(Crossposted from Fight Aging!)

Radical egalitarianism is an impossible ideal: that a utopian society could exist in which everyone is equal in some important way - in possessions, ability, or access to resources. Lesser arguments for egalitarianism are usually heard alongside the blandishments of green-eyed socialism: calls for a levelling brought upon anyone with greater wealth or better access to medicine. That type of egalitarian can often be seen speaking out against research into engineered longevity, on the - mistaken - grounds that it will be "for the rich" or otherwise benefit some small group before it benefits everyone. Death for everyone before inequality for anyone is the mantra there:

I find it very strange that apparently intelligent people can field this sort of argument. Replace working anti-aging medicine with, say, working heart transplants, or working kidney dialysis and see how far you get in trying to convince people that suppliers in the developed world are keeping such technologies out of the hands of others, or that we must stop using medicine that is not universally available. Quite aside from the glaring failure to understand simple economics, it is deeply depressing that we live in a world in which people argue for the enforcement of large-scale, preventable suffering and death.

...

Creating "equality" by taking from the successful ruins the creation of wealth - very much a non-zero sum game - for all. It takes away the vital incentives and rewards for success. At the end of the process, as demonstrated by all that transpired in the Soviet Union, you are left with the same old inequalities, but now taking place amongst ruins, starvation and disease.

In any case, I thought you'd be interested to see the fundament of the egalitarian position turned to support research into ending aging and extending healthy life for a change. Consider this another installment in seeing how mainstream pro-longevity bioethicists think:

Why should the aged have a much greater risk of cancer, heart disease, diabetes, AD, infection and death? The aged do not deserve the cellular and molecular damage that accrues over time; and thus we should seek to mitigate these vulnerabilities. And so I think the aspiration to retard human aging is actually a requirement, not violation, of equality. And this is what I argue at greater length in my paper "Equality and the Duty to Retard Human Aging"

The trouble with radical equality is that the "right" to possess more than you presently own - be it possessions, resources, or young cells - is what's known as a positive right.

Within the philosophy of human rights, some philosophers and political scientists make a distinction between negative and positive rights. According to this view, one's positive right imposes an obligation on another to do something for someone, while a negative right obliges others to refrain from doing something to someone.

A positive right for one person always implies enforced servitude for another person: where do the labor and resources to supply that positive right come from, after all? A system of government that grants positive rights is a system that must be backed up by coercion - taxes, public service, prison, police, and guns. Just try suggesting that you won't supply labor and materials for the postive rights written into law by those who will benefit from them, and see what happens. That is never ethical ... unless you happen to be one of the silent majority who believe it is acceptable to force other people to do what you want them to do. Sadly, if you look outside, you will probably find you live under such a government.

Anyway. It is interesting to see the emergence of attempts to restructure various restrictive philosophies of life to be in favor of engineered longevity, now that the prospect of actually engineering greater human longevity is more plausible. That in and of itself is a sign of progress, I think. Follow the incentives: when people think that they could possibly benefit from a future of rejuvenation therapies, then they will work on the roadblocks they know best. Articles like the one quoted above are a form of vote of confidence in longevity science.

Last week, I pointed out an example of researchers who believe engineered longevity must be accomplished by gene engineering and changing the operation of metabolism to slow aging. In that worldview, any significant progress is far in the future, because the task is very complex indeed. Progress in the future is also largely irrelevant to those of us alive today, as slowing aging does next to nothing for people who are already age-damaged to the point of disease and frailty.

I consider it to be unfortunate that the bulk of the pro-longevity aging research camp is focused on an inefficient path forward that will in the end lead to lesser benefits. It is their belief that this is the only practical way ahead: a laborious slog towards complete understanding of aging and metabolism, followed by an even more complex navigation through re-engineering that metabolism to age more slowly. The sheer scale and difficulty of that task is why many scientists feel that meaningful engineered longevity - more healthy years through science - is a long way away indeed.

Fortunately there is a fast boat in addition to the slow boat described above:

It is likely to be easier and less costly to produce rejuvenation therapies than to produce a reliable and significant slowing of aging. A rejuvenation therapy doesn't require a whole new metabolism to be engineered, tested, and understood - it requires that we revert clearly identified changes to return to a metabolic model that we know works, as it's used by a few billion young people already. Those rejuvenation therapies will be far more effective than slowing aging in terms of additional years gained, since you can keep coming back to use them again and again. They will also help the aged, who are not helped at all by a therapy that merely slows aging.

Today, let me point you to another manifestation of the "we can do no better than slow aging by metabolic manipulation" viewpoint:

The extreme arrogance of anti-aging medicine:

The anti-aging medicine movement proposes to alter the human body in order to achieve extreme longevity. To do this it has to reverse or by-pass the multiple causes of human aging. These include a large number of age-associated pathologies, each of which is being studied in great detail in research laboratories around the world. The protagonists of anti-aging medicine claim that it will be far more successful than the combined efforts of the innumerable scientists carrying out this research. Aging has an extremely long evolutionary history, and the anatomical structure and physiology of animals is directly related to their finite lifespan. The anti-aging movement proposes in a few decades to reverse what has been the result of millions of years of evolution.

The above abstract is wrong-headed, to say the least, but it is an output of the sort of worldview described above: a) that aging can only be slowed, b) that doing so requires the day to day operation of human biochemistry to be changed in non-trivial ways, and c) that this is a very tall order indeed for the medical science of the forseeable future.

So, to point out the errors. Firstly, the causes of aging are not the pathologies of aging. Pathologies are end results - if dry rot is a cause, then failing wooden structural beams are the pathology. Today's prospective longevity engineers talk about causes, about the comparatively few types of biochemical damage that build up in our tissues to create many, many different forms of pathology. Dry rot can make a wooden structure fall apart in any one of a hundred distinct ways - but all are still caused by dry rot.

If you want to tackle aging efficiently - and make no mistake, this whole debate is about efficiency - then pathology is the wrong place to start. If you work on patching up pathologies, then you are Canute against the tide. By failing to stem the underlying cause, your efforts are doomed to inefficiency and ultimate failure. Present day gerontological medicine is largely playing the role of Canute because that has historically been the best medical science can do: throw a huge level of resources at treating the consequences of aging and gain little by it. That little was better than nothing for billions, but it was still little in the grand scheme of things.

We stand in the 21st century now, amidst the early years of a revolution in the capabilities of biotechnology. Scientists can move beyond the historical focus of medical technology on patching end results and instead work on prevention and repair of root causes. Taking a different, more efficient path is why new approaches to longevity engineering will succeed in greatly extending the healthy human life span where decades of scientists and vast expenditures have only slightly raised the bar. Holding out the past as an example of the future is a terrible thing to do. You are rarely going to be right, as the future will be accomplished in a different, usually better way.

I predict that the last sentence in the abstact I quoted above - "reverse what has been the result of millions of years of evolution" - will come back to haunt the author for a good many years. No-one wants to be on record as saying something as bone-headed as that. In the past few decades medical science has reversed any number of evolutionary consequences, some of which have billions of years behind them. As if the number of years a feature took to evolve has any bearing upon the development medicine that acts upon it!

The preceeding point on the structure of living beings, however, is very illustrative of the metabolic manipulation viewpoint: hammering home again that biochemistry will be very hard to re-engineer for greater longevity through slower aging. This is absolutely true, and it would be astoundingly hard to follow though that path to developing longevity therapies. Every biochemical component in our metabolism is a part of many different complex evolved systems - evolution loves reuse and interacting, linked feedback systems. You can't change a thing without having to worry about profound side-effects in every connected process, and the processes important to aging are right in the middle of the engines of life.

But the modern longevity engineers, the heretical minority in the aging research community, are not taking that path forward. Rather, they use the metabolism we have when we are young as the ideal reference model, and seek to reverse all changes away from that reference model that occur with age. No re-engineering, no worrying about how change A affects systems B, C, and D - this is a straightforward repair and restoration strategy. The objective is to restore the metabolism we know works, not create some new metabolism that must be extensively tested and understood.

That is efficiency, and the nature of efficiency in longevity research is the most important debate within the life sciences today, for all that most people know nothing of it. The result of this debate will determine how long we all live in good health.

(Crossposted from Fight Aging!)

I missed a social interest paper from earlier this year, in which gerontologists were questioned on their views of healthy life extension and longevity science. The abstract is a fair summary of what I've seen of ongoing debates on the subject:

It is often assumed that there is broad public support for strong life extension research (i.e. research aimed at the dramatic extension of human life beyond the current maximum), and that there would be a near universal interest in using any life extending technologies that this research may produce.

In this paper we report the opinions of researchers in ageing on the controversial promise of life extension, and compare these views. This paper describes the professional attitudes, personal interest and concerns expressed by Australian and international researchers in ageing (n = 14) as expressed during semi-structured, in-depth interviews.

Researchers held varying opinions about the possibility of significantly extending human life. Some saw a limit to the extension of human life, while others did not. Some felt that research into the fundamental ageing process was a priority; others did not. Researchers tended to weigh up the potential risks and benefits of life extension with most expressing a personal interest in life extension that was contingent on the technology providing a good quality of life. Some participants were not interested in the prospect of life extension for personal reasons, because they felt the potential risks outweighed the potential benefits, or because life extension raised issues of justice and equity.

Compare this with another social science paper from earlier this year that investigates attitudes in the general populace. The results are very similar. On the one hand, it's good to see more researchers publicly expressing positive attitudes towards healthy life extension - that hasn't always been the case. But as always, those of us interested in living longer, healthier lives through science should be concerned that a good fraction of the aging research community - the people best placed to work on the fundamentals of future longevity therapies - is not all that interested in getting the job done.

"Justice and equity" in particular is a poisonous ideal when you attempt to bring it into the real world:

I find it very strange that apparently intelligent people can field this sort of argument. Replace working anti-aging medicine with, say, working heart transplants, or working kidney dialysis and see how far you get in trying to convince people that suppliers in the developed world are keeping such technologies out of the hands of others, or that we must stop using medicine that is not universally available. Quite aside from the glaring failure to understand simple economics, it is deeply depressing that we live in a world in which people argue for the enforcement of large-scale, preventable suffering and death.

Life is unfair, make no mistake. People are unequal in opportunity, capacity and the hand they were dealt at birth. To think that this truth can be removed in any way, shape or form is to betray a profound ignorance of economics and the human condition. You cannot make life better at the bottom by tearing down the top; the top is where progress happens, progress that lifts the quality of life for everyone. Punishing success in order to reward failure has predictable results - more failure and less success. The wealthy of 1950 were far worse off than the poor of today precisely because progress brings economic rewards to the successful.

The work of advocacy for longevity research is as much focused on those within the scientific community as it is on the general public. Not to convince everyone to walk in step, but to at least create a sizeable community of enthusiastic scientists - large enough to get the work done, and to sway conservative regulatory and grant organizations into ceasing their discrimination against this body of research.

(Crossposted from Fight Aging!)

It takes 20 years, give or take, for a new technology to move through multiple cycles of development, commercialization, and competition necessary to evolve from experimental prototype to widespread maturity. A look back at the past few decades of medical progress suggests that 30 years is more likely in that field - there's one effect of regulation for you, a slowing of the technologies that manage to make it over the regulatory hurdle in the first place.

What does this pace of progress in medicine mean for middle-aged and younger people today? It means that the 2030s will see widespread, cost-effective use of the medical technologies you presently read about in the science press. A small selection:

• Replacement organs will be grown to order from your own cells.
• Stem cells will be created, manipulated, and transplanted to direct extraordinary regeneration
• Age-damaged immune systems will be wiped clean and replaced afresh.
• Gene therapy will be a mature technology, and genetic disorders curable.
• Everyone will know their DNA sequence, and have access to a vast database of knowledge that describes risks, therapies, and best practices.
• Cancer will be detected early, and even late-stage metastasis cured with few side-effects by nanoparticle-based, viral, or other therapies.
• The important mitochondrial DNA will be replaced when damaged by disease or age.
• Many of the biochemical processes underlying the benefits of exercise, calorie restriction, and known human longevity-associated genes will be reproduced by cheap drugs.

These are just a few that spring to mind after watching the technology demonstrations in laboratories across the past few years. I've left out much that is promising but not confirmed - and notice that many technologies required for the repair of age-related damage are not yet at the stage where we can be confident that they'll be solved, mature, and widespread 30 years from now. The technology demonstrations haven't yet occurred, or there are too few research groups presently working on the science.

We have years - not too many, but some - to do something about that problem. I'm sure we all know what sort of capabilities in medicine we'd like to see awaiting us 30 years from now. No-one wants to be sick and crippled by age-related degeneration. But based on a survey of work taking place today, there is much left to do before we can look ahead with great confidence.

Remember that even if specific goals in medicine are possible, and even if this is an era of general progress in biotechnology, people still must work to deliberately bring those goals to fruition. The world is filled with examples of the possible and the plausible that have failed to come to pass because no-one has worked to make them real. We'll all be sorry if plausible rejuvenation technologies remain no more than a vision in the decades ahead due to lack of deliberate effort.

(Crossposted from Fight Aging!)

If you're the type who likes to inspect the mechanisms behind the sausage, you should take a look at an article on Alcor's board over at Depressed Metabolism:

In January 2008, Alcor’s self perpetuating Board came under renewed scrutiny after long-time Alcor member and cryonics activist David Pizer tried to raise interest for changing the current system to a member elected Board.

Scrutiny of the board is a fine tradition for stakeholders in for-profit and non-profit initiatives, as is stakeholder activism to produce desired change. The concern voiced in the article is that born of the perceived need for change at Alcor - to better produce growth, increased professionalism, and so forth - and the concern that a self-perpetuating board has little incentive to make the changes that the writer would like to see happen.

Member-voted boards have their own issues, of course, not least that a member (as opposed to stakeholder) has no meaningful ownership right connected to their vote - but the pendulum swings as it chooses.

This is all, I think, I fairly good illustration of the transitionary period from volunteerism to professionalism one sees in any growing industry. The cryonics industry has been going through this phase for a long time, and remaining very small in size, for reasons that are much debated. Is it the fault of the business model, incredulous public perception, heavy regulation, a comparatively undiversified technology base, or the laundry list of other potential factors? Can be solved by changing the way people pay, by changes in regulatory structures, or by increased investment in research and building spin-off technology businesses? And so forth. These are all questions that have been debated at length over the years.

What I think is most telling with regard to where the cryonics industry is at present is that you don't see a lot of discussion focused on change through competition. The traditional solution to undesirable characteristics within an industry is for entrepreneurs to set forth and compete, as "undesirable" usually means "customers will pay for something less undesirable." If you want change, then help to found a new company and do things the "right" way. Ongoing for-profit experiments in any number of different "right" ways are how progress is achieved and benefit brought to customers in the long term.

There needs to be more of that in the cryonics industry if the goal is directed change. The best way to make a board change their stripes is to look like you're going to eat their lunch out from under them; by doing that, you will also have gone a long way towards proving that your "right" way is in fact the right way for progress.

(Crossposted from Fight Aging!)

Via Marginal Revolution:

If [cryonics] works, the benefits are high, and the probability of it working is greater than zero. Yet few people sign up for it. I think that we are afraid of looking weird if we sign up for it.

The way to think about how and why people make decisions is to look at costs and benefits - which go far beyond mere money, of course. The discussion in the post revolves around "looking weird" as a cost. That's important for we folk descended from apes, possessed of a deep-seated and hardwired need for peer validation. Other costs exist, such as the need to get up and sort out paperwork - people die and become sick in many ways through similar laziness, especially in health matters stretched across the years. I think the comments to the post demonstrate that the more important costs are the perceived financial ones, however.

I suspect the eccentric childless millionaire demographic is overrepresented. Who else can afford it?

People look at the pay-at-the-door cost of cryonic suspension and decide they can't afford it, that cryonics is only for the rich. That is very much not the case, however. Next to no-one pays for their suspension in a lump sum at the door. Instead it's done via assignment of a life insurance policy for a very small number of dollars per month. There have been very few cryosuspensions of extremely wealthy people.

This suggests to me that if cryonics organizations want to grow, they should stop outsourcing organization of payment. Cryonics should be marketed from the very first touch to the potential customer as an insurance service you pay for monthly: people understand that, and do it all the time. What you are buying is cryosuspension should you be unfortunate enough to die, and the cryonics company handles the mechanisms of insurance - or however else the finances are sorted out - behind the scenes.

Monthly income for a company also allows for the sort of growth and professionalization that has been a challenge in the cryonics industry under the present model of funding for research and development. All in all, a potential win-win situation. One might ask why it hasn't been tried yet.

(Crossposted from Fight Aging!)

A number of folk from the longevity science and radical life extension advocacy communities were at last month's Idea City conference in Canada. A typically "balanced" but otherwise helpful article from the press showed up recently at the National Post:

The idea of youth restoration and life extension has long captivated the human imagination, from Dorian Gray's cursed portrait and Ponce de Leon's fountain of youth to cryogenic freezing and Botox.

Nowadays, the solutions range from the practical, such as Mr. Rae's extreme caloric tightrope, to the theoretical, which include scientific advances in tissue regeneration, biological tinkering to delay reproduction, and advancing the use of nanotechnology to repair the inner workings of the body with tiny cell-sized robots.

These kinds of futuristic solutions were a major focus of a recent conference in Toronto organized by Moses Znaimer, the 66-year-old media mogul who built his career on youth-driven television channels such as CityTV and MuchMusic and is now bent on rebranding 50-plus as the new watershed age for hip and active lifestyles.

"If you are having a good time and you are not in discomfort or disarray, we all want to live forever. Who wouldn't want to extend a happy and productive life?" he said.

But such a mission - life without end - is not without its detractors.

I can only imagine: "I'm writing an article on how good it is to breathe steadily and repeatedly - quick, find me someone to speak for the contrary viewpoint." Along those lines, here is an argument offered later in the article in favor of standing aside and letting billions of people suffer and die, who might otherwise have been saved:

"It's part of the natural cycle of things that life passes through these rhythms, one generation gives way to the next," he said. "We should be very careful about throwing that out.

"The world goes through change ... but we don't necessarily want to be the agents of some of that change."

Which is the same argument then marshalled by those who want to employ government force to make people suffer and die on a centrally-determined schedule - by blocking medical research and deployment of new technologies. Sometimes it's a challenge to live in peace with the asylum of would-be mass-murderers next door.

(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.