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Living Forever is Hard, or, The Gompertz Curve

"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.

Living Forever is Hard, or, The Gompertz Curve

"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.

Living Forever is Hard, or, The Gompertz Curve

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.

Living Forever is Hard, or, The Gompertz Curve

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.

Intuition and Unconscious Learning

This occurs all the time.

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.

Meditation, insight, and rationality. (Part 1 of 3)

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.

The Psychological Diversity of Mankind

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.

Closet survey #1

"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.

Closet survey #1

"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.

Closet survey #1

"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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