Imagine you had the following at your disposal:

• A Ph.D. in a biological science, with a fair amount of reading and wet-lab work under your belt on the topic of aging and longevity (but in hindsight, nothing that turned out to leverage any real mechanistic insights into aging).
• A M.S. in statistics. Sadly, the non-Bayesian kind for the most part, but along the way acquired the meta-skills necessary to read and understand most quantitative papers with life-science applications.
• Love of programming and data, the ability to learn most new computer languages in a couple of weeks, and at least 8 years spent hacking R code.
• Research access to large amounts of anonymized patient data.
• Optimistically, two decades remaining in which to make it all count.

Imagine that your goal were to slow or prevent biological aging...

1. What would be the specific questions you would try to tackle first?
2. What additional skills would you add to your toolkit?
3. How would you allocate your limited time between the research questions in #1 and the acquisition of new skills in #2?

Thanks for your input.

Update

I thank everyone for their input and apologize for how long it has taken me to post an update.

I met with Aubrey de Grey and he recommended using the anonymized patient data to look for novel uses for already-prescribed drugs. He also suggested I do a comparison of existing longitudinal studies (e.g. Framingham) and the equivalent data elements from our data warehouse. I asked him that if he runs into any researchers with promising theories or methods but for a massive human dataset to test them on, to send them my way.

My original question was a bit to broad in retrospect: I should have focused more on how to best leverage the capabilities my project already has in place rather than a more general "what should I do with myself" kind of appeal. On the other hand, at the time I might have been less confident about the project's success than I am now. Though the conversation immediately went off into prospective experiments rather than analyzing existing data, there were some great ideas there that may yet become practical to implement.

At any rate, a lot of this has been overcome by events. In the last six months I realized that before we even get to the bifurcation point between longevity and other research areas, there are a crapload of technical, logistical, and organizational problems to solve. I no longer have any doubt that these real problems are worth solving, my team is well positioned to solve many of them, and the solutions will significantly accelerate research in many areas including longevity. We have institutional support, we have a credible revenue stream, and no shortage of promising directions to pursue. The limiting factor now is people-hours. So, we are recruiting.

Thanks again to everyone for their feedback.

The paper is called DNA methylation age and human tissues and cell types and it's from Genome Biology. Here is a Nature article based on the paper.

I have submitted this to LW because of its relevance to the measurement of aging and, hence, to life extension. Here is a bit from the Nature piece:

"Ageing is a major health problem, and interestingly there are really no objective measures of aging, other than a verified birth date," says Darryl Shibata, a pathologist at the University of Southern California in Los Angeles. "Studies like this one provide important new efforts to increase the rigour of human aging studies."

Note: The discrepancy in spelling ("ageing" vs. "aging") is in the original.

Givewell’s Holden Karnofsky, who has previously posted his thoughts on Givewell supporting SI/MIRI recently discussed the potential for Givewell to begin evaluating biomedical charities, in Givewell’s Yahoo Group.  Someone suggested (as I have through less direct means) that they take a hard look at SENS Research Foundation, and then Aubrey de Grey appeared and began an interesting discussion with Holden.

The thread begins with Holden’s long initial post about Givewell’s stance on investigating and recommending biomedical charities, which is definitely worth the read for greater insight. The rest of the conversation is aggregated below for anyone else who can’t stomach Yahoo Groups’ interface.

Overall, Holden seems to agree with the goal of SENS, and interested in the details, but the conversation seems to have ended in October 2012 with Holden stating that he was waiting for Dario Amodei’s thoughts on SENS.

Holden,

First, I think that this is an excellent document. I checked for a
number of things that I had heard about (Breakout Labs, John
Ioannidis, Cochrane Collaboration) and they're all there in your
document.

The one thing that's not explicitly mentioned: longevity and life
extension research. At least prima facie, this seems like something
that should be more important than individual disease research, and it
seems like a classic "Valley of Death" case (pun unintended, but
noted) -- T1 stage to use your terminology. I think the SENS website
http://www.sens.org would be a good starting point for one of the (to
me promising) approaches to life extension. I recall from past
conversations that you were aware of SENS, so this is not new to you,
but I think that longevity should be included as part of any
discussion of biomedical research and given separate consideration
given that it has a much lower status than research into specific
conditions such as cancer, dementia, etc. You may ultimately conclude
that not enough can be done in this area, but I think it should be
part of your preliminary stuff. [btw, the United States has a National
Institute of Aging, but it's much lower-status than most of the other
grantmakers mentioned here].

Vipul

---

Hi Vipul,

Thanks for the thoughts. I had a followup conversation with Dario about this topic a few days ago. I think the question of "could one fund translational research to treat/prevent aging?" provides an interesting illustration of some of the tricky dynamics here for a funder:

• It's possible that if there were a great deal more attention giving to treating/preventing aging, we would have some promising treatments. So in a broad sense it's possible that aging is underinvested in.
• A lot of the best basic biology research isn't clearly pointing toward one treatment/condition or another; it's about understanding the fundamentals of how organisms operate. So having an interest in treating aging, as opposed to cancer, might not have a major impact on which projects one funds, if one's main goal is to fund outstanding basic biology research.
• Perhaps because of the lack of emphasis on treating aging (or perhaps because it's simply too difficult of a problem), there don't seem to be promising findings in the "Valley of Death" relevant to aging; the few promising leads have been explored.
• So even if, in a broad sense, there is too little attention given to this problem, knowing this doesn't necessarily yield a clear direction for a relatively small-scale funder of biomedical research.

Best,
Holden

---

Hi everyone,

My attention was brought to this thread, by virtue of the fact that it was my work that gave rise to SENS Foundation, and I'm looking forward to getting more involved here; I've held the Effective Altruism movement in high regard for some time. However, given my newbie status here I want to start by apologising in advance for any oversight of previously-discussed issues etc. I'm naturally delighted both at Holden's post and at Vipul's reply (which I should stress that I did not plant! - I do not know Vipul at all, though I look forward to changing that). I would like to mention just a few key points for discussion:

- Holden, I want to compliment you on your appreciation of how academia really works. Everything you say about that is spot on. The aversion to "high risk high gain" work that has arisen and become so endemic in the system is the most important point here, in terms of why parallel funding routes are needed.

- I'm slightly confused that a lot of Holden's remarks are focused on the private sector (i.e. startups), since my understanding was that GiveWell is about philanthropy; but I realise that there is not all that clear a boundary between the two (and I note the mention of Breakout Labs, with which I have close links and which sits astride that divide more than arguably anyone). The "valley of death" in pre-competitive translational research is a rather different one than that encountered by startups, but the principle is the same, and research to postpone aging certainly encounteres it.

- Something that I presume factors highly among GiveWell's criteria is the extent to which a cause may be undervalued by the bulk of major philanthropists, such that an infusion of additional funds would make more of a difference than in an area that is already being well funded. To me this seems to mirror the logic of focusing on the shortcomings (gaps) in NIH's funding (and that of traditional-model foundations). Holden notes that "Anyone we consider for funding ought to be able to explain why they're better at allocating the funds than the NIH" and I agree wholeheartedly, but my inference is that he thinks that some orgs may indeed be able to explain that. I certainly think that SENS Foundation can.

- Coming to aging: research to postpone aging has the unique problem of quite indescribeable irrationality on the part of most of the general public, policy-makers and even biologists with regard to its desirability. Biogerontologists have been talking to brick walls for decades in their effort to get the rest of the world to appreciate that aging is what causes age-related ill-health, and thus that treatments for aging are merely preventative geriatrics. The concept persists, despite biogerontologists' best efforts, that aging is "natural" and should be left alone, whereas the diseases that it brings about are awful and should be fought. This is made even more bizarre by the fact that the status of age-related diseases as aspects of the later stages of aging absolutely, unequivocally implies that efforts to attack those diseases directly are doomed to fail. As such, this is a (unique? certainly very rare) case where a philanthropic contribution can make a particularly big difference simply because most philanthropists don't see the case for it. It underpins why having an interest in treating aging, as opposed to cancer, absolutely has a major impact on which projects one funds. It's also a case for (if I understand the term correctly) meta-research.

- A lot of the chatter about treating aging revolves around longevity, but it shouldn't. I'm all in favour of longevity, don't get me wrong, but it's not what gets me up in the morning: what does is health. I want people to be truly youthful, however long ago they were born: simple as that. The benefits of longevity per se to humanity may also be substantial, in the form of greater wisdom etc, but that would necessarily come about only very gradually (we won't have any 1000-year-old for at least 900 years whatever happens!), so it doesn't figure strongly in my calculations.

- When forced to acknowledge that the idea of aging being a high-priority target for medicine is an inescapeable consequence of things they already believe (notably that health is good and ageism is bad), many people retreat to the standpoint that it's never going to be possible so it's OK to be irrational about whether it's desirable. The feasibility of postponing age-related ill-health by X years with medicine available Y years from now is, of course, a matter of speculation on which experts disagree, just as with any other pioneering technology. I know that Holden and others have expressed caution (at best) concerning the accuracy of any kind of calculation of probabilities of particular outcomes in the distant (or even not-so-distant) future, and I share that view. However, an approach that may appeal more is to estimate how much humanitarian benefit a given amount of progress would deliver, and then to ask how unlikely that scenario needs to be to make it not worth pursuing. My claim is that the benefits of hastening the defeat of aging by even a few years (which is the minimum that I claim SENS Foundation is in a position to do, given adequate funding) would be so astronomical that the required chance of success to make such an effort worthwhile would be tiny - too tiny for it to be reasonable to argue that such funding would be inadvisable. But of course that is precisely what I would want GiveWell to opine on.

- In the event that GiveWell (or anyone else) were to decide and declare that the defeat of aging is indeed a cause that philanthropists should support, there then arises the question of which organisation(s) should be supported in the best interests of that mission. We at SENS Foundation have worked diligently to rise as quickly as possible in the legitimacy stakes by all standard measures, but we are still young and there remains more to do. If I were to offer an argument to fund us rather than any other entity, it would largely come down to the fact that no other organisation has even a serious plan for defeating aging, let alone a track record of implementing such a plan's early stages.

- A significant chunk of what we do is of a kind that I think comes under "meta-research". A prominent example is a project we're funding at Denver University to extend the well-respected forecasting system "International Futures" so that it can analyse scenarios incorporating dramatically postponed aging.

I greatly welcome any feedback.

Cheers, Aubrey

---

Hi Aubrey,

Thanks for the thoughts.

The NIH appears to have a division focused on research relevant to this topic: http://www.nia.nih.gov/research/dab . Its budget appears to be ~$175 million (per year). The National Institute on Aging, which houses this division, has a budget of about $1 billion per year, including a separate ~$400 million for neuroscience (which may also be relevant) as well as $115 million for intramural research. Figures are from http://www.nia.nih.gov/about/budget/2012/fiscal-year-2013-budget. The Institute states that its mandate includes translational research (http://www.nia.nih.gov/research/faq/does-nia-support-translational-research). How would you distinguish your work from this work?

(For the moment I'm putting aside the question I raised in my previous response to Vipul on this topic, regarding whether it's best to approach biology funding from the perspective of "trying to treat/cure a particular condition" or "trying to understand  fundamental questions in biology whose applications are difficult to predict.")

Best,
Holden

---

Hi Holden - many thanks.

First: yes, there are really three somewhat separate questions for someone trying to evaluate whether to support SENS Foundation:

1) Is the medical control of aging a hugely valuable mission?

2) Assuming "yes" to (1), is it best achieved by basic research or translational research?

3) Assuming translational, is SENS Foundation the organisation that uses money most effectively in pursuit of that mission?

I had rather expected that you would take some convincing on item (1), and much of what I wrote last time was focused on that. Since it isn't the focus of your question to me, I'm now going to assume until further notice that there is no dissent on that.

So, to answer your question: actually you're not putting aside the basic-vs-translational question as much as you may think you are. The word "translational" is flavour of the month in government funding circles these days (not only in the USA), so it's not surprising that the NIA has a public statement of the kind you pointed to. However, notice that the link they give "for more information" is to a page listing ALL "Funding Opportunity Announcements". There is no page specifically for translational ones, and the reason there isn't is that the amount of work that the NIA actually funds that could really be called translational is tiny. In other words, the page you found is actually just blatant spin. The neuroscience slice you mention is an anomaly arising from the way NIA was founded (the natural place for that money is clearly NINDS): the fact that it's NIA money does not, in practice, translate into its being spent on work to prevent neurodegeneration by treating its cause (aging). Instead, just like NINDS money, it's spent on attacking neurodegeneration directly, as if such diseases could be eliminated from the body just like an infection: the same old mistake that afflicts, and dooms, the whole of geriatric medicine.

So, the first answer to your question is that SENS Foundation really DOES focus on translational research, with an explicit goal of postponing age-related ill-health. But there's also another big difference: we can attack this problem relatively free of the other priorities that afflict mainstream funding (whether from NIH or from trasitional foundations). Most importantly, though we do and will continue to publish our interim results in the peer-reviewed literature, we are much less constrained by "publish or perish" tyranny than typical academics are. This allows us to proceed by constructing and implementing a rational "project plan" (namely SENS) to get to the intended goal (the defeat of aging), whereas what little translational work is funded by NIA or others is guided overwhelmingly by the imperative to get some kind of positive result as quickly as possible, even when it's understood that those results are not remotely likely to "scale", i.e. to translate into eventual medical treatments that significantly delay aging. A great example of this is the NIA's Interventions Testing Program (ITP) to test the mouse longevity effects of various small molecules. The ITP only exists at all (and in a far smaller form than originally intended) as a result of several years of persistence by the then head of the NIA's biology division (Huber Warner), and it focuses entirely on delivery of simple drugs starting rather early in life, with the result that no information emerges that's relevant to treating people who are already in middle age or older. (This is despite the fact that by far the most high-profile result that the ITP has delivered so far, the benefits of rapamycin, actually WAS a late-onset study: it wasn't meant to be, but technical issues delayed the experiment.) In a nutshell, there is a huge bias against high-risk high-gain work.

The third thing that distinguishes SENS Foundation's approach is that we can transcend the "balkanisation" (silo mentality) that dominates mainstream academic funding. When one submits a grant application to NIA, it is evaluated by gerontologists, just as when one submits to NCI it is evaluated by oncologists, etc. What's wrong with this is that it biases the system immensely against cross-disciplinary proposals. SENS is a plan that brings together a large body of knowledge from gerontology but also a huge amount of expertise that was developed for other reasons entirely - to treat acute disease/injury, or in some cases for purposes that were not biomedical at all (notably environmental decontamination). It doesn't matter how robust the objective scientific and technological argument is for work of that sort: it will never compete (especially in today's very tight funding environment) with more single-topic proposals all of whose details can be understood by reviewers from a particular single field.

The final thing to mention, and this actually also answers your question to Vipul about basic versus translational research, is that SENS is a plan that has stood the test of time. I've been propounding it since 2000, well before SENS Foundation existed, and it used to come in for a lot of criticism (initially more in the form of off-the-record ridicule, and latterly, at my behest, in print), but in every single case that criticism was found to stem from ignorance on the part of the detractor, either of what I proposed or of published experimental work on which the proposal was based. That's why I'm now regularly asked to organise entire sessions at mainstream gerontology conferences, whereas as little as five years ago I would never even be invited to speak. It's also why the Research Advisory Board of SENS Foundation consists of such prestigious scientists. This is a very strong argument, in my view, for believing that now is the time to sink a proper amount of money into translational gerontology (though certainly not to cease doin basic biogerontology too). It's well known that basic scientists are often not the most far-sighted when it comes to seeing how to apply their discoveries (attitudes in 1900 to the feasibility of powered flight being the canonical example). It is therefore a source of concern that almost all the experts who have the ear of funders in this field are basic scientists, whose instinct is to carry on finding things out and to deprioritise the tedious business of applying that knowledge. SENS has achieved a gratisfying level of legitimacy in gerontology, but it is still foreign to most card-carrying gerontologists, and as such it remains essentially unfundable via mainstream mechanisms. Hence the need to create a philanthropy-driven entity, SENS Foundation, to get this work done.

Let me know if this helps, or if you have further questions.

Cheers, Aubrey

---

Hi Aubrey,

Thanks again for engaging so thoughtfully.

I agree that a new technology/treatment that could delay or reverse aging (or aspects of it) would be enormously valuable. Regarding the rest of your argument, this is a good example of the challenges I've been discussing in understanding biomedical research.

You state that you have a high-expected-value plan that the academic world can't recognize the value of because of shortcomings such as "balkanisation" and risk aversion. I believe it may be true that the academic world has such problems to a degree; however, I also believe that there are a lot of extremely talented people in academia and that they often (though not necessarily always) find ways to move forward on promising work. Without more subject-matter expertise (or the advice of someone with such expertise), I can't easily assess the technical merits of your argument or potential counterarguments. Hopefully we'll have a better system for doing so at some point in the future.

I'll be very interested to see Dario's thoughts on the matter if he responds. I'd cite Dario as an example of an academic who ultimately wants to do work of the greatest humanitarian value possible, regardless of whether it is prestigious work. And as my summary of our conversation shows, he acknowledges that the world of biomedical research may have certain suboptimal incentives, but didn't seem to think that these issues are leaving specific, visible outstanding research programs on the table the way that your email implies.

Best,
Holden

---

Excellent. I too am keen to see Dario's comments. Dario also has the advantage of being based just a few miles from SENS Foundation's research centre, so we can definitely get together f2f soon if he wants.

Cheers, Aubrey

 

Peter Singer, makes a (refreshingly simple) ethical case for anti-aging research, and endorses increased funding.

http://www.project-syndicate.org/commentary/the-ethics-of-anti-aging-by-peter-singer

On which problems should we focus research in medicine and the biological sciences? There is a strong argument for tackling the diseases that kill the most people –diseases like malaria, measles, and diarrhea, which kill millions in developing countries, but very few in the developed world.

Developed countries, however, devote most of their research funds to the diseases from which their citizens suffer, and that seems likely to continue for the foreseeable future. Given that constraint, which medical breakthrough would do the most to improve our lives?

If your first thought is “a cure for cancer” or “a cure for heart disease,” think again. Aubrey de Grey, Chief Science Officer of SENS Foundation and the world’s most prominent advocate of anti-aging research, argues that it makes no sense to spend the vast majority of our medical resources on trying to combat the diseases of aging without tackling aging itself. If we cure one of these diseases, those who would have died from it can expect to succumb to another in a few years. The benefit is therefore modest.

[...]

De Grey has set up SENS Foundation to promote research into anti-aging. By most standards, his fundraising efforts have been successful, for the foundation now has an annual budget of around $4 million. But that is still pitifully small by the standards of medical research foundations. De Grey might be mistaken, but if there is only a small chance that he is right, the huge pay-offs make anti-aging research a better bet than areas of medical research that are currently far better funded.

Previous:

1. "Living Forever is Hard, or, the Gompertz Curve"
2. "Living Forever is Hard, part 2: Adult Longevity"

From the excellent Fight Aging! blog comes a pointer to "A Histogram of Results from Life Span Studies", a graph of thousands of animal studies by Kingsley G. Morse Jr. (updated version from mailing list):

(This is not the same as a funnel plot, as the y-axis is # of studies finding that percentage gain and nothing to do with the n of studies.)

On the closed GRG mailing list, the compiler says:

Many test the same intervention on a different strain of the same species, or with a different dose.

I asked some questions, and Steven B. Harris replied:

“I was gratified to be able to answer promptly, and I did. I said I didn't know.”  (Twain)

Though I can observe that the center of that distribution isn't very far from no-effect, and one would expect that there's a publication bias toward reporting positive effects vs. null effects. I would think that could account for it entirely.

There's also the problem we've discussed before, that feeling animals stuff they don't like the taste off, amounts to calorie restriction. So this clouds the issues terribly in non-CR studies, unless you're very, VERY careful to control them somehow.

The relevance of this summary graph to news like the C60 rodent life extension experiment is obvious. Reading GRG has been interesting and educational about that experiment; a rough summary of points made by various people including myself:

• contradictory median/lifespan figures
• duplicate image
• small sample
• doses of C60 small enough that the direct antioxidant activity can't be responsible
• justifying cites not published when experiment started
• the C60 was administered for brief period (think the analogy given was 'imagine taking a supplement only during your 40s and doubling your lifespan')
• the massive life extension observed in the olive-oil-only rats - not doubling, but still really implausible

TEDGlobal 2011- Cynthia Kenyon: Experiments that Hint at Longer Lives

Video Link: http://www.ted.com/talks/cynthia_kenyon_experiments_that_hint_of_longer_lives.html

Speaker's Bio (from TED):

Cynthia Kenyon is revolutionizing our understanding of aging. As an expert in biochemistry and biophysics at the University of California at San Francisco, she is particularly interested in the influence that genetics have on age-related diseases (from cancer to heart failure) in living things.

Her biggest breakthrough was figuring out that there’s a “universal hormonal control for aging”: carbohydrate intake, which can have a dramatic effect on how two critical genes behave, reducing insulin production and boosting repair and renovation activities. So far, her theory has proved true for worms, mice, rats, and monkeys — and she suspects it applies to humans, too.

By studying aging, Kenyon believes that she and other scientists (many of whom have successfully duplicated her experiments) will be able to pinpoint the molecules responsible for the onset of age-related diseases in people and prevent them. She’s co-founded a drug-development company called Elixir Pharmaceuticals to do just that.

She says: "The link between aging and age-related disease suggests an entirely new way to combat many diseases all at once; namely, by going after their greatest risk factor: aging itself."

"Ten years ago, we thought aging was probably the result of a slow decay, a sort of rusting. But Professor Kenyon has shown that it’s ... controlled by genes. That opens the possibility of slowing it down with drugs."

Jeff Holly, Bristol University

Summary:

Different animals have different lifespans (i.e. mice- 2years, v. bat- 50 years) There must be something in the genes for aging, so you should be able to change the aging gene to expand life span.

They did experiments on a roundworm and found that mutations that damage a gene called daf-2 could double the worm’s lifespan. The daf-2 gene encodes a hormone receptor which promotes aging. (similar to the ones that promote food uptake and growth.)

They did the same mutation in flies and mice, and it worked on them.

People who lived to 90-100 in a population of Ashkenazi Jews were more likely to have mutations to daf-2 which would make it work less well. They are also less susceptible to things like cancer and age related deseases.

She explains how and why it works.

Follow-up questions about- Certain animals that don’t have aging. And can we do this by changing genes instead of developing a medication. (She says that would be a bad idea).

• Previous: "Living Forever is Hard, or, The Gompertz Curve"

Following Fight Aging's "A Primer on Compression of Morbidity" today to Fries's 2011 review article "Compression of Morbidity 1980–2011: A Focused Review of Paradigms and Progress" (Fries, incidentally, introduced the concept of "compression of morbidity" in 1980), I found some interesting details in it.

I recently recalled, apropos of the intermittent fasting/caloric restriction discussion, a very good blog post on mortality curves and models of aging:

For me, a 25-year-old American, the probability of dying during the next year is a fairly miniscule 0.03% — about 1 in 3,000.  When I’m 33 it will be about 1 in 1,500, when I’m 42 it will be about 1 in 750, and so on.  By the time I reach age 100 (and I do plan on it) the probability of living to 101 will only be about 50%.  This is seriously fast growth — my mortality rate is increasing exponentially with age.

...This data fits the Gompertz law almost perfectly, with death rates doubling every 8 years.  The graph on the right also agrees with the Gompertz law, and you can see the precipitous fall in survival rates starting at age 80 or so.  That decline is no joke; the sharp fall in survival rates can be expressed mathematically as an exponential within an exponential:

Exponential decay is sharp, but an exponential within an exponential is so sharp that I can say with 99.999999% certainty that no human will ever live to the age of 130.  (Ignoring, of course, the upward shift in the lifetime distribution that will result from future medical advances)

...There is one important lesson, however, to be learned from Benjamin Gompertz’s mysterious observation.  By looking at theories of human mortality that are clearly wrong, we can deduce that our fast-rising mortality is not the result of a dangerous environment, but of a body that has a built-in expiration date.

gravityandlevity then discusses some simple models of aging and the statistical characters they have which do not match Gompertz's law:

1. 'lightning' model: risk of mortality each period is constant; Poisson distribution:
   

   What a crazy world!  The average lifespan would be the same, but out of every 100 people 31 would die before age 30 and 2 of them would live to be more than 300 years old.  Clearly we do not live in a world where mortality is governed by “lightning bolts”.

2. 'accumulated lightning'; like in a video game, one has a healthbar which may take a hit each period; similar to above:
   

   Shown above are the results from a simulated world where “lightning bolts” of misfortune hit people on average every 16 years, and death occurs at the fifth hit.  This world also has an average lifespan of 80 years (16*5 = 80), and its distribution is a little less ridiculous than the previous case.  Still, it’s no Gompertz Law: look at all those 160-year-olds!  You can try playing around with different “lightning strike rates” and different number of hits required for death, but nothing will reproduce the Gompertz Law.  No explanation based on careless gods, no matter how plentiful or how strong their blows are, will reproduce the strong upper limit to human lifespan that we actually observe.

What models do yield a Gompertz curve? gravityandlevity describes a simple 'cops and robbers' model (which I like to think of as 'antibodies and cancers'):

...in general, the cops are winning.  They patrol randomly through your body, and when they happen to come across a criminal he is promptly removed.  The cops can always defeat a criminal they come across, unless the criminal has been allowed to sit in the same spot for a long time.  A criminal that remains in one place for long enough (say, one day) can build a “fortress” which is too strong to be assailed by the police.  If this happens, you die.

Lucky for you, the cops are plentiful, and on average they pass by every spot 14 times a day.  The likelihood of them missing a particular spot for an entire day is given (as you’ve learned by now) by the Poisson distribution: it is a mere .

But what happens if your internal police force starts to dwindle?  Suppose that as you age the police force suffers a slight reduction, so that they can only cover every spot 12 times a day.  Then the probability of them missing a criminal for an entire day decreases to .  The difference between 14 and 12 doesn’t seem like a big deal, but the result was that your chance of dying during a given day jumped by more than 10 times.  And if the strength of your police force drops linearly in time, your mortality rate will rise exponentially.

... The language of “cops and criminals” lends itself very easily to a discussion of the immune system fighting infection and random mutation.  Particularly heartening is the fact that rates of cancer incidence also follow the Gompertz law, doubling every 8 years or so.  Maybe something in the immune system is degrading over time, becoming worse at finding and destroying mutated and potentially dangerous cells.

...Who are the criminals and who are the cops that kill them?  What is the “incubation time” for a criminal, and why does it give “him” enough strength to fight off the immune response?  Why is the police force dwindling over time?  For that matter, what kind of “clock” does your body have that measures time at all? There have been attempts to describe DNA degradation (through the shortening of your telomeres or through methylation) as an increase in “criminals” that slowly overwhelm the body’s DNA-repair mechanisms, but nothing has come of it so far.

This offers food for thought about various anti-aging strategies. For example, given the superexponential growth in mortality, if we had a magic medical treatment that could cut your mortality risk in half but didn't affect the growth of said risk, then that would buy you very little late in life, but might extend life by decades if administered at a very young age.

Life extension is a relevant topic here, and I was wondering if people are aware of the apparently life-extending effects of calorie restriction (CR) and intermittent fasting (IF). To the extent of my knowledge, this is the best method using currently realized technology that has shown repeated and significant life-extension benefits.

Studies show that reducing calories by 20% to 40% from ad libitum feeding (but maintaining the supply of required protein and micro-nutrients) gives improvements in markers related to aging, and extends life span in rodents and other organisms.

Other rodent studies have also shown similar results in subjects which were kept on various intermittent fasting schedules. Rats that were fed only on alternating days gained up to 25% lifespan (see Table 2).

The benefits of IF are seen even if the total calorie intake is the same as in ad libitum subjects.

There are ongoing full-lifespan studies in rhesus macaques to test the effects in primates, but none of these studies have completed. This abstract of the interim results appears promising, though.

Studies of CR and IF on humans have shown effects consistent with reduced mortality, including:
- Improved triglyceride profiles (a marker for heart disease)
- Increased insulin sensitivity
- Reduced cell proliferation (a marker for cancer)

Generally, these diet modifications appear to not just extend life span, but improve the quality of life too. In aged subjects they improve things like: muscle mass, cognition, energy, appearance, and activity level.

Have people heard about this or tried it? If you are trying to maximize your chance of surviving to the point that technology can lengthen lifespan indefinitely, it seems like something worth exploring.

I tried an IF schedule for about 6 months during 2010. I followed a schedule of 3 x ~thirty hour fasts every 7 days and found it somewhat tolerable. I exercise regularly and found that exercising on the non-fasting days was not a problem. I'm thinking of starting up such a schedule again.