From Michael Rae
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Michael Rae is Aubrey de Grey's research assistant and a man who writes a mean post (and a great article) once he gets going. Here is a good example on the Mprize, aging research and other related topics, made in response to Matt Piles on the Calorie Restriction Society mailing list. I'll let him take it from here:

Matt Piles wrote:
> Michael wrote:

>> Solution: don't get biologically old ;). Keep your
>> Calories low; speculatively, also keep your long-chain PUFA and
>> dietary cholesterol intakes low; and be a luddite
>> in the engines of aging by giving till it
>> hurts to the MPrize .
>
> Actually in my view this would be a huge waste of
> money. Especially if it hurts...... Aubrey de Grey
> grossly misunderstands what motivates biology
> researchers. The analogy with the Ansari X-Prize for
> example is false. In contrast to aerospace engineers,
> gerontologists can easily get *tons* of money from the
> government.

That depends on which "gerontologists," and what exactly they want to do with the money. The NIA curretnly has a budget of just over US$1 bn. Of this, more than half now goes into Alzheimer's disease (plus the amount invested separately by NIMH, NB); much of the rest of its budget goes into other specific diseases; and a large chunk also goes to geriatric (ultimately, palliative) medicine and to "social gerontology" (ie, how to set up social structures to support the frail elderly).

Richard Miller has pegged the total NIA budget actually allocated to the biology of aging at "somewhere between six and ten million dollars a year" [1] -- a blip that would hardly be missed in the US biomedical research budget.

Even this gives an overoptimistic picture of the funds available for INTERVENTION, because almost all gov't-funded biogerontology expenditure is going into curiosity-driven descriptive studies -- trying to tease out the metabolic origins of aging -- and not into intervention-oriented work. Even most CR work, after the failure of the (relatively) massive Biomarkers of Aging study's flop, is oriented toward its impact on specific diseases, or toward testing theories of aging causes, or trying to figure out its human extrapolability, and not into actually doing something about aging as a disease in need of biomedical solution.

I actually asked Huber Warner, the outgoing director of the NIA, why the NIA wouldn't put more money into intervention-oriented work at the last AGE conference. After first either greatly misunderstanding, or trying to politely duck, this question by talking about the difficulties of so-called "accelerated aging" models, he ultimately gave a response that made Aubrey smile in the way that a police officer who's just extracted a confession of a horrible crime must smile. Because Warner's response appeared to confirm key elements of the nasty "vicious circle" that Aubrey has long held to be holding back serious work on anti-aging biomedicine. He said that they receive very few applications for such work, and that the NIA's internal "peer" review process tends to shoot most such proposals down. As I have written in my previous, major post on the MPrize:

Also, gov't funded researchers are not exactly at liberty to pursue whatever they want. They have to write up proposals to explain exactly what they want to do, and exactly why. And here, a nasty vicious circle gets started. Because the people doing the funding decisioins, while they are scientists, are (in their capacity as funding allocators) first and foremost bureaucrats, with political masters. Crazy-sounding (to politicians, or to their electorate) schemes to "engineer negligible senescence" are deadly to a political or bureaucrataic career. Ironically, because of its less cut-and-dried nature, similar bureaucracies in the arts (eg. the NEA in the 'States) are actually more insulated from their political masters, because they can defend the allocation of funds to (say) an exhibition of crucifixes smeared with an assortment of bodily exudae on freedom of expression grounds, and because art is by its nature in the eye of the beholder; neither defense clearly applies for scientific work.

So scientists continue to pursure 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 reinforces the impression, in the mind 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 not to have government funding 'wasted' on such work. Which reinforces scientists playing it safe. And 'round and 'round ...

So how do we break out of these self-perpetuating systems?

In the post in question, I say: the Prize.

Despite his rivalry with de Grey, Richard Miller (unsurprisingly) agreees about the basic structure of the logjam:

"Scientists and their patrons -- even those who have legitimate research interests in interventional gerontology -- do not wish to be seen hanging out with [purveyors of useless nostrums]. Perhaps for these reasons, discussions of research on life span extension are carefully skirted in political discourse at the [NIH] and among similar custodians of public funding. One can sometimes get away with cautious circumlocutions ("we do research on the causes of late-life illnesses"), but to be safe, it is clearly better to focus on how to "add life to years" and how "to learn the secrets contributing to a healthy old age." A president who publicly committed the government's resources to research on extending peoples' life span would be deemed certifiable." (2)

He also lists several less important reasons. Having had a lot more close interaction with the biogerontology establishment in the couple of years since the first SENS conference (reminder: SENS 2 is coming this September -- yeah!!), and especially since early this year when I began formally working as Aubrey's research assistant -- I must now, depressingly, add one more factor: most biogerontologists really aren't actually INHERENTLY interested in their field of study. They are simply intelligent people with enormous curiosity and the skills to do science, who like to exercise their brains and beakers, and who will pursue whatever project that they can get funded that allows them to do so. They got into biogerontology because, as grad students, someone had a grant doing aging-related work, and they just kept pursuing the resulting trajectory -- or, they repackaged their existing work as being in some sense or another "aging research" because the field has recently become somewhat sexier, and perhaps their old niche was not (or was too crowded).

But most biogerontologists would be just as happy to be working in almost any other field of biology: they feel no particular existential urgency about their own aging, nor about the grey holocaust that surrounds them, and would be completely satisfied to simply spend their days teasing apart metabolic pathways and playing with the latest visualization tools for the rest of their careers (which are, of course, doomed to be cut short by the ongoing, progressive, intrinsic degeneration of their bodies and brains -- oops, don't think about that ... focus on your gels ...). They feel no particular urge to damn well DO SOMETHING ABOUT the molecular rot whose progression they so painstakingly document.

This isn't all of them, of course: Richard Miller, Mark Lane, and many of the people who have actually done lifespan calorie restriction (CR) studies (a vanishing breed, alas) are much more conscious of the horrors of biological aging -- and optimistic that something can be done about it -- than their peers. I think, unfortunatley, that the work that most of these folks either are doing, or WOULD be doing if they could somehow beg the farthings, is devoted to a very poor strategy for developing genuine anti-aging biomedicine: the development of CR mimetics and other methods of perturbing the metabolic processes that CAUSE aging damage, instead of work to UNDO the damage itself.

By comparison, the Nationall Cancer Inst gets US$4.7 bn per annum, and almost all of the research dollars (ie, what isn't gobbled up by bureaucracy, outreach, etc) go into work that the researchers have successfully argued will plausibly ultimately result in cures. And it's much more likely that these researchers recognize the seriousness of their work: many of them have watched someone they love suffer and/or die of cancer, and while eveyone has relatives that have suffered and/or died of aging (and everyone has the disease themselves), the nigh-universal state of false consciousness and quietism about the aging plague extends to most biogerontologists as well.

We need to create an independent incentive system, and/or a pump-priming supplement to the existing one, and/or to mobilize the public to demand that the government put money into interventive biogerontology research on a scale proportional to its actual impact on morbidity and mortality -- ie, a scale far exceeding that awarded to the NCI. (As a ballpark: per 1985 figures, the average 50-yr-old woman would gain 2.7 years of life from the utter ERADICATION of cancer from human experience; an effective CR mimetic that could be administered in childhood would gain her over 30 yrs, or more than ELEVEN TIMES as much (2) -- including by greatly reducing the incidence of cancer. Yet it's cancer that gets most of the money: as another ballpark, something like 470 times as much per annum).

The MPrize goes a long way toward addressing all of this.

> And The Methuselah Foundation is viewed
> with suspicion in some circles and even as a bit of a
> joke. Look at Spindler's Web site.
> He doesn't mention that he won one of the Methuselah
> Foundation's prizes.

Well, first, in a real sense he HASN'T won one of the prizes. He was given the inaugural award -- the baseline, against which the first Rejuvenation Prize winners will be judged. This came with no funding at all.

Second, Spindler himself does appear to think that the MMP is a good strategy:

While he concedes that the fruits of his research - in the form of drugs and other biological interventions that could slow aging in the human population - are not likely to appear for several years, Spindler sees tremendous promise in the burgeoning field of anti-aging research. Ventures like the Methuselah Mouse Prize and the research it spurs will help turn skeptics into believers, erasing the public perception that his line of work involves a hopelessly quixotic search for some bogus fountain of youth.

Third, and most important: the impact of the Prize on actual research agendas can't be expected to be much as yet, nor a winner in the near future to trumpet hir results too much, for the simple reason that the Prize is as yet too small. The total pledged pot is now ~US$1.3 million, but most of this is in pledges such as the "300" commitment http://www.mprize.org/index.php?pagename=thethreehundred ; the prize amounts actually available for dispersement are:

Longevity Amount 60,065.84
Rejuvenation Amount 90,329.68

... of which only a percentage will actually accrue on winning, since one only gets a fraction of the prize money available for the Prize in which one is entered, depending on the magnitude by which one exceeds the existing record (see http://www.mprize.org/index.php?pagename=structure ). Even the full $150K would not cover a single mouse lifespan study; a mere slice of said jackpot clearly is not a significant incentive.

To determine if something is a good bet or investment, you take the value of the anticipated reward, subtract the cost of the wager/investment, and multiply by the odds of its occurrence, and compare the result with a similar analysis of all the other things one might do with the wager (including sticking it in one's pocket). The course of action with the greatest result is the rational course of action. If the reward is, as in this case, LESS than the investment risked, and the odds are not overwhelmingly favorable, it's a bad bet.

So as yet, no one is actually gambling. The contestants to date are signed up either for ideological reasons (Bartke) or for publicity (Sinclair) or because Aubrey is just so gosh-darned congenial (Weindruch; probably Leeuwenburgh). When the Prize jumps up by an order of magnitude or two, we can expect a genuine horse race, both because it will actually begin to be a good bet, & becaue the horse race itself will be good enough publicity to make being in the competition valuable to private companies.

> Ergo De Grey's charts about how motivation can be
> altered with the prestige of the prize may be based on
> an utterly false assumption about the prestige of the
> prize.

First, I'm not sure to what chart you refer: the only attempt to estimate the impact of the Prize that I've seen has actual *dollars*, and not prestige, on the X-axis:

http://www.mprize.org/index.php?pagename=lifeline

(Note that I don't take the specific dollar values terribly seriously: it's PAINFULLY back-of-the-envelope. But it does give an accurate impression of HOW it's likely to work based on the history of research prizes).

Prestige as such is not the major reason why the Prize will ultimately succeed. Rather, the Prize will help create radically long-lived mice (and through them, humans) because it will have an award that is actually large enough to (a) keep an academic lab or biotech startup going, and (b) generate excitement and publicity on a scale that (i) is of use to such ventures -- as advertising for private firms (note the enrollment of both Sirtris' Sinclair and Elixir's Guarente), and as a grant magnet for academics -- and that (ii) will rouse the public's anticipation of progress, break their quietism, & spur them to make political and economic demand for a real cure for aging. From a sheer publicity POV, the Prize has been doing very well of late -- but the real effect on the research agenda will come when there really are millions on the table.

And indeed, to the extent that prestige IS a factor, the prestige of a prize is itself in large part a function of its cash value: think about prizes in science or literature, and how much attention tracks dollar value (often explicitly in the media: the XYZ Prize is "the richest prize for Canadian short story writers," "the largest award for an English-language novel," etc. Furthermore, for the political reasons mentioned above, many biogerontologists will shy away from being associated with any efforts to actually intervene -- *now* -- in aging, until the previously-described loggerhead is broken, and the Prize is just too small a juggernaut, as yet, to smash thru'.

To again quote Miller: after listing numerous other political and institutional obstacles to work on genuine anti-aging interventions (the length of time needed to do lifespan studies; the profitability of existing -- yet ineffective and/or unproven -- "anti-aging" "treatments;" active opposition to interventive biogerontology by the Kass gang; etc -- he concludes that "the obstacles blocking the development of the hypothetical discipline of applied gerontology are at this point about 85% political and 15% scientific, and *they will not be overcome by biologists alone*."

I doubt that Miller would publicly endorse the Prize, mostly because of the ongoing feud between him and Aubrey about the proper strategy through which to pursue anti-aging interventions (rather than about the moral imperative to do so -- a subject on which they are in vigorous agreement). However, I suspect that in the secrecy of his own heart he thinks it's a great idea. The MPrize is exactly in a position to deal with this latter side of the equation -- & once it becomes big enough, with the side that is dependent on the scientists and their institutions (academic and capitalist) as well.

> The best thing to do is invest in the right private
> sector research companies,

First, as explained in the previously-linked post and elsewhere, there is a perverse set of anti-incentives keeping VC from seriously pursuing interventive biogerontology. And indeed, thus far, companies originally set up to do so (most prominently, Geron, Elixir, and Sirtris) have all eventually gone into panicked retreat at the behest of impatient financiers, redirecting the intellectual property and reserve of knowledge and skills built up during the initial pursuit of real anti-aging therapies into the development of drugs for specific diseases. Investment in such firms won't work unless $ are specifically tied to doing real anti-aging research. The Prize addresses this because its structure ensures that it only pays for actual life-extending therapies -- and only *successful* therapies, at that.

And second, the problem here is where to put that money even when such companies are available as investment options. Bakcing a losing horse does not help the other horses win a race of this kind. If one is Bill Gates, one can afford to invest in a hell of a lot of horses in hopes of getting just one across the finishing line, but for the rest of us, splitting our investment dollars across several firms with promising-sounding ideas isn't likely to actually push forward the date of their success, even if they actually do turn out to have a viable therapy in the making (tho' if one were right one would at least make oneself a tidy sum). The Prize uses a structure which has historically mobilized private investments in the goal valued at at least ten times the size of the prize itself -- and again, the money only goes out when someone actually pulls off the stunt.

> and to write to the NIA.

Yes, please do! Indeed, there are many ways that one can push forward the day when humans will receive the first radically life-extending biomedical therapies; many of them are here:

http://www.gen.cam.ac.uk/sens/how.htm

... and here:

http://www.longevitymeme.org/projects/

The question is how to get a much wider public doing all of this -- how to extend the political agitation and serious market for genuine, radical anti-aging biomedicine by turning the goldfishbowl of committed life extension fanatics into a big tent of soccer moms who become increasingly unwilling to just go about their (brief) lives watching their parents (and increasingly, their peers and themselves) slowly slide further and further into the yet-implacable maw of biological aging -- physical and mental decay, loss of function, suffering, and ultimately, death -- with every turn of the planet's axis.

Donating to the MPrize is, IMO, the most effective way for any individual who isn't obscenely wealthy to waken the sleeping masses, and to leverage hir very limited dollars directly into the incentive systems governing academics and venture capitalists alike.

REFERENCES

1. http://www.sagecrossroads.org/Default.aspx?tabid=57

2. Miller RA. Extending life: scientific prospects and political obstacles. Milbank Q. 2002;80(1):155-74. PMID: 11933792 [PubMed - indexed for MEDLINE]

Comments

Matt Piles wrote:


>Look at Spindler's Web site. He doesn't mention >that he won one of the Methuselah Foundation's >prizes.

I'd just like to point out that that isn't exactly "Spindler's Web site." It's a faculty information page provided by the biochem department at UC Riverside, not his personal blog for heavens sake. According that page it was "Last modified Tue, 05 Oct 2004 15:43:54 GMT." This doesn't mean Dr. Spindler hasn't accomplished anything worth mentioning since that date, it just means that paying the web master to constantly update standard informational faculty web pages isn't a high priority for the university.

-Liz

Posted by: Liz at July 4, 2005 9:01 AM

Excellent post. I agree entirely that the ethical case against aging is the most solid, and unites all of us.

How does MR determine or even guess-timate that CR will give 30 extra years?

And, I'm curious, what does a research assistant for a theoretical scientist (who is not involved with lab work) do?

Posted by: Kip Werking at July 4, 2005 10:37 PM

All:

> How does MR determine or even guess-timate
> that CR will give 30 extra years?

This was cited from:

Miller RA. Extending life: scientific prospects and political obstacles. Milbank Q. 2002;80(1):155-74. PMID: 11933792 [PubMed - indexed for MEDLINE]

I eyeballed the number out of his Figure 1, which he says was extraplated from rodent data, which (in turn) I *assume* means that it's just a one-to-one, proportional extrapolation of CR data. A quick check with reasonable assumptions seems to confirm this: the most common level of CR in animal studies is 40%, which when implemented in weanlings yields ~ a 40% increase in mean & max LS; the 1985 av'g LS for women was 81 yrs, and a 40% increase therein would yield an increase in av'g LS of 32.4 yrs.


-Michael

Posted by: Michael at July 5, 2005 6:20 PM

All:

> How does MR determine or even guess-timate
> that CR will give 30 extra years?

As cited, it was taken from:

Miller RA. Extending life: scientific prospects and political obstacles. Milbank Q. 2002;80(1):155-74. PMID: 11933792 [PubMed - indexed for MEDLINE]

I eyeballed the actual number from Figure 1, which says that the numbers were taken from extrapolations from rodent data, which in context means from rodent CR data. I assume that this was a pretty rough, straightforward interspecies proportional extrapolation. A quick check based on reasonable assumptions appears to confirm this: the most common level of rodent CR is 40%, which yields a 40% increase in mean LS; the 1985 life expectancy data on which the whole figure is based pegged a woman of 50 yrs' life expectancy at 81 yrs; this would give 32.4 extra years of life.

-Michael

Posted by: Michael at July 5, 2005 6:25 PM
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