gwern comments on Living Forever is Hard, or, The Gompertz Curve - Less Wrong

46 Post author: gwern 17 May 2011 09:08PM

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Comment author: [deleted] 18 May 2011 06:50:13AM 37 points [-]

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.

This isn't an anti-aging strategy, but it is an anti-death strategy: low-dose aspirin. As explained in this New York Times article on December 6, 2010, "researchers examined the cancer death rates of 25,570 patients who had participated in eight different randomized controlled trials of aspirin that ended up to 20 years earlier".

Eight. Different. Randomized. Controlled. Trials. Twenty-five thousand people.

They found (read the article) that low-dose aspirin dramatically decreased the risk of death from solid tumor cancers. Again, this ("risk of death") is the gold standard - many studies measure outcomes indirectly (e.g. tumor size, cholesterol level, etc.) which leads to unpleasant surprises (X shrinks tumors but doesn't keep people alive, Y lowers cholesterol levels but doesn't keep people alive, etc.). Best of all is this behavior: "the participants in the longest lasting trials had the most drastic reductions in cancer death years later."

Not mentioned in the article is the fact that aspirin is an ancient drug, in use for over a century with side effects that, while they certainly exist, are very well understood. This isn't like the people taking "life-extension regimens" or "nootropic stacks", who are, as far as I'm concerned, finding innovative ways to poison themselves.

Yet the article went on to say this:

But even as some experts hailed the new study as a breakthrough, others urged caution, warning people not to start a regimen of aspirin without first consulting a doctor about the potential risks, including gastrointestinal bleeding and bleeding in the brain (hemorrhagic strokes).

“Many people may wonder if they should start taking daily aspirin, but it would be premature to recommend people starting taking aspirin specifically to prevent cancer,” said Eric J. Jacobs, an epidemiologist with the American Cancer Society.

I'm a programmer, not a doctor - but after looking around, I concluded that the risks of GI bleeding were not guaranteed fatal, and the risks of hemorrhagic strokes were low in absolute terms. Also, aspirin is famously effective against ischemic strokes. According to Wikipedia: "Although aspirin also raises the risk of hemorrhagic stroke and other major bleeds by about twofold, these events are rare, and the balance of aspirin's effects is positive. Thus, in secondary prevention trials, aspirin reduced the overall mortality by about a tenth."

So unless aspirin's risks are far more grave than I've currently been led to believe, as far as I'm concerned, people saying "hey, even if you're not subject to aspirin's well-known contraindications, you shouldn't start low-dose aspirin just yet" are literally statistically killing people. Cancer is pretty lethal and we're not really good at fixing it yet, so when we find something that can really reduce the risk (and there aren't many - the only other ones I can think of are the magical substances known as not-smoking and avoiding-massive-doses-of-ionizing radiation), we should be all over that like cats on yarn.

I make damn sure to take my low-dose aspirin every day. I started it before reading this article on the advice of my doctor who thought my cholesterol was a little high - I'm almost 28, so it'll have many years in which to work its currently poorly understood magic.

That said, this reduces the risk of one common cause of death (two or three if you throw in heart attacks and ischemic strokes). There are lots of others out there. Even if you could avoid all of them (including the scariest one, Alzheimer's - it's insanely common, we have no fucking clue what causes it or how to stop it, and it annihilates your very self - even if cryonics is ultimately successful, advanced Alzheimer's is probably the true death), humans pretty clearly wear out with an upper bound of 120 years. Maybe caloric restriction can adjust that somewhat. But I think I'll sign up for cryonics sooner rather than later - I'm in favor of upgrading probability from "definitely boned" to "probably boned but maybe not".

Comment author: gwern 17 January 2012 12:17:03AM *  6 points [-]

And I think I have my answer:

Last week, researchers in London reported that they had analyzed nine randomized studies of aspirin use in the United States, Europe and Japan that included more than 100,000 participants. The study subjects had never had a heart attack or stroke; all regularly took aspirin or a placebo to determine whether aspirin benefits people who have no established heart disease.

In the combined analysis, the researchers found that regular aspirin users were 10 percent less likely than the others to have any type of heart event, and 20 percent less likely to have a nonfatal heart attack. While that sounds like good news, the study showed that the risks of regular aspirin outweighed the benefits.

Aspirin users were about 30 percent more likely to have a serious gastrointestinal bleeding event, a side effect of frequent aspirin use. The overall risk of dying during the study was the same among the aspirin users and the others. And though some previous studies suggested that regular aspirin use could prevent cancer, the new analysis showed no such benefit. Over all, for every 162 people who took aspirin, the drug prevented one nonfatal heart attack, but caused about two serious bleeding episodes.

http://well.blogs.nytimes.com/2012/01/16/daily-aspirin-is-not-for-everyone-study-suggests/

Comment author: jsalvatier 17 January 2012 04:27:46AM 0 points [-]

Thank you, very interesting.

Comment author: [deleted] 17 January 2012 12:46:50AM 0 points [-]

From the abstract at:

http://archinte.ama-assn.org/cgi/content/abstract/archinternmed.2011.628v1

During a mean (SD) follow-up of 6.0 (2.1) years involving over 100 000 participants [...] There was no significant reduction in CVD death (OR, 0.99; 95% CI, 0.85-1.15) or cancer mortality (OR, 0.93; 95% CI, 0.84-1.03)

I am suspicious of the 6-year followup. In the original paper linked elsewhere in this comment tree, the observed reduction in cancer mortality grew over time.

I would be more willing to believe this new study if it followed patients for a longer period of time, observed the reduction in cancer mortality, and still concluded that the risks outweighed the benefits.

Comment author: gwern 17 January 2012 01:04:15AM 0 points [-]

I'd like to point out that this pooled analysis of healthy people covered more than 4 times as many healthy people as your original citation covered sick people.

Comment author: [deleted] 17 January 2012 02:07:29AM 0 points [-]

Do you think that the "sick people" were somehow susceptible to cancer in an aspirin-prevention-friendly manner, while the "healthy people" weren't?

(I am considering cancer separately from cardiovascular disease and bleeding risks, as they can be analyzed separately before overall risk-benefit is determined. I would not be surprised to learn that aspirin is very effective at reducing cardiovascular disease among those at risk, while not being worth it for cardiovascular disease among the general population.)

Comment author: gwern 17 January 2012 02:28:21AM 3 points [-]

I'll try again: your original cite said the cancer benefit was detectable at 5 years, and later. I've presented you with a 4 times larger study, in the relevant subpopulation, at 6 years which found no cancer benefit - and you are still asking rhetorical questions and coming up with excuses.

Do you think that if you had seen the evidence the other way around that you would be asking the same questions?

Comment author: LukeStebbing 17 January 2012 05:32:57AM *  3 points [-]

No matter which study I saw first, the other would be surprising. A 100k trial doesn't explain away evidence from eight trials totaling 25k. Given that all of these studies are quite large, I'm more concerned about methodological flaws than size.

I have very slightly increased my estimate that aspirin reduces cancer mortality (since the new study showed 7% reduction, and that certainly isn't evidence against mortality reduction). I have slightly decreased my estimate that the mortality reduction is as strong as concluded by the meta-analysis. I have decreased my estimate that the risk tradeoff will be worth it later in life. I have very slightly increased my estimate that sick people are generally more likely to develop cancer and aspirin is especially good at preventing that kind of cancer, but I mention that only because it's an amusingly weird explanation.

If this new study is continued with similar results, or even if its data doesn't show increased reduction when sliced by quartile (4.6, 6.0, 7.4 years), I would significantly lower my estimate of the mortality reduction.

I'll continue to take low-dose aspirin since my present risk of bleeding death is very low, and if the graphs of cumulative cancer mortality reduction on p34 of the meta-analysis reflect reality, I'll be banking resistance to cancer toward a time when I'm much more likely to need it. I can't decide to take low-dose aspirin retroactively.

Comment author: gwern 17 January 2012 03:56:32PM 1 point [-]

A 100k trial doesn't explain away evidence from eight trials totaling 25k.

It doesn't have to, since they are not trials involving the same populations.

Comment author: [deleted] 17 January 2012 02:43:43AM 0 points [-]

Perhaps I'm misunderstanding the numbers ("OR, 0.93"), but the new study observed a 7% decrease in cancer mortality, which they called "not significant".

Do you think that if you had seen the evidence the other way around that you would be asking the same questions?

I would be unhappy with the other study's population, but very happy with its followup period. (The fact that the observed benefit grew with the length of time taking aspirin was especially convincing, as I mentioned earlier. That is a property that is very unlike "maybe we're seeing it, maybe we're not" noise at the threshold of detection.)

Last year, I told you that polio had no natural reservoirs, and you continued to believe otherwise, so I am not especially inclined to argue further.

Comment author: gwern 17 January 2012 02:52:47AM 1 point [-]

Perhaps I'm misunderstanding the numbers ("OR, 0.93"), but the new study observed a 7% decrease in cancer mortality, which they called "not significant".

No, that's correct. If you want to use stuff that doesn't reach significance, I can't stop you. (You didn't reply to Yvain's points, incidentally.)

Last year, I told you that polio had no natural reservoirs, and you continued to believe otherwise, so I am not especially inclined to argue further.

And you misunderstood the point about carriers defeating eradication attempts.