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Comment author: [deleted] 19 May 2011 05:51:41AM 1 point [-]

Maintaining moderately high blood levels of vitamin D may reduce over all cancer rates by up to 30%. There is also evidence for green tea significantly reducing cancer rates.

I haven't seen thoroughly convincing studies, but it's quite possible that I missed them (among the blizzard of junk studies).

Aspirin is an anti-coagulant so wounds take longer to stop bleeding.

This is true, although I've noticed no significant effects. (When the air is cold and dry, I'm sometimes prone to nosebleeds, but they didn't get worse after I started low-dose aspirin).

It's also a bug and a feature. Heart attacks and ischemic strokes are no fun at all.

A surgeon will require that you stop taking aspirin long enough for the blood clotting factors to recover. (Surgeons hate it when they can't stop the bleeding.)

Not a problem for elective surgery (just stop taking it). If you need immediate surgery (e.g. because of an accident), then low-dose aspirin may be a slight risk - but it doesn't transform you into an instant hemophiliac.

If I were under 30 I wouldn't take a daily aspirin as I doubt it provides any benefit

Eight different randomized controlled trials suggest you're wrong. I'm unsure as to whether they studied relatively young adults like me - the problem is that it'd take even more decades to notice an effect. I consider aspirin's effects in older men to be persuasive evidence that it has the same effects for women and younger men like me. (In fact, as I mentioned, my doctor saw my slightly elevated cholesterol and told me to start fish oil and low-dose aspirin when I was 25 - it was only later that I saw the article about cancer.)

I recommend baby aspirin for anyone over 40.

Citation needed. Do you really think that, in your 20s and 30s, your cells aren't accumulating damage that eventually leads to cancer, so that low-dose aspirin has nothing to prevent? Really? It's possible that the cumulative damage hypothesis, for lack of a better name, is false, but I consider it overwhelmingly likely to be true.

Obviously, in making this decision, my own health is at stake - and I am very careful. In my judgment, trying to be as rational as possible, I believe that the risks of starting low-dose aspirin in my 20s are very small, and outweighed by the cumulative benefit, when I'm older, of having taken it for so long (the time-dependent nature of the benefit is important).

Comment author: Fly 19 May 2011 07:29:47AM 2 points [-]

"Eight different randomized controlled trials suggest you're wrong."

If the studies were done 20 years ago my guess is that the original trials were performed to see if aspirin reduced the risk of heart attacks. (At least that is what I recollect from that time period.) I doubt there were many people under 30 in those trials. I saw no indication in the linked article that ages were broken out so that one could determine whether people in their 20s who took aspirin for several years had less cancer 20 years later. Since few young people would be expected to get cancer I doubt the studies show that people in their 20s developed significantly fewer cancers from taking aspirin. My guess is that most of the people in the studies were men in their 40s, 50s, and 60s, i.e., those most at risk of heart attack.

"Do you really think that, in your 20s and 30s, your cells aren't accumulating damage that eventually leads to cancer, so that low-dose aspirin has nothing to prevent?"

My opinion is that the typical young person under 30 who doesn't abuse their body by smoking or excessive drinking has sufficient mechanisms to repair molecular damage so that aspirin will provide no additional benefit. Metabolism causes damage but it only becomes a problem when the body systems have deteriorated to the point where the body no longer keeps up with the damage done.

I believe that the cancer and Alzheimer prevention benefits from aspirin are due to reducing inflammation. I doubt people in their 20s typically experience mild chronic inflammation so I doubt aspirin will be beneficial. (I don't have specific papers to cite. This is just my impression from reading about cancer, Alzheimer's Disease, and inflammation for decades. I suspect you could find papers that discuss increasing inflammation levels with age and other papers that discuss the connection between inflammation and cancer and AD and other papers that discuss aspirin and inflammation reduction.) By their 40s such inflammation is common. For people in their 30s I viewed it as a toss-up.

I doubt most people in their 20s or 30s will be troubled by cancer or Alzheimer's Disease. There should be effective cures and preventative measures long before they are at significant risk.

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: Fly 18 May 2011 11:21:05PM 4 points [-]

"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."

Maintaining moderately high blood levels of vitamin D may reduce over all cancer rates by up to 30%. There is also evidence for green tea significantly reducing cancer rates.

Aspirin is an anti-coagulant so wounds take longer to stop bleeding. A surgeon will require that you stop taking aspirin long enough for the blood clotting factors to recover. (Surgeons hate it when they can't stop the bleeding.) If I were under 30 I wouldn't take a daily aspirin as I doubt it provides any benefit and does increase risk slightly. By the time you are 40 your body tissues are in a state of mild, chronic inflammation. That may be good for fighting off infections but isn't so good for the cardiovascular system, lungs, and brain. I recommend baby aspirin for anyone over 40.

Moderate alcohol use is correlated with a significant reduction in cardiovascular events. As with aspirin I would only recommend it for older people and then only if the likelihood of abuse is small.

Comment author: wedrifid 18 May 2011 06:27:32AM 0 points [-]

My guess is that the primary cause of human aging is a combination of "depleted" stem cells combined with a gradual disruption of regulatory homeostasis.

Not Telomeres?

Comment author: Fly 18 May 2011 08:19:58PM *  2 points [-]

Consider spermatogenesis as a model. There is a primary pool of slow dividing stem cells which are maintained in that state by local signaling from neighboring cells. In these stem cells, telomerase is sufficiently active that telomere length is preserved. The primary stem cell pool slowly replenishes a pool of fast dividing secondary stem cells in which telomerase is slightly less active. These are stem cells as the pool is largely self renewing. The secondary stem cell pool also generates progenitor cells which divide and differentiate to become sperm. Telomerase activity is much lower in these later cell generations so telomere length shortens with each division.

My speculation...

Bone marrow niches contain a common primary stem cell pool which has the potential to restore the primary stem pools in local tissues such as the testes. E.g., conditions in testes would cause release of signaling molecules into the blood. Those molecules would stimulate a special bone marrow stem cell causing differentiation into a primary sperm stem cell which is released into the blood. From the blood the stem cell enters the testes where it takes up residence in the local stem cell pool. In a similar manner wound healing recruits a variety of stem cell types from the bone marrow. (This would explain why fast cell turnover tissues don't acquire mutations or shorter telomeres at a significantly higher rate than slow turnover tissues.)

Average telomere length decreases when the primary stem cell pools become depleted. E.g., chronic inflammation or stress might deplete the primary stem cell pool so that the secondary stem cell pools aren't replenished, leading to decreased telomere length in the daughter cells. I.e., short telomeres are a sign of primary stem cell pool depletion, not a cause of aging. (Note that removing chronic stress may result in average telomere length increasing for white blood cells.)

Potential causes of stem cell depletion: 1) Stochastic differences in initial stem cell state. Due to molecular events such as DNA methylation, histone modifications, and differing signaling gradients from the local neighborhood some stem cells will divide faster and produce a higher percentage of differentiated daughter cells. Over time the stem cell pool will consist of cells whose initial internal settings favored slow division and a low percentage of daughter cells. This depleted stem cell pool becomes less and less able to meet the tissue regeneration needs of the body. 2) Gradual dis-regulation of the stem cell niche causes non-optimal functioning of stem cell renewal and differentiation. (With age red, blood cell producing, bone marrow gradually transforms into yellow, fat cell producing bone marrow.) 3) Environmental factors that alter stem cell epigenetic state causing poor functioning.

A strategy for rejuvenation would be to supply new stem cells engineered to be in an optimal epigenetic state for tissue renewal. By itself this would not suffice since mouse studies have shown that merely providing young stem cells won't cause old muscle to heal. Various grow factors and other signaling molecules must also be provided in the target tissue. Eventually the old cells would be replaced and the local tissue would return to a "young" signaling environment.

Comment author: Fly 18 May 2011 06:04:44AM 1 point [-]

Scientists have already demonstrated interventions that significantly extend maximum lifespan in several species. I see no reason to believe humans will be different.

My guess is that the primary cause of human aging is a combination of "depleted" stem cells combined with a gradual disruption of regulatory homeostasis. Part of the problem with "depleted" stem cells is an accumulation of silencing errors in the stem cell DNA. Another part is a gradual breakdown in local cell signaling that regulates cell fate. I believe both problems could be reversed by targeted "rebooting" of stem cell niches. I.e., inject new stem cells which have been engineered to stimulate tissue rejuvenation while also injecting growth factors and cell differentiation factors in the local tissue. (Most likely the would be done by injecting a fluid which forms a scaffolding which then releases the stem cells and factors over time. Such technology is currently being developed to repair cartilage.)

It may also be necessary to kill some existing cells so that they can be replaced by rejuvenated tissue. E.g., rebooting the immune system. This technology is currently being developed for bone marrow transplant, organ transplantation, and training the immune system to target cancers.

I expect such technologies will be common within the next two decades and should make Gompertz curves obsolete for humans.

Comment author: JoshuaZ 06 May 2011 07:02:21PM *  5 points [-]

While base rate neglect is a really interesting problem, I've always been a bit skeptical of it being at all relevant that doctors get it wrong so often. In real medical contexts, not everyone is getting tested for every disease; one is normally going to get tested if one has symptoms or have some risk factor. So in most circumstances, the actual chance that someone who is tested will have a false positive is lower than one would naively expect.

There are on the other hand other circumstances where this precise problem seems to show up (for example, when some people tried to push for mandatory premarital HIV testing).

Comment author: Fly 07 May 2011 03:31:46AM 6 points [-]

This occurs all the time.

http://www.psychologicalscience.org/journals/pspi/pspi_8_2_article.pdf

In 2007, 160 gynecologists were provided with the relevant health statistics needed for calculating the chances that a woman with a positive mammogram test actually has cancer. The correct answer was about 10%. The majority of them grossly overestimated the probability of cancer, answering ‘‘90%’’ or ‘‘81%.’’

When most doctors are asked to interpret probabilistic lab results they suck. The doctors just don't think that way. Instead they have learned what to say so that the patient will immediately take the next recommended step, i.e., get a biopsy. From the doctor's perspective missing a cancer is a much worse outcome than needlessly worrying a patient. Their cached answer is "you have a high probability of cancer so a biopsy is needed immediately" which led to their guessing answers in the 80-90% range.

Comment author: nhamann 29 April 2011 01:09:15AM 2 points [-]

Ahh, good point. My comment is somewhat irrelevant then with regards to this, as it seems that what you're interested in is beyond the scope of science at present.

Comment author: Fly 29 April 2011 04:13:39AM 15 points [-]

My gold standard for understanding reality is science, i.e., the process of collecting data, building models, making predictions, and testing those predictions again and again and again. In the spirit of "making beliefs pay rent" if Buddist meditation leads to less distorted views of reality then I would expect that "enlightened" Buddists would make especially successful scientists. As a religious group the Jews have been far more productive than the Buddists. Apparently Buddist physicists have no special advantage at building models that "carve reality at the joints". The Buddist monk may experience the illusion of knowing reality but actually understand less than a physicist. Or perhaps Buddist meditation trains the mind to "not care" or "not trust perceptions" to a degree that interferes with science? In what fields have Buddist monks excelled?

I am following with interest recent studies on brain changes due to mindfulness meditation, specifically improvements in executive function that accompany the enlargement of white matter tracts connecting the prefrontal cortex to the amygdala. So far I interpret the results as brain circuits being strengthened by attentional focus training so that the prefrontal cortex can inhibit signals arising in the amygdala, insula, thalamus, and hypothalamus. For those lacking such control this may be beneficial, i.e., those with low impulse control, for example children. There may be a motivational downside for those who already habitually inhibit such drives, e.g., those who easily become lost in abstract thought.

Comment author: timtyler 09 May 2010 08:16:05AM *  7 points [-]

I checked the Wiki here: http://wiki.lesswrong.com/wiki/Human_universal

"Let's say that you have a complex adaptation with six interdependent parts, and that each of the six genes is independently at ten percent frequency in the population. The chance of assembling a whole working adaptation is literally a million to one; and the average fitness of the genes is tiny, and they will not increase in frequency. "

Right - but look at the premise. Genes have linkage to other genes on the same chromosome - and so their frequencies may be far from independent. The existence of this possibility actually creates a selection pressure for interdependent genes that contribute to an adaptation to migrate towards each other on chromosomes - so they have more chance of being inherited together.

Comment author: Fly 11 May 2010 03:49:19AM 0 points [-]

Two other factors: 1) Population sub structure matters. Suppose a population of one million is divided into mating bands with 30 individuals. Small bands tend to lose diversity so some bands would have some of the minor alleles at higher frequency. Now suppose band X has minor alleles A1, A2, and A3 at high frequency while band Y has minor alleles A4, A5, and A6 at high frequency. The two bands meet and party. The result is kids with all 6 minor alleles. Those kids have big fitness advantage and those minor allele frequencies are significantly boosted in those bands. The high local concentration of those alleles means even more kids with all 6 alleles are born, further increasing their frequency. (If individuals were equally likely to mate with anyone in the population then local concentrations would be diluted in one generation and there would be no effective selection. But individuals are far more likely to mate with related nearby bands, so high local concentrations of the minor alleles are maintained while the minor alleles slowly become the major alleles.)

2) Gene variants tend to have additive affects. Also most genes affect multiple traits simultaneously. So the all or nothing scenario given above would be rare. More likely you would have a diversity of environmental niches. In some of those niches the minor alleles would provide benefit due to one of their affected traits becoming more important. The frequencies of that minor allele would locally rise (while its frequency in the total population would remain low). E.g., a minor allele might provide protection against a specific pathogen. So there might be local environments where the probability of 6 minor alleles combining could be much higher than would occur in one large population in a uniform environment mating randomly.

In response to comment by Fly on Closet survey #1
Comment author: Jack 30 April 2009 07:39:13PM 0 points [-]

The event has significance to me only because it happened to me. I would significantly discount the event if I heard about it second hand.

Why in the world should who the event happens to make a difference? This is anthropic bias. The fact if these things happen at all they're going to happen to someone. That fact that it was you isn't significant in any way.

In response to comment by Jack on Closet survey #1
Comment author: Fly 01 May 2009 08:41:01PM 4 points [-]

"Why in the world should who the event happens to make a difference?"

I question the surface view of the world and the universe. E.g., I wouldn't be greatly surprised to discover that "I" am a character in a game. To the extent that I understand reality, my "evidence model" is centered on myself and diminishes as the distance from that center increases.

In the center I have my own memories combined with my direct sensory perception of my immediate environment. I also have my internal mental model of myself. This model helps me evaluate the reliability of my memories and thoughts. E.g., I know that my memory is less consistent than information that I store on my computer and then directly access with my senses. I also observe myself making typing errors, spelling errors, and reasoning errors. Hence, I only moderately trust what my own mind thinks and recalls. (On science topics my internal beliefs are fairly consistent with information I receive from outside myself. On religious and political topics, not so much.)

Friends, family, and co-workers fill the next ring. I would treat second hand evidence from them as slightly less reliable and slightly less meaningful. Next would be friends of friends. Then US citizens. Then humans. The importance I place on events and evidence decreases as my connection to the person decreases. Some humans are in small, important sets, while others are in very large, unimportant sets. That some human won the lottery isn't unusual. That I won the lottery is. Of course to some guy in India, my winning the lottery wouldn't be special because he has no special connection to me.

If I won a 1-in-100 million lottery I would adjust my beliefs as to the nature of reality somewhat. I would decrease my belief that reality is mundane and increase my belief that reality is strange.

In response to comment by Fly on Closet survey #1
Comment author: jimrandomh 30 April 2009 07:26:49PM *  0 points [-]

I have no scientific explanation for the event.

Yes, you do: all four dice were weighted. You did your math assuming only one of them was weighted, but if they all were then the event you saw wasn't unlikely at all. Assume that a weighted die rolls the side that it favors with probability p, each of the sides adjacent to it with probability (1-p)/4, and never rolls the side opposite the favored side. How strongly weighted do the dice have to be (that is, what should p be) for 26 consecutive victories for the defender are assured?

The defender automatically wins on a 5 or 6, which come up with probability p + (1-p)/4. If the defender rolls a 2, then for the defender to win, each of the attacker's dice must either be a 1 (which it is with probability p) or a 2 (with probability (1-p)/4), so the defender wins in this case with probability (p+(1-p)/4)^3. The cases where the defender rolls a 3 or 4 are similar. Summing all the cases, we get that the defender wins with probability

p + (1-p)/4 + (1-p)/4 * ((p+(1-p)(3/4))^3 + (p+(1-p)(2/4))^3 + (p+(1-p)(1/4))^3)

Which simplifies to

(1/64)(-9p^4-6p^3+54p+25)

To win 26 times in a row with 50% probability, the defender would have to win each battle with probability 0.974. To win 26 times in a row with 95% probability, the defender would have to win each battle with probability 0.998.

(1/64)(-9p^4-6p^3+54p+25) > .974 --> p > .841

(1/64)(-9p^4-6p^3+54p+25) > .998 --> p > .958

In other words, to produce the event you saw with 50% reliability would require weighted dice that worked 84% of the time. To produce the event you saw with 95% reliability would require weighted dice that worked 96% of the time. I'm unable to find any good statistics on the reliability of weighted dice, but 84% sounds about right.

Comment author: Fly 01 May 2009 07:19:57PM 1 point [-]

"all four dice were weighted"

I used three reddish, semi-transparent plastic dice with white dots (as I always did). My opponent used standard opaque, plastic ivory dice with black dots. I noticed nothing unusual about the dice and by the end of the run I was examining dice, cups, methods of rolling closely.

"Assume that a weighted die rolls the side that it favors with probability p, each of the sides adjacent to it with probability (1-p)/4, and never rolls the side opposite the favored side."

This assumption does not match my recollection of the dice rolls. As I stated previously, I rolled 6's, 5's, 4's, 3's, 2's, and 1's. I also never rolled a 1,1,1 which should happen frequently if my dice were heavily weighed to roll 1's. Nor do I remember rolling large numbers of 1's.

Your probability model for a trick die also fails to match my observations of my opponents die rolls. E.g., in your model my opponent would be expected to roll similar numbers of 5's, 4's, 3', and 2's. However, he only rolled a 2 once and he rolled far more 5's than 3's.

Besides with your probability model for trick dice, I would have easily noticed if my opponent rolled a 6 84% of the time and I never rolled a 6 at all.

PS You used 26 in the above calculation. I had 26 armies and in Risk the attacker must have at least 4 armies to roll three attack dice. So the 3vs1 dice scenario only happened 23 times.

In response to comment by Jack on Closet survey #1
Comment author: glenra 29 April 2009 04:32:03PM *  7 points [-]

1000 is extremely conservative. Every time you play any game with an element of chance - risk, backgammon, poker, scrabble, blackjack, or even just flipping a coin - the odds against you getting the exact sequence of outcomes you do get will be astronomical. So the limiting factor on how many unbelievable outcomes you perceive in a lifetime is how good you are at recognizing patterns as "unusual". Somebody who studied numerology or had "lucky numbers" or paid attention to "lucky streaks" would see them all the time.

In the case at hand, that same series of rolls would be just as unlikely if it had happened at the beginning of the game or in the middle or spread throughout the match and hadn't determined the outcome. Unless there was something special about this particular game that made its outcome matter - perhaps it was being televised, there was a million dollars bet on it, or it was otherwise your last chance to achieve some important outcome - the main thing that makes that sequence of rolls more noteworthy than any other sequence of rolls of equivalent length is selection bias, not degree of unlikeliness.

In response to comment by glenra on Closet survey #1
Comment author: Fly 30 April 2009 07:20:05PM 3 points [-]

"the odds against you getting the exact sequence of outcomes you do get will be astronomical"

People notice and remember things they care about. Usually people care whether they win or lose, not the exact sequence of moves that produced the result. For an event to register as unusual a person must care about the outcome and recognize that the outcome is rare. The Risk game was special because I cared enough about the outcome to notice that I was losing, because the outcome (of losing) with 26 vs. 1 armies was incredibly unlikely, and because I could calculate the odds against such an outcome occurring due to chance.

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