Aging is a Group-Selected Adaptation, by Josh Mitteldorf

Josh Mitteldorf's Aging is a Group-Selected Adaptation places its thesis right in the title. Mitteldorf makes a strong case that aging is under the control of evolutionary pressures, and that the selection pressures for it are based on the benefits to groups, since it's clear there's no evolutionary gain to the individual. The evidence that aging is under evolution's control boils down to a comparison of many lineages that have long lives and have evolutionary cousins that do not. This is straightforward and hard to refute. The question is why.

The book's answer is that lineages that don't limit fecundity overshoot the carrying capacity of whatever environment they inhabit. The consequences are frequent population crashes. The alternative that leads to the possibility of stable populations is some feedback cycle that limits reproduction, combined with some way to ensure that deaths occur at a consistent rate. If the genes are optimized for the longest feasible life, then most deaths will occur in times of stress (resource exhaustion, unusual weather, or other cataclysm). This would lead to a much higher chance of ongoing boom and bust, which is a recipe for inevitable extinction.

There are some great graphs in the book illustrating the huge variety in life histories across many species. This one shows survivorship as a function of mortality and fecundity. When mortality is a horizontal line, survival falls consistently from birth to death. (hydra, hermit crabs, et. al.) Some species show decreasing mortality over their lifespan (desert tortoise, white mangrove, redleaf oak, ...), others only a slight uptick near the end (mute swan, tundra vole, sparrowhawk, ...).

According to Mitteldorf, the outcome of many experiments with artificial life show that one of the most valuable features of a species that has to cohabit with predators and prey is the ability to react to changes in its own population so that they have more progeny when the population density is low, and more individuals die when population density is high. The classical reaction to arguments about group selection says that this requires genes to have some kind of foresight, but the paradigm here is that populations that don't discover a way to reinforce this kind of response to population variation will be much more likely to go through frequent bottlenecks. Each bottleneck is another opportunity to go extinct.

One of the key ideas is that in order to contribute to ecosystem stability, rather than only to individual fitness, the genes must find a mechanism that leads to variation in robustness among the population. If some are slower, some are more susceptible to famine or cold, etc., then when a periodic stressor arises, some of the individuals will die. The alternative, if the genes design for uniform robustness is that all survive except when the stressor is severe, and in that case, nearly all will die. Aging, according to this thesis is a mechanism that causes variation within the population, ensuring a steady rate of death, which evens out rapid rises and falls in population. The population can still expand relatively rapidly when a niche opens up, but when living in a stable location, there are forces mitigating against population swings.

For those thinking about how to extend lifespan, a plausible first reaction to the idea that aging is selected for is to conclude that this means that aging will be harder to defeat. I would argue that the opposite may be true. Mitteldorf makes a good case that many lineages have found ways to allow individuals to live to arbitrarily long ages, so the biological mechanisms can't be infeasible or energetically unaffordable. Evolution's lesson is that we should be aware of the consequences of unlimited population growth, but given the demographic transition affecting most advanced economies, we can reasonably be more worried about the dangers of dropping population levels than of too many people. In any case, the hazards for human populations happen slowly enough that we'd be able to react before populations grow to be dangerous.

Aubrey de Grey wrote a response to Mitteldorf, but it looks like it was to an early version of the argument. (The book is dated 2017, but de Grey's 'response' is from 2015.) It looks to me as if de Grey had the reaction I described just above, and thought it was important to refute Mitteldorf's claims. I don't think de Grey directly addresses the arguments in the book. It seems to me that the argument presented here doesn't rule out the possibility of using de Grey's (SENS) approach to engineering fixes for the causes of aging, and it also provides for the possibility of other approaches that would directly intervene in the body's signaling that encourages aging and early senescence. If it's right, it doesn't reduce the number of possible approaches, it adds to them.

0.3productChris Hibbert

Arthur De Vany: Hollywood Economics

0.3

Chris Hibbert

Arthur De Vany's Hollywood Economics gives a detailed look at an extreme example of a long-tail industry, the movies. The first half of the book consists of some technical papers that De Vany wrote during his career as an economist. Some of them are quite technical, but they lay the foundation for De Vany's contention that making movies is a highly unpredictable business.

These opening articles demonstrate that there is little predictability in the movie business, and investors, directors, producers, and actors who try to improve their odds by spending more money on special effects, hiring people from the A list, advertising heavily, or whatever else haven't studied the numbers well enough.

The old slogan "nobody knows anything" arises because of the nature of movie releases. Audiences vary from week to week, and they have an always changing menu of movies to choose from. Their reaction may depend on what's in the news, what hits have appeared recently, and whether the blockbuster that came out six weeks ago still has legs. And that's before we try to take account of the intrinsic merit of the story, the acting, how broad the distribution is, etc. Every week is a new tournament with some old and some new players. The audience can't make a judgment about any particular movie until they see it, and they don't make their evaluations from a clean slate.

The statistics deriving from this chaotic process produces the now familiar power law distribution. 70% of movies made are unprofitable, but the business makes money on the whole. most of the 30% that make money barely do better than breaking even; only a few a really successful, and the business of Hollywood is all about trying to make enough movies and give yourself enough chances that you can capture one of the few runaway successes. De Vany talks about how how studios, actors and directors should structure contracts so that the right people have the right incentives, and the right people make money when there is a hit. He then analyzes some actual contracts to show that they follow his rules: star players give up some straight pay for a share of the distant upper tail. The contracts talk about events that are meaningful for less than one movie in a hundred, but that's where all the money is, and one hit in that category can make you rich.

After he's laid the groundwork in the first half of the book, De Vany talks about the breakup of the Hollywood studio system at the end of the 1940's. I had no idea the anti-trust crusaders had even done this. The golden age of the Hollywood studio system was ended by a series of anti-trust cases (culminating in the Supreme Court) that denied the studios the ability to own movie theaters, and restricted the kinds of contracts they could write with independent theater owners. The result was that the studios lost certainty about being able to place the films they made, so they had to be much more careful in deciding what movies to fund, and couldn't plan a season's production coherently. De Vany shows how poorly the courts understood the movie business, and that they didn't achieve any of their objectives in terms of making the business fairer for independent distributors, theaters, or production companies.

I found the book to be fascinating, though quite dense. If the technical analysis in the first half of the book seems daunting, I recommend skimming it; just pay attention to his conclusions, since you'll need them to appreciate the findings in the second half of the book. I suspect there are many lessons that are applicable to other people trying to make money in other long-tail businesses. (Most of the discussion about long-tail is about making money by exploiting the long thin tail, but someone's making money from the tall, rich head of that curve.) The dynamics of other businesses are different, so you'll have to figure out what the drivers are for your uncertainty. De Vany does a great job of explaining the vagaries of the movie business, but not every business is an iterated tournament in which some of the contenders are new each week, while others have advantages or disadvantages due to their recent performance. There's a limit to the number of movies that can be playing in first run theaters every week, so some have to be dropped in order to make room for the constant flow of new releases.

I found this book after reading De Vany's blog for a while in 2005 and 2006. His articles on the movie business were quite interesting, but there's also a bunch of interesting material on evolutionary fitness, health, and sports.

Would you Trade your Sense of Smell for a Longer Life?

Recent experiments on fruit flies undergoing Caloric Restriction seem to show that the effect of CR is reduced or eliminated if the flies are exposed to the odor of food (yeast in their case). That led to experiments in which the experimenters genetically eliminated the flies' ability to smell. They found a stronger contribution to lifespan from smelling the food than from how much the flies ate.

Would you give up your sense of smell if it meant living 50% longer? The question is only hypothetical at this point: replications in other species haven't been reported yet.

The SENS debate, continued

As I promised to try to do, I read Estep et. al's submission to TR's challenge, the one the judging panel declared to be the "most eloquent", along with de Grey's response and the author's rebuttal. Estep et. al. misunderstand their role in the challenge from beginning to end. de Grey has been promoting SENS, a proposal for a new approach to combat aging, for a few years. From the beginning he admitted it was a controversial approach combining leading edge biology and an engineering mindset and asked experienced scientists to tell him if he was making any fundamental mistakes in the science. He has led and participated in symposia with experts and published papers in respected journals, after earning a Ph.D. in the relevant discipline. Technology Review solicited written submissions that would demonstrate that de Grey's program was "so wrong that it was unworthy of learned debate."

There are good reasons for practicing scientists to recognize the signs of pseudo-science, and it's appropriate for their first reaction to be outright dismissal when they recognize those signs. When a proposal garners enough attention that outright dismissal is no longer effective, it's still appropriate for most scientists to ignore it until there's more evidence in its favor. But at the point at which someone decides that a head-on confrontation is called for, the participants in the process should no longer expect to get away with derision; their role at that point is to review the science, show that the conclusions are at odds with established results, or demonstrate that they can't be disproved in principal, and thus are outside the bounds of science. Their goal should be to analyze the proposals, and summarize their evaluation in enough detail that other scientist can read their summary rather than doing the primary analysis themselves.

Estep et. al. spend an inordinate amount of time referring to studies of pseudo-science and its practitioners, and explaining in what ways de Grey and his proposal resembles them. But that's of no value at this stage in the process. Pontin (the editor of TR, and instigator of the challenge) and de Grey's other detractors have already pointed out that SENS isn't normal science; the challenge is to come up with an evaluation of the science, and Estep skimps on that.

Estep accuses de Grey of tangling his new proposals in with other scientists' results, making it hard to distinguish what is well-founded from what is not. But that's part of the normal process of science. Scientists build on others' work, expand it in some areas, and correct mistakes in others. In effect, Estep's charge is that scientists perpetrating fraud should clearly separate their new fraudulent work from others' well-founded work in order to make the investigator's job easier. This is nonsense. It is Estep's responsibility to examine the foundations of SENS and find parts that aren't justified or justifiable. If he can't, he has failed to undercut the science. That failure wouldn't by itself show that SENS is valid, but it would be a hurdle passed. Becoming accepted as established science is a process of continuing to get past the hurdles.

Estep shows no evidence that he understands the distinction that de Grey makes in referring to SENS as an engineering approach. de Grey is very clear in drawing the distinction:

Concerning the difference between scientists and engineers in mindset and motivation — as opposed to laboratory expertise — that I have often mentioned, Estep et al. expertly make my point for me by noting that the only reason they engineer model organisms is to find things out. To quote them: "If we could easily predict the outcome, why bother going through all the trouble of actually doing the engineering?". I wonder if Estep et al. think the Wright brothers built their airplane in order to discover whether it would fly? I personally suspect that they built it because they were confident that it would fly and they wanted to build something that would fly. Estep et al.'s oversight of this motivation is quite breathtaking to anyone who understands that, since aging causes immense suffering and death, it is something to be explored not for the sake of curiosity alone but with the goal of actually doing something about it.

In their response, Estep et. al. point out that the Wright brothers used the scientific process to test and evaluate the components they were building, and that they were systematic in their efforts to evaluate all the effects that mattered in getting into and remaining in the air. This response completely misses the point. Estep et. al. think that progress is made by systematically expanding the frontier of what is known. de Grey proposes to take what is known and build an effective mechanism to solve a problem, learning as he goes. The relevant question is whether we know enough at this point to start the process. The Wright brothers didn't know the answers when they started. They weren't satisfied with asking all the interesting questions, either; they asked the questions that were blocking their path to building a successful flying machine. Useful questions for critiquing an engineering proposal include: Do we know enough to get started? Is the cost estimate reasonable? Are there reasons to believe that there is no solution to the problem (within the budget)?

Estep et. al. focus on showing that some of the particular approaches that de Grey suggests aren't completely justified in the literature. But the heart of the SENS proposal is a search for solutions to 7 identified pathologies; de Grey has identified multiple approaches to each of them, and tried to give plausible detail about at least one solution for each problem. The useful counter-arguments are that these 7 aren't exhaustive, or that no (affordable) solution is available to one or more of the seven. Estep et. al. say that de Grey's list of 7 pathologies "unscientifically exclud[es] others"; the only exclusion I can identify in their paper is "unrepaired DNA damage in post-mitotic tissues", though they also mention "largely uncharacterized and undiscovered damage and pathologies". de Grey's original claim about the seven pathologies was that these seven had all been identified and characterized by 1982, and no new ones have become apparent since then despite all the advances and attention in this area, so "uncharacterized and undiscovered" looks like a clear miss to me. de Grey's response to the post-mitotic damage is to point out that he had addressed that issue in a draft paper that Estep has been asked to review. Estep talks about other items covered in that paper, but drops the thread on post-mitotic damage. I count that as no challenge to de Grey's claim that there are only seven pathologies to worry about.

de Grey wrote in his rebuttal:

Particularly incongruous is their accusation that I use the media to skirt expert criticism, when the SENS Challenge itself is my most conspicuous effort to do just the reverse, exposing the public reticence of SENS's off-the-record detractors and thereby forcing them to make their supposed case in print.

(de Grey has made other efforts to get gerontologist to put their objections on the record.) Estep responds thusly:

TR Editor Jason Pontin claims this challenge was initiated by him and all available evidence supports this claim. Furthermore, we have evaluated only a few of SENS' weaknesses, as did Warner and colleagues (Warner et al. 2005), and Aubrey de Grey's responses demonstrate beyond a shadow of a doubt that he is completely insincere in his wish for scientists to critique SENS.

Notice that Estep wrote in the original paper:

This SENS Challenge is itself part of the pseudoscience archetype, and it is simply a culmination of ongoing challenges made by Aubrey de Grey to opponents of SENS to prove him wrong. This is a classic attempt to subvert the scientific process, it is known to be typical of pseudoscience, and it is described as such in Dr. Friedlander's book, which predates SENS by several years.

So, Estep started this particular exchange by saying that the SENS Challenge is stereotypical behavior of pseudoscientists; de Grey rebuts that the challenge is an example of his having solicited criticism, at which point Estep backtracks and says that de Grey wasn't responsible for the challenge anyway. de Grey's Methuselah Foundation had matched Technology Review's prize for which Estep competed. Seems like de Grey is on solid ground in describing his role as helping to encourage debate.

Estep's rebuttal contains a number of explicit "predictions". That interests me because of the obvious application of prediction markets to monitor the argument. Most of the predictions are untestable or uninteresting: "de Grey's complaints that he isn't getting a fair hearing will continue", "Very soon it will be apparent to all [...] that SENS [...] constitutes overt scientific misconduct." Two exceptions are worth noting.

First, Estep et. al. say "[de Grey]'s only contribution to pharmacological inhibition and modification [...] of telomerase, therapeutic deletion of the entire telomerase gene [...] from the genome, will be recognized to be a crude biomedical fantasy. It will be abandoned by all sensible people--and even de Grey's co-authors will cease to [...] discuss it publicly." This is a very hard statement to write a clear prediction market claim for. We've tried before, on FX for claims that a consensus will arise, or that some research field will be dropped, but the claim details are hard to agree on and judge. I'll leave the prediction standing here as a reminder that de Grey's opponents can be judged to have made a valid prediction if, in your opinion, this subfield goes away later.

The second prediction is easier to adapt as a prediction market claim. The background is that de Grey is apparently accepted as an expert in the area of mitochondrial DNA (mDNA) mutation and repair. His proposal to combat progressive damage to mDNA is to ensure that Nuclear DNA (nDNA) can construct the few proteins (that's "allotropic expression") that the mitochondrion can't already get from the cell's nucleus. de Grey's response says

the shallowness of Estep et al.'s analysis is revealed especially starkly by their contradictory statements concerning allotropic expression in cell culture, which midway through their analysis they call an example of "assumptions and technologies that reside firmly in the realm of fantasy" but, in their summary, they call an example of "routine biology experiments."

Estep et. al. respond

successful allotropic expression of all 13 mitochondrial coding regions while maintaining mitochondrial and cellular function is a technology that resides in the realm of fantasy. Nevertheless, attempts to achieve these things are without a doubt routine biology experiments.

This makes it appear that Estep et. al. are willing to use the word "fantasy" to describe things that haven't been achieved yet. At least they didn't make any attempt to show that it couldn't be achieved.

Estep et. al. point out that de Grey bet someone publicly in 2000 that this would be known technology before the end of 2005, and it still hasn't been achieved. de Grey responds that he was counting on the imminent release of a paper showing the technique was possible (which was in review at that point) to spur further work. The paper only came out in 2005, so the follow-on work has only just started.

Estep's one explicit prediction is "We believe that this problem is [complicated] and it will remain unsolved for a very long time--if it is ever solved. Aubrey de Grey will continue to make excuses [...] to explain the lack of progress in this area." This, unfortunately, doesn't give a useful time scale, but de Grey's original projection can be extended to give a reasonable deadline.

Here is the background de Grey gives:

They lampoon my prediction from 2000 concerning AE, without mentioning that I made it assuming that Zullo et al.'s seminal breakthrough ( which I presented at the time I made the bet) would be published imminently in Science (where it was then in review), stimulating effort to perfect this approach; in fact, followup effort remained negligible until it was finally published in 2005. Thus, it is grossly misleading to suggest that my overoptimism arose from underestimating how hard AE is — and I fully explained this recently in a reply to Estep on a well-known mailing list (subscription required in order to review archives).

So in 2000, de Grey expected that imminent publication in Science would produce results by 2005. The paper was published in 2005, but not in a publication as prestigious as Science. Estep says it will be a very long time if ever. I'll propose a claim for the Foresight Exchange that it will be solved by 2012, which is longer than the 5 years de Grey originally expected, but gives some leeway for the reduced publicity the paper actually got. If it still seems to be 5 years away at that point, we'll have to conclude that de Grey's timeframes were way off.

Overall, I have to agree with TR's panel. Estep et. al. may have found some holes in de Grey's specific proposed therapies (it's hard for me to tell; unlike de Grey, Estep et. al. don't provide layman's versions of any of their technical arguments), but they didn't show that these holes make the entire effort unlikely to succeed, and they didn't show that de Grey's proposal doesn't address a useful goal.

As Marc Stiegler commented when I told him who was on the review committee, they seem predisposed to finding merit in de Grey's plan. Ventner is best known for his public commitment to develop technology to sequence the human genome before it was scientifically justifiable--and delivered. Rod Brooks' mantra at the Mobile Robot Lab was "fast, cheap, and out of control"; they were building stuff that worked rather than pursuing pure knowledge. Nathan Myhrvold is more focused on inventions than basic research, even though his academic credentials are impeccable.

added 12/15/2006

I created the mtDNA claim on FX in August.

Filed in:

• Longevity
• LifeExtension

SENS not unworthy of debate

A year ago, I wrote about Jason Pontin (the editor of Techology Review) and his attack on Aubrey de Grey's SENS (Strategies for Engineered Negligible Senescence) proposal. Pontin was so upset at de Grey's efforts to defeat aging, that he offered $10,000 as a prize to anyone who could come up with a convincing argument that the proposal was "so wrong that it was unworthy of learned debate." (de Grey's foundation matched the money, making the prize $20,000.) They appointed a distinguished committee (Rodney Brooks; Nathan Myhrvold; Craig Venter; Anita Goel, a physicist and nanotech entrepreneur; and Vikram Kumar, an innovator and pathologist) which has issued its report. They received only three submissions that merited detailed evaluation, and decided that none of them constituted the convincing rebuttal that Pontin had asked for. (de Grey's response)

The Judges' statement emphasized that de Grey's proposals are closer to engineering than science, and none of the submissions had evaluated them on that ground. Brooks is quoted as having said "I have no confidence that they understand engineering, and some of their criticisms are poor criticisms of a legitimate engineering process." Since de Grey is talking about plausible approaches, fallback solutions, and costs versus benefits, it's not reasonable to attack him for not having proven experimentally all that he proposes, as you might a scientific paper or career. The committee even went so far as to describe some of the attacks as "name calling". That was also the reaction I had to Pontin's original article on SENS.

Pontin seems to have calmed down since he wrote the original diatribe. He salved his pride to some extent by giving MIT's half of the prize money to the entry the judges found to be the "most eloquent", even though that wasn't called for in the terms of the contest. I'll try to read the three submissions and the back and forth between de Grey and their authors. I'd like to understand the best arguments for and against; I'm hopeful that I'll learn something more about the biology and the chances for SENS' success. I somehow suspect that as scientists criticizing an engineering proposal, they'll spend their time showing that his suggestions aren't proven. What matters is whether the proposals are close enough to right that they can be corrected as we learn more. That's much harder to justify in a new area, and also much harder to attack convincingly.

I'm not sure where the burden of proof should be in that part of the argument. The parts of de Grey's proposal that I found most compelling the first time I heard him were that there are only seven interesting mechanisms underlying progressive metabolic deterioration, and that each of them can be defeated if you take an engineering approach. I hope there's at least some discussion of this point.

Filed in:

• Longevity
• LifeExtension

Technology Review against SENS

Jason Pontin, the editor of Technology Review has issued a challenge:

submit an intellectually serious argument that SENS is so wrong that it is unworthy of learned debate, and you will be paid $20,000 if it convinces independent referees.

SENS (Strategies for Engineered Negligible Senescence) is Aubrey de Grey's program to defeat aging. de Grey has put a fair amount of intellectual effort into this fight, and has produced an argument that is convincing to some, but apparently repugnant to others. (See the article in TR, and an editorial by Pontin in which he made it clear that he found de Grey's ideas distasteful, but didn't have anything to say about the science.

The statement above is curious for a scientific inquiry. Pontin isn't asking whether SENS is possible, or might be debugged so as to reach de Grey's goals, he wants someone to show that no one should listen to de Grey or try to convince others that he's wrong. It seems like Pontin has proven the point he's trying to defeat. If it takes $20,000 to convince gerontologists (or if that amount is insufficient) to come up with an intellectually serious argument, then isn't the question worthy of serious debate?

My impression is that serious physicists stay away from claims about perpetual motion machines because they could spend all their time debunking them with no gain. And it would be a pure loss to a particular physicist if he came up against a kook who had built a device that the physicist couldn't figure out in a reasonable amount of time.

But de Grey's proposition is different. He's written serious articles in serious journals, co-authored by serious experts arguing that various aspects of his program make good engineering sense, comport with the standard biological models, and would move us toward longer healthy lives. There aren't an endless supply of other crackpots that the gerontologists would have to debunk if they accepted de Grey's challenge.

Pontin states his rules clearly and simply. #2 is

The purpose of the Challenge is to establish whether SENS is worthy of serious consideration. Submissions are sought that attempt to demonstrate that it is not.

People of the opposite view need not apply. It sure doesn't look like the purpose of the Challenge is to establish whether SENS is worthy of serious consideration.

Pontin's reply at FightAging.org is more ambivalent.

• Indefinite life might be good for me, and I might wish it for those that I love, but an entire world of superagenarians might be a bad thing.
• I am not sure significant life extension is possible [...]
• But if SENS is reasonable, it's obviously very important news, and worthy of serious attention[...]

I got my first pointer into the discussion from the extropians chat list, but there are enough pointers here to connect you to many threads of discussion all over the net.

Longevity Matters

Alex Tabarrok was recently having lunch with Tyler Cowen and Bryan Caplan, and the subject of longevity came up.

At lunch with Bryan and Tyler last week the question arose as to what we would do differently if we were immortal. After a nerdy discussion to clarify what sort of immorality we were talking about; the kind where you can't be killed but can be imprisoned or the kind where you are forever young but may be hit by a truck? (it was the former) - I answered that I would travel more.

They chose the wrong question to answer. Both Alex and Tyler are familiar with Cryonics, and Bryan appears to have discussed health and longevity with Robin Hanson, so I'll assume he's at least passingly familiar with these ideas as well.

It's possible (some would argue likely) that many of us are approaching the latter kind of immortality, (long-term youthfulness) but the former (actual immortality) is still a science fiction dream. Alex implied that he was making choices about how to spend his time based on what he'd do if he couldn't be killed. He said that he would travel more, and at the end of the post he said that he is going on a solo trek to Machu Picchu.

Maybe he would have come up with the same answer if they had addressed the right question. I hope so, since a solo trek in the Andes might be just the kind of risky activity that you'd get a different answer for. Travel more certainly, but a high chance at prolonged health wouldn't convince me to add significantly to my risk level. If Alex is an experienced high-altitude hiker this may not be that high a risk. But for most people, I'd guess that solo hiking in the Andes would cut into your chances of enjoying that long-term youthfulness that makes you think about travelling more widely.