The Methuselah Mouse Prize

From mprize.org:

"The Methuselah Mouse Prize (MPrize), is the premiere effort of the Methuselah Foundation and is being offered to the scientific research team who develops the longest living Mus musculus, the breed of mouse most commonly used in scientific research. Developing interventions which work in mice are a critical precursor to the development of human anti-aging techniques, for once it is demonstrated that aging in mice can be effectively delayed or reversed, popular attitudes towards aging as 'inevitable' will no longer be possible. When aging in mice is shown to be 'treatable' the funding necessary for a full-line assault on the aging process will be made available. This is the true power of the Methuselah Mouse Prize, to demonstrate a proof of principle, and give hope to the world that decline in function and age-related disease are no longer guarantees, for us, or for future generations, if we work together now."

Fellow calorie-restrictor and long-time friend, Michael Rae, describes why he supports the The Methuselah Mouse Prize:

Today, I made the decision to join The Three Hundred.

This essay will explain who The Three Hundred are, why I joined them, and why I think you should do so, too.

The short answer to all of the above is that The Three Hundred is a commitment to strongly and directly support what I believe to be the most effective vehicle for funding genuine anti-aging research - research that could drastically delay, or even ultimately eliminate, the slow, but gradually accelerating downward spiral of physical and mental deterioration with the passing of the years.

In other words, it is our best hope of substantially forestalling or escaping an otherwise-foreordained future of increasing disability, suffering and death - and of watching helplessly as our loved ones undergo the same terrible decline.

While I am still relatively young and believe that I am indeed aging more slower than those around me, I have suffered the loss of my loved ones to the aging process already. It's bad enough to watch allegedly "independently-living" aged strangers out in public, idly shuffling their feet, pushing cleverly designed wheeled walkers or balancing on their canes, unable to open the doors for themselves, faces a mask of apathy. It's much worse to spend even a few minutes in a nursing home, walking out of a world of relative health of body and mind into an asylum of decay: men and women, once fit and optimistic about the future, now tied to oxygen tanks, raving mad or sunk into almost complete retreat from the outside world, sitting down hours in advance of their meals for lack of any better purpose to their lives, needing help to get out of bed or clean their own wastes.

But what is truly terrible is to be in such a house of horrors to visit your grandmother - watching her become increasingly passive, disengaged, and helpless; seeing her unable to carry out the basic activities of daily living until she is a decayed funhouse mirror image of an infant, unable to walk or even control her own bladder; wondering when she will die, and whether that is really the worst fate that you can envision for her.

I am conscious that the advancing process of cellular disorder that took a young woman - a woman that escaped poverty in Scotland, worked through two World Wars to build a home and a family, bore my mother into the world, and cared for me through almost three decades as a mature, increasingly wrinkly, but still proudly independent gra'ma - and slowly sapped her in body and mind ... consciousness that these same processes are invisibly at work in my own flesh, and are now erupting visibly in my own mother and father.

Most people refuse to confront this reality. When the horror of aging is thrust in front of their noses, they push it away desperately, reflexively wrenching their attention toward another subject. They pretend that it is "not so bad," that it is unusual and will not happen to them, or engage in elaborate flights of intellectual apologism for the "natural," "divinely-ordained" order of things. They lie to themselves that they will be satisfied with just a few more years of life after which they will simply check out, well before the full weight of the years begins to crush them.

As even a cursory glance at previous generations would demonstrate, for better or for worse, no one will choose to give up life merely because their bodies are losing the powers and liberties without which they do not believe that they could live. Whether struck by aging or rendered paraplegic by a fall on the ice, they will grasp at the thread of life until their suffering is truly so wracking of body and soul that their will falters and they simply cannot go on. Fundamentally, we all want to live -- in youth and health if possible, in age and misery if necessary.

Many readers will know that I invest a substantial amount of my time and energy into the only scientifically justified method of delaying the horror of biological aging: calorie restriction (CR). It is a measure of my own horror in the face of the aging process that I spend so much of my life's energy in an intervention that I know perfectly well to be crude, weak medicine.

Tragically, those around me are so put off by the bitterness in the medicine that they refuse to take it. But even if they were to join me in massive salads and refusing Rocky Road ice cream, CR is not, ultimately, a solution to the problem. CR will - if, as I believe, the animal experiments translate well into the human case - buy perhaps a couple of decades of middle- and late-middle-aged relative health. It has already granted me improved vitality in many ways, even as it has come with a cost in other areas. But CR is just buying time - and not much time, at that. The specter of biological decay is still before me.

I want to live forever; or if not, I will accept as a second choice to live indefinitely in youth and in health. CR cannot deliver this dream. To do it, we will need a new biomedicine that attacks aging at its most fundamental, molecular roots, in ways that never naturally occurred in our genetic toolkit.

There is reason for optimism in thinking that this goal can be achieved. Decades of research into the biology of aging - much of it using the CR model - have revealed the fundamental molecular lesions that are associated with aging and almost certainly drive it. Theoretically, we could remove or neutralize these toxic wastes, creating interventions that will not just slow down the molecular gumming-up of life's machinery, but halt or even reverse it. We could actually undo the toll of the years ([1-4]; for a very accessible overview, see [5]), and then aging itself could come to an end. We would spend centuries or millennia in youth and health, only falling prey to catastrophic accident or disease.

There is significant progress toward [6,7] - and in some cases even preliminary proof-of-concept for [8-10] - several interventions based on these insights. The problem is to turn these as-yet-theoretical solutions - or any others! - into widely available therapies. As with any medical discovery, this entails a long process starting with test-tube studies and working hypotheses, moving to animal models, and finally progressing to human trials and regulatory hurdles.

Venture capital has demonstrated that it lacks the attention span or patience for such expensive, long-term projects in medicine. One major problem is that there is no way to quickly assess the effect of a new intervention on aging. You can perform a good rodent cancer study in a few months, and Phase II cancer trial work in humans can be accomplished in a year or so, but there's no way to do this with aging. The critical, absolutely essential first step - a full lifespan study in rodents - takes not five months, but five years, and requires many more rodent subjects (and proportionally greater expense).

As a result, all of the biotech companies that initially made their buzz by promising anti-aging drugs have retreated from this vision - more or less as soon as a putative anti-aging drug looks promising as a treatment for some diseases - and lifespan studies are abandoned. Geron, to pick the obvious example, was founded by Michael West to exploit telomerase as the cellular fountain of youth. Venture capital firms were initially excited: West put forward a powerful pitch during the early, optimistic inflation of the biotech bubble. Investors rapidly lost interest in long-term goals, however, and began insisting that Geron work to drugs (and revenue) into the pipeline post-haste. Thus telomerase the anti-aging enzyme became telomerase the target for cancer inhibition. The same thing has happened to Sirtris, Elixir, and all the way down.

Venture firms are not being terribly patient with some of the longer-pipeline ventures which do have obvious disease applications either: Advanced Cell Technology and even Osiris Therapeutics have been treading water financially for nearly three years now.

There are related problems in academic research, alas. For one thing, the length of time required to do a rodent lifespan study, and the nature of the experiment, makes it very unpopular with grad students and thus difficult for senior researchers to implement. No one wants to spend five years of an up-and-coming career minding lab rats in order to produce one single study (a survival curve, plus commentary) at the end. This is particularly true since, historically, these experiments have mostly been flops - not good material for inclusions in one's CV.

Another point worth noting is that government-funded researchers are not exactly at liberty to pursue whatever studies they want. Scientists must write funding proposals to explain exactly what they want to do, and exactly why. Here, a nasty vicious circle is in play: the people making funding decisions, while scientists, are first and foremost acting in their capacity as bureaucrats with political masters. Research thought to be fringe or misunderstood by politicians or the electorate - such as a scheme to "engineer negligible senescence" - is poison to a political or bureaucratic career. Ironically, because of its less cut-and-dried nature, similar bureaucracies in the arts (such as the National Endowment for the Arts in the US) are actually more insulated from their political masters - they can defend the allocation of funds to fringe or unpopular work on freedom of expression grounds, and because art is by its nature in the eye of the beholder. Neither defense applies for scientific work, of course.

Thus scientists continue to pursue relatively modest, uninspiring projects, and to couch their work in modest, uninspiring terms. "We're not looking for a cure for aging. We'd just like to learn how to delay some of the diseases of aging so that Granny can be more comfortable in her old age." This is what obtains funding, regardless of the actual limits on what is possible or plausible in medical research.

This state of affairs reinforces the impression, in the minds of the electorate, of a scientific consensus that real intervention in the aging process is impossible at this time. This reinforces the pressure on politicians to prevent government funding being "wasted" on such work. This in turn reinforces the need for scientists who want public funding to play it safe. Round and round this vicious circle goes...

How do we break out of this self-perpetuating system?

One way would be for people like us, concerned about aging, to fund the work ourselves: to hunt down projects that we consider likely to lead to extended life in mice, raise a huge pile of dollars, and just hand the money over to someone willing to do the study.

The Life Extension Foundations's LifeSpan study illustrates part of the problem with this approach. Having invested - to their credit - large sums of money in seriously testing a dozen or so promising supplements and drugs, they came away with a fistful of failed overlapping lifespan curves, a lot of dead rodents, and many, many millions of valuable dollars essentially wasted.

Another problem is sheer lack of funds - even funds to waste. For now, there are no huge, well-endowed research charities, nor nearly enough concerned individuals, contributing money to work on anti-aging interventions. Charities working on cancer and heart disease raise a lot of money - donors recognize these high profile diseases from which they suffer or of which their mothers, husbands and friends have died. Patients and their advocates are also very politically active in pushing for - and obtaining - public funding for work on their specific diseases. The present state of AIDS funding is perhaps the most spectacular and successful example of this form of activism, but the results of cancer and Alzheimer's advocacy are also impressive. Yet only a few people with the universal disease - aging - are prepared to make the same sort of effort. So long as people refuse to think of aging as a disease, as something that is not "a normal part of life," and as a medical condition that can be cured, then we will not see this kind of mass mobilization (or, in the case of AIDS, a mixture of an energetic and effective activist core coupled with widespread public sympathy and sense of urgency).

We have to come up with a creative way to mobilize the funds sitting amply in other coffers - the aforementioned government medical research bureaucracies and venture capital firms. From this starting point, we arrive quickly at the Methuselah Mouse Prize - http://www.mprize.org.

Structured as an improvement on the X Prize model, and enjoying that organization's Peter Diamandis as a chief advisor, the Methuselah Mouse Prize (or M Prize) actually consists of two related prizes. The Longevity Prize is to be awarded for the next record in single-animal lifespan in the laboratory mouse, the second Rejuvenation Prize for the greatest extension of lifespan in a mouse that is already elderly. The former will likely lead to advances in our understanding of the mechanisms of aging, while the latter is more likely to lead to viable anti-aging therapies for people who (as biogerontologist Aubrey de Grey once put it) have the misfortune of already having been born.

The M Prize has the potential to remove the stumbling blocks preventing scientists in government and industry from taking on the aging process as a curable disease. On the one hand, it reorients the incentives for industry. Right now, there is no specific incentive for private researchers to perform lifespan studies in mice: at most, they are a stepping stone toward long, expensive, human trials - and as noted, even the rodent studies are long and expensive. When a significant financial reward - and the promise of substantial publicity - is put in place, however, suddenly there is a business case for spending a few years rather than a few months in testing a compound in mice. Should you succeed in rejuvenating mice, you can bet that Big Pharma will be beating down your door for the rights to translate the intervention to the human case.

The M Prize can dislodge the vicious circle that drives the lack of serious anti-aging biogerontology in academic research. For the scientists, it creates an incentive to write those grant proposals, in hopes of obtaining more funding directly and greater prestige for their institutions - prestige itself tends to attract more funding. On the side of public opinion, the Prize structure, by its nature, captures public imagination and provides a dramatic way to educate the public and media that scientists are working on extending healthy lifespan in mammals. This increases the credibility of any similar reputable efforts and wins acceptance for the idea that it can be done in humans. In turn, changes in public opinion eases political constraints on awarding public funding for such projects - and may even lead to active pressure to make such awards.

The real tipping point, however, comes when aging is demonstrably reversed in an elderly mouse. Aside from the obvious point that success in mice implies a parallel success in humans with adequate further research, it may initiate a sea change in public opinion as people allow themselves to believe that aging could be cured in humans. I envisage this leading to a public and political demand for a War on Aging. At this point, the whole field of serious anti-aging research will become scientifically respectable. It will attract scientists and funding; this will further fuels the expectations of the public and pressure for public and private funding.

Before you know it, a virtuous circle has taken over from the vicious circle. Scientific results will drive public optimism, in turn driving political acceptability, public and private funding. Funding will eventually lead to the results we wish to see: breakthroughs in the science of longevity and aging.

The bottom line, however, is that breaking the existing vicious circle will require a substantial reserve of money, even if accomplished the efficient M Prize way. Here, again, we are confronted by the relatively small people who are willing to set aside their protective apologism for aging, and to recognize it for what it is: a degenerative medical condition no more worthy of respect and no more inevitable than syphilis. As I am sure many of you know, most people will not allow themselves to dream of an ageless future, or even acknowledge that it is desirable. Justification and peace of mind was necessary when nothing could be done - but that is no longer the case. Precisely because aging is universal, viewed as inevitable and "natural" because it happens after a relatively extended period of time, we don't see the sense of urgency or injustice that fueled the successful campaign to make AIDS a research priority in the 1980s.

To make it work, more of us are going to have to stop avoiding the issue and stare unblinkingly at the horror of aging. We must accept that aging is simply a medical condition, subject to research and treatment, and realize the magnitude of the moral obligation and personal stake resting in putting an end to biological aging.

To join The Three Hundred - named for a heroic force of 300 Spartan warriors who held back the invading Persian hordes at the narrow pass of Thermopylae, buying the Greeks time to mobilize an effective defense - is to commit to a donation of US$1000 per year for the next 25 years. The donations of the The Three Hundred will help build up the M Prize into an effort mighty enough to mobilize the scientific community into action for a concerted, all-out campaign to defeat aging and age-related disease.

The need is great for people to sign on to The Three Hundred - I have now answered the call. As you consider whether you, too, will step forward and make the financial commitment needed to fuel this critical change in the direction of aging research, bear several things in mind.

First, remember "you can't take it with you." You may think that you have an unusually well controlled case of aging, but it's still a terminal, degenerative disease. Even the best available treatment (calorie restriction) has some risky side effects associated with it. If a cure is not found, your fate will be sealed in a few short decades.

Second, this is a crucial time to contribute to the M Prize, as is begins to garner serious attention from the media and scientific community. You can help show the world that people are serious in the fight to cure aging!

Third, for every day of delay in the march towards a cure for aging, tens of thousands of people - men and women; parents, brothers, wives - will die. This is the daily body count resulting from biological aging. Can we really afford to wait?

We need an intervention that will fundamentally arrest, or reverse, the biological decay that creeps into our every cell with each passing year. Too few people are pushing this agenda. We - the healthy life extension community - must put our hands upon the wheel. If not us, who else, after all? We must wake up to the reality of an epidemic in slow motion: a medical condition rendered paradoxically invisible by its very ubiquity is slowly debilitating and killing us all. We should write to our politicians and legislators and demand they stop interfering with science and start working to support cures. Relevant resources for those ready to do battle with their pens and at the ballot box can be found here:

http://www.longevitymeme.com/topics/activism.cfm

We must also realize that if we don't invest what we can to fight aging, this slow degeneration will take it all anyway. What value has money if our loved ones are dying in front of our eyes? What is the value of a dollar when wallets are emptied by the cost of fighting age-related disease as our bodies fall apart? What use are coins and notes when we have been trapped in the final stages of Alzheimer's? He who dies with the most toys is still dead - and likely received little pleasure from his toys in the gloomy final years of age-related illness and decay.

The success of the M Prize is not guaranteed - but as nearly as I can see, it is the only currently available way to make effective use of our resources to bring an end to the Gray Holocaust and commence an endless summer of healthy vitality. Time is growing short: we don't have many years or many chances to defeat aging.

Sign up at http://www.mprize.org . Give what you can. Your youth, your health, your life, your loved ones, and the future of humanity are riding on it.

1. de Grey AD, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CA, Porterg AC.
Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers.
Ann N Y Acad Sci. 2004 Jun;1019:147-70. Review.
PMID: 15247008 [PubMed - indexed for MEDLINE]

2. de Grey AD.
An engineer's approach to the development of real anti-aging medicine.
Sci Aging Knowledge Environ. 2003 Jan 8;2003(1):VP1. Review.
PMID: 12844502 [PubMed - indexed for MEDLINE]
http://www.gen.cam.ac.uk/sens/focusPP.pdf

3. de Grey AD.
Challenging but essential targets for genuine anti-ageing drugs.
Expert Opin Ther Targets. 2003 Feb;7(1):1-5.
PMID: 12556198 [PubMed - as supplied by publisher]
http://www.gen.cam.ac.uk/sens/manu21.pdf

4. de Grey AD, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter RJ, Stock G.
Time to talk SENS: critiquing the immutability of human aging.
Ann N Y Acad Sci. 2002 Apr;959:452-62; discussion 463-5.
PMID: 11976218 [PubMed - indexed for MEDLINE]
http://www.gen.cam.ac.uk/sens/manu12.pdf

5. http://www.speculist.com/archives/000056.html
(This is also pretty good: http://www.longevitymeme.org/articles/printarticle.cfm?article_id=15)

6. Khan SM, Bennett JP Jr.
Development of mitochondrial gene replacement therapy.
J Bioenerg Biomembr. 2004 Aug;36(4):387-93.
PMID: 15377877 [PubMed - in process]

7. Gonzalez-Halphen D, Funes S, Perez-Martinez X, Reyes-Prieto A,
Claros MG, Davidson E, King MP.
Genetic correction of mitochondrial diseases: using the natural migration of mitochondrial genes to the nucleus in chlorophyte algae as a model system.
Ann N Y Acad Sci. 2004 Jun;1019:232-9. Review.
PMID: 15247021 [PubMed - indexed for MEDLINE]

8. Bendiske J, Bahr BA.
Lysosomal activation is a compensatory response against protein accumulation and associated synaptopathogenesis--an approach for slowing Alzheimer disease?
J Neuropathol Exp Neurol. 2003 May;62(5):451-63.
PMID: 12769185 [PubMed - indexed for MEDLINE]

9. Du H, Schiavi S, Wan N, Levine M, Witte DP, Grabowski GA.
Reduction of atherosclerotic plaques by lysosomal acid lipase supplementation.
Arterioscler Thromb Vasc Biol. 2004 Jan;24(1):147-54. Epub 2003 Nov 13.
PMID: 14615393 [PubMed - indexed for MEDLINE]

10. Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, deGroof RC, Lakatta EG.
Improved arterial compliance by a novel advanced glycation end-product crosslink breaker.
Circulation. 2001 Sep 25;104(13):1464-70.
PMID: 11571237 [PubMed - indexed for MEDLINE]

Michael's article also appears on The Longevity Meme web site and The Calorie Restriction Society Community Mailing List Archive.