(Crossposted from Fight Aging!)

There's nothing wrong with becoming old, but everything wrong with aging. Old means experienced, invested, wealthier, time-tested and just all-round better for having been around the block. Aging, on the other hand, is the direct result of biochemical damage you picked up along the way - ongoing deterioration that is a side-effect of being alive. The passage of years brings a constant flow of opportunities for growth and self-improvement, until aging takes away your ability to compete, your ability to take care of yourself, and eventually your life. Someone should look into that.

If you're not one to think much about medical research, you might be under the impression that aging is fairly mysterious, a primal and inevitably metered process quite separate from the diseases of old age. In fact that's not the case. Aging is exactly and precisely the root cause of those diseases of old age, and scientists have a good understanding of what aging actually is, once you get under the hood and start looking at cells and the cellular environment:

• Loss of important cells without replacement over the years
• Accumulation of damaged, malfunctioning and senescent cells
• Free radical damage resulting from damaged mitochondrial DNA
• Accumulation of waste chemicals that cannot be broken down inside cells
• Accumulation of biochemicals gummed together by sugar outside cells
• Formation of amyloid deposits throughout the body
• Breakdown of cell control processes, leading to the runaway growth of cancer

The short story is that aging is damage and change, rust and wear for our biology that is caused by the normal operation of human biochemistry. You can't run machinery without causing wear, and you can't run factories full of machinery without creating waste by-products. Machinery with a lot of rust and wear breaks down in any number of ways, and biological machinery is no exception - just a few classes of wear, rust and buildup of waste lead to a vast array of different malfunctions.

When you can't do anything about the rust, wear and waste, you put on the best face possible under the circumstances and soldier on. Perhaps you convince yourself that the miseries of an increasingly damaged body and mind are for the best. It's a slowly boiling pot, but it's our slowly boiling pot, and it's all we have. We humans are good at that sort of proactive self-deception for the sake of sanity in the face of the inevitable - we've been doing it for a very long time indeed.

All habits outlive their usefulness, however, and self-deception about aging has lingered past its time. These early years of the 21st century are the opening notes in a symphony of biotechnology, an expanding revolution in medicine, research and computation. The breadth and speed of research in modern biotechnology is breathtaking; already, the laboratories of of this decade are far beyond those of the 1990s:

• Cancer researchers are developing targeted, precise, safe cell destruction therapies that will applicable to any unwanted, damaging cells.
• Scientists are turning the immune system to destroy the amyloid buildup of Alzheimer's disease, and other amyloids of aging will follow.
• Methods to repair and replace damaged mitochondrial DNA are emerging from the laboratory.
• The regenerative medicine community is deciphering the genetic and chemical controls that will make our stem cells do our bidding, to replenish cells lost to age.
• Researchers are plundering the bacterial world for enzymes that can break down damaging biochemicals that build up with age.

If you think aging is inevitable, and that we should make the best of it, then you're probably not helping the world's researchers in their efforts to repair the damage that causes aging. You see, funding for research is very dependant on the zeitgeist of the age. If most people think that aging is inevitable, conservative funding bodies won't fund research aimed at the repair of biochemical damage that causes aging. Thus little progress occurs, no-one in the public is given any reason to doubt that aging is inevitable, and medicines to repair aging are pushed further into the future, perhaps out of reach for you and I.

Given the choice to be old, wise and better without being aged, frail and ill, wouldn't you choose to repair the damage? It's not a hypothetical question anymore, and the number of years it takes to develop medicines of repair for aging depends upon your answer.

(Crossposted from Fight Aging!)

The rough estimate of resources required to develop - for mice - the medical capabilities called for by the Strategies for Engineered Negligible Senescence (SENS) is presently $1 billion over ten years, give or take.

Each of these [six lines of research] would require total funding in the range of $2m to $15m per year, spread over at least three and sometimes ~15 research teams. These teams will typically be working in a university or other research setting. [The lines of research] span six of the seven types of "damage" that Dr. de Grey has identified as the key intermediates in aging; the one not listed here is cell loss, whose rectification by stem cell and growth factor therapies is the subject of sufficient existing work worldwide.

That's for the whole spectrum of longevity therapies: engineering the body to make cancer impossible; replacing lost cells; ensuring mitochondrial DNA damage can no longer cause issues; destroying unwanted cells that cause damage; breaking down crosslinks and amyloid that gum up biochemistry; removing hard-to-degrade biochemicals in old cells. Given all that, you should be able to rejuvenate aged mice, and extend their healthy lives considerably. Then it's onto moving the technology to work for humans, where the cost really starts to rack up - but with the technology demonstrated in mice, there should be plenty of enthusiasm to pay that cost.

What does a billion dollars and ten years really look like when you're taking about warm bodies, concrete and conferences? It turns out to represent something like 500 researchers, plus resources for equipment, facilities and support staff, if you keep things lean and distributed, making the best use of existing research facilities and ongoing programs.

If you apply the 1:9:90 rule to a research community, you can expect that a 500-scientist strong group will include perhaps 5 researchers who are very respected and appear in the media in connection with their research, 50 who are well known in the field and very capable, and the remaining 445 ranging from research associates to skilled scientists yet to reach the heights of their careers. This community might take the form of ten dedicated laboratories at large universities, a few for-profit enterprises, and more than fifty significant initiatives within other large research organizations.

For comparison, that is considerably larger than the present calorie restriction research community but considerably smaller than either the cancer or Alzheimer's research community. Calorie restriction research and development is probably well over $1 billion in investment to date, but only if you count funds for trials and commercialization employed companies like Sirtris; I would imagine that basic and animal research has consumed rather less than that.

At the present time, I would be surprised to find more than 50 scientists worldwide working to develop biotechnologies that would fit into SENS as-is. Outside the regenerative medicine and cell therapy community, that is. Clearly, there is a way to go for fundraising and other efforts to influence the direction of research in the broader scientific community.

(Crossposted from Fight Aging!)

As you might know, Aubrey de Grey's Strategies for Engineered Negligible Senescence (SENS) places the known forms of biochemical damage that cause aging into seven categories, each with a recommended path towards repair or prevention:

1) Too few cells: Some tissues lose cells with advancing age, like the heart and areas of the brain. Stem cell research and regenerative medicine are already providing very promising answers to degeneration through cell loss.

2) Cancer: We must eliminate the telomere-related mechanisms that lead to cancer. de Grey suggests selectively modifying our telomere elongation genes by tissue type using targeted gene therapies.

3) Mitochondrial damage: Mitochondrial DNA is outside the cellular nucleus and accumulates damage with age that impairs its critical functions. de Grey suggests using gene therapy to copy mitochondrial DNA into the cellular nucleus. Other strategies for manipulating and repairing damaged mitochondrial DNA in situ were demonstrated for the first time in 2005.

4) Molecules gummed together with crosslinks: Some of the proteins outside our cells, such as those vital to artery walls and skin elasticity, are created early in our life and never recycled or recycled very slowly. These long-lived proteins are susceptible to chemical reactions that degrade their effectiveness. Scientists can search for suitable enzymes or compounds to break down problem proteins that the body cannot handle.

5) Too many cells: Certain classes of senescent cell accumulate where they are not wanted, such as in the joints. We could in principle use immune therapies to tailor our immune systems to destroy cells as they become senescent and thus prevent any related problems.

6) Junk between the cells: As we age, junk material known as amyloid accumulates outside cells. Immune therapies (vaccines) are currently under development for Alzheimer's, a condition featuring prominent amyloid plaques, and similar efforts could be applied to other classes of extracellular junk material.

7) Junk inside the cells: Junk material builds up within non-dividing, long-life span cells, impairing functions and causing damage. The biochemistry of this junk is fairly well understood; the problem lies in developing a therapy to break down the unwanted material. de Grey suggests searching for suitable non-toxic microbial enzymes in soil bacteria that could be safely introduced into human cells.

The Methuselah Foundation has modestly funded work on items #2 and #7 above since 2006, whilst research fundraising was in the early stages, as MitoSENS and LysoSENS:

The most promising approach [for LysoSENS], in my view, is to enable cells to break the junk down so that they don't fill up after all. This can be accomplished by equipping the lysosome with new enzymes that can degrade the relevant material. The natural place to seek such enzymes is in soil bacteria and fungi, as these aggregates, despite not being degraded in mammals, do not accumulate in soil in which animal carcasses are decaying, nor in graveyards where humans are decaying. This suggests that the micro-organisms present in soil have enzymes capable of breaking these aggregates down, and preliminary work in my old department in Cambridge, as well as work now being carried on at Arizona State University, has already confirmed this optimism.

...

MitoSENS research began at Cambridge University, in the MRC-Dunn Human Nutrition Unit. Ian Holt, Ph.D., head of the Mitochondrial Diseases research at the Dunn - who supervised the first MitoSENS projects - commented, "For over 30 years mutations in mitochondrial DNA have been suspected to be important contributors to aging. If we can incorporate working copies of that mtDNA into our nuclear DNA, the mtDNA will be rendered superfluous and any mutations it suffers will be inconsequential. Researchers have tried to do this for many years, with only limited success. The work that Mark will perform in my lab is the most systematic attempt yet to get this technology to work."

This March 2008, the Methuselah Foundation has transferred its MitoSENS Research program to the lab of Dr. Marisol Corral-Debrinski in the newly opened Institut de la Vision in Paris. Dr. Corral-Debrinski began her career studying mRNA localization to the mitochondria in yeast, a process which she identified as essential for mitochondrial gene therapies. She now heads a lab that is applying the mRNA localization approach to the development of gene therapies for treating inherited mitochondrial diseases. The same approach can, in theory, be used to treat the somatic mutations of mitochondrial DNA that play a definitive role in aging. For this reason, we have chosen to collaborate with her to hasten the development of gene therapies that may obviate mitochondrial DNA mutations.

With growth in philanthropic research funding through to the present day, thanks to many generous donors and the rising profile of the Foundation, these promising research programs are expanding. In addition, looking ahead, we can see the groundwork taking place for Methuselah Foundation-funded programs in the other categories of SENS:

AmyloSENS - cleaning up extracellular junk:

The Methuselah Foundation is presently in discussion with leading researchers in this field with a view to initiating work on a vaccine - similar to that developed by Elan for Alzheimer’s disease - to stimulate the aged body to clear the widespread amyloids (particular of transthyretin) responsible for senile systemic amyloidosis.

ApoptoSENS - removing senescent and other "gone bad" cells:

During 2008, the Methuselah Foundation will launch a project to develop a procedure for clearing aged T cells from the blood of mice, and potentially thereafter in primates. This work will be supervised by one of the top professors in the immunosenescence field.

GlycoSENS - breaking down crosslinks and AGEs:

The Methuselah Foundation is currently planning out a project to engineer enzymes capable of cleaving the ubiquitous glucosepane crosslinks, which may comprise as much as 98% of all the long-lived crosslinks in aged human tissue. This work is still in the early planning stages, but we hope to be able to begin full-time research before the end of 2008.

OncoSENS: alter cells to prevent cancer:

The Methuselah Foundation is planning to launch three projects in the OncoSENS strand during 2008.

The first project aims to characterise the enzyme responsible for [alternative lengthening of telomeres], which is still unknown. Recently, however, observations in two different organs have given good reason to consider a hitherto unsuspected gene. A relatively simple series of experiments could test this hypothesis.

The second project addresses a potential problem with the WILT strategy. It’s possible that telomerase activity per se - independent of telomere length - may have roles in maintaining the health of the stem cells themselves, or of their rarely-dividing neighbours in the so-called "stem cell niche". We are arranging a project to address this question, in the blood of mice, with the world’s leading professor in the area.

Finally, the theory that non-cancer-causing mutations are unlikely to be harmful in a normal lifetime - protagonistic pleiotropy - is not yet widely accepted. We are therefore initiating a rigorous study into the effects of such mutations in mouse brains.

RepleniSENS - replacing lost cells:

We need more work in all these areas, even though they are all progressing very encouragingly. However, the current fashion for stem cell research in the international scientific community means that the Methuselah Foundation does not currently intend to allocate its limited resources to projects in this area.

Stem cell research is a well funded field indeed, moving rapidly. I'd wager that the most important technologies for the repair of age-related tissue loss will be developed before 2020, if not fully commercialized (given the present state of what it takes to push anything past the FDA). What I'd also like to see by that time is the growth of active, well-funded research communities for the other areas of SENS. I think that this is very likely: even modest early success in SENS research will gather more established research groups to the fold, more independent funding for the science, and accelerate the process of change and progress in the broader aging research community.

(Crossposted from Fight Aging!)

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.

(Crossposted from Fight 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.

(Crossposted from Fight 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.

(Crossposted from Fight Aging!)

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.

(Crossposted from Fight 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.

(Crossposted from Fight Aging!)

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?

(Crossposted from Fight Aging!)

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?