$36,000
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The Immune Response Connection to Alzheimer's Disease

A number of interesting new directions in Alzheimer's research have been emerging over the past few years. There's the choroid plexus connection, and the possibility of repairing the normal mechanisms of amyloid removal, for one. It turns out that amyloid creation and removal are actually very rapid, dynamic processes, and the buildup towards Alzheimer's is a slowly growing imbalance between ongoing creation and removal. Also, the realization that Alzheimer's looks an awful lot like type 2 diabetes at a biochemical level, with all the same lifestyle risk factors relating to exercise, eating and visceral fat. Lastly for this list, there is some form of biochemical connection between Alzheimer's and the inflammatory immune response.

Chronic inflammation crops up everywhere you look in the pathology of aging, and as a risk factor for all the common age-related diseases. More chronic inflammation isn't a good thing, but an age-damaged immune system will give you more of it whether you want it or not. Excess visceral fat will add even more inflammation on top of that.

The latest Alzheimer's science to catch my eye springs from research into inflammation and amyloid plaques, but turns up a result that looks a lot like immune therapy:

Earlier studies had shown that Alzheimer's patients tend to have elevated amounts of TGF-β, which plays a key role in activating immune system response to injury. Some had thought the presence of the molecule was simply an attempt to quiet the inflammatory response caused by a buildup of plaque.

Instead, the team found that as much as 90 percent of the plaques were eliminated from the brains of mice genetically engineered to block TGF-β in the peripheral immune cells.

...

Amyloid plaques are thought to damage brain nerve cells (neurons) and stimulate a response in nearby inflammatory cells called microglia. Theoretically, Alzheimer's might be treated by somehow preventing or removing the plaque buildup and calming the inflammation.

...

When TGF-β was blocked, the immune system seemed to unleash immune cells known as peripheral macrophages. The macrophages passed through the blood-brain barrier and surrounded the neurons and plaques in the brains of mice. "If results from our study in mice engineered to develop Alzheimer's-like dementia are supported by studies in humans, we may be able to develop a drug that could be introduced into the bloodstream to cause peripheral immune cells to target the amyloid plaques."

This wasn't the result researchers were expecting when they engineered these mice. So much of progress comes about through unintentional discoveries in the course of sensible exploration.

We Have Artificial Viruses Now, Also

Researchers can build artificial cell components, and are well on the way to artificial cells, so why not artificial viruses as well? "Natural viruses are extremely effective at transporting genes into cells for gene therapy; their disadvantage is that they can initiate an immune response or cause cancer. Artificial viruses do not have these side effects, but are not especially effective because their size and shape are very difficult to control - but crucial to their effectiveness. A research team [has] now developed a new strategy that allows the artificial viruses to maintain a defined form and size. ... Glucose building blocks on the surfaces of the artificial viruses should improve binding of the artificial virus to the glucose transporters on the surfaces of the target cells. These transporters are present in nearly all mammalian cells. Tumor cells have an especially large number of these transporters. Trials with a line of human cancer cells demonstrated that the artificial viruses very effectively transport an siRNA and block the target gene. ... researchers were able to attach hydrophobic (water repellant) molecules - for demonstration purposes a dye - to the artificial viruses. The dye was transported into the nuclei of tumor cells." A nice technology demonstration, and the wave of the future in making gene therapy more effective, no doubt: we can take from the mechanisms we find in nature, and then improve on them.

Link: http://www3.interscience.wiley.com/journal/26737/home/press/200820press.html

Why Is Cryonics So Unpopular?

People are clearly interested in cheating death. Why, then, do they chase all sorts of magical thinking and pseudoscience rather than one of the few methods that should actually work? From Depressed Metabolism: "In his 1998 essay 'The Failure of the Cryonics Movement' (part 1, part 2), Saul Kent stresses that cryonics has remained so unpopular because nobody thinks it will work. ... The view that acceptance of cryonics is being held back by the perception that it is not technically feasible is hard to reconcile with the observation that increased technical progress in cryonics does not translate into rapid membership growth. It is also hard to reconcile with the fact that millions of people hold on to views that cannot be falsified with any scientific method whatsoever. Perhaps there is a scientific tipping point beyond which people will sign up in droves for cryonics. For example, some cryonics activists argue that demonstration of reversible vitrification of a small animal will have such an effect. This may or may not be the case, but it still leaves the puzzle unresolved as to why cryonics organizations were not swamped with membership requests after publishing electron micrographs that demonstrated excellent ultrastructural preservation of brain tissue after vitrification."

Link: http://www.depressedmetabolism.com/2008/05/29/why-is-cryonics-so-unpopular/

The Million Year Lifespan

Aschwin de Wolf continues to republish important writing from the early days of the modern healthy life extension community at Depressed Metabolism. Those were the years of the late 1960s, in which the seeds were laid for the cryonics community on the one hand and pro-longevity supplement and "anti-aging" groups on the other. There's really a deep divide between the two factions in terms of fundamental philosophy: on the one hand aiming a few more years (or decades, as they overoptimistically thought at the time) of healthy life via applied pharmacology, on the other the engineer's path to defeating death completely. Quite different worlds of ambition - and as it turned out, rationality. The cryonicists, with visions of immortality in their sights, were far more correct about the bounds of the possible, given scientific knowledge at the time.

Once vitrified and stored at low temperature, a cryopreserved individual has time and the astounding curve of scientific progress on his side. The laws of physics and our present understanding of brain biochemistry place no obstacles in the path of restoring cryopreserved people - it's a matter of developing the necessary medical technology, and remaining well-stored until that time comes to pass.

Now "immortality" is a much abused term, cast widely and with many colloquial meanings. Linguistic drift has come to put it somewhere between "long-lived" and "ageless but vulnerable to accident" in all but more precisely spoken communities. But it was much used by the early cryonicists in a way closer to the dictionary definition, and that more than anything else I think captures their excitement at having envisioned the scientific doorway out of the trap - a tool that could provide a possible way around death. For example, the early cryonics book "Immortality: Physically, Scientifically, Now" by Ev Cooper, subtitled "A reasonable guarantee of bodily preservation, a general discussion, and research targets":

Though few, if any, cryonicists today can retrace their personal interest in cryonics to Ev Cooper, and despite the broader recognition of Robert Ettinger’s later-published work, “The Prospect of Immortality,” Ev Cooper’s privately published 1962 manuscript, “Immortality: Physically, Scientifically, Now,” represents the first major treatise on what would later become known as cryonics. Soon afterward Ev also started the first cryonics organization, the Life Extension Society (LES), from which several other cryonics societies eventually emerged.

...

A handful of prophets: H. G. Wells, G. B. Shaw, Jules Verne, Capek, and Tsiolkovsky made some startlingly accurate predictions in the late 19th and early 20th centuries. The more sober members of mankind never held to them seriously, neither then nor now, passing them off as the successes amongst the law of chance. No matter how it came about - and some of these men were of acute scientific understanding and broad perspective - many of the possibilities they spoke of did come to pass: rocket travel, atomic energy, automatons that work in offices and run factories - too many to list.

Now in the last half of the 20th century, to take seriously that physical immortality, here on earth, is scientifically possible is almost as much as dream can encompass, certainly more than sobriety can allow. This is perhaps a necessity, for it is only more absurd to chase after every South Sea bubble. And, ever since prehistoric man first imagined the possibility of life forever, the countless rolling centuries have not given him one shred of material verifiable evidence. Now, however, when some of the scientific possibilities appear on the horizon, someone has to form the question, consider a reversal of the skepticism engendered by centuries of disappointment and prepare the way for the reality of the incredible.

Why was cryonics envisaged as the step directly to immortality? Because, should the plausible outline of the process work, it is a gate to the future of far more capable technology. A future after the biotech revolution, in which our biochemistry does our bidding, aging can be repaired, and molecular manufacturing is in full swing. An age of bioartificial bodies, minds transferred to new and more robust mechanisms, strong artificial intelligences, and indeed, anything you might imagine that the laws of physics permit and enough time has passed to develop.

I'm not going to try to convince you that the future will be a golden, wondrous place: either you accept the implications of the present rate of progress towards what the laws of physics make possible, in which case you've probably thought this all through at some point, or you don't. Life, space travel, AI, the building blocks of matter: we'll have made large inroads into bending it all to our will within another half century. Many of us will live to see it even without the benefits of medical technology to come: growing up in a 1970s urban area will be the new 1900s farmboy youth come 2040; a strange and primitive near-past erased by progress, for all that so many people still alive actually lived it, time travellers in their own lifetimes.

In any case, I think it's interesting to ponder why cryonics is no longer seen quite so stridently as the gate to immortality, despite the fact that cryonics technology has advanced steadily since the 1960s, as has our understanding of our brain's biochemistry. Could it be because that the horizon for successful restoration has pulled in - perhaps as early as the 2040s? Cryonics advocates no longer expect to be restored to a time massively different to our own, because the journey will likely be one of decades rather than centuries.

The vision of immortality can still be conjured just as stridently, should we so wish, but it's somewhat fashionable at the moment to distance oneself from talking about immortality. There are practical aspects too. Now that we have serious, scientific work taking place aimed at the repair of aging, and fundraising for faster progress is an earnest endeavor, one can't afford to be throwing around words that can be easily misconstrued. The path to moderation of the vision is hard to avoid once money starts flowing in.

I started on the path that led to the Longevity Meme and Fight Aging! from the position that immortality was a good thing, and knowing that the laws of physics did not disallow a damn good attempt at actual immortality - the "no death, ever" dictionary definition - or at least a life span of millions of years on the way to that end goal. If that's not long enough to figure out the aspects of the problem that cannot be answered today, I'm not sure what would be. If I'd been born two decades earlier, I'd have been a cryonics advocate and volunteer. As it is, it looks like these first decades of the 21st century are the era in which step one (of thousands, no doubt) of simply remaining alive forever - continuously repairing aging in these bodies of ours - can be achieved.

A philosophy of first things first is a good way to temper visions of steps two through however many thousand, and explains why I spend my time talking about the Strategies for Engineered Negligible Senescence and the biotechnology revolution. If we don't complete the first step, sufficient control over our biochemistry to repair aging, then it's all for nothing.

So, the million year life span: how could that be achieved? The short, and not terribly informative answer is that you get it done by using advancing technology to dramatically reduce your vulnerability to fatal accidents, murder, and the like. If you project out the accident rates for life today, you'll see that an ageless human, sustained by forseeable biotechnologies of cellular and biochemical repair, has a life expectancy in the 1000 to 5000 year range. Sooner or later that piano is going to fall on you hard enough that even advanced medical technology can't fix you up.

Once you start looking at living for 100,000 years in much the same shape as you are today, it becomes apparent that almost any activity bears a level of risk that'll jump up and kill you. Eating, swimming, reading ... breathing. Stretch out the time for long enough and the improbable and fatal will happen to you.

The answer is to change the shape you are. Getting past step one, the repair of aging, gives you a few hundred years of comparative statistical safety. I can't imagine that much of the technology needed for step two will remain beyond the human civilization of the 2200s. Your step two will no doubt vary, but I would get my neurons replaced (slowly, one at a time over time, to ensure continuity of the self) with some form of much more robust, easily maintained nanomachinery. That allows these sorts of engineering possibilities:

  • Swapping out the body for whatever machinery of transport and support best minimizes risk
  • Moving most of the business of life into simulation
  • Physically separating my neurons while still remaining alive, conscious and active

It's that last point that's key, as physical locations have the same sort of issues with time, probability and bad events as people do. Meteorites happen, as do landslides, earthquakes and volcanoes. The way to reduce your risk function dramatically is to spread out. You can imagine a wireless brain (using whatever the most robust communications technology of the time happens to be be) scattered in a thousand separate locations across a continent, or the whole planet.

That should be good for 10,000 years of falling pianos of various types. However, once you start digging back into the geological and astrophysical history of the solar system, it's clear that spreading out over an entire planet still leaves you at risk on longer timescales. Probably not from impacts: I'll be surprised if we can't solve that problem within few centuries from now. There's always war, nearby supernovae, massive unexpected solar flares, and other unpleasant items, however. The supernovae are the biggest of the known concerns, given that I expect it'll be a long, long time before preventing them is a practical and ongoing business for the civilizations that follow man.

Spreading out is an option again: boost up the size of your components and neuromachinery for worst-case-scenario radiation projections, provide them with the means to move about the solar system, and become a spacefaring entity, spread out over a sizeable selection of orbits. By that point in time, your physical presence resembles a small country of nanomachinery, automation and delegation. The trade-off for spreading out and further greatly reducing your long-term risk of death is that you slow down. The speed of thought is determined by the speed of communication between neurons in components in different orbits. If your brain is light hours wide, you will live very slowly indeed - but for so long, that you come out ahead.

There are other paths forward, of course, with varying degrees of risk and invention. I haven't touched living very fast in simulation by running your brain on faster hardware, for example. The practicality and possibilities as determined by the laws of physics and what we have invented to date have been debated well over the past decades of the transhumanist community; if you head out there online to look, you'll find a wealth of fascinating material.

Is immortality impractical? Given the risk functions and uncertainty in the timeline for completing the repair of aging, it might be unlikely for most of us alive today because we won't get past step one. But it's far too early to say whether immortality, the "no death, ever" version, is actually impossible for all of us. Give it a million years and ask me again. The slope of technology and possibility is curving up ahead of us to great heights, and it'll be a wild ride either way.

An Interview With James Thompson

Some interesting comments in this Forbes interview with stem cell researcher James Thompson: "Most of the hype about embryonic stem cells has been about replacing damaged body parts, but Thomson sees real promise in drug discovery. ... These cells suddenly give us access to all the bits of the human body we've never had access to. That's going to lead to understanding why certain cells are dying, and more traditional therapies are likely to prevent them from dying. Parkinson's, if you can diagnose somebody early in the course of that disease and arrest it, that's as good as a cure. And that I think is fairly probable. ... I'd actually be fairly shocked if 10 or 20 years from now we didn't have such a good understanding of the biology of [Parkinson's] that we didn't have to do transplantation [of new neurons]. And although human embryonic stem cells and induced pluripotent stem cells are not the whole story for doing that, I think they're going to be one critical component of it."

Link: http://www.forbes.com/business/2008/05/28/stem-cells-biz-healthcare-cx_mh_0528medtech_thompson.html

Exercise and Cancer

From EurekAlert!, another way in which exercise helps healthy longevity: "Men who exercise often are less likely to die from cancer than those who don't exercise ... In the study, the researchers looked at the effect of physical activity and cancer risk in 40,708 men aged between 45 and 79. Over the seven year period of the [study], 3,714 men developed cancer and 1,153 died from the disease. Men who walked or cycled for at least 30 minutes a day had an increased survival from cancer with 33 per cent, than the men who exercised less or did nothing at all. The researchers also found that a more extensive programme of walking and cycling for between 60 and 90 minutes and a day, led to a l6 per cent lower incidence of cancer. But these activities only led to a five per cent reduction in cancer rates among the men who walked or cycled for 30 minutes day, a finding which could be due to chance." One might speculate that this has to do with maintaining a more capable immune system (which can destroy cancer at the earliest stages) and losing the visceral fat, thereby reducing chronic inflammation. Less biochemical damage to the body's vital systems means a lower chance of runaway failure in your cells.

Link: http://www.eurekalert.org/pub_releases/2008-05/ki-ecc052908.php

The Importance of the Stem Cell Niche

A stem cell niche is an environment within the body where a specific variety of stem cell is nurtured:

Stem-cell populations are established in 'niches' - specific anatomic locations that regulate how they participate in tissue generation, maintenance and repair. The niche saves stem cells from depletion, while protecting the host from over-exuberant stem-cell proliferation. It constitutes a basic unit of tissue physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms. Yet the niche may also induce pathologies by imposing aberrant function on stem cells or other targets. The interplay between stem cells and their niche creates the dynamic system necessary for sustaining tissues, and for the ultimate design of stem-cell therapeutics ... The simple location of stem cells is not sufficient to define a niche. The niche must have both anatomic and functional dimensions.

Niches age with the rest of your tissue, and for much the same reasons; an accumulation of a variety of types of cellular and biochemical damage. The machine gathers faults and rust over the years, and gradually moves towards serious failure.

There has been some debate over the past few years as to whether the well-known decline in function of stem cell populations with age occurs because of changes in the stem cells, or because of changes in their niches. It seems that the consensus is presently leaning towards the niche explanation:

Adult stem cells provide the basis for regeneration of aging tissue. Their dual ability for self-renewal and multilineage differentiation is controlled by direct interaction with a specific microenvironment - the so called "stem cell niche".

Hematopoietic stem cells (HSC) reside in the bone marrow. It is still under debate if HSC can rejuvenate infinitively or if they do not possess "true" self-renewal and undergo replicative senescence such as any other somatic cell. Furthermore, the question arises to what extent age-related changes in HSC are due to intrinsic factors or regulated by external stimuli. There is growing evidence, that the stem cell niche is most important for the regulation of cellular aging in adult stem cells.

It is the stem cell niche that (i) maintains HSC in a quiescent state that reduces DNA damage as well as replicative senescence, (ii) protects from radicals and toxic compounds, (iii) regulates cell intrinsic signal cascades and (iv) modulates gene expression and epigenetic modifications in HSC. Thus, the interplay with the stem cell niche controls HSC function including the aging process of the hematopoiesis.

As accumulating age-related damage causes the cells and processes of the niche to malfunction, the stem cells it supports suffer. One consequence of the dominance of the aging niche is the direction taken in order to develop the next generation of stem cell therapies. Clearly it's not enough to gain far better control over stem cells if the damaged niche then sabotages your efforts.

I believe that this will likely see the large and well-funded regenerative medicine industry start down the path of trying to rejuvenate and repair stem cell niches. I don't know when that will start in earnest, but it will be a tremendous opportunity for those of us interested in the success of more general strategies for biochemical repair throughout the body - a chance to apply large-scale funding and a large research community to specific challenges in repairing the damage of aging.

Efficiency In Engineered Pluripotency

Infrastructural improvement is key; making the tools faster, better and cheaper will speed progress. Here's another good example via EurekAlert!: "The ability to drive somatic, or fully differentiated, human cells back to a pluripotent or 'stem cell' state would overcome many of the significant scientific and social challenges to the use of embryo-derived stem cells and help realize the promise of regenerative medicine. Recent research with mouse and human cells has demonstrated that such a transformation ('reprogramming') is possible, although the current process is inefficient and, when it does work, poorly understood ... We used a genomic approach to identify key obstacles to the reprogramming process and to understand why most cells fail to reprogram ... Previous work had demonstrated that four transcription factors - proteins that mediate whether their target genes are turned on or off - could drive fully differentiated cells, such as skin or blood cells, into a stem cell-like state ... Interestingly, the response of most cells appears to be activation of normal 'fail safe' mechanisms. Improving the low efficiency of the reprogramming process will require circumventing these mechanisms without disabling them permanently."

Link: http://www.eurekalert.org/pub_releases/2008-05/biom-nii052708.php

What To Rejuvenate First?

Hypothetical choices from FuturePundit: "Suppose you find a lamp that contains a genie. Suppose the genie grants you 3 wishes to make parts of your body young again. You have to use the wishes by age 55 (before most old age diseases become apparent) or immediately if you are already over 50. The wishes are for only parts of the body. Each could make an organ (and the skin is an organ) or subsystem (e.g. immune cells or spine) young again." This is something of a proxy for the question "what specific rejuvenation research would you fund if you had a vast sum of money?" Tissue engineering for a new heart, plus the necessary understanding to repair any damage in your stem cells? One problem you quickly run into in this sort of thought experiment is that everything of importance is influenced by everything else. New cells will be damaged by the old intracellular environment, as well as by the actions of old cells next door. An age-damaged immune system can't protect rejuvenated cells in a new heart. The interconnectedness of the body's systems is one of the reasons I favor the fundamental engineering approach: get to the bottom of the biochemical damage and fix it. Take care of the cells and the environment and the organs will take care of themselves.

Link: http://www.futurepundit.com/archives/005222.html

IGF-1 and Life Expectancy in the Elderly

Insulin-like growth factor 1, IGF-1, is one of a number of items of great interest for the mainstream of gerontology, those researchers focused on the workings and manipulation of metabolism. It also remains an area of uncertainty at this time, with apparently contradictory results abounding:

it has become apparent that single gene mutations in the insulin and insulin-like growth-factor signalling pathways can lengthen lifespan in worms, flies and mice, implying evolutionary conservation of mechanisms. Importantly, this research has also shown that these mutations can keep the animals healthy and disease-free for longer and can alleviate specific ageing-related pathologies. These findings are striking in view of the negative effects that disruption of these signalling pathways can also produce. ... The underscored passage brings up an issue that we've discussed here previously: Why is it that IGF-I pathway mutations can confer long healthy lives on organisms, even though supplementation with IGF-I is often quite beneficial, and depletion of IGF-I is often bad for individual organ systems? Indeed, according to another recent study, low doses of IGF-I appear to protect the mitochondria in aging rodents - why then do completely IGF-I-deficient animals enjoy extended and healthy lives?

Adding more IGF-1 in an unmodified metabolism seems to be good, but modifying metabolism to completely remove it seems to be much better. To add to these results in animals, an improved testing methodology for humans shows that more IGF-1 activity is apparently better in the elderly:

Elderly men with higher activity of the hormone IGF-1 - or insulin-growth factor 1 - appear to have greater life expectancy and reduced cardiovascular risk

...

In this study, researchers evaluated 376 healthy elderly men between the ages of 73 and 94 years. A serum sample was taken from each subject at the beginning of the study and researchers were contacted about the status of the participants over a period of eight years.

Subjects with the lowest IGF-1 function had a significantly higher mortality rate than subjects with the highest IGF-1 bioactivity. These results were especially significant in individuals who have a high risk to die from cardiovascular complications.

These new findings come as a result of a new form of testing for IGF-bioactivity. Researchers in this study used a new method, a bioassay, to measure the function of IGF-1 in the blood. Compared to commonly used methods to measure IGF-1, the IGF-1 bioassay gives more information about the actual function (bioactivity) of circulating IGF-1 in the body.

What this doesn't tell us is whether IGF-1 activity is a cart or a horse in this correlation - cause, consequence, or a little of both? I suspect that levels of IGF-1 activity are greatly influenced by obesity, metabolic syndrome, diabetes, general aerobic fitness, risk of atherosclerosis, levels of oxidative stress, and other line items of biochemical damage and poor choice that correlate with a lowered life expectancy.

So eating yourself into an early grave and hoping to dig your way out with hormone supplementation is not the way to go, as always. Neither life nor your metabolism works that way.

More On Infection and Telomere Length

Ouroboros comments on recent research indicating that infection shortens telomeres in immune cells: "Chronic stress has been associated with decreased telomere length in lymphocytes. The association is robust and has been observed in multiple studies ... The question still remains, however, whether the relationship is correlative or causative. Do stress and other lifestyle factors somehow cause shortened telomeres, or are the two phenomena otherwise-unrelated indications of some common underlying cause? ... Chronic infection requires increased production of lymphocytes, which overworks the stem cell compartment from which these cells are derived; increased cell divisions leads to decreased telomere length - a perfectly satisfactory explanation for the observation. If that is true, then chronic infection in the absence of lifestyle risk factors should cause telomere shortening on its own (let's stipulate for the moment that stress increases susceptibility to disease, an idea supported by my own anecdotal experience of college finals). Ilmonen et al. have demonstrated that this is indeed the case, at least in [mice]."

Link: http://ouroboros.wordpress.com/2008/05/27/chronic-infection-shortens-telomeres/

On Aging Presented as a Disease

From Existence is Wonderful, thoughts on presentation: "Nowadays, there are a lot of people (perhaps even a majority!) interested in mitigating common age-related health problems. Very few people would answer 'Yes!' if asked, 'Are you looking forward to experiencing heart problems, increased susceptibility to infections and cancer, and eventual death?' However, most people also accept certain things as inevitable or at least highly probable, and may strongly object to the characterization of the aging process as a 'disease' in and of itself. ... To some, calling aging a 'disease' implies that there is something 'wrong' with old people as they exist today, and that us younger folks all ought to feel sorry for these poor, sick individuals. I know that not everyone has this interpretation, but that interpretation does exist, and I believe it to be a rather problematic one." I don't agree with this line of reasoning - you should read the whole thing - but I do agree that there's a lot of work left to do on the presentation and perception of longevity science and the degenerations of aging.

Link: http://www.existenceiswonderful.com/2008/05/is-aging-itself-disease.html

Envisaging a World Without the FDA

Incentives matter in all areas of human endeavor. When people gather to develop and deploy new medicines, for example, they are more incentized by the prospect of personal gains - reputation, profit, feeling good by doing good, and so forth - than by the benefits brought to people they have never met. This is simple, hardwired human behavior. Exceptions are few and far between.

That we instinctively work to improve our own lot first is why progress for all happens so much faster in free, open marketplaces under the rule of law. There, everyone can trade to make themselves better off: specialization and comparative advantage means that trade benefits both sides. Trade is not zero-sum; we grow the whole pie by specializing and trading the results of our work. You go off and work to make the medicine I want, and many people like myself give some our our resources to purchase the end result. Both sides benefit, exchanging - what is for them - lesser value to receive greater value.

There is no open marketplace for medical technology in the developed world, however. Instead, we see a very different set of incentives dominating the state of research and development. Regulatory bodies like the FDA have every incentive to stop the release of new medicine: the government employees involved suffer far more from bad press for an approved medical technology than they do from the largely unexamined consequences of heavy regulation. These consequences go far beyond the obvious and announced disapproval of specific medical technologies: the far greater cost lies in all the research, innovation and development that was never undertaken because regulatory burdens ensure there would be no profit for the developer. Personal gain for the regulator is thus to destroy the gains of people they will never meet, the exact opposite of what occurs in an open marketplace.

An article that looks at one small part of the destruction caused by the FDA caught my attention, and particularly these snippets:

Since 2005 the FDA has approved 18 new cancer drugs, many of them breakthrough products. But the pipeline contains hundreds more that will never get to market because corporate developers aren't able, or willing, to come up with the money, time, and patients necessary to establish acceptable data.

...

The clinical trial process now is a three-part, years-long effort that effectively kills off all but a handful of once-promising drugs.

...

It would have been the first new drug for prostate cancer in 20 years

Twenty years! Just stop a moment and think about how far and fast biotechnology and medical science has moved in the past twenty years. Think about what the far less regulated computing industry has achieved in the same timeframe. We live in the early years of the biotechnology revolution, with something amazing and new demonstrated in laboratories every week. Yet the dominant regulatory body for one of the most advanced regions of the world has managed to stop the clock at 1988 for a major disease, the subject of research in a hundred laboratories worldwide.

This sitation exists in every field of medicine, and all participants labor under the crushing burdens imposed by regulators incentivized to stop progress from happening. The same will be true of the future of longevity medicine, unless we do something about it.

The insanity of this all is quite staggering - that people largely accept and defend the need for regulation that achieves this sort of result, that is. I have heard it said that the failure of libertarianism, of the urge to freedom and personal responsibility, is a failure of imagination on the part of those who have been brought up knowing nothing other than government and regulation on a massive scale. The majority cannot make the leap to see an unregulated marketplace for medical development that works in the same way as the unregulated marketplace for computers - enormous choice, low barriers to innovation, efficiency and low cost, competing review organizations, accountable sellers, rapid progress and responsiveness to customers driven by fierce competition, and so forth.

What is, is, and to propose another way is already an uphill battle regardless of merits. That is also hardwired into the human condition. But the present dismal state of affairs must be changed if we are to see the defeat of degenerative aging in our lifetime - nothing short of a revolution is called for, given just how far in the hole we find ourselves. The technologies needed to repair aging will take only a few decades to develop, and indeed some already exist in prototype, but the present regulatory burden placed upon medical technology will ensure we are all dead and buried, that wondrous potential squandered.

Upgrading Cells With Intrabodies

EurekAlert! examines another technology with the potential to clean up cells of compounds that accumulate and damage us with age. Here it's aimed at Huntington's disease, but you can see the potential for broader application: "researchers engineered a virus to make an intracellular antibody or 'intrabody' against huntingtin, the protein whose mutant forms poison the brain cells of people with Huntington's. Injecting the virus into the brains of mice that make mutant huntingtin improves their ability to move their limbs ... Delivering the intrabody to brain tissues in people would be a formidable challenge, because it would require some form of gene therapy ... finding an antibody that prefers to bind mutant, aggregated protein could also prove useful in the study of other neurodegenerative disorders, such as Alzheimer's disease or Creutzfeldt-Jakob disease. ... Several neurodegenerative diseases appear to involve defects in protein folding and metabolism, leading to the accumulation of protein aggregates inside cells. Our study suggests a strategy for dissecting the harmful effects of these protein aggregates in other diseases."

Link: http://www.eurekalert.org/pub_releases/2008-05/eu-cm052308.php

Aging Is An Anti-Process

Thoughts from grailsearch.org: "In essence, aging is not a process but rather an anti process. As DNA driven life forms, we are the sum of our gene expression driven by numerous molecular dials turning protein production up and down. As time passes though, the optimal concentration of the expressed proteins within us slowly becomes unbalanced. This imbalance leads to dysfunction, disease states and exposes us to many forms of environmental, microbial, viral and even self-induced damage. The good news is that the network of gene regulation has a tremendous amount of redundancy and fault tolerance designed into it from millions of years of evolutionary pressure which allows us to live as long as we do. From a systems perspective, how long we live is quite extraordinary, however [we're] probably getting close to pushing the limits on how far this system can perform without any assistance. Even with calorie restriction, optimal nutrition, supplementation, exercise and stress management, it's unlikely that a system with so many variables cannot lose its fidelity with the passage of this much time." Assistance means biotechnologies of repair and gene network control - which could be well underway if enough people wanted it to be well underway.

Link: http://www.grailsearch.org/?q=node/78

A Good Basic Introduction to SENS Longevity Research

Over at the Electric Pulse, you'll find a good introduction to the Strategies for Engineered Negligible Senescence, aimed at those folk completely unfamiliar with longevity science and the work of scientists like Aubrey de Grey:

Japanese women now have a life expectancy of 85 years. In other words, a Japanese woman who died at 82 would have passed "before her time." As a society, we’ve slowly become more accustomed to the decreasing relevance of age, whether that be Madonna dancing in cut-offs at 50, or John McCain seeking to be the oldest elected president. This societal change is a reflection of statistics. Over the past 100 years, the average American has gained two years of life expectancy every decade. This pace, however, will soon be eclipsed as science effectively ends aging. The unquestioned leader in this drive is Dr. Aubrey de Grey.

Dr. de Grey came up with SENS: Strategies for Engineering Negligible Senescence. In layman’s terms, de Grey wants to keep us from becoming frail and dying. How we get old is relatively simple and uncontroversial. As a by-product of being alive, our bodies start to build up damage, and eventually this damage causes disease.

...

The difference between us and cars is that we know everything there is to know about repairing cars. Just as a Ferrari would have been impossibly complex to build two hundred years ago, so is the body today. The difference is that biology is quickly becoming an information science. As loyal readers of this column know, information technologies increase at an exponential rate. Just like computers, biotechnology such as DNA sequencing or fMRI imaging roughly doubles in capability every year.

We will soon be able to deal with the nanoscale devices that make up the human machine and fix the damage that occur to them.

This is a great piece to send to friends and relatives who don't follow scientific progress at the Methuselah Foundation, and don't know about relevant new research out in the wider life science community - indeed, to anyone you know who doesn't spend much time thinking about aging at all. The article is simple and to the point, framing aging as the consequence of known forms of biochemical damage, presenting the best path forward as the development of therapies to repair that damage.

The biggest hurdle to the future of healthy life extension not the science, but rather that most people in the world take aging and its degenerations as writ in stone, an immutable fact of life. Only when many more folk appreciate that aging can be defeated - and defeated within our lifetimes - will we see rapid progress, large-scale funding, and the growth of a large research community to get the job done. That's something we can all help to bring about by talking more often about real science and real prospects for engineered longevity.

Another Way Your Aging Immune System Harms You

An interesting paper: "Recent studies suggest that activation of the peripheral immune system elicits a discordant central (i.e., in the brain) inflammatory response in aged but otherwise healthy subjects compared with younger cohorts. A fundamental difference in the reactive state of microglial cells in the aged brain has been suggested as the basis for this discordant inflammatory response. Thus, the aging process appears to serve as a 'priming' stimulus for microglia, and upon secondary stimulation with a triggering stimulus (i.e., peripheral signals communicating infection), these primed microglia release excessive quantities of proinflammatory cytokines. ... there is a propensity for this response to be maladaptive in aged subjects, resulting in greater severity and duration of the sickness behavior syndrome." Your immune system evolved for a life span of a few decades, optimized to help you live long enough to pass on genes. It's all downhill after that, as some of those optimizations start to be actively harmful later on in life. Repairing these deficiencies in the aging immune system is an important component for future longevity science.

Link: http://www.ncbi.nlm.nih.gov/pubmed/18495785

Upgrading Cells With Artificial Organelles

If you can build artificial cells, why not build artificial organelles within natural cells? From the New Scientist, a look at the future: "Human cells could have their metabolisms upgraded without altering their genes by inserting tiny plastic packages of enzymes ... [researchers] coated their polymer vesicles in a chemical that encouraged human white blood cells called macrophages to engulf them. The small capsules contained enzymes, just like natural organelles. The enzymes chosen produced fluorescent chemicals, signalling they were working without problems inside their new host. ... Artificial organelles might also be able to treat conditions caused by a deficit of a particular enzyme. For example, someone with lactose intolerance could have their digestive cells given artificial organelles containing lactose-digesting enzymes. In the far future, it might be possible to introduce non-human metabolic functions into human cells. ... We could, in principle, bring in a nanoreactor that [lets] your skin do something like photosynthesis. So if you are hungry, you just lie in the Sun." For "in the far future," read "twenty years from now." I'm sure you can imagine a thousand and one other, more directly beneficial applications of this technology: for example, enzymes to degrade damaging aggregates that accumulate with age.

Link: http://technology.newscientist.com/article/dn13967-cell-organs-get-plastic-upgrades.html

Engineering an End to Aging

Michael Anissimov is back to writing on the topic of healthy life extension once more, and a good thing too. As more writers craft works of common sense on aging and advocacy for longevity science, it becomes easier to raise significant funding for research and development aimed at repairing the damage of aging. Raising the tide of awareness to float the boats of endeavor is a labor in and of itself - but it must happen if we are to succeed.

You'll find Anissimov's latest piece hosted at the Immortality Institute:

Age-defying creams and lotions, esoteric herbs and elixirs, botox and plastic surgery, what do they all have in common?

None of them will actually increase your lifespan. Usually, they're snake oil. At best, they improve external appearance without actually extending life. We deserve better, and we'll need it if we want to live longer than the typical four score and ten years.

...

Enter Dr. Aubrey de Grey, a biogerontologist from the UK, and his "strategies for engineered negligible senescence" (SENS) plan. Instead of exclusively studying the complex biochemical processes of aging in detail, as in gerontology, or ameliorating the worst symptoms of age-related decline, as in geriatrics, de Grey and his supporters advocate an "engineering approach" to aging, which asks: what are the main categories of age-related biochemical damage, and how can we fix them? The idea is not to eliminate the sources of age-related damage, but fix the damage fast enough that it doesn't accumulate to cause health problems. This is far easier than deciphering all the intricacies of the biochemistry of aging.

Go and read the whole thing. One of the pleasant aspects of this new publishing paradigm we've engineered for ourselves on the web is that there is less of a need to forge your work, complete in every aspect, prior to presenting it. One can publish early and iterate the publication often, which I think tends to lead to a better result. In that vein, Anissimov is soliciting constructive criticism for the next iteration:

Check it out, and let me know if there’s any way it might be improved or modified.

Aging sucks! Let’s end this terrible disease, and let people live as long as they desire.

Watch Those With Money at Risk

If you want to see what people really think about the future of longevity, don't listen to what they say. Rather, watch what they do when money is at stake. The pension, insurance and actuarial industries are good places to start: the institutions are very conservative in their worldviews, but a great many people stand to lose a great deal of money by being wrong about the timeline for longevity medicine. That's a powerful incentive to make good, informed predictions. Here's an update from the BBC on a few of the changes that have been taking place in the past few years: "Many UK companies are now assuming their male pensioners will live, on average, one year longer than they assumed in 2006. ... The assumed life expectancy has steadily risen in recent years to 86. ... It was 83 in 2004, 84 in 2005 and 85 in 2006. ... It's interesting they are going by one year, every year. There is an element of catch-up but there is great uncertainty about how this trend will go in the future." That uncertainty is driven by the tremendous promise offered by research programs like the Strategies for Engineered Negligible Senescence, and prospects for breakthroughs in related fields.

Link: http://news.bbc.co.uk/2/hi/business/7413120.stm

Understanding Embryonic Stem Cells

Continuing the infrastructural bioscience theme, ScienceDaily notes new knowledge that will lead to greater and more effective control over totipotent stem cells: "Our study suggests that what we believe about how embryonic stem cell self-renewal is controlled is wrong. Our findings will likely change the research direction of many stem cell laboratories. ... Contrary to the current understanding of stem cell self-renewal and differentiation, the findings suggest that embryonic stem cells will remain undifferentiated if they are shielded from differentiation signals. By applying small molecules that block the chemicals from activating the differentiation process, the natural default of the cell is to self-renew, or multiply, as generic stem cells. ... This study presents a completely new paradigm for understanding how to grow embryonic stem cells in the laboratory. The discovery has major implications for large scale production of specialized cells, such as brain, heart muscle and insulin producing cells, for future therapeutic use." Replacing cells lost to aging is one important part of any suite of longevity therapies, and advances that bring that goal closer are welcome.

Link: http://www.sciencedaily.com/releases/2008/05/080521131538.htm

Improving Gene Therapy Thirtyfold

When watching progress in medical science, you have to keep your eye on less flashy improvements in infrastructure and methodology. It is progress at that level that enables the later big, bright advances that capture all the attention. Here's an example of the type from ScienceDaily: "geneticists say they have developed a new version of the adeno-associated virus used in gene therapy that works about 30 times more efficiently in mice than vectors scientists currently rely on ... Based on our studies and those of others, it's become clear that the reason you need so much is because about half the [adeno-associated virus (AAV)] particles get stuck in the cytoplasm. It doesn't get to the nucleus very efficiently. The reason for that is obvious. AAV is seen by the body as an invading protein and it tries to block it ... We didn't change anything except the amino acid that does not allow phosphorylation to occur ... We were very surprised. It's amazing to think that changing one amino acid could produce these results." Gene therapy is a very important tool, and order of magnitude improvements in cost and efficiency here will ripple out through the cutting edge of medical research - including many areas important to the longevity medicine of tomorrow.

Link: http://www.sciencedaily.com/releases/2008/05/080520090529.htm

Robert Butler's View of Longevity Research

Via Longevity Science: "This book about the ongoing revolution in human longevity and its implications for society was written by Robert Butler, a professor of geriatrics who is still working at the age of 80. ... Butler states that his proposed program 'could be dubbed the Apollo Program for Aging and Longevity Science' and goes on to explain that 'the present level of development of aging and longevity research justifies an Apollo-type effort to control aging. ... Now we have both past work as a foundation and new scientific tools offering hope that we may soon have a more prolonged, vigorous and productive life and added longevity. During the twenty-first century, the century of the life sciences, longevity science should truly come of age.' Butler believes that 'it may soon be possible to delay both aging and age-related disease in humans' but that 'an orbital jump in financing of science is required to advance longevity and health as well as national wealth.'" Butler is one of the folk behind the Longevity Dividend initiative, you might recall.

Link: http://longevity-science.blogspot.com/2008/05/new-initiative-to-combat-human-aging.html

Digging Into Clam Biochemistry

You'll recall the arctic quahog - a species of bivalve clam - has a maximum lifespan somewhere north of 400 years. Other bivalve species fall into the 30 to 100 year range, with a fair degree of uncertainty. While you can age a bivalve by the growth rings in its shell, there are a lot of different species, and not that many people out there performing a rigorous analysis of growth rings. The range of 30 to 400 years is not out of line with the range of life spans in mammals, and one might expect to see similar biochemical reasons for differences in life span between bivalve species. In mammals, it appears to have a lot to do with mitochondria:

In animal cells, mitochondria are semiautonomous organelles [with] their own code and genome (mtDNA). The semiautonomy and restricted resources could result in occasional 'conflicts of interests' with other cellular components, in which mitochondria have greater chances to be 'the weakest link,' thus limiting longevity. ... (1) to what extent the mammalian maximum life span (MLS) is associated with mtDNA base composition? (2) Does mtDNA base composition correlate with another important mitochondria-associated variable - resting metabolic rate (RMR) - and whether they complement each other in determination of MLS? ... Analysis of 140 mammalian species revealed significant correlations ... To the authors' knowledge, it is the highest coefficient of MLS determination that has ever been reported for a comparable sample size. Taking into account substantial errors in estimation of MLS and RMR, it could mean that [this explains] most of the MLS biological variation. [This leads us to] mitochondria as a primary object for longevity-promoting interventions

Back to the bivalves: you can do more with growth rings than count them, as this research paper demonstrates. Growth rings contain a record of some aspects of the biochemistry of the clam over its life:

The ocean quahog Arctica islandica is the longest-lived of all bivalve and molluscan species on earth. Animals close to 400 years are common and reported maximum live span around Iceland is close to 400 years.

High and stable antioxidant capacities are a possible strategy to slow senescence and extend lifespan and this study has investigated several antioxidant parameters and a mitochondrial marker enzyme in a lifetime range spanning from 4-200 years in the Iceland quahog.

In gill and mantle tissues of 4-192 year old A. islandica, catalase, citrate synthase activity and glutathione concentration declined rapidly within the first 25 years, covering the transitional phase of rapid somatic growth and sexual maturation to the outgrown mature stages ( approximately 32 years). Thereafter all three parameters kept rather stable levels for > 150 years. In contrast, superoxide dismutase activities maintained high levels throughout life time.

These findings support the 'Free Radical-Rate of Living theory', antioxidant capacities of A.islandica are extraordinarily high and thus may explain the species long life span.

A little explanation here:

  • Mitochondria churn out damaging free radicals as a side-effect of their job as the cell's power plants. The chain of biochemical events that follows on from this fact is a major component of age-related damage, disease and degeneration. You can look back into the Fight Aging! archives for an introduction to that topic.

  • It has been demonstrated that soaking up the free radicals produced by mitochondria right at the source extends life span. This has been achieved by means of antioxidants like catalase, targeted to the mitochondria by gene therapy or other bioengineering means. This is quite different from taking antioxidants as a supplement, I should add; those don't go anywhere near your mitochondria, and thus don't do much good.

  • So it's reasonable to theorize that if you happen to be a member of a species that naturally generates a lot of antioxidants around the mitochondria, you're going to live longer than members of another, similar species with worse luck in the antioxidant stakes.

It remains to be seen if this is enough to explain all of the disparity in bivalve life spans. Certainly, researchers are aiming in that direction to explain the ninefold difference in life span between naked mole-rats and other rodents of similar size, so it seems at plausible at this point in time. Personally, I hope that researchers demonstrate that mitochondrial biochemistry accounts for a very large chunk of aging and relative life span, given that the medical technology needed to repair and upgrade our own mitochondria is right around the corner.

To Conquer Aging

The goal of the more activist end of the healthy life extension community is nothing less than to engineer the defeat of degenerative aging: to develop medical technologies that make it possible to live in good health with no ticking clock driving you ever closer to suffering and death. This has been the case across decades of the modern community, from pre-internet years through to present day Methuselah Foundation initiatives, online collaborations and cryonics industry. Over at Depressed Metabolism, Aschwin de Wolf has republished a fine discovery from the late 1960s:

Aging is a biologic phenomenon. It involves basic changes that occur within living cells. The key to halting or reversing the aging process is our understanding of the life processes. It is most encouraging, therefore, to discover that we are beginning to understand the precise manner in which our bodies function.

The most spectacular advances in the past decade [the 1960s] have been in biology. With the use of equipment like the electron microscope and techniques such as X-ray crystallography, scientists have been able to examine the structure and workings of living cells on a molecular level. Light has been shed upon the mechanism by which genetic information is transferred from cell to cell, and simple types of DNA & RNA, the master chemicals involved in the process, have been duplicated in the laboratory.

As our understanding of the life processes increases, it is reasonable to assume that it will become possible to devise bio-engineering techniques to modify the aging process.

But this is all in the future. How far in the future depends upon us. It is common to hear people say that they believe that someday it will become possible to extend the human life span. This kind of prediction is misleading.

The problems involved in conquering aging have not been solved. They will never be solved unless people decide that they want to conquer aging - that they want to extend their lives. History has shown that man is capable of solving monumental problems once he sets his mind to it. At the turn of the century heavier-than-air flight was believed to be impossible, but the Wright brothers wanted to fly; just a few years ago rocket travel to the moon was looked upon as a fantasy, but scientists such as Werner Von Braun wanted to go to the moon. If we truly want to extend our lives - to maintain youth, vigor, and vitality indefinitely, we must become emotionally involved in the project.

This is just as true today, and it will continue to be true in the years ahead, right up until ongoing Strategies for Engineered Negligible Senescence (SENS) and related research mature into a grand scientific community and the first working technologies of rejuvenation. That will happen when enough people want it to happen, and are willing to devote their time and resources to the quest. The gathering of those people is going very well today, but many more are needed, and a road of decades lies ahead.

We know far, far more today about the aging process than the biologists of the 60s; specifically we have a good idea as to what aging is at the cellular and molecular level, and how we can repair it. The tools of biotechnology are many magnitudes more effective; a single laboratory can accomplish far more than the entire research community of four decades past. The initial era of basic discovery in aging biochemistry is done: now is the time to work hard to produce the first rejuvenation therapies and round out the gaps in knowledge.

Growing Body Parts In the Laboratory

RedOrbit looks at tissue engineering: "Other alternatives to organ transplants have proved elusive. Transplants from animals, for example, face serious risks of rejection or viral infections. And mechanical organs, such as heart pumps, have been only a temporary solution. ... If we want to live forever, we need to do better ... Engineering body parts - tissues and whole organs that are genetically compatible and available on demand - sounds like science fiction. But researchers at medical centers around the world are working to make it a reality. Already, a handful of children with spina bifida have received new bladders. Replacement blood vessels are being tested on dialysis patients. And researchers have re-created a beating rat heart. ... [The] first wave of tissue engineering did yield some useful products, such as artificial skin grafts that are used to treat diabetic skin ulcers. But many of the awe-inspiring breakthroughs that scientists are talking about are still many years away ... The real potential for tissue engineering is the vital organs, but we're a ways away from that, even though there's some exciting things being done." The article looks at some of the more recent advances in engineering blood vessels, building complete hearts using a novel scaffold method, and of work on tissue engineered bladders.

Link: http://www.redorbit.com/news/health/1390940/growing_body_parts_in_the_lab_becomes_reality/

Longevity Science at the Methuselah Foundation

Future Current provides a transcript and video for a February presentation by Aubrey de Grey on new longevity science at the Methuselah Foundation: "will be able to initiate at least three, and perhaps even more, projects this year ... There are [problems caused] by cells that are actually not dividing, but they are not dying either, and they are accumulating slowly as a result. They get in the way and cause various problems just by being there. Probably the most serious example of this is the immune system. ... there is a good chance that we are going to be able to fund a project starting this year that will get a good deal further towards the goal in mice of [eliminating] clonal expansions of what are called anergic - essentially broken - CD8 cells. The hope certainly is that this will play a large role in rejuvenating the immune system. There is one other thing that we want to do that is also required for rejuvenating the immune system, and that is to restore the size of a very important organ in the immune system called the thymus, [which] shrinks throughout life [down] to 10 or 15% the size that it was in early life. It is believed that this has also a rather large role to play in the increasing dysfunction of the immune system. We want to regrow the thymus as well."

Link: http://www.acceleratingfuture.com/people-blog/?p=2119

The Methuselah Foundation Invites Us All To Aging 2008 At UCLA

Publicity and volunteer work is gearing up for Aging 2008 at UCLA in late June. The event is a combination of free public symposium and scientific conference on developing the means to repair the cellular and molecular damage of aging. The symposium is one in a series of planned events to raise awareness and educate the public as to the real potential of longevity science:

On Friday June 27th, leading scientists and thinkers in stem cell research and regenerative medicine will gather in Los Angeles at UCLA for Aging 2008 to explain how their work can combat human aging, and the sociological implications of developing rejuvenation therapies.

...

  • Dr. Bruce Ames, Professor of Biochemistry and Molecular Biology at UC Berkeley
  • G. Steven Burrill, Chairman of Pharmasset and Chairman of Campaign for Medical Research
  • Dr. Aubrey de Grey, Chairman and CSO of Methuselah Foundation and author of Ending Aging
  • Dr. William Haseltine, Chairman of Haseltine Global Health
  • Daniel Perry, Executive Director of Alliance for Aging Research
  • Bernard Siegel, Executive Director of Genetics Policy Institute
  • Dr. Gregory Stock, Director of Program on Medicine, Technology & Society at UCLA School of Medicine
  • Dr. Michael West, CEO of BioTime and Adjunct Professor of Bioengineering at UC Berkeley

...

The speakers at Aging 2008 will argue that the near-term consequences of intense research into regenerative medicine could be the development of therapies that extend healthy human life by decades, even if the therapies are applied in middle age. Peter Thiel, president of Clarium Capital, initial investor in Facebook, and lead sponsor of Aging 2008, said, "The time has come to challenge the inevitability of aging. This forum will provide an excellent opportunity to look at the scientific barriers that must be overcome to substantially extend healthy human life, as well as the ethical implications of doing so."

We're all invited, so make your plans accordingly:

   
 

The Methuselah Foundation
invites you to attend the FREE symposium:

   
AGING. The disease | The cure | The implications
June 27, 2008  -  UCLA, Royce Hall 405 Hilgard Ave, Los Angeles, CA
FREE Registration Required - Click to Attend

Regenerative medicine may eventually deliver the genuine defeat of aging.

How do you and your loved ones stand to benefit from the coming biomedical revolution? Are you prepared? Is society prepared?

At Aging 2008 you will engage with top scientists and advocates as they present their findings and advice, and learn what you can do to help accelerate progress toward a cure for the disease and suffering of aging.

To learn more, see our press release.

Aging 2008 also serves as the opening session for the technically focused Understanding Aging Conference (learn more), running June 28th-29th at UCLA.

The Methuselah Foundation is looking for additional volunteers to help make this event a resounding success:

We need your help to prepare for and publicize these events - especially the June 27th symposium, when we have to fill Royce Hall with 1,800 people. Here's how you can immediately help to publicize this event:

1) Blog about Aging 2008; if you do, let us know and we'll add you to the Aging 2008 Blogroll

2) Put up a banner or button, and send banners/buttons to others:

http://mfoundation.org/aging2008/promote/

3) Send the May 18th press release to your network and media contacts:

http://mfoundation.org/aging2008/promote/Aging2008PressRelease.pdf

4) Promote through social networks, Twitter, and mailing lists

5) Put up/hand out flyers and postcards at colleges, bookstores, etc. in L.A. and surrounding regions:

http://mfoundation.org/aging2008/promote/#flyers

6) Help us get pre-event coverage: online, print, radio, and TV

7) Share Aubrey's videos (TEDTalk, Colbert Report, etc.) by putting them on your blog or sending them to friends:

http://mfoundation.org/aging2008/promote/#video

There's something for everyone - invite any friends that can help volunteer too! We need to tell the world that the aging process is an approachable challenge with the technologies we have at hand. Regenerative medicine is still in its infancy, and we can work to make the defeat of aging a key goal for this emerging field.

Those of you with connections to Facebook's UCLA network could do a lot of good here.

More Progress Towards Alzheimer's Vaccines

EurekAlert! reports on another promising Alzheimer's vaccine in the works: "Vaccinated mice generated an immune response to the protein known as amyloid-beta peptide, which accumulates in what are called 'amyloid plaques' in brains of people with Alzheimer's. The vaccinated mice demonstrated normal learning skills and functioning memory in spite of being genetically designed to develop an aggressive form of the disease. ... vaccinated mice not only performed better, we found no evidence of signature amyloid plaque in their brains ... The mice [also] harbored a mutation that causes the tau-related tangle pathology ... What we found exciting was that by targeting one pathology of Alzheimer's - amyloid beta - we were able to also prevent the transition of tau from its normal form to a form found in the disease state ... due to the number of studies required to satisfy regulatory requirements, it could be three or more years before human trials testing this type of Alzheimer's vaccine occur."

Link: http://www.eurekalert.org/pub_releases/2008-05/uorm-vti051908.php

On Using the Tools to Hand

FuturePundit on the education-longevity correlation, which he presents as more of an intelligence-longevity correlation: "My guess is that as the amount of useful knowledge available to influence longevity has increased (e.g. results from dietary and lifestyle research and new types of treatments that require patients to do much self-administration of drugs and therapies) the advantage of being smart has been amplified. If you get sick and you are smart you have more clinical trials to investigate, diets to try, and treatments to follow carefully. You are better able to understand why a treatment should benefit you and therefore more motivated to stick with it. Rather than follow the advice of one doctor you can seek out multiple experts, ask tough questions, and compare notes with other smart people chasing better treatments. You are better able to see through self-serving advice of specialists who are trying to boost their income. You are more likely to recognize serious side effects of treatments and challenge the wisdom of continued use of a treatment."

Link: http://www.futurepundit.com/archives/005202.html

Waking Up

One day, you wake up to realize that a particularly vital assumption about the world is wrong. Everyone who buys into it is wrong. Which is almost everyone in the world. Everything in the world that depends on it is wrong. Which is almost everything in the world. Now what?

Waking up is an apt way to put it; the reconfiguration of realization is not unlike passing through a slow instance of the stage of booting up in the morning. (Who am I? What am I doing today? How did I get here? What are my axioms? Oh, right, got it). The "oh, right" part might take longer, however, as pulling out one of the pillars of your constructed world generally means radical change. We humans are hardwired to hate change almost as much as we hate failing to share the same worldview as our peers.

But there's no going back from realization. Either you proceed according to your new understanding of the world, and figure out just what that implies, or you become good at living a large and uncomfortable lie. Embrace revelation or run from it.

So, one day, you wake up to realize that aging is the worse bane suffered by humanity, and the people of the world sleepwalk through an unending holocaust of suffering and death caused by the decay of their bodies. Furthermore, it quickly becomes apparent that large-scale work over a few decades will plausibly lead to medical technologies that prevent age-related frailty, disease and death. Acceptance of aging in this circumstance is like a slow-motion mass suicide, day after day after day.

But still it goes on, the grinding of the cogs, the great wrong that everyone just goes along with as though it were nothing.

Now what? You've seen behind the curtain. You have a secret that no-one you know takes seriously. Yet, you realize with clarity that nothing else you ever do in your life will be as important to the future - your future, humanity's future - as any time and effort you put towards bringing forward the defeat of aging. That's going to be hard to put back into the box, trust me.

Prototyping Artificial Cells

The first generation of mass-deployed medical microrobots is likely to consist of many different types of artificial cell, designed and grown to perform specific tasks in the body. As ScienceDaily notes, scientists are already making inroads into the basic tools and techniques: "researchers has developed a simple artificial cell with which to investigate the organization and function of two of the most basic cell components: the cell membrane and the cytoplasm - the gelatinous fluid that surrounds the structures in living cells. ... Many scientists are trying to understand cells by turning off genes, one at a time, and are observing the effects on cell function, but we're doing the opposite. We're starting from scratch, adding in components to find out what is needed to simulate the most basic cell functions. Our goal is to find out how much complexity can be observed in very simple collections of molecules. ... By creating a model cytoplasm with different compositions, we demonstrated that we can control the behavior of cell membranes. Now we want to find out what will happen if, for example, we add an enzyme whose activity depends on the compositions of the cytoplasm and cell membrane."

Link: http://www.sciencedaily.com/releases/2008/05/080515171023.htm

Surveying Ageing Research

Chris Patil of Ouroboros recommends we take the time to look through the ongoing review of aging science at Ageing Research, "a blog for those interested in learning more about the ageing process, specifically concentrating on cellular senescence and it's impact on age-related tissue dysfunction and disease development/progression." Patil suggests starting with the posts on what we know of cellular senescence: "I'm going to beseech the readers to check out the ongoing series on cellular senescence over at Ageing Research. Dominick has now turned to the relationship between senescence and human disease states, focusing first on atherosclerosis and vascular calcification ... For those of us working on senescence, Dominick's ambitious and thus far unflagging efforts to review the entire field are sure to generate a gold mine, and perhaps the gold standard online reference on this subject."

Link: http://ouroboros.wordpress.com/2008/05/16/cellular-senescence-and-disease-at-ageing-research/

On the Erosion of Telomeres

Going forward, NIH funded medical research is open access, the full papers being freely available at PubMed Central. This is one modest part of a very necessary evolution in the way in which information is handled and organized in the broader scientific community. Dropping the cost of access to scientific data to near zero is a requirement to evolve the next generation of correlators, synthesists, research automation and toolsets. The level of complexity in the life sciences is so great, and growing so rapidly, that effective progress in the years ahead depends upon the development of a powerful organizational layer above the raw mass of scientific data.

But back to PubMed Central. You should take a drive around the site, see what's out there. A paper on telomere erosion caught my eye while I was doing just that, an illustration that we there is a way to go yet to fully understand how telomere shortening relates to longevity, health and life circumstances:

Telomeres - the terminal caps of chromosomes - become shorter as individuals age, and there is much interest in determining what causes telomere attrition since this process may play a role in biological aging. The leading hypothesis is that telomere attrition is due to inflammation, exposure to infectious agents, and other types of oxidative stress, which damage telomeres and impair their repair mechanisms. Several lines of evidence support this hypothesis, including observational findings that people exposed to infectious diseases have shorter telomeres.

...

Our results show that repeated Salmonella infections cause telomere attrition in [white blood cells (WBCs)], and particularly for males, which appeared less disease resistant than females. Interestingly, we also found that individuals having long WBC telomeres at early age were relatively disease resistant during later life. Finally, we found evidence that more rapid telomere attrition increases mortality risk, although this trend was not significant.

...

Our results indicate that infectious diseases can cause telomere attrition, and support the idea that telomere length could provide a molecular biomarker for assessing exposure and ability to cope with infectious diseases.

Funnily enough, it's a PLoS One paper - open access twice over. Now, one might cast telomere erosion in white blood cells, a component of the immune system, as one of the more direct biological forms of wear and tear through repeated usage. More infections, more work for the immune system, more immune cell division, and so forth. This is probably quite separate from other mechanisms relating to telomere length in other tissues in the body - for example the link between oxidative stress due to mitochondrial free radicals and telomere shortening.

I'd be willing to wager that changes in telomere length will turn out to be a very complex topic across the body as a whole, with many different dominant mechanisms, circumstances and degree and type of effect on health. The one thing we can point to is a consensus that accelerated shortening of telomeres is not a good thing for the normal operation of your body.

An Update on Bladder Regeneration

It sounds like preclinical work is proceeding well at Tengion: "Growing a replacement organ for a patient using his or her own cells presents a new option. After a bladder biopsy is obtained from a patient, bladder progenitor cells are grown in culture and seeded on a biodegradable bladder-shaped scaffold made from collagen and/or polyglycolic acid. The neo-organ is then implanted into the patient. The neo-organ is then implanted into the patient. Fourteen large mammals [were] implanted with the neo-bladder construct and within six months, structure and pharmacological characteristics of the neo-bladder were similar to the native bladder. There was no evidence of abnormal tissue development, immune response or evidence of systemic response to the neo-bladder regeneration. Results suggest that the new organ had successfully and safely regenerated. ... This treatment option essentially regenerates the patient's own bladder, reducing the risk of rejection and the need for immunosuppressant drugs. If successful in human clinical trials, patients should expect to regenerate normal bladder structure and function."

Link: http://www.auanet.org/press/WebContent/WebView_News_Releases.asp?iRecordid=53

AGEs, RAGE and Diabetes

More reasons to spur the development of effective AGE-breaker therapies in this paper: "Non-enzymatic modification of proteins by reducing sugars, a process that is also known as Maillard reaction, leads to the formation of advanced glycation end products (AGEs) in vivo. There is a growing body of evidence that formation and accumulation of AGEs progress during normal aging, and at an extremely accelerated rate under diabetes, thus being involved in the pathogenesis of diabetic vascular complications. Further, recently, engagement of their receptor, RAGE with AGEs is shown to activate its down-stream signaling and evoke oxidative stress and inflammation in diabetes. Since oxidative stress generation and inflammation are closely associated with insulin resistance as well, it is conceivable that the AGEs-RAGE system could play a role in the pathogenesis of insulin resistance and subsequently the development of diabetes." All this could be prevented or fixed if we just had periodic applications of a therapy to break down the major types of AGE.

Link: http://www.ncbi.nlm.nih.gov/pubmed/18473850

Bone From Embryonic Stem Cells

A glance at ongoing progress in control over cells and tissue via ScienceDaily: researchers "break new ground by successfully creating bone tissue 'in vivo', using embryonic stem cells. They imitated bone formation in embryos and children, which uses cartilage as a template. ... While searching for a suitable scaffold to use for cartilage tissue engineering with mouse embryonic stem cells, the researchers selected a ceramic material that is often used as bone void filler. Other materials appeared to be unsuitable or they made it difficult to locate the implanted cells. In the lab, mouse embryonic stem cells were seeded onto this ceramic material and induced into the developmental pathway leading to cartilage formation. ... a scaffold with cells that had already formed cartilage, was implanted into a rat with a defect in its skull. Besides under the skin, bone was also formed in this bone defect. Therefore, this approach seems to be a promising new technique for repairing damaged bone."

Link: http://www.sciencedaily.com/releases/2008/05/080514091744.htm

Things We Don't Need To Know In Order To Cure Aging

Engineering might be regarded as the process of production of working technology in the absence of complete knowledge - the strategies for managing the unknown, and applying what we do know with rigor and to good effect. Bridge building and large-scale construction came to a fair and effective maturity long before the scientific, mathematical and computation tools that enabled rigorous models and full understanding of the underlying principles, for example. So too with medicine: it is an engineering discipline aiming for the best possible results with the information we have right now.

More information is better - bridge building was greatly improved through the development of those mathematical and computational tools - but we don't need to know everything to make significant progress. We just need to know enough; I think that the history of medicine to date amply demonstrates that maxim. You can find the argument that we know enough now, today, to make significant progress in repairing the damage of aging at the Strategies for Engineered Negligible Senescence section of the Methuselah Foundation website, and the details backing up that argument in the book Ending Aging.

The short of it: aging is the consequences of an accumulation of a small number of different types of cellular and molecular damage throughout the body. Scientists know what those forms of damage are, and have good ideas as to how to proceed with repair or removal. In some cases, that repair has already been demonstrated in the laboratory.

The biggest problem I see today for the future of longevity science is that the bulk of the aging and longevity research and development community is not focused on goals in medicine and engineering near-term therapies of rejuvenation. There is no urgency and directed purpose analogous to that in the cancer research and development commmunity. The community is instead mostly focused on observation and complete understanding of biochemical changes with aging. This state of affairs is much as if we lived beside a great chasm, but instead of engineering bridges for the benefit of all, we held off any such work until the full modern science and understanding of architecture was developed. Waiting too long has costs. In longevity science, waiting is measured in millions of lives lost with each passing month.

Here's a good example of the sort of productive research that takes place in the mainstream of aging science:

The major cell signaling pathways, and their specific mechanisms of transduction, have been a subject of investigation for many years. As our understanding of these pathways advances, we find that they are evolutionarily well-conserved not only individually, but also at the level of their crosstalk and signal integration.

Productive interactions within the key signal transduction networks determine success in embryonic organogenesis, and postnatal tissue repair throughout adulthood. However, aside from clues revealed through examining age-related degenerative diseases, much remains uncertain about imbalances within these pathways during normal aging.

Further, little is known about the molecular mechanisms by which alterations in the major cell signal transduction networks cause age-related pathologies. The aim of this review is to describe the complex interplay between the Notch, TGFbeta, WNT, RTK-Ras and Hh signaling pathways, with a specific focus on the changes introduced within these networks by the aging process, and those typical of age-associated human pathologies.

Is this important and useful? Yes, of course, very much so. Is this knowledge necessary for us to proceed to reverse and repair aging? No. We already know what the damage of aging is, at the cellular and molecular level. Knowing more about the way in which that damage twists our metabolism and controlling biochemistry will help, in the same way that modern techniques of architecture improve bridge building, but the absence of that knowledge does not hold back significant advances in the engineering of healthy longevity.

The only present barriers hindering rapid and aggressive progress towards rejuvenation of the aged are those of will and funding. That is why we can all help to make a difference to the future of aging science - you don't have to be a scientist to help make will and funding a reality.

Comparing Calorie Restriction and Exercise

ScienceDaily looks at the beneficial effects and mechanisms of calorie restriction and exercise: "We know that being lean rather than obese is protective from many diseases, but key rodent studies tell us that being lean from eating less, as opposed to exercising more, has greater benefit for living longer. This study was designed to understand better why that is ... Rats that exercise regularly will, on average, live longer compared to a group that eats the same amount but does not exercise. This is because exercise prevents some diseases, which allows more individual animals to live out their expected life span. However, when comparing the rats in these two groups that eat the same amount, the longest-lived animals in the exercise group don't live any longer than the longest-lived rats in the non-exercise group. Taken together, these findings indicate that exercise can prevent an early death from disease in some rats, but does not extend the maximal lifespan of any of the rats." The obvious choice for we humans is to both exercise and practice calorie restriction, obtaining all the benefits of both.

Link: http://www.sciencedaily.com/releases/2008/05/080514064921.htm

Thoughts On Aging

From "an open source mind blog": "Aging isn't a roadblock created by one inefficient system in the body. No system of the body had [evolutionary] pressure to create a perpetual repair mechanism and so every system of the body decays. ... Any individual that spent energy on repair would have been more likely to have been eaten by a saber tooth tiger or stomped by a mammoth. Modern life spans, then, are a function of historical danger. ... We don't age because its advantageous or nature wills it. Its simply because nature, until now, had no reason to do anything about it. Today, however, scientists are taking charge and developing the ability to increase human life span exponentially. Researchers like Aubrey De Grey are finally looking at aging as a very serious problem instead of an inevitability. That we can postpone aging is certain. The speed at which we develop these technologies, however, will depend on how quickly universities, scientists, funding boards, and the public adopt this same view on aging."

Link: http://djstrouse.wordpress.com/2008/05/08/the-evolutionary-accident-of-aging/

The Value of a Longevity Therapy

It is useful to think about the potential cost of future longevity therapies in the clinic - and changes in that cost over time - and compare this with the value people place on the results. This sort of exercise can help guide our expectations on commercialization: how long will it take for companies to form and deliver laboratory results to the clinic?

Progress is a matter of incentive. If you have the new science to produce a super-widget for $1 that happens to solve a common problem that people value at $100 of inconvenience, then the world will beat a path to your door. There won't be any path-beating going on if your super-widget costs $1000, however, save for some far-sighted people who think they might, maybe, be able to cut down the super-widget cost to a point at which it makes sense to sell it.

Incentives make the world go round.

So on to longevity therapies, where the math is more fuzzy. The value placed on healthy life in the developed world is the better known side of the equation:

So, how much is your life worth? You may think the answer is infinity, that no amount of money could compensate you for the loss of your life. But people do put a price tag on their existence. Workers accept riskier jobs for higher pay, for example. And the rich tend to think their lives are worth more than poor people’s.

Studies of real-world situations produce relatively consistent results, suggesting that average Americans value a year of life at $100,000 to $300,000, said Peter J. Neumann, director of a program at Tufts-New England Medical Center that measures the cost-effectiveness of new treatments.

That's mid-2007 dollars, so adjust accordingly. On the longevity therapy side, we have to look at anticipated benefits rather than actual benefits. No-one will know for certain the benefits of longevity therapies - in terms of additional years of healthy life, and varied effects between patients - for decades following their introduction. Value will be estimated by the marketplace from the available information, such as effects on biomarkers of aging, comparison with known biology, related therapies, and the like, and that value will move over time as estimates are adjusted for new science and new data.

So let's take the hypothetical of a longevity therapy that the consensus believes will add ten healthy years to the average life. Replacing age-damaged mitochondrial DNA might do that in humans, for example. This suggests that to bring a first widespread commercial version to the high-end medical practices of the world, the price tag on the therapy has to be brought down below $1-3 million, or the value of a decade of healthy life.

There are plenty of entities in the marketplace that sell goods and services to wealthy individuals at this sort of cost; you can build a profitable business on these figures, especially if the cost is paid over years. So I think that a fairly brief stage of expensive longevity clinics is to be expected in the early development of working methods to repair age-related damage in the body. I say brief, because the cost of medical services tends to fall fairly rapidly to a minimum set by the wages of the specialist staff involved. High prices in the beginning allow investors to profit by their investment, while also acting as a beacon for other businesses to enter the market, and prices then fall with competition and increased development and efficiency fueled by ongoing re-investment of profit.

The stable state for a medical treatment is that in which many specialist staff are available, and a competitive marketplace exists to train those staff and supply needed raw materials. At that point, the cost is much the same for medical procedures across the tiers of specialist labor and complexity - it's largely down to the wages of those folk performing the work.

Replacing mitochondrial DNA should be a hands-off outpatient procedure, once the technology is mature. Have a sample taken, send it off to the lab to work up a repaired genome and the viral vector, get injected with the vector that will replace your mitochondrial DNA with repaired versions, and then come back for regular testing for a couple of months. That is nowhere near as labor intensive as, say, heart surgery today. So one could look at comparable procedures that require supporting individual lab work on the back end, such as limited genetic testing, and take a stab at the price tag in the $10-30,000 range.

That's a hundred times smaller than $1-3 million, which seems fair for the progression from early version to mature technology, especially in this age of rapidly advancing biotechnology. It's also a hundred-for-one bargain on the consensus expectation of value of life gained, which is a pretty good deal - good enough to tempt a very broad customer base, and enough profit for a large and competitive industry to form.

The interesting question is how long it will take to get from point A (millions of dollars, hundreds of customers) to point B (tens of thousands of dollars, millions of customers). That's very much determined by the level of competition and regulation - is it easy to enter the marketplace? Is it easy to market new versions of the technology? Sadly, the answer in medicine is "no." Government employees work very hard to slow down progress, add cost and stifle competition. That's going to have to change if we want to see effective, widespread longevity medicine in our lifetimes.

The last thought for the day: regular exercise might just add a decade of healthy life, and I could argue for that as an expected benefit, even prior to the studies of the past decade. How much do you think average enthusiasts spend on the tools and perks of organized exercise over a lifetime? $10-30,000 perhaps?

On Gerontologiphobia

Via In Search of Enlightenment: "There is an irrational public predisposition to regard research on specific late-life diseases as marvelous but to regard research on aging, and thus all late-life diseases together, as a public menace bound to produce a world filled with nonproductive, chronically disabled, unhappy senior citizens consuming more resources than they produce. No one who speaks in public about longevity research goes very far before encountering the widespread belief that research on extending the life span is unethical, because it will create a world with too many old people and not enough room for young folks. ... our attitudes towards aging and the science of longevity could stifle one of the most significant medical breakthroughs we could make this century. Retarding aging would significantly improve the health prospects of all persons." The Tithonus Error and knee-jerk Malthusianism remain large hurdles for healthy life extension advocates to overcome, despite the progress of recent years. Enhanced longevity will be enhanced healthy longevity, and advancing technology and free markets ensure there is more than enough room and resources for everyone.

Link: http://colinfarrelly.blogspot.com/2008/05/are-you-guilty-of-gerontologiphobia.html

On Expanding the Audience

As you might know, generating a growing audience online is hard work. Writing the content has little to do with that hard work, and is in fact probably a distraction from the thousand and one tasks, trades and optimizations needed to involve more people in reading your work. If you're the sort of person who cares deeply about the content, you're also probably not cut out for the sausage-making details and compromise involved in building an audience. There are always exceptions, often very successful exceptions, but this seems to be the way it goes for the most part.

Needless to say, I'm not cut out for sausage-making and compromise, and have never more than dabbled on the optimization side of things. I'm more interested in building an ongoing conversation and repository of information to better engage those folk who have sparked an interest in healthy life extension, in directing advocacy and volunteerism to the best present ends, and in providing an example for others to follow.

However, it's hard to argue that there would be any net loss if the audience were much larger. Traffic to Fight Aging! has been roughly static for a year or two now, and I can't see it growing further through what little time I have to be proactive. With the ebb and flow of ourside events, sure, but that's no way to build a readership. So, a few axioms, which you can take or leave as you like:

  • Breadth of readership will help to grow the healthy life extension community
  • Breadth of readership will bring more support for initiatives like the Methuselah Foundation
  • Breadth of readership will not happen through my efforts
  • I'm certainly not going to change the way I write to gain readership
  • Breadth of readership is more important than control over content

Or I should say the illusion of control over content. No-one really controls text that is placed online; intellectual property is more a set of narrowly observed manners in this environment. As I see it, I have a few choices here:

1) Join a well-trafficked, established syndicate

For example, Seed's ScienceBlogs, which I passed on back when they started up. The downside there is that they own your content completely, putting their copyright on it, or such was the case when they were trying to recruit me. It's more of a newspaper-columnist relationship than anything else. The inability to change your mind later about your writing, or engage other efforts in parallel to gain readership, is a big disincentive.

2) Open source your content

Remove any copyright or copyleft and let anyone do as they will with it. I suspect the net effect here would be zero. Those who were going to use my content already are, and they are largely a collection of spam machinery that provide zero value to my goals. It takes work to obtain readers, or indeed to make the world aware of your existence - it's far from the case that simply opening up the gates will do anything.

3) Deal with the Devil

The few entities who would be easily approached to take on the sausage-making are in the "anti-aging" marketplace. While the nature of digital media means that someone, somewhere is at this very moment selling magic potions and faery dust by reworking my posts on legitimate longevity science, I don't wish to be proactively helping that cause.

4) Find a better syndicator

The ideal for me would be to hand off content, but not ownership of that content, to a non-devilish third party who simply goes ahead and uses the content for profit in the traditional audience-growing fashion. Meanwhile, I'll sit back here as I've always done, writing on the topic of longevity science, aging research, and the work needed to make it a reality. All very hands off.

Now, of course the issue with #4 above is that it requires many of the same skills and initiatives as does growing your readership in the first place. If you're the sort to have easy access to syndication offers, odds are you're not the sort to need them.

These are all things I'm chewing over as I look at the past years and contemplate the years ahead. Comments are welcome.

The Argument to Moderation

The argument to moderation says, more or less, that you'll get more funding for longevity science if you stop talking about the logical result of successful longevity science - thousand year life spans and such. An example of the type can be found at Amor Mundi by way of the author's dislike for goal-oriented futurism above a certain threshold of ambition: "It seems to me that the resistance to de Grey's SENS research program and its 'engineering' focus [in] some quarters of biogerontological orthodoxy looks to be pretty well described in [terms] of incumbent resistance to a possibly promising scientific paradigm shift. ... at the level of rhetoric it seems to me were one to embrace the more 'bioconservative' [ideal] of a medical practice that would confer on everybody on earth a healthy three-score and ten years or even the 120-years some lucky few humans may have enjoyed this would be little distinguishable in the therapeutic effects it would actually likely facilitate (as a spur to funding, research, improvement of tools and techniques, theoretical publications, and so on) from those facilitated by the more 'transhumanist' ideal of technological immortality." I couldn't disagree more - progress in advocacy is achieved by pushing the boundaries of discussion as far out as possible. The further they go, the further goes the reasonable centerpoint.

Link: http://amormundi.blogspot.com/2008/03/aubrey-de-grey-technological.html

The Nonsense of "Human Dignity"

"Human dignity" is a keyphase used by conservative bioethicists to justify relinquishing progress in longevity science - to permit the preventable death and suffering of billions to continue in the decades ahead. It is also nonsense in this context: "The problem is that 'dignity' is a squishy, subjective notion, hardly up to the heavyweight moral demands assigned to it. The bioethicist Ruth Macklin, who had been fed up with loose talk about dignity intended to squelch research and therapy, threw down the gauntlet in a 2003 editorial, 'Dignity Is a Useless Concept.' Macklin argued that bioethics has done just fine with the principle of personal autonomy - the idea that, because all humans have the same minimum capacity to suffer, prosper, reason, and choose, no human has the right to impinge on the life, body, or freedom of another. This is why informed consent serves as the bedrock of ethical research and practice, and it clearly rules out the kinds of abuses that led to the birth of bioethics in the first place ... [but] this government-sponsored bioethics does not want medical practice to maximize health and flourishing; it considers that quest to be a bad thing, not a good thing."

Link: http://www.tnr.com/story_print.html?id=d8731cf4-e87b-4d88-b7e7-f5059cd0bfbd

David Deutsch Speaks With Aubrey de Grey

Via Thoughtware.TV, a video interview on the science of the Strategies for Engineered Negligible Senescence (SENS), a path to repairing the biochemical damage of aging and greatly extending the healthy human life span: "Renowned Quantum Physicist, and father of the Quantum Computer, David Deutsch [speaks] with Aubrey de Grey about the scientific details, and feasibility of life extension technology SENS ... Filmed in the Natural History Museum, Oxford, with kind permission of the trustees." Beneath the dinosaur skeletons, in fact. SENS is far more than just research and medical technology, just as the challenge in engineering longevity is far more than a matter of science. SENS is also very much about educating the public of the potential of today's science, raising support for directed funding in longevity science, and forging a new research community enthused to intervene in the aging process as soon as possible rather than just passively documenting it.

Link: http://www.thoughtware.tv/videos/show/1989

The Future of Regeneration

If only the future of longevity science was as widely supported, understood and acclaimed as the future of regenerative medicine and tissue engineering. The Times Online notes that "within decades stem-cell technology will make it possible to grow replacements for virtually any part of the human body ... the emerging field of regenerative medicine would enable a patient's own cells to be used to build hearts, livers and kidneys, complete with their own blood supply, to replace diseased organs. The advance could make many transplants unnecessary and allow the regeneration of brain tissue and limb parts. ... We know the human genes that can do this do exist, because human foetuses can do it. If a finger is lost before three months' gestation in the womb, it will grow back. The genes are there; we just need to know how to reactivate them. When we started on this work in the 1960s, we knew all these things would become possible . . . it will not be far off. The biggest stumbling block has been money, but now there is huge investment in the field and things are moving rapidly."

Link: http://www.timesonline.co.uk/tol/news/uk/science/article3867838.ece

Timelines For Agelessness Through Medical Technology

I thought I'd point out a couple of Future Blogger posts today, as it's good to be able to demonstrate the spread of ideas when it comes to longevity science and the future of longer, healthier lives through advanced medicine. Let's start with a life span of 1000 years - which is the average age you'd reach if you lived as incautiously as folk do today, but age-related cellular and molecular damage in your body was regularly repaired:

10 Reasons You Will Live to 1000

#9: Human Desire. I understand perfectly well that a vast majority of people are terribly uncomfortable with the idea of radical life extension. Nevertheless, there are thoughtful and intelligent people such as Aubrey de Grey who are actively challenging society to think differently. Rather than accepting aging as an inevitable aspect of life, they are instead encouraging society to view aging as a disease - something to be treated. This is a profound paradigm shift, but is it any more profound than Copernicus telling people 500 years ago that they were not at the center of the universe? History has a way of demonstrating that the future often turns out much different than most people appreciate and that what constitutes "conventional wisdom" in one era is laughed at and mocked by future generations. Our "acceptance" of death might be one such issue.

A triad of things to think about in this context: firstly, moment to moment, people want to continue to live in good health. Secondly, people will do almost anything to avoid change, and death and aging are presently the status quo. Thirdly, people still, nevertheless, manage to plan the course of their changing financial lives decades ahead of time.

The future of progress in the science of longevity will be formed of a million little personal thinking wars; planning versus fear of change versus the desire to live and take part in the world. How many will help to develop the technologies of rejuvenation, versus sit on the sidelines and hope? It is the foresightful and energetic who shape tomorrow, setting out plans and taking actions that will lead to better lives for their future selves.

By 2040, we will live in ageless, disease-free bodies, experts say

Imagine living in a body fashioned from "designer cells" that can never age or get sick; and sporting a mind that thinks millions of times faster than today’s brain. Though this may seem too optimistic to happen in just 32 years, experts believe that nanotech, biotech, infotech, and cognitive science advances over the next three decades could create this future by 2040.

...

[Nanotechnology researcher] Robert Freitas believes that tiny medical nanobots expected by late 2020s will help us upgrade our bodies. "However we won’t reengineer ourselves all at once," he stresses, "It will be an incremental process one step at a time; and it could begin with artificial respirocytes replacing red blood cells, giving us an immense energy boost."

I suspect the timeline is somewhat aggressive. You have to count business cycles when thinking about how long it takes before products arrive; until we have general artificial intelligence or greatly augmented natural intelligence, human organization is going to be the incompressible element in broad progress. It takes ten years to move from laboratory to halfway decent product with widespread adoption in the least regulated markets, and twenty years to see mature products in that market. Little of that time was research and development - time is constrained by fundraising, organization, legal barriers, weight of regulations, and so forth.

I think that it's a viable prediction to say that the fundamental building blocks of artificial bodies will mostly be demonstrated by the 2040s: advanced nanorobotics; artificial cells; bioartificial organs; massive computational capacities; a complete control over evolved biological cells; a working understanding of all human biochemistry (with small gaps, rather than the present great gaping unknowns); reverse engineering of much of the brain's functionality. Biology and machinery will be well blended by that time, as much of the new nanomachinery in the molecular manufacturing industries will operate at the scale of cells and molecules.

However, it's a big jump from what is demonstrated in the laboratory and what is commercialized, proven and widely available as a product, especially in oppressively regulated areas like medicine. We live in interesting times, in that the rate at which new medical technologies become available over the next few decades - and therefore the length of healthy life we can expect - is much more dependent on what we want and are willing to pay for, and, sadly, what regulators are willing to forbid, than on constraints imposed by what is scientifically possible.

The 2050s could see the medical technologies necessary for agelessness available to the masses ... or their development might still be in the future at that time, buried beneath decades of delay, regulatory costs, suppression, and lack of advocacy for development. The future we get is very much up to us.

Improving Targeted Nanoparticles

A great deal of tomorrow's better, more effective medicine will rest on targeting nanosystems that can deliver therapies to specific cell populations in the body. Much of this development is taking place in the cancer research community, but you can be sure there are a thousand and one other uses: "Using nanoworms, doctors should eventually be able to target and reveal the location of developing tumors that are too small to detect by conventional methods. Carrying payloads targeted to specific features on tumors, these microscopic vehicles could also one day provide the means to more effectively deliver toxic anti-cancer drugs to these tumors in high concentrations without negatively impacting other parts of the body. ... Most nanoparticles are recognized by the body's protective mechanisms, which capture and remove them from the bloodstream within a few minutes. The reason these worms work so well is due to a combination of their shape and to a polymer coating on their surfaces that allows the nanoworms to evade these natural elimination processes. As a result, our nanoworms can circulate in the body of a mouse for many hours. ... We are now using nanoworms to construct the next generation of smart tumor-targeting nanodevices."

Link: http://www.sciencedaily.com/releases/2008/05/080506200531.htm

CIRM Funds For the Buck Institute

The Buck Institute for Age Research is one of the recipients of research funds awarded by the California Institute for Regenerative Medicine (CIRM): CIRM "has awarded $20.5 million to the Buck Institute for Age Research to build a 'CIRM Center of Excellence' on its Novato campus. ... The Buck Institute's proposed research program for the Center of Excellence is guided by the promise that human embryonic stem cells may provide a model system to study and understand the process of human aging and age-related disease. ... The specific aims are to use human embryonic stem cells or their differentiated progeny to study how cells self-renew and to examine processes involved in the biology of aging including DNA repair, genome integrity and programmed cell death. The long-term goal of the program is to unravel the mysteries of aging and age-related human diseases by understanding the fundamental biological process of aging in appropriate human cell models." Which is an excellent summary of the slow boat, look-but-don't-intervene approach, and shows why those researchers invested in this approach - rather than the much more direct repair of damage approach and the goal of curing aging as soon as possible - believe, incorrectly, that any successful intervention in aging is a long way away.

Link: http://www.buckinstitute.org/site/index.php?option=com_content&task=view&id=462

Understanding Aging Conference, Los Angeles, June 27th

Don't forget to mark your calendars for the Understanding Aging conference at UCLA, Los Angeles this June 27th, organized by the Methuselah Foundation and biomedical gerontologist Aubrey de Grey. Despite the unassuming name, this is all about how to develop the medical technologies of rejuvenation by repairing the damage of aging:

You are cordially invited to participate in the scientific conference "Understanding Aging: Biomedical and Bioengineering Approaches," which will be held from June 27-29, 2008 at UCLA. The conference includes a free symposium for the general public on June 27th focused on public policy implications of successfully postponing aging. The scientific conference, on June 28th and 29th, will be focused on the science and technology of aging and its postponement.

The opening symposium has its own website; the scientific conference is much like the influential Strategies for Engineered Negligible Senescence (SENS) conference series of past years, while the symposium is intended to catch the public eye and draw attention to this very important field of research:

AGING The Disease - The Cure - The Implications (ADCI)

Applying the new technologies of regenerative and genetic medicine, the engineering approach to aging promises to dramatically extend healthy human life within the next few decades.

How do you and your loved ones stand to benefit from the coming biomedical revolution? Are you prepared? Is society prepared?

At ADCI you will engage with top scientists and advocates as they present their findings and advice, and learn what you can do to help accelerate progress towards a cure for the disease and suffering of aging.

The Methuselah Foundation volunteers are working hard in the background to make this all as successful as past SENS conferences; if you are in the Los Angeles area, why not dive in and help out?

Upgrading Mitochondrial DNA to Cause Less Damage

Hopefully you know the story behind mitochondrial DNA, free radicals and the accumulating damage to our biological machinery that we call "aging." If not, a summary of the modern mitochondrial free radical theory of aging can be found back in the Fight Aging! archives, and a more detailed version in the book "Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime".

The very short summary: mitochondria inside your cells produce fuel to power cellular machinery, but side-effects of that process tend to damage the DNA the mitochondria carry within them - quite separate from the DNA in the cell nucleus, and much more fragile. An accumulation of damaged mitochondria over the years leads to more free radicals in the body, which in turn cause all sorts of varied destruction to molecular machinery and important molecules. That contributes to, and some would say is the dominant cause of, aging and age-related disease.

The best way to deal with all this? Either replace all the mitochondrial DNA with fresh undamaged versions every few decades, a feat demonstrated in mice a few years ago via protofection, or make the damage to mitochondrial DNA irrelevant by blocking its ability to generate more free radicals. This latter approach is used by Methuselah Foundation funded researchers, amongst others, and is a part of the Strategies for Engineered Negligible Senescence.

So, with the background out of the way, I can now point out some interesting research via FuturePundit. It seems that not all human mitochondrial DNA (mtDNA for short) is created equal: some leads to a more rapid accumulation of age-related damage than others. Perhaps not in all tissue in the body, and perhaps not of great enough relative significance to spend a lot of resources investigating, but take a look and see what you think based on this evidence:

Genetic variation in the DNA of mitochondria - the "power plants" of cells - contributes to a person’s risk of developing age-related macular degeneration (AMD)

...

Variation in the mitochondrial genome reflects human migrations and different environmental exposures. Changes in the mitochondrial DNA can alter the efficiency of energy generation and lead to over-production of "reactive oxygen species" - free radicals that can damage the cell.

"By identifying genetic changes associated with the mitochondria, our results lend additional confirmatory evidence for the role of oxidative stress in AMD. This supports study of interventions that attempt to bolster our antioxidant defenses."

The interesting question: if you're going to use protofection to replace your mitochondrial DNA every few decades, is it worthwhile to replace it with the best of breed, most efficient human mitochondrial DNA? Since you're wiping the slate clean every time regardless, and the normal course of human life suggests that 30 years is a fine length of time to be carrying a set of mitochondrial DNA without replacement, the answer might be "no," unless the additional cost is very small.

Looking at research priorities, identifying best of breed mitochondrial DNA, or manipulating our mitochondrial DNA to look more like it via some form of gene therapy, is clearly nowhere near as important or impactful as wholesale replacement and repair of all our mitochondrial DNA.

A Discussion on Animal Longevity

Researchers talk about the basis for animal longevity at the Post-Gazette: "What is it about tortoise biology that makes them so long-lived? The same thing can be asked of some even more intriguing creatures in the Methuselah Club, including the rough-eye rockfish (up to 205 years), the bowhead whale (211 years) and the ocean quahog clam (225 years). ... In the bowhead whales, researchers have been able to chart the slow change in the orientation of amino acids in their eyelids, he said, while the rockfish and quahog lay down age-related rings, the rockfish in an ear bone and the quahog on its shell. ... Dr. de Magalhaes said he did a survey two years ago of hundreds of species of mammals, and 'what we showed is there is really no correlation between metabolic rate and life span in mammals.' ... 'I'm a little bit skeptical about the idea that telomeres contribute that much to aging,' said Dr. de Magalhaes, given the fact that mice, which live about four years, have longer telomeres than humans. ... scientists have been able to create mice with short telomeres and with long telomeres, and 'the mice with long telomeres don't have a significant difference in life span.' Unfortunately, the article doesn't delve into mitochondrial biochemistry, which looks like it might be much of the root of differences in life span, in mammals at least.

Link: http://www.post-gazette.com/pg/08128/879500-51.stm

$7 Million For Longevity Research

The Methuselah Foundation has reached $7 million pledged to Strategies for Engineered Negligible Senescence research, aimed at the repair and reversal of molecular and cellular damage that causes aging. "Congratulations are due to all the Methuselah Foundation volunteers and generous donors who have made our ongoing SENS research programs a reality. Thank you all! You can find out more about the SENS research funded and organized by the Methuselah Foundation at our website, and in the most recent progress report ... The Foundation currently sponsors research in two of the seven strands of the SENS program: preventing the harm caused by mitochondrial mutations (MitoSENS) and degrading damaging, long-lived cellular debris (LysoSENS). ... A selection of [further] projects within the SENS plan are ready to be launched as Foundation-sponsored research programs. [As] for MitoSENS and LysoSENS, these projects will start small (likely with only a single researcher), with the aim of delivering high leverage in terms of the credibility of the approach."

Link: http://blog.methuselahfoundation.org/2008/05/7_million_pledged_to_sens_long.html

Our Bioartificial Future

Sixty years ago, room sized computers for extremely specific applications were an impressive technology demonstration. We all know how that evolved. At a comparable stage in the advance of biotechnology, today we see that bioartificial implants - cells combined with microscale and chemical engineering - can perform one of the tasks of a pancreas:

Encapsulating a large collection of islets has been difficult, he says, because the material to make that capsule has never been designed for that purpose.

"This device differs because its polymer membrane has been designed to have the optimal properties for encapsulating islets," Rosenthal tells C&EN. "It allows for free movement of insulin and glucose but restricts access of immune molecules that might attack the encapsulated islets." Likewise, any viruses that might be piggybacking on the islets are trapped behind the membrane.

"Because of that, we can use pig cells, and the only thing that communicates between them and the patient are the small molecules and small proteins," Rosenthal notes.

The polymer can also sequester oxygen from the environment, thanks to its silicone-based components. This oxygen nourishes the encapsulated islets cells. "These membranes are biocompatible, flexible, transparent, autoclavable, and they're easily synthesized and relatively inexpensive," Rosenthal says.

Those room sized computers were pretty clunky and dedicated; the real challenge was in integrating such a beast with the processes and organization it was intended to help. The same is true of medical implants and helper devices, as we're just not very good at putting things in the body yet, measured on the grand scale of what is possible. It's tough, expensive and often damaging to the patient. But take a look at the computer you're using to read this post. Sixty years ago, you'd have had to build a city of rooms to match its power. Integration of that power for use in specific tasks is easy now, and an entire infrastructure exists to handle the tasks that are beyond one person's time and energy.

So to the future of bioartificial organs. A computer doesn't look much like a brain, a slide-rule, or a typewriter. The bioartificial pancreas of the future won't look a whole lot like the pancreas you're carrying around with you at the moment. In parallel to work on regenerative medicine and repair of aging - aiming to maintain the body we have - we will see a great breadth of development in semi-organic prostheses and other functional replacements, and the growth of support infrastructure for that technology.

There is a certain logic here that suggests bioartificial bodies as an end-point: consider that researchers can build a bioartificial pancreas, but it's still that case that long-term use of implants is a burden in the best cases, and simply impossible in most others. The problem is the integration between systems we have built and evolved systems in the body: everything from matching blood vessels to dealing with the immune system response is a challenge. So instead of hooking your new bioartificial organ up to a body, wouldn't it be easier to hook it up to another collection of bioartificial organs, where it is perfectly feasible to control all the interactions? The end of that line of thinking is a comprehensive support machinery for the human brain, an entirely different form of body and technology base in beneficial competition with regenerative medicine. Choice is good; mix and match.

It's a challenge to say what will be hard and will be easy 20 years from now, never mind further out. Maybe controlling the body to accept long-term implant use is trivial in 2030, and everyone queues up for the latest blood filter device from a Japanese fashion house, as it's substantially better than the one you were born with. But if you're interested in living for a long time, it's a benefit to keep up with what is happening today, and think about what is plausible in the years ahead.

Rebooting the Immune System Repairs MS

This is interesting news from the Australian, considering past work on rebooting the human immune system to repair otherwise irreversible damage: "Dr Freedman, who specialises in treating [multiple sclerosis (MS)], wanted to study how the disease unfolds. He set up an experiment in which doctors destroyed the bone marrow and thus the immune systems of MS patients. Then stem cells known as hematopoeitic stem cells, blood-forming cells taken from the bone marrow, were transplanted back into the patients. ... We weren't looking for improvement. The actual study was to reboot the immune system. ... Once MS is diagnosed [you've] already missed the boat. We figured we would reboot the immune system and watch the disease evolve [but] have yet to get the disease to restart ... Not a single patient, and it's almost seven years, has ever had a relapse ... We are trying to find out what is happening and what could possibly be the source of repair." This is still a comparatively unsafe procedure, but with enough incentive, resources will be allocated to make it safer and better. This is good, because benefits to health and longevity are likely to result from a safe way of rebooting an age-damaged immune system.

Link: http://www.theaustralian.news.com.au/story/0,25197,23658555-12377,00.html

Regenerating the Trachea

Regenerative medicine moves forward, organ by organ: "The trachea and other respiratory tubes, like most tubes in the body, have an intricate, three-layer architecture. The inner layer, or epithelium, interacts with whatever is flowing through the tube; in the case of the trachea, air. The middle layer is composed of muscle that constricts or relaxes the tube, and the outer layer consists of connective tissue that supports microvessels and small nerves. ... researchers found that it is not necessary to recapture the ordered layering to heal injuries. Instead, they concentrated on restoring cellular health. When cells are intact and have regained their biological function, they need only reside near the injured tissue to enhance overall repair. [Scientists] achieved this repair state by delivering a mixture of new healthy cells derived from the epithelial lining and the nourishing blood vessels. The combination of epithelial and endothelial cells take over the biochemical role lost with cell damage. The healthy cells release growth factors and other molecules necessary for healing tissue, and can modulate their delivery in response to physiological feedback control signals."

Link: http://web.mit.edu/newsoffice/2008/trachea-0505.html

What is Cryonics?

The Depressed Metabolism blog includes a wonderful introduction to cryonics that leads in from the use of other forms of metabolic arrest in medicine. It's far better than the one I put up some years back at the Longevity Meme. You should head on over and take a look:

Ethically, what is the correct thing to do when medicine encounters a difficult problem? Stablize the patient until a solution can be found? Or throw people away like garbage? Centuries from now, historians may marvel at the shortsightedness and rationalizations used to sanction the unnecessary death of millions.

...

Cryonics does not involve the freezing of dead people. Cryonics involves placing critically ill patients that cannot be treated with contemporary medical technologies in a state of long-term low temperature care to preserve the person until a time when treatments might be available. Similar to such common medical practices as general anesthesia and hypothermic circulatory arrest, cryonics does not require a fundamental paradigm shift in how conventional medicine thinks about biology, physiology, and brain function. Although current cryopreservation methods are not reversible, under ideal circumstances the fine structure that encodes a person’s personality is likely to be preserved. Complete proof of reversible vitrification of human beings would be sufficient, but is not necessary, for acceptance of cryonics as a form of long-term critical care medicine. The current alternative is death; or for persons who are at risk of suffering extensive brain injury, loss of personhood.

For very old and fragile patients, meaningful resuscitation would require reversal of the aging process. Obviously, the objective of cryonics is not to resuscitate patients in a debilitated and compromised condition, but to rejuvenate the patient. Ongoing research in fields such as biogerontology, nanomedicine, and synthetic biology inspire optimism that such treatment will be available in the future. The fortunate thing for cryonics patients is that even if fundamental breakthroughs in these fields will be the result of long and painstaking research, the cold temperatures allow them time - a lot of time.

Interviewing the CSO of CIRM

Over at Nature, an interview with the new chief science officer of the California Insitute for Regenerative Medicine: "I really think that we're getting awfully close to working with patients now. We will never institutionally neglect basic science, but the shift to translational work is definitely now a priority ... The unknown is that we have no control over the cells once they're transplanted or transfused. I feel very strongly that the animal models of disease do not reflect the heterogeneity of the environments into which we will be putting the cells in diseased humans. Pharmacologically induced Parkinson's disease is not the same as the natural human disease, for example. ... The immunogenicity issue of the transferred cells is far from solved. People are also concerned about tumorigenesis, and there's been a lot of in vitro progress in addressing that. ... I think people underestimate how expensive this research is. Yes, it's a lot of money, but it's certainly not unlimited. We have to figure out a way to be involved in clinical trials, and how best to use our resources in clinical trials. ... We've got to make concrete decisions, at least as far as phase I trials, in the next couple of months."

Link: http://www.nature.com/stemcells/2008/0804/080410/full/stemcells.2008.59.html

What If Cryonics Wasn't Cold?

The purpose of cryonics is to preserve the body and brain with as little small-scale damage as possible for revival via plausible future technologies, most likely medical nanomachinery. To save lives, in other words. Depressed Metabolism has previously argued that it's something of an accident of history that the cryonics industry uses cold-based preservation rather than a form of warm chemical preservation, and here elaborates on future molecular nanotechnologies that may achieve warm biostasis: "To see how one approach would work, imagine that the blood stream carries simple molecular devices to tissues, where they enter the cells. There they block the molecular machinery of metabolism - in the brain and elsewhere - and tie structures together with stabilizing cross-links. Other molecular devices then move in, displacing water and packing themselves solidly around the molecules of the cell. These steps stop metabolism and preserve cell structures."

Link: http://www.depressedmetabolism.com/2008/05/01/warm-biostasis-through-nanotechnology/

Calorie Restriction and Dietary AGEs

It looks plausible that some portion of the health and longevity benefits of calorie restriction stem from a reduction in the intake of dietary advanced glycation end products (AGEs). AGEs are created in the body as a metabolic side-effect, but also found in your food: "Increased oxidative stress (OS) underlies many chronic diseases prevalent in aging. Data in humans confirm the hypothesis that [AGEs] and other oxidants derived from the diet may be major contributors to increased OS in normal adults as well as those with diabetes mellitus or kidney failure. Mice fed a diet with a lowered (approximately 50%) content of AGEs or a typical calorie-restricted (CR) diet, accumulated a smaller amount of AGEs [and] did not have increased oxidant stress or cardiac or kidney fibrosis with aging. However, the findings in mice fed a CR diet with an increased content of AGEs resembled those in mice fed a nonrestricted diet that had the usual higher content of AGEs. Thus, there was an inverse correlation between the dietary AGE content, [oxidative stress], organ damage, and life span."

Link: http://www.ncbi.nlm.nih.gov/pubmed/18448795

Electric Pulse Interview With Aubrey de Grey

Some novel questions for biomedical gerontologist and healthy life extension advocate Aubrey de Grey in this short blog interview at the Electric Pulse. It is interesting, but not entirely unexpected, that one has to break out of the mainstream media stockade to see unexplored lines of thought:

EP: There have been a lot of advances in the realm of cosmetics or so called cosmeceuticals. Partially this has been because of the relaxed approval process compared to traditional drugs. Do you believe, as age defying cosmeceuticals get more powerful, that these regulations will be tightened?

Aubrey de Grey: Hard to say. I don’t really see why they should, because there are no powerful groups with vested interests in making that change occur - but also, there’s only so powerful that cosmetics are likely ever to get against aging, because if people are crumbling on the inside the it gets progressively harder to patch up the outside.

EP: As a follow up, do you think that advanced, highly effective cosmetics could have the same effect on breaking the "pro-aging trance" that successful mouse rejuvenation would have?

Aubrey de Grey: No. I think cosmetics have their place in enhancing people’s self-image and quality of life, but they don’t fool the wearer whose joints are hurting and who can’t run up the stairs any more, and that won’t change.

As I've pointed out in the past, the massive "anti-aging" marketplace sometimes looks as though it could provide great benefits to the healthy life extension community - a group of enthusiastic people and their delivery and marketing networks, flush with money, just lacking any product that actually works. But in practice, it just doesn't work out that way. Merchants focused on making money from things that don't work will keep doing just that and no more. The people buying the products show little to no sign of crossover to support of real longevity science.

If there really was a significant spill-over of sentiment and support from consumers of "anti-aging" brands to meaningful, scientific anti-aging research - or even between different "anti-aging" brands in the marketplace - I don't think we'd be seeing quite the same sort of hostile confrontation between brand-holders and scientists as takes place today. More to the point, I suspect that volunteer organizations like the Methuselah Foundation would be having far less of an uphill struggle than has been the case to attain their present level of success, and scientists backing rapid progress towards working anti-aging therapies would not be struggling to raise large-scale funding and fight conservatism within their ranks.

In essence, if there was any benefit to be had from the millions of Revlon customers, any tendency for these enthusiastic purchasers of potions to stand up for Strategies for Engineered Negligible Senescence research or similar efforts to repair aging, we'd have seen the signs by now. The "anti-aging" marketplace is its own closed world, ultimately irrelevant to the road to a cure for aging.

My own thoughts on the matter are that people aren't stupid. They know these potions don't do anything other than paper over the cracks (on a good day), and they're paying for a chance of papering over the cracks. That's an entirely different proposition from extending healthy life span, or actually repairing the damage of aging through medicine. The majority of the world is still firmly set on the idea of aging to death as something set in stone, but they want to look as good as possible while doing it.

More Stem Cells Than Thought, Perhaps

Ouroboros on just how many stem cells we have: "It is widely accepted that stem cells are involved in tissue regeneration. It is also widely accepted that (in most organs) stem cells are vanishingly rare. So: if there doesn't happen to be a stem cell adjacent to a site of damage, how can stem cells be involved in the process of tissue repair? There might be more stem cells than we think, because we've been missing them for some reason. This possibility is strongly supported by the recent findings of Zuba-Surma et al., who have discovered a population of tiny pluripotent cells (termed, appropriately, very small embryonic-like, or VSELs) scattered throughout the body. ... Note that both VSEL number and potency diminish with age, consistent with the decrease in proliferative and regenerative capacity that we see in older animals. ... Required skepticism: VSELs are both brand new and (so far as I can tell) idiosyncratic to a single group's work. Before we get too worked up about this, I'd like to see the work reproduced by other labs and in other systems. Hopefully that sort of confirmation is already underway." The easier stem cells become to source, the faster research and development will proceed.

Link: http://ouroboros.wordpress.com/2008/05/01/widdle-biddy-stem-cells/

Targeted Chelation Versus Lipofuscin Buildup?

In a similar fashion to the way in which antioxidants change from dubious to demonstrably beneficial for lifespan when targeted to mitochondria, it is proposed that chelation targeted to the cell's lysosomes can slow the accumulation of lipofuscin in your cells. You might recall that lipofuscin buildup with age contributes to age-related degeneration by eventually destroying the ability of cells to function. "Since the sensitivity of lysosomes to oxidative stress can be manipulated by altering the intralysosomal level of redox-active iron, it follows that lipofuscin formation might also be influenced. It is suggested that pulse doses of iron chelators that easily penetrate membranes could be used to diminish lipofuscinogenesis." But don't run out to buy chelation products - ingesting that stuff won't send it anywhere near your lysosomes, just as swallowing antioxidant products won't affect your mitochondria. More engineering is needed, and in this case a technology demonstration to confirm the proposal.

Link: http://dx.doi.org/10.1089/rej.2007.0621

Stress and the Damage of Aging

Stress speeds some modes of age-related decline, probably via the mechanisms of chronic inflammation: "Responses to stress anticipate adaptation to an unacceptable disparity between real or imagined personal experience and expectation, including adaptive stress, anxiety, and depression. However, if stress persists, it may lead to chronic diseases, ranging from inflammation and cancer to degenerative diseases. For some time, only remarkable stress was acknowledged to induce immune and vascular alterations, such as infection or hypertension. Now it is known that moderate stress independent of conventional risk factors can induce a potent alteration of health conditions and consequently shorten life quality and lifespan. ... Stressful life conditions turn out to induce a diffuse (systemic) pro-inflammatory status. Subclinical chronic inflammation is an important pathogenic factor in the development of metabolic syndrome, a cluster of common pathologies, including cardiovascular disease." As for other lifestyles that induce chronic inflammation, you can wait (and suffer) while researchers build drugs that block the mechanisms at fault, or you work to change your circumstances to cause less damage over the long run.

Link: http://dx.doi.org/10.1089/rej.2008.0667

"Should" is a Dangerous Word

"Should" is right up there with "we" as a dangerous word, one of the signposts you'll see as you're sliding down the slope to signing away your life and rights to collectivism. For example, the sentence "Should we want to live longer?" A lot of foundational assumption is slipped in underneath that one. "Should" according to who? Who is "we?" Who are these people with the veto over our desires implied by "should?"

It is usually the case that you will see sentences containing "should" and "we" in this way when you're being sold up the river. There exists some group of people who think you should live your life a certain way, regardless of your opinions on the matter, and this is a little of the manner in which they build up a rhetoric to justify their eventual use of force and constraint of law. Assumptions of inclusion and unity via "we" and assumptions of authority via "should." Neither are true; you're not a member of their little group unless you choose to be, and there is no authority beyond that which you grant them of your own choice.

If we didn't live in a world of huge, intrusive governments, in which the writing of law and use of force is up for grabs by any sufficiently well-organized and unethical group, then rhetorical dishonesty would just be part and parcel of persuasion. A tactic of the low road, and probably not a very good one at that, but there's nothing wrong with persuasion.

Sadly, we do live in a world in which freedom, beyond lip-service to the concept, is unfashionable and no-one is safe from the mechanisms of government. Those mechanisms are presently sitting atop medical research and development, for example, ensuring it proceeds far more slowly than is possible. It is plausible that access to life extension technologies, once developed, will be limited by goverment employees and their enablers. So we must be deeply suspicious of everyone who invokes unity, collectivism and authority in their speech.

When you see "should" think instead about your own opinion and reasoning. Don't let anyone tell you what to do with your life, or how long you can aim to live in good health. No more justification for is needed for working towards healthy life extension than "I would like to."