Cell Funding In New York

For those keeping score at home, The Scientist looks at public funding for stem cell research in New York: "Within his first two months in office, New York Governor Eliot Spitzer presented an initial budget proposal slotting $1 billion over the next 10 years for stem cell research. A final version of the budget must be approved by the three power centers of New York -- the Governor's office, the State Assembly and Senate. A similar effort proved unsuccessful -- former New York Governor George Pataki proposed a $1 billion allocation of funding to support stem cell research for the 2006-2007 budget, but it was not passed by the State Senate. Although the details of the budget are ever-changing, [those] closely involved in the process anticipate a $100 million appropriation each year for the next 10 years, beginning in 2008. ... Others involved in the process of designing the budget have raised concerns that both the Governor's and Senate's bills are too vague and may end up funding more capital projects, such as new buildings, than actual research. ... If [the New York stem cell bill] is an alternative mechanism to provide funding to research institutions, that's fine, but lets call it what it is. It's all going to depend on who's on that [oversight] board."

Link: http://www.the-scientist.com/news/home/52995/

Engineering the Immune System to Attack Cancer

I have a deep and abiding interest in the development of a cure for cancer, or better still, an absolutely effective method of prevention. This should be true of anyone who plans for longevity. Live long enough and you'll meet a fatal cancer with your name on it - unless something is done about that unfortunate fact in the intervening time.

Cancer researchers are hard at work on a number of very promising strategies for eliminating cancer with near-perfect targeting. If you couple that with a methodology of detection sensitive enough pick up the first few hundred cancer cells as they develop, and at a price point to run all the time, then that might make a good method of prevention - at least until we can engineer our aging biochemistry to stop generating cancers in the first place. But first things first.

I noticed a couple of items regarding the use of the immune system as a cancer therapy; targeting is still the name of the game, but the biotechnology that actually kills cancer cells is home grown rather than developed in a lab.

Targeting tumors the natural way:

The new tumor targeting strategy [cleverly] harnesses one of the body's natural antibodies and immune responses. "The killing agent we chose is already in us," says UW-Madison chemistry professor Laura Kiessling, who led the work with postdoctoral researcher Coby Carlson. "It's just not usually directed toward tumor cells."

In a series of cell-based experiments, the researchers' system recognized and killed only those cells displaying high levels of receptors known as integrins. These molecules, which tend to bedeck the surfaces of cancer cells and tumor vasculature in large numbers, have become important targets in cancer research.

...

"What we've shown is that you don't need a receptor that's found solely on tumor cells," she says. "You just need one that's found in significantly higher numbers on cancerous cells than on normal ones."

Immune response to cancer stem cells may dictate cancer's course:

Although stem cells hold incredible promise in the fight against certain diseases, in cancer they're anything but helpful. In fact, mounting evidence is showing that a tumor's growth and spread may depend on "cancer stem cells," which comprise only a very small subset of the tumor. Now, a new study by Rockefeller University scientists shows that immunity to cancer stem cells may help protect people with a precancerous condition from developing the full-blown disease, and that these cells could be an important target for cancer vaccines.

...

This immune response, which correlates so closely with clinical outcome, appears to be targeting the cancer stem cells rather than the bulk tumor cells in myeloma - something that gives researchers hope for a completely new approach. "In immunology for the longest time, we've tried to focus on targeting bulk tumors. But maybe we should be targeting stem cells," Dhodapkar says. "You need to target the roots to really kill the tree, but what we've been doing is trimming the branches and it hasn't worked."

If, ten or twenty years from now, as seems likely, we have access to robust cancer therapies and even more robust methods of detecting cancer early, will that be enough? Will that keep someone cancer free between 60 and 120, for example? It's an interesting question, given that the chances of contracting new cancers are an accelerating prospect with each passing year.

The risk of cancer in any tissue increases with age - and as for most failing machines, quite dramatically so in later life. This stems from underlying changes in biochemistry and the simple rules that determine failure rates in machinery based on gradual wear in component parts - possibly the shortening of your telomeres, possibly damage to stem cells, possibly something else, possibly all of the above. Is it good enough to have a good after-the-fact cure on hand when the risk of occurance is increasing enormously with each passing year? Is there a point past which a good therapy is just overloaded by sheer weight of new cancer bursting from your cells, and where does that point occur?

Food for thought.

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Lysosomal Storage Diseases and Aging

Lysosomes are the incinerators of your cells, breaking down junk and old, damaged components, such as mitochondria, so that the raw materials can be reused - a process called autophagy. Some portion of aging is caused by the buildup of materials that the lysosomes cannot degrade, a situation that looks something like lysosomal storage diseases (LSDs) wherein lysosomes are flawed to start with. LSDs "are debilitating genetic conditions that frequently manifest as neurodegenerative disorders. They severely affect eye, motor and cognitive functions and, in most cases, abbreviate the lifespan. Cell death is well documented in parts of the brain and in other cells of LSD patients and animal models ... We suggest that the lysosomal deficiencies in LSDs inhibit autophagic maturation, leading to a condition of autophagic stress. The resulting accumulation of dysfunctional mitochondria [increases] the vulnerability of the cells to pro-apoptotic signals." Which is another way of saying that the worn parts pile up until the cell self-destructs in the process called apoptosis. Some of the possible approaches to dealing with LSDs - such as the bioremediation research funded by Methuselah Foundation donors - are likely to prove useful in reversing this contribution to age-related degeneration.

Link: http://www.ncbi.nlm.nih.gov/pubmed/17329960

On Observed Behavior

Following on from a discussion on priorities and healthy life extension at Fight Aging!, more thoughts from Infidel753: "If I chose to be flippant, I might argue that the number of people who say they would not take advantage of life-extension technology if it were available refutes the proposition that life extension would reduce the death rate to near zero ... Observed behavior is a much better predictor of future behavior than verbal statements are. Many of the dramatic medical innovations of the twentieth century were at first viewed with suspicion as hubristic meddling with nature, but later widely accepted once people got used to them. ... As anti-aging technologies become available, I believe the same process of general acceptance will happen -- probably quite quickly. ... There is a vast difference between contemplating aging and death in the abstract, and confronting them as immediate realities. In fact, almost all humans in situations where they are faced with the possibility of imminent death react by taking any necessary measures to survive. I can't prove it, but I think that almost any person on his deathbed, if offered access to treatment that would restore his health and allow him to return to a normal life, would seize the opportunity, not wave it away."

Link: http://infidel753.blogspot.com/2007/03/taking-stand-for-life-revisited.html

An Actuarial View of Limits to Longevity

The succinct version of the actuarial viewpoint on limits to the healthy human life span is as follows:

  • limits to life span presently exist
  • these limits are increasing at a modest rate, something like 1 year every 5 years
  • there appears to be no ceiling to life span in the future

This viewpoint is derived from an examination of mortality rates in various population groups over time, but still comes to the same answer as a consideration of the operation of our biology from first principles, such as the reliability theory of aging and longevity. Our bodies are enormously complex machines and, like all machines, the life span and failure rates are determined by the degree and capabilities of maintenance.

So: more knowledge, better medicine and better biotechnology means longer, healthier lives. This will happen slowly as a matter of course, since better medicine reduces the rate at which damage accumulates over a lifetime. It could happen much faster if we put our minds to it and there was a much greater level of support for moving directly and deliberately to extend healthy life span by the most efficient means possible.

Here is the abstract for another recently published paper giving support to the actuarial viewpoint outlined above; hopefully you recall a little of statistics lessons from past years. If not, then skip to the last line and the explanation below:

Increase in common longevity and the compression of mortality: The case of Japan

This study shows a strong increase in the modal age at death (M) in Japan over a period of 50 calendar years, accompanied by a clear decrease in the standard deviation of ages at death above M (SD(M+)) until the 1990s for men and the mid-1980s for women. For the most recent periods SD(M+) appears to have stopped decreasing, even though M has continued to increase linearly. This stagnation in SD(M+) has been accompanied by stagnation in q(M). The number of deaths at M (d(M)) and the number of deaths at and above M (d(M+)) have increased, but significantly more slowly since the period 1975-79. Since the 1980s an acceleration in the increase of M+kSD(M+), our indicator of the longest life durations, has been essentially due to the pause in SD(M+). Our data do not suggest that we are approaching an upper limit in human longevity.

Translated for those of us far past our school days: the most common age of death is increasing with no signs of slowing down. If there was a compression of mortality - in other words, if medicine was only succeeding in pushing all our life spans ever closer up to some absolute limit - then we would see the distribution of ages at death compressed down into a smaller span of years. However, this distribution of age of death for the longest lived people continues to expand ahead in years. Compression of mortality is not what we are seeing here, but rather something much more like the scenario of better maintenance leading to longer-lasting machinery.

This bodes well for the future, should we get our act together and push harder for the development of better medicine aimed at the repair of damage that causes aging.

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Nitric Oxide Everywhere

Nitric oxide (NO) is everywhere you look, assuming you're looking at changes in human biochemistry with aging, and the resultant degenerations and diseases of the body. I ran across one example not too long ago: nitric oxide is a part of the control mechanism for blood vessel dilation (vasodilation), located in the blood vessel lining, or endothelium, amongst other things. We know that a range of age-related conditions are related to degradation in the flexibility of blood vessels, and it seems this has more to do with damage to the control mechanisms, rather than incapacity of the tissue:

Endothelial dysfunction, often demonstrated by the loss of the endothelial cell’s ability to cause vasodilation in response to appropriate stimuli, is one of the earliest events in the development of atherosclerosis. This has led to intense investigation of the factors affecting both the production and the degradation of NO, the endothelium-derived relaxing factor and a primary mediator of endothelial function. Reactive oxygen species (ROS), particularly superoxide anion, are well known to inhibit NO, and therefore the mechanisms by which endothelium regulates production of ROS are also of high interest. In this issue of The American Journal of Pathology, Zhang et al demonstrate regulation of such events by a mitochondria-specific thioredoxin, which reduces oxidative stress and increases NO bioavailability, thus preserving vascular endothelial cell function and preventing atherosclerosis development.

Another good reason to damp down the production of reactive oxygen species is the way they damage mitochondrial DNA, leading to even more ROS being produced and exported into the body at large:

Cholesterols, such as low-density lipoproteins (LDL) are used everywhere in the body and travel widely. If ROS reacts with nearby LDL - and there will always be nearby LDL - to form damaged, oxidized cholesterol, that damaged cholesterol can then be incorporated into and further damage biochemical processes throughout the body. For example, its effects on our arteries is well known. In conditions with elevated concentrations of oxidized LDL particles, especially small LDL particles, cholesterol promotes atheroma formation in the walls of arteries, a condition known as atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease.

The body is a fascinating, complex, roiling sea of mechanisms and chemicals, many of which have evolved into use in multiple mechanisms and delicate balances between too much and too little. Nitric oxide seems to be important to stem cell activity, for example:

In the body, nitric oxide occurs naturally. It helps the repair cells move out of the bone marrow where they are made, and it opens blood vessels and improves the uptake of oxygen.

...

"We went on to show that actually what's happening is nitric oxide is affecting the skeleton, or scaffold of the cell, and by adding nitric oxide we're able to rearrange the scaffold," Segal said. "When we rearrange the scaffold, the cells are able to migrate. The benefit of this is that when cells have improved movement they are able to repair the endothelium (the lining of the blood vessels) better and perhaps prevent atherosclerosis."

Moving on, calorie restricted mice produce more nitric oxide - one of many pieces of the puzzle surrounding the mechanisms for the benefits to health and longevity provided by calorie restriction.

The results showed that mice that were fed 30% to 40% fewer calories produced more nitric oxide than those who followed an unrestricted diet. Calorie restriction also caused the mice to increase production of another chemical messenger that stimulated production of new mitochondria (the main energy source in cells) and increased oxygen consumption and expression of a protein previously shown to play a role in calorie restriction's effect on life span. These beneficial effects of calorie restriction were not found in mice that lacked the enzyme necessary to synthesize nitric oxide. Therefore, researchers say the findings suggest that nitric oxide may play a critical role in calorie restriction's effect on longevity.

Lastly, for this selection at least, suggestions that nitric oxide - like most chemicals in the body - isn't always a good thing:

An enzyme [iNOS] that triggers the production of nitric oxide (NO) - a gas that helps immune cells fight off invading pathogens - accelerates the formation of brain lesions in Alzheimer's-prone mice ... For nearly a decade, researchers have known that iNOS was present in the brain lesions of patients with Alzheimer's disease, but nobody had addressed whether its presence was making the disease worse. Nathan and colleagues now show that Alzheimer's-prone mice that lack iNOS live twice as long and develop fewer brain lesions than iNOS-expressing mice.

It all depends on context and circumstance - but a far greater level of understanding of our biochemistry will certainly lead to better ways to extend and improve health and longevity.

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The Havoc Wrought By CMV

From the open-access journal Immunity & Aging, a look at cytomegalovirus (CMV) and what it does to your immune system over the years: "Ageing is associated with multiple immune system dysfunctions. An important current direction for immunosenescence research is towards assessing the clinical impact of age-associated modifications of immunity and modulating them. ... Lifelong and chronic antigenic load may represent the major driving force for immunosenescence, which impacts on human lifespan by reducing the number of virgin antigen-non experienced T cells ... Gradually, the T cell population shifts to a lower ratio of naive cells to memory cells ... Thus, the repertoire of cells available to respond to antigenic challenge from previously unencountered pathogens shrinks. ... Many of the clonal expansions filling the individual's immune system seem to result from previous infections by persistent viruses, especially CMV, but also, to a lesser extent, EBV and possibly other herpesviruses. A high number of CD8+ cells are found to be specific for a single epitope of cytomegalovirus: in some individuals up to a quarter of circulating CD8 cells carry receptors for a single CMV epitope." CMV is cluttering your immune system with uselessly specialized cells, leaving you with too few capable defenders in later age - and thus shortening your life.

Link: http://www.immunityageing.com/content/4/1/2

Patching, Regulation, Trial and Error

Via USNews, an example of the not-so-great methodology of medicine that presently dominates: trial and error over understanding mechanisms; attempting to patch over damage and slow progression of diseases rather than aiming at root causes to repair and reverse them; taking these less effective paths because regulation makes the more effective paths much more expensive. "Researchers are for the first time testing to see if creatine, a nutritional supplement popular with weightlifters, might hold Parkinson's at bay. Creatine works by increasing the body's levels of phosphocreatine, which serves as an energy source for muscle and brain. In Parkinson's, nerve cells in the brain are damaged and eventually die. 'We're not entirely sure what the reason is for the cell death. One reason might be that the cells run down; they lose energy. Creatine feeds into the little power plants, the mitochondria, that provide energy for the cell. ... Creatine is one of several over-the-counter supplements being investigated as a Parkinson's treatment.' There you have it - unambitious, of only minor benefit even if successful, yet forging ahead. An example in miniature of everything that is wrong with medical research and development today.

Link: http://www.usnews.com/usnews/health/articles/070322/22health.parkinsons.htm

Growing Replacement Enamel

Dentists are eagerly embracing regenerative medicine, as well they might. Here, EurekAlert! reports on progress towards one component of new teeth: "Dental enamel is the hardest tissue produced by the body. It cannot regenerate itself, because it is formed by a layer of cells that is lost by the time the tooth appears in the mouth. The enamel spends the remainder of its lifetime vulnerable to wear, damage, and decay. For this reason, it is exciting to consider the prospect of artificially growing enamel, or even whole teeth, using culturing and transplantation techniques. In the emergent field of tooth-tissue engineering, several groups have developed their own approaches. Although there has been some success in producing enamel-like and tooth-like tissues, problems remain to be solved before the technology comes close to being tested in humans. One of the issues has been how to produce, in culture, sufficient numbers of enamel-forming cells. ... Now that dental epithelial cells can be propagated in culture, the next step will be to achieve the same success with their partners in tooth formation, the dental mesenchymal cells. Further development of this technique will be aimed toward production of tissue to replace damaged or missing enamel, and ultimately, regeneration of whole teeth."

Link: http://www.eurekalert.org/pub_releases/2007-03/iaa-srd030707.php

1% Of Novamente Donated To the Methuselah Foundation

Illustrating the strong connection between the general artificial intelligence community and healthy life extension community, the owners of Novamente have donated 1% of their company in support of meaningful longevity research: "Currently in stealth mode, San Francisco-based Novamente is working on revolutionary Artificial Intelligence products. The Methuselah Foundation is a non-profit 501(c)(3) organization dedicated to accelerating the development of foreseeable, science-based therapies to combat aging. ... We are grateful to Novamente for its generous donation, the first we hope of many that will follow as part of the Methuselah Foundation's newly launched '1% for Life' program, for far-sighted corporations that want to support the rapidly accelerating efforts to find solutions to the debilities caused by aging. ... Since both Novamente and the Methuselah Foundation are operating at the leading edge of scientific progress, we at Novamente appreciate the enormous benefits that progress in Artificial Intelligence and Life Extension will confer on humanity. We consider our donation a wise investment in a brighter future for us all."

Link: http://blog.methuselahfoundation.org/2007/03/novamente_joins_the_methuselah.html

Rejuvenation Research, Volume 10, Number 1

The latest Rejuvenation Research is available online, and microglia are the order of the day, it seems. Microglia are a component of the immune system, scavenging debris and defending the central nervous system. What is their role in the degenerations of aging, and what is there to be done about it?

Evidence That Aging And Amyloid Promote Microglial Cell Senescence

Advanced age and presence of intracerebral amyloid deposits are known to be major risk factors for development of neurodegeneration in Alzheimer's disease (AD), and both have been associated with microglial activation. However, the specific role of activated microglia in AD pathogenesis remains unresolved. Here we report that microglial cells exhibit significant telomere shortening and reduction of telomerase activity with normal aging in rats, and that in humans there is a tendency toward telomere shortening with presence of dementia. Human brains containing high amyloid loads demonstrate a significantly higher degree of microglial dystrophy than nondemented, amyloid-free control subjects. Collectively, these findings show that microglial cell senescence associated with telomere shortening and normal aging is exacerbated by the presence of amyloid. They suggest that degeneration of microglia is a factor in the pathogenesis of AD.

Cellular Therapy Using Microglial Cells

Recent insights into the function and dysfunction of microglia may inform future therapies to combat neurodegeneration. We hypothesise how different aspects of microglial activity including migration, activation, oxidative response, phagocytosis, proteolysis, and replenishment could be targeted by novel therapeutic approaches. A combined approach is suggested, encompassing opsonization and anti-inflamatory strategies in conjunction with an engineering of microglial precursors. Xenoproteases for bioremediation could be used to enhance intracellular and extracellular proteolytic capacity. The capacity of microglial precursors to cross the blood-brain barrier and to home in on sites of neural damage and inflammation might prove to be particularly useful for future therapeutic strategies.

One of the names attached to this second paper is John Schloendorn, who works on bioremediation research funded by donations to the Methuselah Foundation. "Xenoproteases for bioremediation could be used to enhance intracellular and extracellular proteolytic capacity" means "let's adopt some useful biochemicals from bacteria that can help microglia clean up cellular debris by degrading harmful metabolic byproducts." Our metabolism generates damaging chemicals as a side-effect of its operation. When these build up with age, they damage the workings of our cells - and thus damage the workings of our bodies. So why not try to help the body out by removing the source of damage?

Given that many types of bacteria consume human remains - and also consume the damaging biochemical junk that builds up in and between our cells - it stands to reason that researchers can find the basic components of biochemical tools in those bacteria that will enable us to safely decompose damaging chemicals while we're still alive. Given that some fraction of aging is due to the buildup of these compounds, that should benefit us greatly.

Shifting topics, here is another interesting paper; it doesn't sound like a practical line of research to me, but it's still an intriguing idea. A popular science article from yesterday is somewhat more informative for the layman than the abstract of the paper:

Food containing heavy isotopes of hydrogen, carbon and nitrogen could slow down the aging process. That's the claim of Oxford-based researcher Mikhail Shchepinov, who suggests that seeding key biological molecules with deuterium or carbon-13 could drastically reduce oxidative damage or even avert it altogether.

Reactive oxygen species (ROS) are a staple of ageing research, as they are believed to cause cumulative damage to biomolecules such as DNA, proteins, and lipids. Typically, breaking a carbon-hydrogen bond is the rate-limiting step of these reactions. But if the carbon or hydrogen atoms involved were replaced by a heavier version of the same element (13C or D), the reaction will be slowed down due to a well-established phenomenon known as the kinetic isotope effect.

...

Heavy water (D2O) is toxic to higher organisms, but Shchepinov argues that isotopes would only be incorporated in the sites that need to be protected from oxidation. 'Ideally, they will slow down the oxidation reaction so much that they will never be released to take part in other reactions. If some of them do break free, they will only occur in small concentrations,' he said.

As for the other folk quoted in the article, I'm dubious - it seems to me that the level of technology required to target the isotopes reliably (and keep them targeted) would enable far more effective methdologies of repairing rather than preventing oxidative damage.

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"Cellular Aging Is a Reversible Process"

An interesting abstract published earlier this year: "Ageing is often defined in the context of telomerase activity and telomere length regulation. Most somatic cells have limited replication ability and undergo senescence eventually. Stem cells are unique as they possess more abundant telomerase activity and are able to maintain telomere lengths for a longer period. Embryonic stem cells are particularly resistant to ageing and can be propagated indefinitely. Remarkably, adult somatic cells can be reprogrammed to an ESC-like state by various means including cell fusion, exposure to ESC cell-free extracts, enforced expression of specific molecules, and somatic cell nuclear transfer. Thus, the rejuvenation of an 'aged' state can be effected by the activation of specific key molecules in the cell. Here, we argue that cellular ageing is a reversible process, and this is determined by the balance of biological molecules which directly or indirectly control telomere length and telomerase activity, either through altering gene expression and/or modulating the epigenetic state of the chromatin."

Link: http://dx.doi.org/10.1016/j.mad.2006.11.020

Scaffolds To Regenerate Ligaments

(From the Technology Review). Scientists continue to explore the use of scaffolds to convince the body to heal and regrow where it normally will not: "Surgical reconstruction is typically required to repair the [anterior cruciate ligament (ACL)], but current methods continue to take significant recovery time, during which a patient may sustain a loss of strength and function. Now, [researchers]have bioengineered a new ACL replacement using a 3-D polymeric fiber braiding process. It's the first synthetic scaffold design to demonstrate exceptional tissue regeneration and healing, and it could lead to a promising ligament-replacement technology. ... Our goal was to regenerate the ACL using classic design principles from engineering and material that has mechanical properties that mimic the natural ACL ... There just hasn't been very much successful work done on tissue-engineering ligaments. This [is] a very significant discovery. I haven't seen anybody do what they are doing with ligaments before." This work is still in the animal study stage; a few years yet before human trials start by the look of it.

Link: http://www.technologyreview.com/printer_friendly_article.aspx?id=18421

On the Way To "Faster, Better, Stronger"

At some point, 20 to 30 years from now, advances across the board in medical engineering will lead to artificial organs that are better, safer and more reliable in every respect than those you can grow (or regrow, with the help of regenerative medicine) youself. Blood, immune systems, bones, muscle, kidneys and so on - everything is open to improvement. Just as the room-sized computers of the 1960s have given way to handheld devices vastly more powerful and reliable at a fraction of the cost, so too will today's cutting-edge (but still large and cranky) life-support devices give way to low-cost artificial organs inside you - organs which will fail far less often than their organic counterparts.

It will be interesting to see how increasingly sophisticated engineering measures up against the increasing capabilities of regenerative medicine in the years ahead, but a great deal of work lies betweeen here and 2030. A couple of articles I noticed today give a hint of the progress underway, present challenges, and the progress yet to come:

Nanotechnology could lead to improved implant devices:

Unfortunately, in many cases these metal alloys with a life time of 10-15 years may wear out within the lifetime of the patient. They also might not achieve the same fit and stability as the original tissue, and in a worst case, the host organism might reject the implant altogether. While available implants can alleviate excruciating pain and allow patients to live more active lives, there often are problems getting bone to attach to the metal devices. Small gaps between natural bone and the implant can increase over time, requiring the need for additional surgery to replace the implant. In the quest to make bone, joint and tooth implants almost as good as nature's own version, scientists are turning to nanotechnology.

...

Rather than just experimenting by trial and error, scientists are aiming to intelligently design implant surfaces to control protein interactions important for subsequent cell adhesion that may provide answers to those problems which have plagued current orthopedic implants.

The devil is in the detail, and you have to start with the basics. If you want to integrate compact new biotechnology into the body, replacing damaged or aging organs with machinery that will eventually function far more efficiently than the original, you have to ensure that the interface between the two sides is far better than was possible in the past.

An insight into the rewarding world of biomedical engineering:

The phrase ‘engineers make a difference’ is used in virtually every branch of engineering, and no doubt the structural, civil, chemical and other engineers would all argue that they make the biggest difference of all. But there is one branch of engineering that has a direct affect on our lives that the other disciplines cannot. Biomedical engineering helps to relieve pain, repair damage, improve the quality of life, deliver faster, non-invasive diagnoses - and more.

...

Regardless of the branch of biomedical engineering, one of the biggest challenges is the patient interface. Colin Hunsley explains: “For a routine hip replacement, the surgeon will select modular components to build up a joint that will suit the patient. However, for some reconstructive surgery there may be a requirement to use rapid prototyping technologies to create prosthetics that are unique to the patient. We also have to be aware of biocompatibility, as the human body can be a harsh environment for many engineering materials; and, conversely, the body will reject most materials. Various surface treatments have been developed to help overcome this, but the latest developments seek to go beyond a material or device being merely tolerated by the body; rather the aim now is to create something that will function with the human body as well as - if not better than - what it replaces.”

In the future, everyone who cares to look after themselves will be a little bit cyborg. It'll be simple common sense. Why settle for a cranky old natural human immune system when you can buy one far better and more durable? Why stick with version 1.0 kidneys when the hybrid bioartificial models filter out chemical byproducts of metabolism that accumulate to damage your body in old age? The decades ahead are golden - well worth sticking around to see.

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The State of Stem Cells and Heart Disease

A reminder from the Technology Review that for all the speed of modern stem cell science, turning knowledge into new therapies is a slower process; the devil is in the detail and the regulation. "It's a tantalizing thought: injecting stem cells isolated from a person's own blood into an ailing heart in hopes of repairing years of accumulated decay. But so far, human trials testing cell therapies for heart attacks have yielded mixed results, creating controversy over various aspects of the treatment: the types of cells that are used, the way they are delivered, and when in the course of the disease they are given. With the next round of trials, scientists hope to nail down the precise set of conditions needed to effectively heal a sickly heart. ... In terms of the clinical testing of stem-cell therapies, heart disease is arguably the furthest along of the common diseases. But cell-based therapies are proving trickier to test than traditional drugs and medical devices are. They seem to require the perfect combination of ingredients and execution. Scientists must determine the best cells to transplant, the best way to prepare cells, and when and how they should be delivered."

Link: http://www.technologyreview.com/printer_friendly_article.aspx?id=18414

More On Nanofactories

An interesting hint of medicine to come from ScienceDaily; nanofactories, tiny artificial structures that act like cells: "these ingested nanofactories, using magnetism, could detect a bacterial infection, produce a medication using the body's own materials, and deliver a dose directly to the bacteria. The drug would do its work only at the infection site ... we can produce a tiny nanofactory and attach it to a target cell magnetically. The nanofactory then makes small molecules from surrounding materials and delivers the molecules - potentially drug molecules - to the targeted cell. ... the nanofactory could produce signaling molecules that communicate with the target cell or block the target cell from communicating with other, similar cells (a process called 'quorum sensing') and thus prevent infection. The researchers attached the nanofactories to E. coli cells, targeting them with the help of a mixture of iron particles and chitosan ... The nanofactories then produced a signaling molecule that could render the E. coli harmless. Nanofactories could be designed to produce the needed drug molecules over an extended period of time."

Link: http://www.sciencedaily.com/releases/2007/03/070320125351.htm

From the Healthy Life Extension Blogosphere

A couple of items of interest showed up in my wanderings today. Firstly, Bruce Klein notes his modest profile in the recently released "How to Live Forever or Die Trying":

Bruce Klein founded The Immortality Institute (Imminst) in 2002 as a non-profit organisation with the aim of ‘conquering the blight of involuntary death’. ... Klein was thirty-one when I met him at Imminst’s conference at the Georgia Tech Conference Center, Atlanta, in November 2005. The conference turned out to be a snapshot of the immortalist front line. It is a movement that is part cult and part serious science. But all were united by the fervency of their belief in the rightness of the project of extending life and by their vehement rejection of deathism and scepticism.

The world "cult" is thrown around all too easily these days; I can only think that it is a symptom of the absence from public view of human activities that truly deserve the label. Strive to support the development of cures for age-related disease and you're a patient advocate. Strive to support the repair of the root causes of all age-related disease - via the same scientific processes and methods, I might add - and you're a cultist, hairstyle and clothing choices open for comment. Such blind, irrational creatures, we humans; I consider a wonder that anything of ambition is ever accomplished. A larger excerpt can be found elsewhere online; see what you think of the rest of it.

Why? Because, says Klein, ‘oblivion is the issue’. He says: ‘I came to a point about five years ago where I realised I can’t do all of this unless I’m alive . . . The thing that human beings, I think, are evolved to do is put the issue of oblivion to one side. What I try to do is address that problem with writings, with film scripts and the thing is not only to address it but to provide a solution, the solution of infinite life span.’

He speaks, as does everybody in this business, of the 150,000 people who die in the world every day, 100,000 of them from the diseases of old age. For him, this is not acceptably explained as the natural order of things, rather it is a disaster to which we are called to respond.

‘I call it the Silent Tsunami, every day more than 100,000 people die quietly and acceptingly, saying their time has come or some other euphemism. But, with a real tsunami, they say this is a tragedy, we must do things to prevent this in the future.’

Switching topics, we have some thoughts on calorie restriction from a member of the community who thinks that the arguments for significant human life extension via this methology are plausible:

Think of the differences in human longevity, from person to person. One person can live decades than another. Isn't that AMAZING?! Calment lived DECADES longer than the average person... Her aging was much slower than the average person. There are centenarians that live to old age and centenarians that survive to old age. Calment lived and survived to old age with luck, genetics and possibly lifestyle factors. But it shows you just how much of a degree there can be between how much longer one can possibly live.

...

The huge difference between when the average person dies, and when the oldest human ever documented lived is huge, spanning over 40 years? That’s a remarkable reduction in the rate of aging. Aging must have been slowed in her, and damn right, CRON will slow the aging for us. To what degree is up for debate. But I would bet that our average life expectancies will be up their with those lucky few who survived to extreme old age without the help of calorie restriction.

There is a very good weight of science backing the fact that calorie restriction will do very good things for your health and resistance to the more common aspects of age-related degeneration today. But will that add a couple of years to your life, ten years, or how long? Good question, but look at exercise as a comparison - the difference between fit and unfit is large once you make it into later life. Just as for staying fit with exercise, you'd be a fool not to look into calorie restriction, given the impressive health benefits demonstrated in human studies.

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A Look At Cancer Vaccine Research

Cancer vaccines have been in the popular science press over the past couple of years. Here is more from ScienceDaily: "At the root of most cancers is a single cell going awry and dividing uncontrollably, producing a tumor. As cells become cancerous, they produce proteins that are unfamiliar to the human immune system, which should prompt a protective response from the body. Yet somehow, these stealth proteins evade the body's defenses and allow the cells to grow into a tumor. In results from animal studies, pre-vaccination with these foreign proteins creates an immune response that prevents the tumor from forming. Unfortunately, each tumor's protein signature can be slightly different. In other words, even if two individuals have the same type of cancer, their tumors may be slightly different, and therefore the concept of a widespread preventative vaccine that would be effective in large numbers of people has been a daunting task. However, if common themes could be identified, it could provide a means for solving this problem." We should all be most interested in progress towards the defeat of cancer - the longer you live, the more likely it is that you'll experience it.

Link: http://www.sciencedaily.com/releases/2007/03/070319180031.htm

Visit the Methuselah Foundation Forums

By way of a reminder, the Methuselah Foundation recently set up a forum accessible to the public; if you'd like to hobnob with the researchers and volunteers presently working on Foundation science projects, or discuss the Strategies for Engineered Negligible Senescence and other directions for near-future longevity research, then this is the place to be.

See, for example, a posted overview of the MitoSENS project, and thoughts on RAGES and bioremediation:

When trying to bioremediate AGE crosslinks from aged tissues, a major concern would be that the crosslink might be buried by the protein fibers it crosslinks, so that the bioremediation enzymes might be unable to access it. The utility of using enzymes to bioremediate AGEs has been questioned based on this (Furber, 2006).

I think a partial objection is provided by the existence of receptors of AGEs (RAGEs). RAGEs are large, even cell-bound signaling proteins that recognize AGEs. Thus, any AGE accessible for the AGE-RAGE interaction should also be accessible to a bioremediation enzyme.

LysoSENS is the first strand of bioremediation research funded by Methuselah Foundation donors; a search for bacterial enzymes capable of safely digesting one set of the damaging chemical junk that builds up in our cells over a lifetime. The term bioremediation has traditionally applied to environmental issues, but it is just as applicable to our biochemistry. Obviously, the LysoSENS folk have ambitious thoughts about future work - good for them. Given that bacteria can digest all of the human body after death, there should be a bacterial enzyme out there somewhere for any given harmful organic chemical you'd like to get rid of.

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More Viruses Versus Cancer

Scientists are making strides in adapting various viruses to kill cancer - there is a certain satisfaction inherent in turning the tools of disease for use in healing. Medical News Today tells of another groups hard at work to this end: "an attenuated -- or non-virulent -- form of poliovirus is effective in obliterating neuroblastoma tumors in mice, even when the mice had been previously vaccinated against the virus. By its nature, poliovirus destroys the cells it infects in an attempt to replicate copies of itself. ... The [researchers] took advantage of this viral property by injecting a stable, attenuated strain of poliovirus directly into neuroblastoma tumors transplanted into 12 mice engineered to contract polio. The virus was able to destroy tumors in all 12 mice; however tumors reoccurred in two mice by the end of the 180-day study period. .... None of the mice experienced any ill effects from the virus itself. ... any viral particles that make it to the bloodstream would be destroyed by antibodies created through poliovirus vaccination. The researchers believe that their findings, if developed to work in humans, could represent a safe, practical means of treating [many] other cancers in adults."

Link: http://medicalnewstoday.com/medicalnews.php?newsid=65408

A Glance at Basic Stem Cell Research

A release at Newswise is indicative of the sort of progress presently underway in the study of stem cell biochemistry. Piece by piece, scientists are uncovering the knowledge needed to fully control our cells, and thereby regenerate damage on demand: "A newly discovered small molecule called IQ-1 plays a key role in preventing embryonic stem cells from differentiating into one or more specific cell types, allowing them to instead continue growing and dividing indefinitely ... This discovery takes scientists another step closer to being able to grow embryonic stem cells without the 'feeder layer' of mouse fibroblast cells that is essential for maintaining the pluripotency of embryonic stem cells ... Such a layer is needed because it is currently the only proven method to provide the stem cells with the necessary chemical signals that prompt them to stay undifferentiated and to continue dividing over and over. ... Stem cells that grow on feeders are contaminated with mouse glycoproteins markers. If you use them into humans, you'd potentially have a horrible immune response. ... If we can create a totally chemically defined system for growing human embryonic stem cells without any risk of contamination, it would make life much easier for scientists than it is at the moment. And that's our goal."

Link: http://www.newswise.com/articles/view/528206/

Thoughts on Aging Research

An interesting piece from Medical News Today: "The early development of humans and animals, the time between conception and maturity, has an enormous influence on their lifespan. ... Zwaan [had] just been stressing how important it is for the medical world to become convinced that factors at the very start of life have an enormous influence on life expectancy. So that we can make an early start on taking appropriate, and preferably preventive, action. Don't wait until middle age! ... Early influences late. But how does it work? We're all well aware by now that pregnant women shouldn't smoke. But there are many more things we are not aware of. These are the things we want to find out more about. And more importantly: we want to understand the biology behind them. ... From time to time somebody will claim to have found the gene for longevity. The rest of the field is then silenced. And it means so little. The fact that a mutated gene may lead to longer life, does not mean that the gene contributes to variation in natural populations, including that of man." It makes for interesting reading in the context of the reliability theory of aging and longevity, which suggests we are born with an initial load of damage.

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=65473

Efficiency Matters - But How Do You Identify the Efficient Path?

I stumbled over a couple of items on the direction of cancer research today, both of which are views into the issue of efficiency in research. This is a topic I discuss quite often here, in connection with the Strategies for Engineered Negligible Senescence (repairing the damage of aging) versus metabolic manipulation (slowing aging). One path is most likely much more efficient than the other in terms of achieving the end goal of a longer, healthier life - but the more efficient path is not the one gaining the greatest level of funding. Yet.

In any case, the two articles on cancer research are illustrative of the sort of debate one sees over questions of direction and efficiency in research. For a field in which not everything is known, how do you establish which direction is the most efficient? See what you think:

Arresting Stem Cells May Trump Tumor Shrinkage in Rating Cancer Treatments, Researcher Says

Failure to recognize the role of stem cells in metastasis may have led cancer researchers up "blind alleys" in countless clinical trials, said Max S. Wicha, M.D., founding director and distinguished professor of internal medicine at the University of Michigan Comprehensive Cancer Center, speaking at the National Comprehensive Cancer Network's 12th Annual Conference.

With tumor shrinkage the primary guidepost of any new treatment, valuable therapies may be aborted too early in their experimental life, he said. At the same time, clinical-trial measurements that focus only on a tumor's diminishing size may explain why some new therapeutic treatments have failed to work. If the tumor's stem cells run amok even as the tumor's girth diminishes, a patients' life may be at stake.

The answer? Begin monitoring whether chemotherapy and radiation treatments work to arrest cancer's stem cells and their progenitors - i.e., those cells that can make exact copies of themselves and "differentiate" to play specific roles. Then find ways to make chemotherapy and radiation treatments more powerfully target the tumor's stem cells while sparing healthy stem cells the body needs.

Cancer stem cells do not enjoy universal support as a potential line of greatest efficiency in cancer research - it would certainly be a very good thing if they are the path of least resistance to a cure for cancer, but the arguments of the skeptics are not to be neglected. Still, the degree of potential efficiency is so great in this case, and the level of funding for stem cell biochemistry and cancer research so high, it seems certain that this line of research will be chased down to its logical conclusion comparatively soon.

This Is No Way to Cure Cancer

Called the Cancer Genome Atlas, it aims to identify mutations in tumor cells from the 50 most common kinds of human cancer. (A genome is the full set of genetic information in, in this case, all the malignant cells in these 50 cancers.) You can think of the mutations as misspellings in the cells' DNA; the hope is that designer drugs tailored to a patient's mutations will cure the cancer just as spellcheck cures typos. Now beginning a three-year, $100 million pilot phase, the atlas threatens to suck up ever-dwindling resources at a time of budget carnage at the National Institutes of Health, which funds it. But there's a bigger problem: the atlas's very premise may be fatally flawed.

"From a clinical and drug perspective, the cancer-genome project is so shallow it's worthless," says George Gabor Miklos, who has served as a consultant on genome projects, the holy grails of biology for a decade. NIH, he says, has "made an enormous mistake that will cost the taxpayer billions." Scientists from top institutions including the Mayo Clinic, the University of Chicago and Harvard Medical School are weighing in to denounce the project as "high-cost, low-efficiency," "not informative" and "naïve."

I'll spare you the longer version of my comments on government-funded work, efficiency and incentives. If there's less of a material incentive to produce actual results and keep costs down, you'll see far less progress per dollar spent; pretty simple, really.

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There is Nothing Past the First Step Until You Complete the First Step

People being people, you'll hear vigorous, speculative discussion of the last mile of any journey long before the first step has been planned and completed. It's no different in the community of folk supportive of healthy life extension. We're just about as short-lived today as we were the day before - compared to what is clearly possible and not yet achieved - but you'll still find a thriving conversion taking place on the far future and speculative topics: on uploading; replacing the brain with something more durable via nanotechnology; pattern versus continuity identity as it applies to life and death; cosmological limits on future technology rescuing the dead from the past; whether the many worlds interpretation of quantum mechanics implies we're already immortal in a way that matters - and back to pattern versus continuity after that.

Here are a couple of recent examples, two amongst the great many:

When are you not you?

Lets say that we have the technology to constantly back up our brains onto a computer through some wireless connection so that at any one time the computer has a snapshot of your brain in its current state. Now lets say that you get in an accident and 50% of your brain is damaged, so they take that backup and use it to replace 50% of your brain. Would you still consider yourself to be you and not some copy? what about 40% or 20%? What about 5%? Are you still you?

Lets say that you get in an accident and need 95% of your brain replaced and you use the backup image of your brain, are you still the original? Lets say that you get in an accident and are killed and lose 100% of your brain. But doctors take the image of your brain and put it into a new body that is exactly like your old body with all your memories right up to and including the accident which caused your death, are you still you? What if they replaced your brain while you were still healthy?

Consider now a future technology which allows for the slow conversion of your brain from flesh and blood to hardware. It's a slow process taking up to 3 years, no one really knows when the process is entirely finished. You notice no difference in your daily life as the process occurs but at some point in the future your brain goes from being 100% natural to being 100% artificial. Are you still you? Are you still the original? You obviously feel like the original but your brain is no longer original it's just a pattern of your old brain running on hardware.

How to be copied into the future?

In Arthur C Clarke's and Stephen Baxter's "The Light Of Other Days", posthumans develop quantum technology that enables them to look back in time, through wormholes in spacetime, at whatever point in time and space they wish (but only all past time and up to their present time). For example, they can watch everything we all have done with our lives, even when we (thought we) were alone. Later on, this technology is further developed by future generations, posthumans, so that they can use it to copy all human beings who have ever lived, and "resurrect" them in the future (the time of those posthumans). By being saved by posthumans in such a way, all humans will get a much longer life, as the future into which they are saved has far more advanced life-prolonging technology than humanity has today. If we are only our information, not our matter, and if this kind of technology will sooner or later be invented, it may seem that we are all already guaranteed immortality even if we die today.

And so forth. For all we know, yes, the projected rise of technology will lead to immensely powerful individuals and societies, as well as a complete understanding of the universe to the point at which every past event can be recreated. It's an idea that has been explored with serious intent by cosmologist Frank J. Tipler as well as in the fiction of other authors, such as Greg Bear. But I don't think it's wise to live one's life under the assumption that any of this is plausible - letting what-if speculation in physics be the guide to your life is just as much a leap of faith as temples, the supernatural and the grave.

There's nothing wrong with looking at the far future and speculating wildly. Just don't let it distract you from the fact that you are aging, and that you can help to do something to defeat aging. There is a first step to be built on the long journey to the future; the step of plausible, projected healthy life extension medicine capable of providing a few additional decades of healthy life.

Until a research and development community is massively funded and well underway towards this first step - and note that, for all the effort of advocates to date, this is not the case today - talk of uploading and cosmology is nothing more than recreation. Nothing wrong with that, so long as you recall that a city is burning beneath the balcony where you play.

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More CIRM Grants Disbursed

For those following developments at the California Institute for Regenerative Medicine (CIRM), the San Francisco Chronicle reports on the latest set of grants: "Twelve institutions, all nonprofits or part of the UC system, shared 29 large 'comprehensive' grants worth $74.6 million. Two other smaller grants, totaling $1.1 million, were added to a previous list announced last month. Scientists at UCSF and its affiliated J. David Gladstone Institutes, followed closely by Stanford University researchers, topped the comprehensive grant totals, receiving seven grants worth about $18 million. Dr. Deepak Srivastava at the Gladstone Institute received the biggest single grant, $3.1 million, for a project to unravel how molecules known as microRNAs help guide the development of stem cells into heart muscle cells. Stanford got seven grants, for $17.7 million, including a $2.4 million grant to a UCSF researcher, Renee Reijo Pera, who recently announced a move to Stanford to pursue a cloning technique known as somatic cell nuclear transfer." The full list of grants and research programs can be found in the PDF release at the CIRM website.

Link: http://sfgate.com/cgi-bin/article.cgi?f=/c/a/2007/03/17/BAG0GON6M11.DTL

Another Way To Target Cancer

Researchers and medical engineers are taking the building blocks provided by modern biotechnology and assembling impressive technology demonstrations of effective cancer therapies. VOA News reports on one of the latest: "We put radio-labeled antibodies that we know bind to breast cancer on the nanoparticles' surface, and then injected them into mice in which we had implanted a very aggressive human breast cancer. ... The antibody-nanoparticle combinations attached themselves to the breast cancer tumor cells. Then the researchers applied an external 'alternating magnetic field' (AMF) to the area around the tumors [causing] the iron nanoparticles to become very hot. The heat then kills the breast cancer cells without harming the healthy tissue around the tumor. ... If we give, in 20 minutes, a certain dose of the alternating magnetic field into the tumor area, we know the dose of heat we should have created on the tumor. .. The tumors basically responded, some of them going away, some of them slowing in their growth rate, and that correlated closely with the calculated heat dose."

Link: http://www.voanews.com/english/AmericanLife/2007-03-18-voa21.cfm

On Old Age to Come and Regret Anticipated

The only worthwhile regret is regret anticipated - the regret yet to happen, and which there is yet time to ward off through action. The past is a stone table, and regret for past inactions at the root of present circumstances serves no purpose other than education. Learn quickly and put those regrets to one side; look instead to the future and the regrets yet to come - let that guide your actions.

Look around you the next time you're out and about; the tapping cane of a bent old man who can no longer walk unaided; the nagging cough of the elderly woman possessed of an age-damaged immune system; the pained hesitance of an arthritic senior citizen organizing materials to write a check. Folk all around you struggle and suffer over matters to which you give little thought; worse, the ones you recognize will vanish, day by day and one by one. Aging keeps death busy.

Barring sufficiently rapid and radical progress in medical technology, the pain and frailty of the old form a mirror for your future regrets. Two decades hence, three decades, five, will you regret your inaction, your failure to materially support the advance of medicine at a time when your contributions would have made a great difference?

Regrets are best anticipated, and this is an easy regret to anticipate. Perhaps you didn't know that there are a number of very easy ways to help make the science of longevity move more rapidly. Perhaps you didn't know that gaining an additional 20 years of healthy life within the next 20 years is plausible, if levels of funding and support increase greatly. You know now.

You have a chance today, this year, to help tip the fulcrum to bring great change, speed and growth in longevity research and the fruits it will bear in decades ahead. To have a chance to gain many more healthy years of life. Don't blow it.

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Longevity and Evolution

It is interesting that scientists are finding so many comparatively minor mutations that extend the healthy life spans of lower animals; why didn't evolution lead to those mutations in the first place? From Ouroboros: "Why, then, are these artificially created mutant alleles not the wildtype? In other words, if lacking a particular gene makes an animal longer-lived and more vigorous, why do all wildtype members of the species have the gene in the first place? ... longer-lived mutants are significantly less fit, in an evolutionary sense, than the wildtype. ... the fitness decrease isn't caused by the overall decrease in lifetime fertility, but rather the delay in early-life reproduction. This makes sense, in the relentless logic of exponential growth: The earlier one reproduces, the earlier one's progeny are available to do reproduction of their own. ... It's pretty clear that eventually the short-lived early-reproducer would out-compete the long-lived late-reproducer, even though [the] total lifetime fertility of the longer-lived variant is actually higher. ... Traits that shorten the overall lifespan can be positively selected for if they increase the reproductive success (fitness) of the organism." Which is a tragedy of biology inflicted upon our ancestors - but we are now in a position to start to do something about it.

Link: http://ouroboros.wordpress.com/2007/03/16/longevity-vs-evolutionary-fitness/

Thoughts on Degeneration and Repair

FuturePundit contemplates degeneration and repair as they pertain to our eyes: "Some people are content to grow old and even try to justify the changes which happen to our bodies as the various pieces break down. But this all seems like loss to me and with no compensating upside. The tiny muscles in your irises become less able to adjust pupil sizes and so your pupils can't dilate as far and as quickly to let in more or less light as needed. As far as I'm concerned this is yet another argument for treating the development of rejuvenation therapies as an urgent matter deserving a massive research push. ... Some labs are working on designs of artificial replacement lenses. Also, other labs are working on ways to grow natural replacement lenses using cells and tissue engineering. One way or another we'll some day be able to replace aged lenses with lenses as young as those of a baby. But we need much more in order to do eye rejuvenation. ... Further on down the road we'll eventually witness the development of tissue engineering technologies so advanced that they can grow whole organ replacement parts. Replacement eyeballs will then provide much more thorough and comprehensive solutions to the problems of aging eyes."

Link: http://www.futurepundit.com/archives/004126.html

Growing Replacement Cornea Tissue

One small piece at a time, scientists are developing the means to replace damaged portions of your body. Here, via the Daily Yomiuri, is another part of the eye, to go along with progress in regenerating retinal cells: "A team of researchers at Tokyo University Hospital has succeeded in using a cornea cell to grow cornea epithelial tissue, which is essential for treating deteriorating eyesight caused by damage to the surface of a cornea caused by the side effects of medicine or drugs. ... [the researchers] harvested limbal cornea from the peripheries of the pupils. The team then used an enzyme to turn the limbal cornea into pieces to cultivate it. The pieces grew into clumps with a diameter of 0.3 millimeters in about one week. Three weeks later, they became cornea epithelial tissue in sheets with a diameter of about two centimeters. The three-dimensional tissue is similar to ordinary cornea epithelial tissue. Yamagami said he planned to make a clinical application for it in several years."

Link: http://www.yomiuri.co.jp/dy/features/science/20070316TDY03002.htm

Transhumanism is Common Sense

On the day it comes to you that living a longer, healthier life is something you'd like to do, that an extra year or ten of good health (or hell, why not more?) would be just peachy keen, think of the transhumanists - because you just became one. You saw a limit in the human condition, thought about what life would be like with that limit removed, and liked it.

Welcome to the party!

Transhumanism, make no mistake, is just a fancy name for common sense. Change for the better is good, right? Common sense. It's what we humans do in our scattered finer moments - we work to change things for the better. It's common sense to fetch in the harvest on wheels rather than on foot, and it's common sense to repair the biomolecular damage of Alzheimer's before the mind begins to rot. It's common sense to build perfect immune systems from nanomedical robots, and it's common sense to develop the technologies of regenerative medicine to their logical end.

It takes work, but what is work compared to a world of suffering? Choosing not to attain these goals makes about as much sense as standing out in the rain to spite yourself.

New technology cannot set slaves free, remove poverty brought of corruption, make the willfully blind see, or the unhappy bring themselves to good cheer of their own free will ... but it can remove the limits placed upon us by evolution, and it will one day give us all much, much more time in health and life to work on our other, very human issues. You can't rid the world of poverty when you're sick, decrepit and aged to death. The limits to our lives that we cannot negotiate away by talk and travel are the most confining, don't you agree?

Transhumanism, common sense with a slick name, is really simple humanism - which is also really no more than a name for common sense. It is only humanist to work to give people the choice to live without suffering, and without death. To live, for without life, there is nothing.

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Towards New, Engineered Immune Systems

The New Scientist reports on another step forward for medical engineering: "a 'bioscaffold' made of collagen impregnated with stromal and dendritic cells extracted from the thymus of newborn mice [was] then implanted into mice with healthy immune systems that had been vaccinated against a harmless antigen (something that triggers an immune response). ... After the artificial node had filled with antigen-specific T and B cells, Watanabe transplanted it into a mouse with no functioning immune system. The lymphocytes quickly spread out from the artificial node into the animals' own lymph nodes ... After a month, these cells' 'memory' was still maintained, and they were able to fight off challenges from the antigen. ... The next step is to use human cells in humanised mice. Then, maybe in four or five years, we might be able to make the first prototypes of a human model ... By implanting artificial nodes plump with healthy T and B cells in AIDS patients, he believes he might be able to revitalise their damaged immune systems. For cancer, he hopes to adopt a similar approach in which the transplanted nodes will contain T cells trained to hunt down the antigens produced by tumour cells and kill them off."

Link: http://www.newscientist.com/article/dn11389-artificial-lymph-node-transplanted-into-mice.html

The Slow Creep of Ideas, Part 2

Here is another characteristically mixed article from the Herald; There is progress in awareness of present scientific backing for healthy life extension, but the default position still seems to be to "reach for the off switch," as Aubrey de Grey puts it. "Pupils will gather in Edinburgh tomorrow for the Scottish finals of the Institute of Ideas' Debating Matters competition. The motion? 'Attempts to extend radically the human lifespan should be welcomed, not feared.' Naturally, as a judge I'll be assessing how well they argue their case and stand up to cross-questioning, but I know which side I'd prefer to be on. It may be easier to support the motion. Expanding lifespans are a fact, after all. In 1899 there were probably about 10 centenarians in Scotland and we know nothing of their frailty or mental capacity. When I set out to track down Scotland's "super-old" in 1999, there were more than 1000. ... The point was that we are not just getting older but staying fitter for longer too. Today about 35% of our over-75s do some volunteering work. Seen in this light, what we emotively call 'the demographic timebomb' looks like a blessing in disguise. But hang on. Just because some people's longevity defies our expectations, just because we CAN stretch lifespans, doesn't mean we should."

Link: http://www.theherald.co.uk/features/features/display.var.1259939.0.0.php

Continued Progress in Tissue Engineering

Scientists are making progress in growing more lifelike and larger masses of tissue: researchers "have created new heart muscle with its own blood supply through the use of human embryonic stem cells. ... Despite progress over the past two decades in treating cardiac disease, there are few good ways to fix damaged heart muscle. One possibility would be to rebuild a broken heart with a transplant of healthy heart tissue. However, scientists have been stymied in these efforts by a lack of human heart tissue to work with and the failure of transplanted tissue to thrive in its new home. ... heart tissue grown by the [researchers] is threaded throughout with a network of tiny blood vessels that would improve the tissue's survival after being transplanted in a human heart ... researchers engineered the heart muscle by seeding a sponge-like, three-dimensional plastic scaffold with heart muscle cells and blood vessel cells produced by human embryonic stem cells, along with cells called embryonic fibroblasts. ... Four to six days after being seeded on the scaffold, patches of the new muscle cells began to contract together, a movement that spread until the entire tissue scaffold was beating like normal heart muscle."

Link: http://www.juf.org/news_public_affairs/article.asp?key=7884

That Didn't Take Long

It wasn't all that long ago that I was pointing out a couple of interesting articles on the financial markets, the insurance industry and growing healthy longevity in the population at large - if you want to see what people really think about the prospects for healthy life extension over the next few decades, follow the actuaries and the money of those who employ them. The controllers of vast sums of money are becoming more convinced that they do not fully understand the risk involved in betting against a large growth in life expectancy amongst the old in the years ahead.

On Longevity Insurance

In its simplest form, the premise of longevity products is that by making a one-time payment, you will start receiving guaranteed lifetime income at a designated point in the future. Your projected income stream is calculated at the time that you invest. ... The insurance companies rely on the fact that people aren't going to live that long to provide the payouts to the select few that will.

Take the Money and Run?

Here is a knee-jerk response: unless these products are stunningly bad value for money under very conservative estimates for growth in life expectancy in the old, those companies to offer longevity insurance packages will be taking a bath twenty to thirty years from now.

Longevity and the Financiers

Some are cynical about whether the longevity market will ever come to life - or at least on a meaningful scale. ... some banks are already testing schemes: Deutsche Bank is considering creating bonds using the cash flows from life insurance portfolios. It believes that it will receive a credit rating for these instruments soon, which should allow trading to start this year. Several other banks are experimenting with bonds and derivatives linked to longevity risk.

The game is afoot already, it would seem, judging by this press release:

Taking an important step in creating a traded market for a major risk faced by the pension industry, JPMorgan today launched its LifeMetrics Index, the only international index designed to benchmark and trade longevity risk. The LifeMetrics Index is part of an overall platform the investment bank has created called "LifeMetrics," aimed at measuring and managing both longevity and mortality exposure.

JPMorgan has designed the LifeMetrics Index to be the leading industry index used to create securities, derivatives and other structured products. LifeMetrics will enable pension plans to calibrate and hedge the risk associated with the longevity of their beneficiaries. The index incorporates historical and current statistics on mortality rates and life expectancy, across genders, ages and nationalities. Initially the index is available for the United States and England and Wales. JPMorgan intends to introduce similar indices for other countries in the coming months. The index is calculated by an independent calculation agent and will be governed by an international advisory committee including experts from different organisations.

The potential for the development of a traded market rests on the standardisation of the measurement of longevity risk associated with pension funds and the mortality risk facing life insurers. "We believe this index will facilitate the development of a market in tradable longevity risk," said Patrik Edsparr, global head of Rates, Securitised Products, Proprietary Positioning and Principal Investment businesses at JPMorgan. "JPMorgan is committed to leading the development of this market."

I view the present turning of cogs and expectations in the financial community as a net benefit to longevity research and advocacy five years hence: as it trickles down through this huge industry, the message of longer, healthier lives will become a powerful source of reinforcement to the same message coming from scientists.

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The Slow Creep of Ideas

For all the progress that has been made in healthy life extension advocacy, it's still taking a good long time to move ideas, knowledge and expectations into the mainstream. Take this half doom-and-gloom piece, for example, from the LA Times: "And it's not just an extension of working years that individuals will have to accept. We can also expect health problems to multiply, at least temporarily, as people live longer in bodies that didn't have the benefit of the latest in nutritional knowledge, new treatments or better working conditions. The good news is that science is going to be offering better cures faster than most expect. ... Pharmaceutical companies are developing drugs to fight the crisis of obesity, which leads to diabetes, heart disease and premature death. British bio-gerontologist Aubrey de Grey and others are pursuing a goal of 'engineered negligible senescence' - which would in theory eliminate most of the physical damage of aging and lead to indefinite life spans." The most basic of basics regarding modern longevity science - that extended healthy lives are possible, plausible, and closer than you think, provided the work is funded - are still to be communicated to the majority of people. Only when the man in the street responds to aging in the same way as cancer will we be fully underway on the road to defeat aging.

Link: http://www.latimes.com/news/opinion/la-oe-arrison13mar13,0,3383835.story?coll=la-opinion-rightrail

More On Telomerase and Body Mass

Ouroboros follows up on recent work on telomerase levels by size of species: "An outstanding question in the evolution of aging is whether telomerase activity (which preserves the ends of linear chromosomes and lengthens the replicative lifespan of cells) is related to lifespan per se. On on hand, it seems likely that it would be related positively: The longer one lives, the longer one's cells need to continue regenerating. On the other hand, the longer one lives, the more likely one is to accumulate [damaged, cancer-prone cells]. Since telomere maintenance is essential for tumor cell viability, one might not want these damaged cells to have ready access to telomerase expression ... and this logic might lead us to the opposite conclusion. ... Seluanov et al. show that among rodents, telomerase activity has co-evolved with body mass, but not lifespan. Furthermore, the correlation is negative: telomerase activity is more restricted in larger animals, perhaps as a defense against the increased cancer risk that comes from having more cells."

Link: http://ouroboros.wordpress.com/2007/03/14/telomerase-negatively-correlates-with-body-mass/

If the Purpose of Medicine Is To Save Lives...

As Anne C. says, "if the purpose of medicine is to save lives, medicine shouldn't limit its sphere of effectiveness only to younger people." I am reminded of a recent item in the science press:

A year of added life more valuable for the young, study suggests

"Our paper reviews recent studies related to how society values health gains for people of different ages," Eisenberg said. "These studies generally suggest that health gains for people at younger ages should receive higher priority than equivalent health gains for older people. When we incorporate these values into standard cost-effectiveness analysis methods, then interventions for young people, such as recently developed vaccines for HPV or meningitis, look significantly more appealing from a cost-effectiveness perspective."

...

"This study illustrates that the way we have been performing cost-effectiveness studies devalues the effect of interventions on children relative to adults and seniors," said Freed, who also has an appointment in the school of public health.

"As a nation, we must take a fresh look at how we measure the benefit of interventions focused on children. Likely, they represent the best investment we can make in our country's health now and in the future."

The paper does not suggest that society should divert health care from adult and senior programs, Eisenberg stressed. It is unknown how often economic methods such as cost-effectiveness analysis are actually used to allocate health care dollars---many other factors contribute to the decision making process, particularly in a decentralized health system such as ours, he said. Rather, the study suggests that age should be accounted for in future economic calculations and that the evidence on societal values for this issue should continue to be developed.

When people say "society" in this sort of context, they really mean "whichever govenment pen-pusher happens to be put in charge; a person who cares nothing for you, your specifics or your wishes" - a ringing endorsement for not letting "society" have any say in any matter. People are quite capable of making their own choices based on value, using information specific to the case at hand. You wouldn't let a random stranger drive your car - why let faceless government employees decide whether you live or die? Step up to the plate and help make sure that the medical technology you want to see is developed and available in time for your old age!

If you look for the greatest source of suffering and death in this world, you will find aging:

Because saving lives is the most valuable thing anyone can spend their time doing, and since over 100,000 people die every single day of causes that young people essentially never die of, you'll save more lives by helping to cure aging than in any other way.

There is no greater single target for medicine - and yet we advocates for healthy life extension are forced to fight an uphill battle to effectively direct research to this end. There may be a cancer research establishment, an Alzheimer's establishment, even an aging research establishment, and so forth, but there is no longevity research establishment.

People are working on it, in a variety of ways. But, again, there is no longevity research establishment at the present time. No research and development community is aimed squarely and forthrightly at the defeat of aging in the same way as the cancer establishment is dedicated to ending cancer. What an irrational state of affairs this is - doesn't it make you want to step in and help change the world in this one important way?

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Following Up On Catalase and Longevity

I'm sure you recall the experiments demonstrating life extension in mice through boosting the level of catalase in the mitochondria. Here, The Scientist follows up with a few interesting notes in their Hot Paper series: "Replicating the findings has proven difficult. Rabinovitch says that changes in veterinary care have led to euthanasia of mice that develop dermatitis and other ailments at early ages. This practice has confounded the replication of past longevity observations. ... Richard Miller at the University of Michigan, Ann Arbor, offers his opinion: 'If [catalase-boosting mutations] do increase lifespan in mice, the effect may depend in complicated ways on a specific and not well-characterized set of background genes and environmental factors.' ... Rabinovitch says he's about two-thirds of the way through aging studies with two different mouse strains. New data, he says, clarify the protection against age-related cardiac changes and nonhematologic cancers, and they are working on new transgenic models." Stay tuned.

Link: http://www.the-scientist.com/article/home/52893/

Revisiting Fat and Inflammation

Becoming overweight sounds like ever more of a bad idea with each passing year. From EurekAlert!: "the research team decided to analyze the blood that ran through it to determine whether visceral fat was involved in inflammation or whether, like subcutaneous fat, it was merely a marker of potential problems. ... the research team says visceral fat likely contributes to increases in systemic inflammation and insulin resistance. They sampled blood from the portal vein in obese patients undergoing gastric bypass surgery and found that visceral fat in the abdomen was secreting high levels of an important inflammatory molecule called interleukin-6 (IL-6) into portal vein blood. ... Increased IL-6 levels in the portal vein correlated with concentrations of an inflammatory substance called C-reactive protein (CRP) in the body. High CRP levels are related to inflammation, and chronic inflammation is associated with insulin resistance, hypertension, type 2 diabetes and atherosclerosis, among other things. ... These data support the notion that visceral fat produces inflammatory cytokines that contribute to insulin resistance and cardiovascular disease."

Link: http://www.eurekalert.org/pub_releases/2007-03/wuso-bfm031307.php

The Deep Roots of Aging

Why does aging exist? Why don't we live in a world in which higher animals are built to take a best-shot attempt at biological immortality? We know it's not impossible from a purely technical, biological perspective: the existence of children proves that much.

for all that we suffer age-related degeneration - and frailty, pain and death as a result - we produce healthy, youthful children with each new generation. Our cellular biochemistry contains the potential to rejuvenate and repair itself: children are the demonstrable proof that decay and entropy are not inevitable.

The bottom line is that it all comes down to evolution; I've looked at the way in which evolutionary realities tend to rule out immortality in the past:

[A] worthy summary article for the layman can be found at Joao Pedro de Magalhaes' website.

A perhaps more striking, if overly simplistic, explanation for the existence of aging was given by Jaque Cousteau - no immortality because change is the lowest common denominator, and immortality in a species that cannot radically change itself spells extinction. It will ultimately find itself doomed by environmental changes, if not by evolutionary competition.

This doesn't preclude the possibility of an evolving clade of species with the necessary biochemistry for physical immortality; individual animals just won't have the chance to make much use of it. The Ageless Animals website provides an interesting view of outliers in the evolutionary processes that determine aging.

If you wander over to EurekAlert! today, you'll find another viewpoint on the way in which evolutionary mechanisms lead to the rise of aging, starting with the simple organisms right back at the beginning:

Scientists have puzzled over just why organisms evolved aging as a strategy, and now there appears to be an answer. Allowing one individual to carry all the cellular damage inflicted over time, rather than dividing it between two organisms during reproduction, increases the chances that the individual's line will continue to reproduce for many generations to come, a new study indicates.

The earliest organisms, single-celled creatures called prokaryotes, which include bacteria, probably did not age but rather divided damaged material equally among new cells. There was not a parent cell, but rather the original cell divided into two siblings that were, in effect, the same age and shared the damage from the original cell equally.

Somewhere along the way, that strategy changed so that a parent cell retained most of the damage from aging and the offspring started with a mostly clean slate.

...

The implication is that evolution favors individuals aging as a means of allowing their lineage to persist longer.

"A lineage is more likely to survive in the long run if one individual falls on the grenade of its own cellular damage," Bergstrom said.

On it went from there.

We will understand aging in the course of defeating it, but defeat it we will, just as we are working to defeat disease and other forms of damage to the human body. The only question is whether we can engineer the support and understanding to defeat aging within our lifetimes, or not.

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The Key To Muscle Regeneration?

ScienceDaily reports on a new discovery in the biochemical regulation of stem cells: "After injury, even adult muscles can heal very well because they have a reserve supply of muscle stem cells, called satellite cells, which they can utilize for repair. Until now, it was unclear how this supply of satellite and muscle progenitor cells, out of which both muscle cells as well as satellite cells develop, keeps itself 'fresh'. ... a molecular switch, abbreviated RBP-J, regulates this 'fountain of youth'. If the switch is absent, the satellite cells generate muscle cells in an uncontrolled way, resulting in the depletion of the satellite cell reserves." It doesn't look like the researchers have yet conclusively proven that this switch controls the age-related decline in the satellite cell population (and resulting loss of healing capacity), however. The root cause of this decline is likely an evolutionary adaptation to avoid cancer resulting from age-damaged stem cells - so even if manipulation of RBP-J can induce elderly muscles to vigor, you'd better have a good cancer therapy to hand.

Link: http://www.sciencedaily.com/releases/2007/03/070311202116.htm

On Metabolic Rate and Longevity

Joao Pedro de Magalhaes, who maintains the rather excellent senescence.info and associated resources for scientists, has been keeping himself busy with an examination of metabolic rate and life span: "One of the oldest and most popular explanations is the idea that short-lived animals like mice and shrews have high metabolic rates and thus accumulate molecular damage faster than animals with lower metabolic rates, such as elephants. ... The new study, however, disproves this simple, even intuitive explanation by finding no correlation between metabolic rate and longevity using data for several hundred species, the largest dataset ever employed in such an analysis. ... Not only the study disproves the "rate of living" theory, but it also raises doubts regarding another popular theory of aging: the free radical theory of aging, which argues that damage caused by toxic by-products of oxygen metabolism called reactive oxygen species accumulates with time resulting in aging. Because metabolic rates were estimated from oxygen consumption at rest, the study also raises questions of whether damage caused by reactive oxygen species plays a role in differences in longevity between species. ... However, we know that not all things are equal. For example, there could be differences in antioxidant levels that we did not take into consideration."

Link: http://genomics.senescence.info/news/120307.html

Clonal Evolution or Cancer Stem Cells?

Nothing biological is ever as simple as it could be - and it usually isn't as simple as your scientific predecessors hoped it to be either. So here we are again, revisiting skepticism on the whole cancer stem cell issue:

According to a longstanding cancer model, known as "clonal evolution," tumors arise from normal cells that mutate and generate abnormal offspring that also mutate, forming a mass of genetically varied cancer cells. However, there has been a new wave of interest in an alternative explanation - that tumors are initiated and driven by a single, abnormal type of adult stem cell found in, for example, breast tissue, resulting in a population of genetically identical tumor cells. Moreover, several pathways and genes required for normal stem cell function are activated in cancer cells and play essential roles in the development of tumors.

It would be a wonderous development if it turns out that a significant fraction of cancers are driven by errant stem cell populations - because that would mean (a) we are very close to being able to efficiently detect and destroy them, (b) the vast influx of resources into the field of regenerative medicine and stem cell research will also contribute to meaningful cures for cancer.

In effect, this is one aspect of asking just how hard it will be to transform cancer into a managed chronic condition. Easier than we thought if it's all stem cells going bad in clearly identifiable ways ... but that may not the case. Nothing is ever simple in biology, remember? I looked at the skeptical viewpoint on cancer stem cells a little while back, and here is a little more context in terms of present research:

According to the cancer stem cell hypothesis, the few self-renewing stem cells that fuel the cancer are difficult to kill, and their persistence may explain why tumors so often recur following successful therapy. In 2003, scientists purified what they proposed were breast cancer stem cells from patients’ tumors. The distinctive molecule, or marker, on the cells’ surface, known as CD44+, was identical to the marker on normal breast cells. When injected into mice lacking an immune system, the CD44+ cells demonstrated the ability to initiate breast tumors. The scientists also found closely related cells with a CD24+ marker and suggested that they were offspring of CD44+ cells.

The team led by Polyak and Michail Shipitsin, also of Dana-Farber and HMS, used gene activity analysis to clarify the relationship of the two cell types. They generated gene libraries from CD24+ and CD44+ cells purified from normal mammary epithelium and fluids within the chest, and from primary invasive tumor samples collected from breast cancer patients.

The findings, the scientists reported, fit more closely with the clonal model than the cancer stem cell hypothesis. That is, the CD24+ cells were very similar to the CD44+ cells, but not always genetically identical - which they would have been if the CD44+ cells were true stem cells and the CD24+ their offspring.

"Although CD44+ cells appear to express many stem cell markers, the genetic difference between CD24+ and CD44+ cells within a tumor questions the validity of the cancer stem cell hypothesis in breast cancer, and suggests clonal evolution involving intra-tumoral heterogeneity as an alternative explanation," the authors wrote.

However it happens, we must see cancer wrestled into control as a part of living much longer lives through advanced medicine. Easy or hard, that goal must be accomplished - otherwise the only benefit resulting from the defeat of other age-related conditions will be a much greater chance to experience death by cancer.

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Don't Wait For the World To Change

I position I wholeheartedly endorse from Veritas, posting at Betterhumans:

We pour over the newest science and technology magazines. We visit tons of future-oriented sites (or better yet, subscribe to their RSS feeds). We keep an ear to the wind, straining to hear any mention of advances in nanotechnology, AI, VR, renewable energy, healthy life extension research, or the latest hint of a cure for cancer.

But too many of us have been complacent for too long.

"I'm just a student"
"I don't have enough money to make a real difference."
"What can one person do?"

Wrong, wrong, and so damn wrong. There's plenty of stuff you can do.

You futurists in the audience, those looking forward eagerly to a world of advanced technology and medicine capable of defeating ageing, think on this: just who else is most likely to help make that future a reality if not you? Progress does not take place in a vacuum; it requires growing support, both vocal and material, of first tens, then hundreds, then thousands, then millions of people.

If you're not helping to make it happen, then you're not helping - and you have but yourself to blame when the desired future lingers upon the edge of possibility, its benefits denied to you.

It doesn't take much to tip the balance: a single action on the part of thousands can change the world. A few hundreds of people have brought the Methuselah Foundation from nothing to its present position, for example: more than $8.5 million in pledges in support of serious longevity research, and a growing influence on the culture, aims and future of aging research. You too can help accelerate this success higher and onwards, as Veritas advocates:

Donate some loot to the Betterhumans' 300 seat on the Methuselah Foundation's MPrize. The purpose of the group seat was to let people who didn't have tons and tons of money to make a difference and achieve something grand. Funding research for healthy life extension is one of the grandest goals man has ever had. Doesn't take more than a couple of $20s to step up and make a difference. Every bit helps.

Don't stand to one side when you could help bring the future closer - and we can all help in one way or another.

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Groundwork For Stem Cells Versus Neurodegeneration

From EurekAlert!, a taste of the groundwork presently taking place: "To determine whether stem cell biology might play a role in benefiting [neurodegenerative] diseases, the investigators [used] mouse neural stem cells (NSCs), a type of "adult" stem cell, to establish the parameters of what might or might not be achievable in this disease. Then, having demonstrated success with mouse cells, they extended those insights to stem cells of human origin, both human neural stem cells and human embryonic stem cells ... The results [in fact] prove to be the first successful use of human embryonic stem cells in treating a degenerative disease, significantly preserving function and extending life. ... implanted neural stem cells, which migrated and integrated extensively throughout the brain, did much more than replace brain tissue destroyed by the disease. Some of the transplanted cells replaced damaged nerve cells and transmitted nerve impulses, offering the first evidence that stem cell-derived nerve cells may integrate electrically and functionally into a diseased brain. ... [the] treatment also dampened the inflammation that typically occurs in the brains of most degenerative diseases."

Link: http://www.eurekalert.org/pub_releases/2007-03/bi-sca030907.php

Rebooting the Immune System

A release via Medical News Today looks at a drug-based approach to clearing out problems in an aging or otherwise errant immune system: "Revimmune works by temporarily eliminating peripheral immune cells, including the immune cells causing the autoimmunity, while selectively sparing the stem cells in the bone marrow. Investigators at Hopkins discovered that stem cells uniquely have high levels of a particular protective enzyme that can be measured in advance of therapy, which makes them impervious to Revimmune, and allows the surviving stem cells to give rise to the new immune system over 2 to 3 weeks. The newly reconstituted peripheral immune system typically lacks the misdirected immunity to self-antigens, which is characteristic of autoimmune diseases. ... Based on follow-up of up to 2 years, most people have a substantial improvement and many have a complete elimination of disease activity." Would this help with aspects of immune system aging, such as the diminished pool of naive T cells? Or would it cause more harm than good by forcing further, excessive wear and tear on the stem cells responsible for regenerating the immune system? We will no doubt hear more of this class of therapy in the years ahead.

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=64250

Things We Don't Know About Biochemistry

It should be no surprise that vast swathes of uncharted territory remain to be explored regarding the biochemical workings of our bodies - yet many newly discovered items still have the capacity to surprise; the discovery of yet more uncharted territory in locations previously unsuspected of such. Take this, for example:

"Although cells are basic building blocks, their metabolic rates depend on where they find themselves living," said Van M. Savage, Ph.D., the lead author of the research and an instructor in the department of systems biology at Harvard Medical School. "Conceptually this is important because huge amounts of research on human diseases are done on single cells or cultured cells that come from other animals and little is done to place these findings within the context of the size or other whole-body properties of the animals."

...

The question of whether cells are bigger in larger mammals than in smaller ones -- think of an elephant's liver cell compared with a liver cell from a mouse -- is usually answered by saying that larger mammals don't typically have bigger cells, they just have more of them.

Liver cells, red blood cells and other cell types that frequently divide and replace themselves are about the same size, but more permanent, long-lived cells, such as brain and fat cells, are indeed larger in large mammals.

"Fat cells increase in size tremendously if you move from a mouse to an elephant," said James Gillooly, Ph.D., an assistant professor in the zoology department of UF's College of Liberal Arts and Sciences. "Neurons also increase in size. But red blood cells are the same size whether they are in a mouse or an elephant. The reason brain and fat cells grow bigger could be because they live longer and have important long-term functions. In these cases, the properties of the cell are linked to the whole organism. But the sizes of quickly dividing cells are independent of the organism."

...

"Despite the progress that has been made in cell biology, we still have a relatively poor understanding about general characteristics of cells across species," Savage said. "The focus has been on how cells affect the whole organism, not on how the size of the organism and its energy requirements affect the cells."

Size is a fundamental property of a cell; one would think that differences then lead to important differences in function. How then, do we account for this in our many experiments in animal models, as science grows in sophistication and level of attention to detail? Biochemistry is always more complex that we'd like to think it is - if it was simple, we'd be done already with the defeat of disease, aging and all other unpleasant realities resulting from absent knowledge and technology. It is humbling to see gaps in our knowledge still looming large in very basic areas of comparative biology.

This should be all the more reason not to regard rapid progress in medicine as a done deal, and this a world in which we just have to sit back and wait for the results. A great deal of hard work lies ahead in order to understand and control our bodies sufficiently well to avoid the fate of aging, suffering, disease and death that has met all of our ancestors to date. If you want to see that happen in time to help you, then you have to get up out of your seat and contribute.

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The Dangers of Overthinking

Russell Blackford walks us through some of the - to my mind at least - sillier debates in mainstream utilitarian thought on healthy life extension. The punchline: "When we look at what we actually value, there is no need to adopt any paradoxical theory such as the total view. Think of it like this. The future society with life extension technology, as depicted in Singer's scenario, will not contain people whom we should feel sorry for. Nor need it be a society that lacks complexity or creativity, even it is smaller in its space-time population than the alternative society without life extension technology. The people who live in this society will be glad to do so, and glad of the enhanced lives that life extension technology will enable them to have. In short, no important value should lead us to try to avert such a society - all we need to do is abandon total-view utilitarianism, which gives a crude and unhelpful picture of what actually underlies our moral thinking." People, life and individual choice, in other words, not airy and overconstructed principles, and not regulation of the many by the few. Too many have died for a slavish devotion to that in the past few hundred years.

Link: http://metamagician3000.blogspot.com/2007/03/utilitarianism-life-extension-and-total.html

Health in Old Age: We Can Do Better Than This

As WebMD notes, the state of health in the old today is better than it used to be, but pretty horrible from the perspective of the healthy young. "Nearly 80% of Americans aged 65 or older have at least one chronic condition such as heart disease, diabetes, arthritis, or depression -- and half have at least two chronic conditions. ... One in five people aged 65 and older is obese. Nearly one in three (32%) is sedentary (no physical activity in the past month). Only 30% eat at least five fruits and vegetables daily. More than 20% don't have any of their own teeth. 34% are disabled. ... Our main message is really that Americans of all ages can reduce their risk of developing chronic illnesses, as well as preventing disabilities." We can do far better than this - both for ourselves, by taking better care of the health basics throughout life, and for others, by supporting medical research to extend healthy life. Biotechnology and medical science is advancing rapidly, but don't expect to be saved from the consequences of negligence if you let your body go to rust. That way lies greater suffering, illness and an early death.

Link: http://www.webmd.com/healthy-aging/news/20070308/80-percent-older-americans-have-chronic-ills

EIW Audio Podcast on SENS

The latest podcast from Anne C. over at Existence is Wonderful is focused on Aubrey de Grey's Strategies for Engineered Negligible Senescence (SENS): "I like to think of SENS in terms of it being a useful framework to approach aging from an engineering standpoint, as explained in the podcast. It's not a recipe for making people live longer in and of itself, but rather, a good start in terms of viewing age-related health problems as potentially solvable. ... In this episode, I briefly outlined the Seven Deadly Things associated with aging. These Seven Deadly Things are: 1. Cell loss, cell atrophy. 2. Nuclear mutations and epimutations. 3. Mutant mitochondria. 4. Death-resistant cells. 5. Extracellular crosslinks. 6. Extracellular junk. 7. Intracellular junk." As is pointed out, a great many recordings of discussions between scientists on the components of SENS can be found at the SENS website; these are primarily recordings from the IABG10 and SENS2 conferences of recent years. If you want to learn about the technical side of real anti-aging science from researchers who think age-related degeneration can be effectively tackled, then this is a good place to start.

Link: http://rationallongevity.blogspot.com/2007/03/eiw-audio-episode-9-special-sens.html

Regenerative Scaffolds In the Eye

From UCSF Today, a look at yet another group working to apply regenerative medicine to age-related damage in the eye: "experiments intended to restore vision to blind rodents failed when either retinal stem cells or their first-generation descendents, called progenitors, were injected into the eye. The cells were unable to network successfully within the eye and perform their necessary roles, and they eventually died. ... cues tell cells where to go and when to increase their numbers, and help determine the specialization of progeny cells. Scientists do not know what all the cues are, or which ones are lost after early development is complete. The biomimetic scaffolds developed by Tao substitute in part for the guidance provided naturally by these cues during early development. The scaffolds hold stem cells in place and more accurately guide them as they go through the long process of developing into working photoreceptors. ... Cells delivered using Tao's scaffolds have been able to integrate into the mouse's retina and to begin developing into different cell types. The next step is to use Tao's scaffolds to try to restore vision in blind mice. Ultimately, Tao's scaffolds may lead to new treatment strategies to reverse macular degeneration and related eye diseases in humans."

Link: http://pub.ucsf.edu/today/cache/feature/200703083.html

The Evolutionary Argument Against Antioxidants

In the wake of more attention being drawn to the general ineffectiveness of ingested antioxidants as even a marginal tool for health and longevity, Randall Parker remarks in passing:

Biogerontologist Aubrey de Grey makes what to to my mind is a persuasive argument against the expectation that antioxidants will deliver large health benefits: The metabolic cost of making and retaining antioxidants in the body is pretty low. If antioxidants could deliver benefits as large as some of their advocates claim then natural selection would long ago have selected for mutations that boost body antioxidant levels. So why expect consumed antioxidants to deliver a big benefit?

So (I hear you asking) why wouldn't the body make more detoxifying enzymes even in the absence of foods consumed that up-regulate detoxifying enzymes? My guess is that those enzymes are more metabolically expensive to keep around.

Human metabolism certainly isn't the most effective possible from a perspective of longevity, but one would expect that any easily attainable and practical change that benefits health in youth would already have been selected over the generations. On the other side of the coin, simple changes that benefit health in old age and extend longevity do in fact exist, and have not been selected for - for example, mutations to boost the level of naturally occuring antioxidants in the mitochondria:

The catalase soaks up some portion of free radicals before they can attack your vulnerable mitochondrial DNA. Damage to this [DNA] leads to an unfortunate chain of events that causes entire cells to rabidly produce damaging free radicals and export them throughout the body. But stop a fraction of the original mitochondrial free radicals from attacking their birthplace, and you have slowed the rate at which one cause of aging happens - you have slowed down aging, and extended healthy life.

Evolution cares not for your old age - if you're past the point of reproductive fitness, you're on your own. So mutations that might help your longevity, but have little benefit in youth, are unlikely to have prospered and spread in the dark days of cave living, disease, parasites and short, brutish lives.

It seems there is something to be done with antioxidants and advanced biotechnology in combination, given the evidence to date of the effectiveness of targeting to the mitochondria via gene therapy or other clever science. But the salesmen of the "anti-aging" marketplace - those folk energetically waving pills and potions in your face today - are most likely sitting on a pile of junk and nonsense rather than any even marginally effective product.

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Ceramide and Type 2 Diabetes

ScienceDaily look at another step towards controlling age-related diabetes through medical science: researchers have "identified a common link between multiple assaults on the body, including saturated fats, obesity, and certain types of drugs, all of which can lead to insulin resistance. The researchers found that these metabolic stresses lead to an upswing in production of a particular kind of fat molecule, known as ceramide. ... We've found that ceramide has a big effect on insulin resistance. In some animal models, ceramide inhibition led to an almost complete restoration of insulin sensitivity. ... Insulin hormone stimulates the uptake and storage of blood sugar and other nutrients in skeletal muscle and fat tissue while simultaneously blocking the release of blood sugar stored in the liver ... Insulin resistance occurs when a normal dose of the hormone becomes incapable of eliciting those responses. The condition is a characteristic of or risk factor for many metabolic diseases, including diabetes, hypertension, atherosclerosis, and cancer." Exercise and losing the excess fat have demonstrated merits to the same level or better than new therapies - something to remember as you move through life. The health basics pay dividends.

Link: http://www.sciencedaily.com/releases/2007/03/070307075807.htm

What To Make Of This Mitochondrial Research?

From The Scientist, a challenge to the details of the mitochondrial free radical theory of aging: "Point mutations in mitochondrial DNA do not cause signs of aging in mice ... The data, which contradict a prominent theory that mitochondrial mutations drive the aging process, show that mice with mitochondrial mutations 500 times higher than normal levels do not show signs of premature aging. ... mutation frequency in mouse mitochondria is more than 10 times lower than that reported in previous studies, suggesting earlier work overestimated the rate of these mutations. 'The technique we are using is much more sensitive' than previous assays, which had very high background levels ... Since their assay examined point mutations only, it remains possible that large deletions in mitochondrial DNA could still underlie aging." The article contains further caveats on what this all means - we shall see where it all goes as researchers continue to hold up a light to mitochondrial biochemistry and its role in the aging process.

Link: http://www.the-scientist.com/news/home/52925/

The High Level View of Human Calorie Restriction

The abstract of a recent review paper nicely sums up the very high level view of what is known of the practice of calorie restriction in humans. No biochemistry here - just results and conclusions presently backed by science:

CONTEXT: Excessive calorie intake and subsequent obesity increases the risk of developing chronic disease and decreases life expectancy. In rodent models, calorie restriction with adequate nutrient intake decreases the risk of developing chronic disease and extends maximum life span.

OBJECTIVE: To evaluate the physiological and clinical implications of calorie restriction with adequate nutrient intake.

EVIDENCE ACQUISITION: Search of PubMed (1966-December 2006) using terms encompassing various aspects of calorie restriction, dietary restriction, aging, longevity, life span, adiposity, and obesity; hand search of journals that focus on obesity, geriatrics, or aging; and search of reference lists of pertinent research and review articles and books. Reviewed reports (both basic science and clinical) included epidemiologic studies, case-control studies, and randomized controlled trials, with quality of data assessed by taking into account publication in a peer-reviewed journal, number of animals or individuals studied, objectivity of measurements, and techniques used to minimize bias.

EVIDENCE SYNTHESIS: It is not known whether calorie restriction extends maximum life span or life expectancy in lean humans. However, calorie restriction in adult men and women causes many of the same metabolic adaptations that occur in calorie-restricted rodents and monkeys, including decreased metabolic, hormonal, and inflammatory risk factors for diabetes, cardiovascular disease, and possibly cancer. Excessive calorie restriction causes malnutrition and has adverse clinical effects.

CONCLUSIONS: Calorie restriction in adult men and women causes beneficial metabolic, hormonal, and functional changes, but the precise amount of calorie intake or body fat mass associated with optimal health and maximum longevity in humans is not known. In addition, it is possible that even moderate calorie restriction may be harmful in specific patient populations, such as lean persons who have minimal amounts of body fat.

All of this should be just as much common sense on diet and health as avoiding the accumulation of excess fat and exercising regularly.

  • Eat less, but obtain adequate nutrition - calorie restriction is not starvation
  • No-one knows the absolute, optimal, best level of calorie restriction for you - and no-one is likely to find out any time soon
  • But an 80/20, unoptimized practice of calorie restriction that costs little in time and effort and provides additional years of health appears to be a very practical goal
  • Experiment! Find a point that makes you feel healthier and your physician approve of your vital statistics
  • Involve your doctor in any sort of diet change for health reasons; everyone is different, and your doctor is there to help you understand whether you suffer from any medical condition that might put you at risk

The effects on general health in human trials are quite eye-opening, and the effects in long-running primate trials are even more so. If you can practice calorie restriction safely, then you owe it to your future self to look into it.

Take a little time to read through the following resources, set out there on the internet to help you: calorie restriction isn't anywhere near as hard as some folk make it out to be, and the benefits can be great.

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The Right Side

Some thoughts at Ouroboros, following up on a recent article on engineering our biology for longevity: "The reader commentary is worth checking out as well, not because it's particularly informative but because it distills some of the opposition that confront a life-extension-motivated biogerontologists - even those who aren’t committed to making germ-line modifications to the human organism, as most of the arguments here are directed against extending the lifespan, rather than the means by which this extension might be achieved. Among the commenters are the folks who don't see the point in living longer (then don't); those who either profoundly misunderstand evolutionary theory or idolize the concept of species-level evolution as a moral good; the infamous 'think of the children' argument; and - of course - invocations of God, who apparently wants us all to die so that we can join Him and Jebus up in Heaven. If one happens to be a pro-life-extension biogerontologist, their rants provide a refreshing bit of evidence that you're on the right side."

Link: http://ouroboros.wordpress.com/2007/03/07/what-if-humans-were-designed-to-last/

More On Bone Scaffolds and Stem Cells

The sophistication of scaffolds in research for regenerative medicine continues to advance. From the Technology Review: researchers "created a new tissue-engineering material that could help cells survive the harsh transplant environment - a key step in cell-transplant therapies. Scientists are now testing the material in animals to see how well it can help heal fractures. ... Creating instructional biomaterials like this is an entirely new way of thinking about what could be put in the human body. It could become an important component of regenerative medicine ... [scientists] have developed materials called comb scaffolds that have been employed for a variety of tissue-engineering uses, such as growing new blood vessels. The comb consists of a Plexiglas backbone studded with molecular tethers that can hold different protein growth factors at their tips. In their latest round of experiments, the researchers modified the scaffold to hold epidermal growth factor (EGF) molecules, a protein that plays a role in growth and differentiation of many cells, including stem cells. ... adult stem cells grown on the EGF scaffolds were better able to survive. And preliminary evidence suggests that the scaffold also boosts cell proliferation, potentially increasing the number of cells available to make new bone after transplantation."

Link: http://www.technologyreview.com/Biotech/18274/

A Few Interesting Recent Research Publications

Via the science watchers who post to sci.life-extension, I noticed a couple of interesting recent papers.

An anti-aging drug today: from senescence-promoting genes to anti-aging pill

Numerous mutations increase lifespan in diverse organisms from worms to mammals. Most genes that affect longevity encode components of the target of rapamycin (TOR) pathway, thus revealing potential targets for pharmacological intervention. I propose that one target, TOR itself, stands out, simply because its inhibitor (rapamycin) is a non-toxic, well-tolerated drug that is suitable for everyday oral administration. Preclinical and clinical data indicate that rapamycin is a promising drug for age-related diseases and seems to have anti-tumor, bone-sparing and calorie-restriction-mimicking 'side-effects'. I also discuss other potential anti-aging agents (calorie restriction, metformin, resveratrol and sirtuins) and their targets, interference with the TOR pathway and combination with antioxidants.

Calorie restriction mimetics are attracting a great deal of funding these days, which of course means that researchers are picking back through the existing drug library in search of items that might be useful (or, cynically, made fundable) in this context. Chris Patil of Ouroboros is skeptical in this case:

I’m a little surprised that the author is proposing that rapamycin itself be used as an anti-aging drug: it’s an immune suppressant used to prevent transplant rejection, after all, and long-term immune suppression is usually considered one of the downsides of receiving a transplant. Furthermore, there are concerns that rapamycin can impair wound healing - another trait I wouldn’t look for in a chronically administered pharmaceutical.

He suggests that the paper is much more interesting for its discussion of the TOR pathway; how researchers presently think it fits in with the beneficial effects of calorie restriction on healthy longevity. It's a good reminder that sirtuins are not the end of the path insofar as the biochemistry of calorie restriction goes. There is much more yet to come.

Epigenetic control of hematopoietic stem cell aging, the case of Ezh2

During aging the integrity and functioning of a wide variety of tissues is gradually deteriorating, ultimately resulting in a spectrum of diseases, including cancer. We propose that somatic stem cells, which can be found in most adult tissues, play a crucial role in the aging process. We recently described that enforced overexpression of the chromatin modifying Polycomb group gene Ezh2 results in prevention of stem cell exhaustion. This provides a novel insight into the molecular pathways regulating this process, and we hypothesize that chromatin modifications play a key role in maintaining a stem cell-specific transcriptome. It is likely that the identification and functional characterization of genes that affect chromatin modifications in stem cells will provide important information on the molecular mechanisms that regulate cellular aging.

You might recall that recent study on Polycomb genes; I noted at the time that, if we're lucky, the root of all cancer may just look something like this - a matter of stem cell regulation at the epigenetic level, and cancers resulting from nothing more than aging stem cells run amok. But any insight into stem cell regulation across a lifetime also helps us to understand the mechanisms behind the decline in stem cell activity with age; it seems obvious that this decline is an anti-cancer adaptation, but how does it work? If we don't know how it works, it'll be hard to do something about the problem.

It seems too much to hope for that the understanding needed to maintain the regenerative capacity of stem cells with age will be the very same understanding needed to prevent most cancers - but you never know.

Let's finish up with more scientific support for common sense health practices:

Unhealthy lifestyles during the life course: association with physical decline in late life

These data suggest that overweight in old age, and chronic exposure to physical inactivity or overweight throughout life, increases the risk of physical decline in old age. Therefore, physical activity and prevention of excessive weight at all ages should be stimulated, to prevent physical decline in old age.

It's not rocket science; listening what your doctor tells you to do in terms of health basics will make a great deal of difference over a lifetime. Calorie restriction makes even more of a difference on top of that. A golden future of greatly extended longevity, cures for all disease and wonderous technology lies a bare handful of decades ahead. A revolution of accelerating growth in the enabling technologies of medicine is in full swing. Do you really want to throw away the very decades of your life that will enable you to live into the era to come? Take care of the health basics - care today will pay great rewards in the long run.

Technorati tags: aging, health, life extension, medical research

Gene Therapy To Tackle Neurodegeneration

Medical News Today notes continued efforts to employ gene therapy against neurodegenerative conditions like Parkinson's disease (PD): researchers will "test the feasibility of delivering condensed DNA nanoparticles that encode for a neurotrophic factor to the brain as a means to halt or prevent the neurodegenerative process in an animal model of PD. Neurotrophic factors are capable of protecting neurons from dying, thereby rescuing essential neurons in the brain. In animal studies, neurotrophic factors have revived dormant brain cells, caused them to produce dopamine, and prompted dramatic improvement of symptoms. ... said this relatively new gene therapy strategy holds potential to help repair faulty genes. It entails transduction, a technique for expressing a particular gene in a cell by delivering DNA into the cell and making the cell synthesize the protein that corresponds to that DNA. ... We plan to use this technology to transduce brain cells so that they express proteins beneficial to the cell's survival."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=64348

Building a Better Antioxidant

Nanowerk looks at efforts in materials science to produce a better antioxidant and thereby increase longevity: "Can a major component of a catalytic converter or a fullerene derivative lead to an eventual treatment for Parkinson's disease or arthritis? ... Oxidative stress is believed to play a role in neurodegenerative diseases such as Alzheimer's and Parkinson's. Some of the symptoms of aging such as arteriosclerosis are also attributed to free-radical induced oxidation of many of the chemicals making up the body. Despite the broad role that oxidative stress plays in human disease, medicine has been limited in its development of treatments that counteract free radical damage and the ensuing burden of oxidative stress. In contrast, in the field of engineering, considerable effort has been developed to counter the effects of oxidative stress at the materials science level. ... Our initial results suggest that cerium oxide nanoparticles extend cell and organism longevity through their actions as regenerative free radical scavengers. Additional studies suggest that these nanoparticles are also potent anti-inflammatory agents. Although much work remains to be done in this realm, ceria nanoparticles hold high promise for future development of nanopharmacological agents to treat age related neurodegenerative disorders and inflammatory disorders."

Link: http://www.nanowerk.com/spotlight/spotid=1570.php

On Engineering Longevity

They're talking about engineering longevity in the present issue of The Scientist. It is promising to see more talk of such in the scientific community, even if it is more the Longevity Dividend and not at all SENS. More discussion means growing support for extending the healthy human lifespan.

George Bernard Shaw commented on how ridiculous it is that just as we are reaching the age at which we begin to acquire some wisdom, our faculties start to deteriorate and our bodies let us down. So, when we should be applying our hard-won experience to solving the problems of human conflict, overpopulation, and the degradation of our planet, we spend a disproportionate amount of our remaining lifespan worrying about our failing health and memory.

How different our lives could be if we lived twice as long and retained full possession of our health and senses, and no one would have to retire unless they wished to.

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So, all we need do is hurry up and solve the medical problems of aging - the sooner the better for all of us.

Michael Anissimov catches a few interesting quotes while commenting on the same subject:

Is living forever a lost cause? No. Biological tissue works according to the same physical principles as any machine, and is subject to analysis and fine-grained repair just like any other system. Some people view radical life extension as impossible because to equate the human body with a repairable machine is seen as blasphemy.

In related news, one of the most popular economist bloggers on the net, Arnold Kling, writes:

"I tell my high school students now that I think there is a good chance that they will be immortal."

James D. Miller, an associate professor of economics at Smith College, also writes:

"I have told my college students the same thing, and will even be discussing this possibility in my upcoming intro micro textbook.

Obviously, immortality would change the world beyond measure. But long before we achieve immortality people will realize that immortality will someday be within our grasp. This expectation alone will radically alter human society."

It's only human nature to lose sight of the trends in technological progress that will take us from the world we recognize today to the radically different and improved future of 20, 40 and 60 years hence. It's easy to take for granted the amazing technology of today, and forget just how different it was to live 20 years ago.

The biotechnology revolution is taking us into a whole new world of control over our own bodies, our biochemistry and its failings. Help yourself and help others to live to see that world - the rewards will be great for all of us.

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Examining Unfortunate Attitudes

Via Spiked, a look at attitudes towards aging and medical progress: "the future is one of transformation and adaptation, not extrapolation. This is the statistical distinction between 'projections' and 'forecasts', which invariably get mixed up in everyday discussion. This confusion is a boon to those who make fearful speculations about the future. ... more research can accelerate building upon the existing indications of scientific and medical progress in this area. But this gets a little lost in the hyperbole. ... The general trend is that in most countries a symptom of living longer healthier lives is that the age of onset of particular illnesses is postponed. The average 65-year-old today is much healthier than one in 1950 due to a combination of improvements in living standards and medical progress; healthy life expectancy is growing with increases in overall life expectancy. The only uncertainties are the pace of improvements in healthy life expectancy and total life expectancy - and the relation between them. ... All this pessimism about the human success story of people living longer older tells us more about society's collective sense of uncertainty and anxieties about where we are heading, than it does about a rational understanding of any of these age-related issues."

Link: http://www.spiked-online.com/index.php?/site/article/2915/

Calorie Restriction, Longevity and Mitochondria

Another round of calorie restriction research from PLoS Medicine: "Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals [and] delays the onset of age-related chronic diseases such as heart disease and stroke. There are also hints that people who eat a calorie-restricted diet might live longer than those who overeat. ... But how might caloric restriction slow aging? A major factor in the age-related decline of bodily functions is the accumulation of 'oxidative damage' in the body's proteins, fats, and DNA. Oxidants - in particular, chemicals called 'free radicals' - are produced when food is converted to energy by cellular structures called mitochondria. One theory for how caloric restriction slows aging is that it lowers free-radical production by inducing the formation of efficient mitochondria. ... The observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults."

Link: http://dx.doi.org/10.1371/journal.pmed.0040076

The Long-Term View: Talking to the Younger Folk

Advocates and scientists supportive of healthy life extension research, like the nanotechnologists, are looking ahead to a timeline of development that spans decades, the time between now and the first meaningful waypoints on the road to defeating age-related frailty, suffering and death. Given the length of planning, just how important is it to direct some efforts towards talking to the younger folk - those who may be embarking upon scientific careers in the late 2010s and early 2020s, or themselves decide, as did I, that advocacy and support is vital?

WIth that in mind, I note that Shannon Vyff recently asked me, a couple of times, to point out her new children's book. Vyff and her family generously support the present Methuselah Foundation initiatives, so I see no issue with a little extra pro quo. Take a look and see what you think:

The main characters in the story are a brother and sister, Avryn and Avianna, who are ‘killed’ in a car accident in the year 2008. But their bodies and minds have been preserved through cryonics and they are ‘re-animated’ in the year 2189. And WOW - has the world changed during the nearly 200 years that they were in preservation.

They discover that while they were ‘resting,’ ideas that were the subject of great debate in their day have now become reality. Humans no longer age, they can be re-animated if they were cryonically preserved and thanks to nanotechnology, the human body can repair itself.

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21st Century Kids also explores the controversial subject of cryonics, or the frozen preservation of a person’s body after legal death occurs, in a positive way. The characters all share their viewpoints on cryonics and the impact it could have on families and the world in general.

Interestingly, this isn't the only fiction aimed at younger folk in which cryonics features prominently; I seem to recall that Anne C. found such a book in the teen literature section.

The book's overall tone is one that assumes that being alive is inherently good, and that freezing -- er, vitrifying -- people is a compassionate and proper thing to do in the event of fatal illness. ... It is more than refreshing to read a book, albeit one aimed at teen girls, that not only presents life extension technology in a positive light, but that is completely devoid of annoying, moralizing messages about how death is somehow 'natural'and that cryonics is some kind of abomination.

I rather hope that the new young adults of the 2020s look back and wonder what the big deal was with all the advocacy and persusion. Why were people running around trying to convice the world that extending healthy life span is a good thing, and that cryonics is a responsible attempt to save as many people as possible. Isn't it obvious? Aren't a raft of scientists working on it? Why all the fuss? The mark of success in a hard-fought endeavor is the utter failure of the next generation to understand why you had to expend all that effort - to them, it is normal and unremarkable to work towards longer, healthier lives.

We can hope, in any case, and work hard to make it so.

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Exploring the Biochemistry of Klotho

I'm sure you recall news and discussion - back in late 2005 - of the effects of the klotho gene on longevity in mice: "Those mice proved to have life spans 20 percent or more longer than mice with the ordinary version of the gene ... The upper bound of life span extension in the study was 30% or so, in the same ballpark as the results of calorie restriction." Scientists are presently working on following the biochemical paths to understand how it works: "Klotho gene mutation leads to a syndrome strangely resembling chronic kidney disease patients undergoing dialysis with multiple accelerated age-related disorders ... Conversely, mice overexpressing klotho show an extended existence and a slow aging process through a mechanism that may involve the induction of a state of insulin and oxidant stress resistance. Two molecules are produced by the klotho gene, a membrane bound form and a circulating form. However, their precise biological roles and molecular functions have been only partly deciphered."

Link: http://www.ncbi.nlm.nih.gov/pubmed/17332731

CALERIE Calorie Restriction Study Recruiting

2theadvocate.com notes that the CALERIE study of calorie restriction in humans is once more looking for volunteers: "Scientists at the Pennington Biomedical Research Center are looking for volunteers to figure out how cutting calories daily by 25 percent helps people live longer and healthier lives. A team led by Eric Ravussin recently found that cutting calories in an otherwise nutritious diet causes a slowdown of the aging process. Participants were also healthier, but Ravussin doesn't yet know what caused it. ... All participants in the calorie restriction study ate less and exercised more, so they also lost weight. We're not sure if their bodies reacted biologically to the decrease in calories or to the weight loss. That's what we're trying to learn now, but we need help. ... the clinical study requires participants to enroll in a 26-month trial. Pennington is looking for lean or slightly overweight volunteers who will eat either a restricted calorie diet or a normal diet. Both groups will also visit the center for a sophisticated series of tests to determine health status, metabolic rate, DNA damage and other measures." Find out how to enroll at the CALERIE website.

Link: http://www.2theadvocate.com/news/business/6083936.html

The Unthought Conservatism of the Deathists

You might recall Sherwin Nuland as the author of a pro-death piece on the work and aims of biomedical gerontologist Aubrey de Grey published - to much furor from the healthy life extension community - two years ago. Nuland stands in much the same camp as another noted deathist, Leon Kass - both labor under the singularly strange viewpoint that the present length of human life is just as it should be, and we should do nothing much to change it.

A chapter of "The Art of Aging" is given over to a [biogerontologist] named Aubrey de Grey, who believes that, through manipulations at the cellular and molecular levels, death itself can before too long be all but eliminated. In measured prose, Nuland states his own belief that eternal life is a bad idea. "For reasons that are pragmatic, scientific, demographic, economic, political, social, emotional and secularly spiritual," he writes, "I am committed to the notion that both individual fulfillment and the ecological balance of life on this planet are best served by dying when our inherent biology decrees that we do." Not nice, in other words, to fool with Mother Nature.

I would hope that I don't have to work too hard to point out just how nonsensical this position is. Let us start by asking whether a Nuland transposed to 1900 would argue the same point, back when life expectancy at birth was 40-something years and all older people suffered far more than they do today. Think about that a moment: in an upward trend over centuries, there have always been those who stood astride the engine of progress and said "enough - it's fine just here, danger lies ahead." The opponents of progress always been wrong to do so, and they're just as wrong today.

Our present length of healthy life and life expectancies at various ages are already highly unnatural; clearly Nuland does not advocate a return to a primitive era of no medical intervention and short lives of suffering, yet there is no such thing as "dying when our inherent biology decrees that we do" today. To support such a thing is senseless. From cradle to old age, modern medical technology increases our health and our odds in the life expectancy game - and those odds continue to improve.

As for Kass, I see this viewpoint as an unthought conservatism (in the sadly fading, non-political sense of the word) - the knee jerks in response to change, and the knee's owner thereby justifies the present state of being as the best possible. The gut drives the brain. But you don't have to look far afield at all to see that such a position is utter nonsense, the "justifications" all smoke and mirrors. Worse, it is a veil, an excuse of the flimsiest sort, for failing to work to prevent billions of unnecessary deaths from age-related disease in the decades ahead.

As we see in the world about us and our long human history, there is no position simultaneously so vile and nonsensical that it fails to attract defenders and advocates to paper over the horrors of the basic premise with serious-sounding words and scholarly writing. In the article I link to above, it's clear that the journalist buys into Nuland's view, for example, and more is the pity thereby.

Remember this: there are many people in the world who want you and everyone you know to suffer and die on their schedule, far sooner than you might. There are people in the world who would suppress all medical research for increased longevity - exactly the sort of research that has increased the healthy life expectancy of the old over the fifty years, and will accelerate this trend going forward. If everyday folk like you and I go along with these deathists in silence, if we do not loudly point the nature of the Emperor's clothes, then we will get what we deserve - suffering and death for failing to stand up for ourselves, failing to support longevity research, and failing to build a better future for all.

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What Do We Know About Stem Cells, and What Can We Do With Them?

Loss of needed cells is one cause of age-related degeneration; this comes in many flavors, however, ranging from the loss of dopamine cells in the brain that leads to Parkinson's disease to the loss of muscle mass called sarcopenia. It is unclear in many specific cases whether - and to what degree - this loss is secondary to other biochemical damage that accumulates with age. Still, it seems obvious that stem cell research, and the regenerative medicine derived from new knowlege, will play an important role in addressing some forms of detrimental change involved in aging - and the suffering and death that follows.

There are most likely limits to what can be done to lengthen our lives if we focus on stem cells and regenerative medicine alone for the next couple of decades: you might take a look back at a couple of recent posts on that topic:

After that, it's all an open road ahead. It's hard to speak cogently of what will be possible in 2040, for example - computers vastly more powerful, biotechnology vastly more capable, a molecular manufacturing technology base at some stage of development, medical nanorobots out in force, and so on. Cancer will be ancient history in much of the world, alongside heart disease; how far along will we have come to extending healthy life spans or eliminating neurodegenerative disorders by that time? It'll be well worth doing your best to ensure you are around to see it!

Back to the present day, however, and researchers are still taking the first steps with the new tools of the biotechnology revolution in this first decade of the 21st century. Stem cell research, like cancer research, demonstrates what can be accomplished when the will and funding are present. A recent conference overview from the New York Academy of Sciences gives a feel for where the field of stem cell research stands today, in comparison to the golden future of healing that lies ahead:

The recurring theme of the day-long conference was, exactly what do we know about stem cells, and what can we do with them? Scientists from around the world discussed the most recent findings in the most promising research areas: somatic cell nuclear transfer (SCNT), diabetes, heart disease, cancer, and neurology.

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Scientists working with human cells are interested in using SCNT both as a reproductive technology and as a way of producing stem cell lines, which they hope to use to replace a variety of tissues that don't regenerate on their own.
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Yet all stem cell researchers face the problem that the path from totipotent stem cell to fully differentiated cell is not clear. Some scientists are tracing the lineage of cells using fluorescent markers while others are looking for genes and growth factors that are required to commit a cell to a specific developmental pathway.
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Neuroscientists face the same challenges as other researchers trying to replace fully differentiated nonregenerating cell types. Thus, they are also studying basic stem cell biology, cell lineages, and factors required to stimulate differentiation to the appropriate cell fate. Once these difficulties are surmounted, scientists may be faced with the extraordinary complexity of restoring appropriate connections in the brain and spinal cord.

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Stem cell biologists are attempting to recapitulate development from beginning to end, and this is no easy feat. But the enormous benefits that will be reaped upon success ensure that the endeavor will not be abandoned any time soon.

A great deal of work is yet to be accomplished - yet another illustration of the importance of materially supporting medical research as an investment in your future health and longevity. Why stand to one side and wait when the job might not be done in time to help you?

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Reworking Humans For Longevity

An article at The Scientist is illustrative of the focus of that portion of the gerontology mainstream presently supporting healthy life extension: work to change human metabolism so as to slow the rate of degeneration. "In the absence of planned form and designed function, what we have is a living machine that appears well thought out, but which fails when operated beyond its biological warranty period. ... Anyone who understands how time takes its toll on the body and mind, however, will recognize that designing a human body built to last requires far more substantive changes than meddling with simple anatomy. So we've asked our experts to fiddle with physiology and tinker with the inner mechanics of life at its most basic biologic level. Although it is inevitable, for now, that all systems in the body experience some level of functional decline with the passage of time, not all components of the body degrade at the same rate. Furthermore, some structures are more vulnerable than others." And herein lies the problem - reengineering metabolism is an inefficient and difficult path in comparison to working to repair the damage of aging.

Link: http://www.the-scientist.com/2007/3/1/28/1/

The Science of Cryonics

FirstScience looks at the present science behind cryonics: "cryonically preserving a body, or a brain, after death doesn't actually involve freezing - at least not anymore. The problem with freezing is that the structure and growth of ice crystals in cells is very damaging - anyone who has eaten dried-out food damaged by freezer burn has direct experience with the destructive effects of ice crystals. To avoid ice formation, cryonics has been moving towards a process called vitrification. To vitrify a body, a machine replaces blood with a solution containing a high concentration of chemicals called cryoprotectants that chill the body while preventing ice formation. ... The water molecules don't have time to form the rigid crystalline structure of ice, but instead maintain a fairly random arrangement that is referred to as a glass-like state. After vitrification, cryonics labs suspend people in liquid nitrogen at temperatures below -180 degrees C." Debates of the merits of the science usually devolve to "we can't restore cryopreserved people now," which rather misses the point. Our knowledge of physics and biochemistry show no roadblocks to the development of a future technology capable of restoring cryopreserved people - and they have all the time in the world to wait.

Link: http://www.firstscience.com/home/articles/humans/suspending-life-the-science-of-cryonics_14148.html

A Thought For the Day

Picking out the high notes from writer David Ewing Duncan at the MIT Technology Review: "You and I and our children may soon be living in a world where damaged hearts and shattered spines are routinely regenerated, or spare ones are regrown using stem cells; where a human egg containing a person's DNA can be engineered by adding and subtracting genes; where genetic fixes or perhaps a pill can be popped that extends lifespan, and keeps one young, fit and lean up to age 150, or longer. ... I believe this is the greatest story of our time, perhaps of all time. A species is developing the tools to redesign itself, to self-evolve in a way Charles Darwin never imagined." I can't say I agree with his message on the risks of progress, however. The greatest risk we face is the certain suffering, degeneration and death of billions should we fail to engineer greater and more rapid progress in the biotechnologies of longevity. What could be worse than everyone you know suffering and dying? Yet that is exactly what will happen if we don't get our act together.

Link: http://www.technologyreview.com/blog/duncan/17542/

Whose Life Is It Anyway?

Reason Online reminds us that government regulators of medical research and development are not our allies - their incentives are quite opposed to ours in the matter of health, responsibility and access to new medical technology. "Self defense is the most obvious and self-evident rights of men. No state can deny someone self-defense in the face of an attack. ... if the law recognizes that people have the right to defend themselves from attack by a bear or infectious bacteria, then surely they have the right to defend themselves against a rogue cancer cell. ... a patient who has exhausted standard treatments for some kind of severe disability, say, Parkinsonism, macular degeneration, or dementia, could argue that they have a right to access potentially better drugs that the FDA has not yet approved. ... Thousands died waiting for the FDA bureaucracy to let cancer drugs that would have lengthened and perhaps even saved their lives onto the market. Perhaps finding that mentally competent terminal cancer patients do have a fundamental right to access investigational drugs will finally spur the FDA to stop clinging to an outdated mid-20th century cancer clinical trial system and embrace one more suited to the 21st century science."

Link: http://reason.com/news/show/118930.html

More on How Medical Science Works In Practice

A few days back, I suggested that everyone with an interest in increasing human longevity would do well to become more familiar with the way science works in practice. How else to determine the importance of what you read in the popular press? Scientists are human like the rest of us, which means mistakes, poor first tries, overattachment to ideas, institutional bias and other human failings are mixed in with the long record of triumphs and progress produced by the scientific community - people acting in accordance with the scientific method.

A while back, an examination of just how much research turns out to be wrong caused something of a stir amongst the public at large - no new news to those involved in science, of course, but many people treat the distinct findings of individual scientists and single teams with a touch too much reverence.

I could - and should - have added that most of what was written on these topics would turn out to be wrong. It might contain useful ideas, or prompt other people into useful directions, but it will be wrong. This is taken for granted by scientists; after all, the scientific method and the community that supports it form a system that makes useful, rapid, solid progress even though the individual components of that progress are largely flawed. Science is built by consensus and aggregation, a form of ongoing, distributed cross-checking of information. Every single collection of data could be 99% wrong, but you'll still get the right answer in the end if you have enough of those collections to compare.

The nature of the ongoing search for truth - or something close enough to be useful in the production of new technology - encourages me to me a late adopter, and wait a decade or so where I can for the engine of science to clarify each new result. It only makes sense not to rush in at the cutting edge.

The scientific method and the community of science that surrounds it is truly a powerful machine - able to take the worst aspects of human nature, sailing atop a river of garbage specked with half-wrong answers, and spin that mix into the gold of technology. It doesn't matter what your right to wrong to nonsense ratio is when it comes to deciphering the world; so long as you have the will to progress and your sifting mechanism is good enough, accumulating a whole pile of right is just a matter of time.

The front line of science is a messy place; a mostly wrong messy place, as any of us who have spent time there know. A recent study claimed massive error rates across all scientific papers - which is not a surprise to scientists. The closer to the edge of knowledge you come, the more wrong you'll find - a great frothing sea of wrong, enthusiastically generated by scientists in search of nuggets of right. It's all part of the process, and you have to step back from the details in order to see where the process is taking you. In any complex field, and biotechnology and medicine are about as complex is it gets outside astrophysics, validating truth takes time. Scratch any unanswered question and it'll bleed papers and reviews, a dozen for any given position on the topic.

Following up on the nature and character of wrong results, you'll find another paper well worth reading at PLoS Medicine. If you like to keep track of medical research, or are looking for specific answers in any field of new medicine, this should be required reading. It's one thing to see widely varied, changing, condradictory information presented by reputable researchers - but it's quite another to be able to put this in context, as a part of an ongoing and very human process, and therefore understand the likely weight behind each position.

In a recent article in PLoS Medicine, John Ioannidis quantified the theoretical basis for lack of replication by deriving the positive predictive value (PPV) of the truth of a research finding on the basis of a combination of factors. He showed elegantly that most claimed research findings are false. One of his findings was that the more scientific teams involved in studying the subject, the less likely the research findings from individual studies are to be true. The rapid early succession of contradictory conclusions is called the “Proteus phenomenon”. For several independent studies of equal power, Ioannidis showed that the probability of a research finding being true when one or more studies find statistically significant results declines with increasing number of studies.

As part of the scientific enterprise, we know that replication - the performance of another study statistically confirming the same hypothesis - is the cornerstone of science and replication of findings is very important before any causal inference can be drawn. While the importance of replication is also acknowledged by Ioannidis, he does not show how PPVs of research findings increase when more studies have statistically significant results. In this essay, we demonstrate the value of replication by extending Ioannidis' analyses to calculation of the PPV when multiple studies show statistically significant results.

Here are the underpinnings of the common sense approach to scientific research - listen when many teams agree with their findings, and expect widespread disagreement and contradictory findings in any young, but well-funded or popular field. Those of us following stem cell research these past few years have certainly seen a great deal of that, for example.

To finish up on this topic for today, here is another paper worth reading on the nature of truth and results in clinical trials, or the translation of research into action:

The credibility and replication of research findings evolve over time, as data accumulate. However, translation of postulated research promises to real-life biomedical applications is uncommon. In some fields of research, we may observe diminishing effects for the strength of research findings and rapid alternations of exaggerated claims and extreme contradictions - the “Proteus Phenomenon.” While these phenomena are probably more prominent in the basic sciences, similar manifestations have been documented even in clinical trials and they may undermine the credibility of clinical research. Significance-chasing bias may be in part responsible, but the greatest threat may come from the poor relevance and scientific rationale and thus low pre-study odds of success of research efforts. Given that we currently have too many research findings, often with low credibility, replication and rigorous evaluation become as important as or even more important than discovery. Credibility, replication, and translation are all desirable properties of research findings, but are only modestly correlated. In this essay, I discuss some of the evidence (or lack thereof) for the process of evolution and translation of research findings, with emphasis on the biomedical sciences.

All science is a process, not a printed statement of fact. The results are amazing and accelerating - if all too often taking for granted - when you consider the fallible nature of humanity. It goes to show that the scientific method is the only game in town when it comes to reliably providing the raw materials needed to advance and improve the state of being human.

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"What Have the Scientists Ever Done For Us?"

A reminder, from the Times, that it's often a hurdle even to obtain an acknowledgement of the value of medical science, let alone help to advance the cause of longevity research: "A recent [poll] found that less than half of people surveyed disagreed with the statement that 'the risks of science outweigh the benefits'. This is rather as if less than half of bodies believed that, on balance, the circulation of blood was a good thing. But this dismal statistic is perhaps not as surprising as it should be; for it is increasingly fashionable to assert that science is in trouble and that its troubles spell trouble for the human race. Scientific expertise and science itself are regarded with suspicion, while nonsense about science and nonsense passing itself off as science are given an easy ride. ... The figures on life expectancy are worth dwelling on: between the years 1800 and 2000, the worldwide average increased from less than 30 years to just under 67 years. ... None of this may cut much ice. Part of the problem is that the scientific basis of our current lengthened life and comfort span, and the huge enrichment of our lives, is rendered invisible through ubiquity."

Link: http://www.timesonline.co.uk/tol/comment/columnists/guest_contributors/article1449416.ece

RNA In Aging Research

Via EurekAlert and the Ellison Medical Foundation, a look at one small slice of the aging research community: "We found that genes that regulate the timing of events during C. elegans development also regulate timing of aging and death during adulthood ... Consistent with the lifespan analysis, mutants he studied were stress-sensitive and aged prematurely. Since some of these genes coded for small non-coding RNAs called microRNAs, his work provided some of the best evidence for a novel role for microRNAs in aging, and opened the potential of using microRNAs to regulate human health during aging. ... Our work has revealed unexpected connections between RNA misfolding, radiation damage repair and autoimmune disease. ... Damaged RNAs have often been detected in the brains of aging animals and patients with neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, because the cellular pathways for recognizing and degrading these RNAs are unknown, it has not been possible to determine whether RNA damage contributes to aging or to age-related diseases. ... Knowing how RNA damage contributes to aging or to neurodegeneration could be of broad importance for designing therapeutics that slow the aging process."

Link: http://www.eurekalert.org/pub_releases/2007-02/yu-yrn022807.php

Clever Medical Engineering

The road to the future of medicine is being paved by clever engineers - the folk who use new tools and knowledge to build impressive new technologies. As the capabilities of biotechnology advance, so too does the quality of the engineering; it'll really take off once the cost drops to the point at which the talented amateurs join the party. There's no such thing as too many cooks when it comes to progress.

A couple of good examples of clever medical engineering caught my eye today, starting with another piece on developments contributing towards the future development of artificial eyes - to go alongside the few noted at the Longevity Meme in past weeks.

Development Could Lead To Creation Of An Artificial Retina

The process starts with a glass plate and then builds a layer-by-layer sandwich of two kinds of ultra-thin films, one made of mercury-tellurium nanoparticles and another of a positively charged polymer called PDDA. The scientists then added a layer of ordinary clay and a cell-friendly coating of amino acid, and placed cultured neurons on the very top.

When light shines on them, the mercury-tellurium nanoparticle film layers produce electrons, which then move up into the PDDA film layers and produce an upward-moving electrical current. "As you build up the layers of this, you get better capabilities to absorb photons and generate voltage," said UTMB research scientist Todd Pappas, lead author on the Nano Letters paper. "When the current reaches the neuron membrane, it depolarizes the cell to the point where it fires, and you get a signal in the nerve."

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The researchers caution that despite the great potential of a light-sensitive nanoparticle-neuron interface, creating an actual implantable artificial retina is a long-range project. But they're equally hopeful about a variety of other, less complex applications made possible by a tiny, versatile light-activated interface with nerve cells - such things as new ways to connect with artificial limbs and other prostheses, and revolutionary new tools for imaging, diagnosis and therapy.

This second release is illustrative of a range of inventive work that is taking place in the cancer research community these days.

Researchers Wake Up Viruses Inside Tumors To Image And Then Destroy Cancers

Researchers have found a way to activate Epstein-Barr viruses inside tumors as a way to identify patients whose infection can then be manipulated to destroy their tumors.

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A variety of blood and solid cancers are more likely to occur in people who have been infected with the Epstein-Barr virus (EBV), but not everyone with these cancers has such infections. For those who do, researchers, such as Hopkins oncologist and co-author Richard F. Ambinder, M.D., Ph.D., have been working on ways to activate the reproductive, or "lytic" cycle, within the virus to make it replicate within the tumor cell. When enough viral particles are produced, the tumor will burst, releasing the virus. In animal experiments, this experimental therapy, called lytic induction therapy, results in tumor death.

Other groups are achieving similar results with other viruses - everything in biochemistry can be a tool for medicine when viewed by the right set of eyes.

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