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While I agree with the logic of avoiding subjecting highly unsaturated oils to heat we do have to be cautious here with speculation.
When you say things like that: "Nonetheless, if these things are poisonous at high concentrations, they're probably not great at low concentrations."
It does not clearly follow that such a dose-response exists. The word "hormesis" gets thrown around a lot in the lay press, and there is actually some truth there. Plenty of moderate (even genotoxic) stressors have health benefits at lower doses. Of course, I would not gorge on lipid hydroperoxide based on this, because we have better evidence-based "hormetic" stressors, but it also does not follow that lipid oxidation products at low doses are harmful.
If the treatment is relatively mild, the dropouts are comparable between groups then I am not sure that per protocol will introduce much bias. What do you think? In that case it can be a decent tool for enhancing power, although the results will always be considered "post hoc" and "hypothesis-generating".
From experience I would say that intention-to-treat analysis is the standard in large studies of drugs and supplements, while per protocol is often performed as a secondary analysis. Especially when ITT is marginal and you have to go fishing for some results to report and to justify follow-up research.
The supplement industry and similarly the cosmetics industry is a jarring example of what can happen with no oversight or the wrong kind of oversight. Although, to be charitable to the libertarian position, one can argue that many supplement and cosmetics companies are forced to provide inferior products since efficacious products, even when rather safe, cannot be sold on the free market for various reasons (e.g. higher doses of potassium or retinoids for photoaging).
Thank you for the write-up! Just as a minor quibble, veganism has not been considered the "healthiest choice" ever, or at least not for a long time, if I were to make a guess about "consensus" in the field. While it has been clear for a while that a diet biased towards plants is healthy, the data for the addition of certain food groups (fatty fish, fermented and low-fat dairy, etc) is pretty strong as is the data for the health benefits of individual carninutrients (creatine or even taurine).
As you correctly point out, the issue of residual confounding is unsolvable. All we can take from these studies are hints and ideas. The recent failure of Vitamin D to live up to the hype, initially generated by observational studies, is a case in point.
I am particularly weary of studies of dietary patterns, whether they are vegetarian or Mediterranean or others, since I would expect to see the strongest biases here (because these patterns are associated with lifestyles, class, belief etc). Nevertheless, studies on surrogate endpoints like cholesterol and studies on single food groups do support the whole idea of reducing meat consumption.
I think the consensus among nutritionists is that a well-planned vegan diet is among the healthiest possible diets. Almost everyone in the US would benefit from "going a bit more vegan". Nevertheless, it is probably not optimal on certain axes.
It would seem that the best diet to improve long-term health is a flexible pescolacto-vegetarian diet supplementing certain carninutrients, e.g. creatine. So not vegan.
Tradeoffs are real and you have to optimize for one thing over another. For example, a standard (unsupplemented) vegan diet may not be optimal for mental and physical performance due to the higher risk of iron deficiency, low protein intake and lack of dietary creatine intake, among other things. A lot of those issues can be alleviated through careful planning. However, it may very well be that low-moderate intakes of protein and iron are one of the reasons why a vegan diet is healthy and you will have to weigh this against the potential performance aspect.
We have two types of evidence in favour of veganism:
We can extrapolate that veganism is healthy from first principles by studying individual foods and nutrients. For example, we know that saturated fat often found in animal foods increases LDL which is a validated marker of cardiovascular disease. Saturated fat intake will be low on a vegan diet. Another example is iron, we know that even unprocessed red meat is problematic because it is a rich source of iron and we know that many men consume too much iron (whereas some women consume too little). We know that iron intake and availability will be lower on a vegan diet and we have relatively strong evidence that elevated iron levels are harmful to health.
Or we can be lazy and just take a bird's eye view and look at mortality data in observational studies. These studies clearly show that both vegetarian and vegan diets are associated with reduced mortality and superior health outcomes. Unfortunately this kind of study design is subject to different biases like residual confounding, e.g. it may be that vegans are healthier than average even after we controlled for obvious variables associated with health like income, cholesterol, body weight, etc. While this does not prove that veganism is healthy, it definitely shows that veganism is consistent with above-average health outcomes.
We have to be careful not to offset the health benefits of a vegan diet. There is a surprising amount of evidence suggesting that low-normal iron stores are beneficial and may reduce cancer incidence, mortality and perhaps increase longevity. Specifically, as strongest, I would point out the FeAst study and numerous recent Mendelian randomization studies on iron and longevity (e.g. Daghlas and Gill 2021). It is prudent to test ferritin to know whether you are too low or too high.
Vitamin D testing certainly could be useful, even though recent clinical trials testing vitamin D supplements are between somewhat to highly disappointing, but deficiency is presumably not strongly linked to veganism.
I do not think this is entirely accurate. Lung cancer in smokers hits unusually young people because, well, they are smokers. Heart disease is a disease of old age and accelerating it somewhat through an unhealthy diet would have complex effects. However, making matters even more complicated, ultraprocessed foods also promote cancers and obesity -- the latter is definitely a huge healthcare burden which does not kill people immediately.
This is hard to model since there can be a shift from a disease that kills slowly to one that kills quickly and early (dementia to lung cancer), but you can have also the opposite shift (e.g. from a non-disease state to chronic COPD and frailty preceding death).
All we can say for sure is that the harmful effects of smoking and junk food diets may be offset to some extent. More so for smoking than junk food.
Either way, it would appear the consensus is that "in high-income countries, lifetime health care costs are greater for smokers than for non-smokers, even after accounting for the shorter lives of smokers"
https://www.tobaccoinaustralia.org.au/chapter-17-economics/17-2-the-costs-of-smoking
While the term "healthspan" can be useful for public messaging it is not necessary to use it instead of "lifespan" as study after study shows. When the word "lifespan" is used in the correct context people are very willing to embrace even radical lifespan extension. It seems prudent to combine both concepts.
Asked “If doctors developed a pill that enabled you to live forever at your current age, would you take it?” a surprising number of people turned out to be hardcore life extensionists: "There were no differences by age...Among young adults, 40.0% indicated they would not take the pill, 34.2% indicated they would take the pill, and 25.8% indicated they were unsure."
Barnett, Michael D., and Jessica H. Helphrey. "Who wants to live forever? Age cohort differences in attitudes toward life extension." Journal of Aging Studies 57 (2021): 100931.
Knowing your risk does not change behavior, at least that seems to be the case with genetic risks. That means dietary and lifestyle approaches towards cardiovascular disease are out. As a good approximation, everyone who wants to have a healthy lifestyle already has one*.
On the other hand, it is possible that more people would benefit from wide-spread use of statins and that they could be convinced to actually take them.
Cardiovascular disease is definitely not a neglected cause area. It is a multi-billion dollar industry and a very popular research field. Neither is targeting cardiovascular disease an effective approach towards improving population health due to Taeuber's paradox:
"..[the complete] elimination of neoplasms as an underlying cause would result in 3.83 life years to be gained among men, and 3.38 life years to be gained among women. Elimination of cardiovascular diseases results in a larger gain in life expectancy: 4.93 years among men and 4.52 years among women. "
https://jech.bmj.com/content/53/1/32.short
As you can imagine the benefit to human healthspan and lifespan due to a marginal reduction in cardiovascular disease achievable through refinements of diet and drugs would be minuscule.
The only way to significantly (and efficiently) improve human healthspan in developed countries is through slowing aging which is a risk factor for all major diseases.
*A potential cause area would be to work on legislative change that will compel people to change their lifestyle, this could be feasible, e.g. via taxation.
I enjoyed a lot of the other content and hence am now much more inclined to read the EA forums rather than lesswrong. These changes could mean that people like me, who are primarily interested in progress studies and applying science and reasoning to better humanity and themselves, may miss out on relevant AI content when they move to another site. Then again perhaps the EA forums are more relevant to me anyway and I should spend more time reading these.
Nutritionists are not dumb
Let's not be too cynical here. While, yes, nutrition science is short on definite conclusions, it still remains a science. If you want to figure out how to eat healthy, you would find this out the same way you would check whether aspirin prevents cardiovascular disease in certain subgroups or whether paracetamol extends the duration of symptomatic respiratory tract infections.
Step 1: Is there a consensus statement from a reputable professional society? Do different organizations and groups agree? If yes, here is your conclusion. Most sources agree that saturated fat is unhealthy. This is not controversial in nutritional science.
Step 2: Lacking consensus, what do up-to-date reviews and meta-analyses in reputable journals say? Maybe the data is so new that no consensus has emerged or maybe it is controversial for a reason. I find that a good review often presents both sides to the argument. This would be the case with moderate alcohol consumption. Last I checked, there is no consensus and both sides have good arguments.
Step 3: What are the implications if something were true or wrong? How do I balance my own time, money and quality of life against the promise of extended healthspan? Now here you will need a bit of statistical knowledge or intuition as well as a general understanding of biology. In the case of alcohol, given the doses and effect sizes involved, the harm or benefit of either side being correct would be very small.
More importantly, the healthier you are, the less you will benefit from optimizing your diet. Nutrition is an extreme example of diminishing returns. This is because the most important paradox you have never heard of, Taeuber's paradox, clearly shows that any improvement in healthspan (without slowing the aging rate) runs into tremendous diminishing returns.
To be worth your time, promising nutritional interventions above and beyond the basics must have certain properties, i.e. they must slow aging, potentially slow aging, improve non-health related quality of life, or address multiple health-outcomes at once. In this regard, all-cause mortality is the surrogate outcome worth paying the most attention to - although it is still imperfect.
I am not sure why we cannot have a vaccine against both strains. The HPV vaccine protects against 9 HPV subtypes, for example. Either I am missing something or it's just the medical establishment moving slowly, as always.
Given the data we have getting an "illicit" fourth booster shot might be the safer play. The mRNA vaccines continue to work, especially against severe disease, the effect is just much diminished.
Also, is there even any evidence for this assertion? If we stipulate that absolutist monarchies are about as bad as a dictatorship then how did that assertion work out historically? Over the last 10'000 years when lifespans were much shorter dictatorships and related systems flourished. The ascent of democracy has paralleled an increase in lifespans. Correlation does not imply causation, but at least it makes it more likely, whereas the dictator argument is just speculation as far as I can tell.
- Thank you for making a great point! Large countries do implement limits on internal migration to ensure political stability. The Chinese system is called hukou if anyone wants to read up on it; I am no expert myself. I would, however, disagree that these limitations suggest there is no free movement. In fact, the very existence of these limitations suggests we should open up compared to the baselines, but perhaps not fully.
The population of Shanghai grew almost 100% from 14M to 27M within the last 20 years - and the city transformed into a wealthy metropolis like NYC. According to Wikipedia, consistent with my intuition, a relaxation of Hukou migration restrictions coincided with the (post-)Deng Xiaoping era of stability and prosperity. So internal migration in China is enormous and while it is hard, it can't be that hard to move. Now, of course, these people are mostly Han Chinese and it is an interesting question how many immigrants of a different cultural background we could handle in Europe. - Agree, it is naive to argue for a "free lunch". As far as I recall, there is good economic evidence that migration from e.g. Afghanistan is a net cost for the taxpayer in Germany despite the younger age structure of the immigrants. (It only works out under extremely optimistic assumptions, if the immigrants can find higher-paying jobs than expected.) Migration (from [very] poor countries) should be considered a form of "foreign aid", it is a cost; and it is a question of political stability. Having many immigrants is useless if the AfD or Front National then rises to power, reverts your measures and sabotages democracy.
How does political stability change, though, is it linear with the number and type of immigrants or are there thresholds? - Does this point argue strongly against open borders? Both systems could work fine and strike a similar balance. Higher migration, lower migrant rights. Lower migration (but still higher than the status quo), better migrant rights. Either way, we are trying to maximize the same product: [Number of immigrants] x [net improvement in migrant life = wellbeing(home country) - wellbeing (target country)]. Europe opts for the former, the Gulf or Singapore for the latter. Neither can tell us if a deviation from the status quo towards more migration would be beneficial or not since the systems are so different.
You are right, the same is true in Germany as well. There is even some evidence for lower crime rates for certain immigrant groups (e.g., first generation immigrants from Turkey, or SE-Asian/Chinese immigrants, if I recall correctly). Still, more crimes means more crimes, even if this is due to demographics, and the voters will punish the pro-immigrant parties accordingly.
How limiting are poor corpus quality and limited size for these models? For example, Megatron-Turing NLG was only trained on PubMed extracts but not on PubMed Central, which is part of the Pile dataset. Was this perhaps intentional or an oversight?
Regarding medical texts, I see many shortcomings of the training data. PubMed Central is much smaller at 5 million entries than the whole PubMed corpus at 30 million entries, which seems to be unavailable due to copyright issues. However, perhaps bigger is not better?
Regarding books, how relevant is the limited size and breadth of the corpus? Books3 contains 200k books out of some 10 million that should be available via amazon.
Regarding copyright, could a less ethical actor gain an advantage by incorporating sci-hub and libgen content, for example? These two together claim to include 50 million medical articles and another 2 million books.
As far as I can tell, if they suspend one of two available mRNA vaccines this is bound to have zero effect on vaccination rates in the young because the other one can fill the gap.
Do you think this is a problem? It appears to me that no development is possible without some tail risk (which we obviously want to minimize wherever possible!). Can we come up with a realistic world in which technologic progress is used for peaceful purposes exclusively and never causes any negative surprises? Or a world that develops with zero tail risk?
My personal experience is that it's true hence I would caution against too much rest. Wrist pain is a very vague term, no idea what you have, but I have battled RSI for over half a decade (mostly of the fingers) and at some point it got so bad that I wanted to quit my degree and it felt like even reading a book or newspaper was too painful. By all means, use your voice, contralateral arm or legs and feet to take over some repetetive tasks.
However, you need to use, strengthen and stretch your wrists as well. Targeted massage and strengthening with a physiotherapist should help. As workoholics we often forget how to listen to our body. Pain tells you to take a break, not do an allnighter. Then when having pain, it is easy to try to "protect" the affected bodypart, putting undue stress on other parts of the body, while the muscles, tendons, ligaments of the affected bodypart continue to weaken because they are unloaded and/or not used throughout their physiologic range of motion.
Before I jump to SSRIs I would start with psychotherapy, meditation, taking a real vacation, a healthy anti-inflammatory diet (standard food pyramid will do as a start), sleep hygiene to get 8h+ for recovery, sports (both endurance and strength, preferably something involving your arms and hands!), whole body sports massage etc.
I did find that the pain was to some extent in my head, to some extent real, and exacerbated by both overuse and chronic misuse.
Trying to organize my thoughts on progress a bit:
I do not think we lack a "philosophy of progress" as much as the OP. I would like to argue that progress is real and that there is decent literature on this topic that not enough people read. Moreover, the topic of progress is a good recruitment tool for EA and rationalism. I find it more exciting and powerful than the bleak nihilism offered by atheism, meek criticism of pseudoscience offered by “the skeptics” movements and the vague (but obviously not misguided) appeals to the noble human nature proffered by humanism.
The distinction between descriptive and prescriptive optimism raised in this thread is a very interesting one. Are these entirely distinct concepts, though? It would stand to reason that there is a virtuous circle where descriptive evidence of tangible progress promotes optimism and a desire to further improve the world – because it seems possible. Therefore, it would be great if the world were improving. If it isn’t, we shouldn’t lie about it, but still it better be improving given the industrial revolution and the internet and all the things we invented. If this has not improved the world, what else will? AI? Anarcho-primitivism and yoga?
Improvement and progress come in many forms and shapes. Progress will never be an entirely objective measure, but it also is not purely subjective. Human desires are hard coded in our DNA, as most animals we seek safety, health, freedom, stability, psychological fulfillment (think Maslow) etc. As also pointed out in this thread, Stephen Pinker has written several books about progress. He is perhaps the 20th century’s most prominent chronicler of progress. By and large, his books have made a good case that the world is improving and all the attacks on their contents I have seen were feeble at best. Homicides, press freedoms, democracy, armed conflict. No one can claim these aren’t markers of progress, nor that they haven’t improved markedly. Not yet mentioned, I do think the Oxford team around Our World In Data is continuing in a Pinkerian vein, but doing so live, around the clock.
Case in point, their current entry on Human Rights is a masterpiece of public education (1). Not only is it well presented, but it is also up to date referencing the work of Fariss (2019). This paper importantly argues that the democratic recession is an artifact of stricter human rights standards over time. Whether this is true or not is not even relevant. Temporary stagnation is entirely compatible with long term progress.
People tend to get way too caught up in one dimensional measures of progress. To some it is only ecology, so the world is dying. To some it is only press freedoms, so China is an evil empire, and the democratic recession is perhaps the biggest problem we face. Humans in practice, however, do not have such one-dimensional desires. And I mention China on purpose, because no discussion of progress in the 20th century would be complete without this country. Here, I highly recommend reading Joe Studwell. Briefly put, China exemplifies how and why the world is improving; also given its size recent shifts in China are major drivers of aggregate improvement in human welfare. (I am sorry to all the China haters). Roughly speaking, since reform and opening by Deng Xiaoping and his political allies, the country has lifted hundreds of millions out of poverty. Civil liberties have not deteriorated since this major reform (again please read reference 1). There is ongoing concern that they may be deteriorating; and one would have hoped for more progress, but no one can claim it isn’t a net improvement.
If we want to instill optimism, a “philosophy of progress”, Pinker and Our World in Data must become mandatory reading in high school and university. Please, share other similar books and sources if you know them. Already mentioned was Joe Studwell. I can also think of Yuval Harari's Sapiens which is obviously Pinkerian but more accessible and shallow than “Better Angels of Our Nature”. Francis Fukuyama's "The End of History" was already mentioned and I hope to read it some day. Could someone comment if the books is just popular with libertarians or if it really does have a libertarian slant? (I have mixed feelings about libertarian support for progress. Personally, I do feel like hybrid models have been exceedingly successful in the 20th century if you look at Scandinavia, Germany’s “Soziale Marktwirtschaft” or Asia.)
If you ask me, reasonable controversy does not exist on the topic whether the world has improved or not. Cautious optimism is objectively warranted. On the other hand, there are important issues that are still contested. Does it continue to improve? Who was left behind? Is the democratic recession real? How much progress happened at the cost of environmental damage? Why is inequality still increasing? How much was due to chance and will we fall back? What is the importance of existential risks? It very well may be the case that existential risks have increased while the world became better and safer in aggregate on the “classical” measures. All these are important debates.
1/ https://ourworldindata.org/human-rights
Yes, Human Rights Practices Are Improving Over Time. Farris (2019).
I do not think that is true, at least in Europe where hundreds of millions of people use generic drugs every day. In Germany, in the UK and in Austria a doctor will amost always prescribe a generic when available and people will often buy a generic over the counter. While sometimes too conservative, the very reason why we need the FDA, the EMA, et al. is exactly to make sure that generics* work well -- and they almost always do, one cannot use rare counter examples to disprove that. Do we have any hard data to suggest that generics are somehow unsafe?
* i.e. not some Indian blackmarket knock-off that isn't FDA/EMA approved
With such highly subjective soft outcomes a lot depends on the way the question is phrased and interpreted (if self-reporting). Thus comparing different populations and studies is almost impossible without really carefully digging into the original publications and even then it is fraught with problems.
If I have a rash post-vaccine and I go to see my GP or pharamcist, am I seeking medical help and is this worrisome? If I get up and later realize that I need to lie down or else I will faint (vasovagal syncope, around one in ten people have some form of needle phobia), am I seeking medical help for a side-effect? Technically yes, but a saline injection would cause the same. If I have asthma or hayfever, issues with breathing, and later misattribute this to the vaccine, is this a side-effect? (around 1 in 10 people or so have asthma)
Finally, you cannot compare the serious side-effects in a trial (if this CDC figure really comes from a trial) with mild self-reported side-effects from Israel or American postmarketing surveillance. Trial participants will be monitored closely and will include a large number of at risk indiviudals (>60yo) so it is again a statistical artifact of data collection.
IMHO all the data is worthless without a very well-matched control group.
The sad fact is that we do not even understand mice very well. There is this old joke that can be paraphrased like this: if I were a mouse I could be cancer free and live forever, because it is so easy to cure these guys of diseases. As it turns out, however, this is not true. Within my field it was long gospel that caloric restriction (discovered some 100 years ago) can robustly extend mouse lifespan until studies in the last 20 years called this into question.
What the joke gets right is that we understand humans even less than mice. In fact, despite the controversies several interventions are relatively robust in mice when it comes to extending their life and health span (rapamycin, caloric restriction, growth hormone loss) while the evidence in humans is much weaker for these.
Delivering useful drugs, hopefully faster not slower than in the past, despite these issues will be an interesting challenge.
I guess this goes back to the issue of defining things and what you mean by hallmarks. If you define your hallmarks broadly enough they may include almost anything while being so vague that they are only useful for posters and ads. In the case of vague hallmarks you'd be right, if you fix them you're all good. But even in this extreme case I do expect the number of vague hallmarks to grow a little bit over time as we learn more. In fact, to me they feel incomplete and ill-defined already.
Looking at the classic "The Hallmarks of Aging" paper (first published as López-Otín et al. 2013 I think) or Aubrey's seven causes of aging I do feel like they are way too vague. Let's take genomic instability as an example. Fix it and you make progress against aging. However, that is just an empty phrase like "repair the engine of the car"; that's usually the reason why it stops in the middle of the highway. Which genome, mitochondria, nuclear? Which pathway do you target? Hundreds of genes involved in repair, hundreds of genes involved in prevention of DNA damage via the intricate ROS- and stress-sensing pathways. Which type of lesion to prevent? Damaged bases or strand breaks? Which type of existing damage to repair and remedy post facto? Actual mutations (not just temporary damage), small indels, aneuploidies, large deletions, inversions, translocations or more complex chromosomal rearrangements and clonally expanded cell populations? Don't forget to fix chromatin organisation and epigenetic marks and all the inter-related extra-nuclear factors that promote genomic instability (could be inflammation, could be reduced autophagy, let's speculate). Want to use nanobots instead? Be my guest, then you are solving advanced physics, engineering and AI problems.
Regarding incompleteness and definitions: Why did they choose to define telomere attrition as its own hallmark? First of all, this is an incredibily specific problem and secondly telomeres are part of the nuclear genome, i.e. they fit entirely within the scope of genomic instability. On the other hand, extracellular matrix aging is not part of The Hallmarks even though it has been suggested to be a life-limiting pathology since the early 20th century with good supporting evidence (think vascular aging).
As you can see these Hallmarks are a political, strategic and scientific compromise. (One can guess telomeres are on there because of the Nobel prize, public perception that they matter or some telomere researcher on the paper.)
However, I do see the appeal of these words, hallmarks, causes, even if their use in practise is limited.
My reply comes a bit late since I managed to write a long comment without clicking send and only noticed this now. I will address the errors I see in the TL;DR summary from the POV of a semi-professional biogerontologist:
The disease-based approach to aging this seems to favour is useful, but limited. In fact, if you genuinely want to extend both lifespan and healthspan this excessive focus on the disease-based approach would be inefficient because is inconsistent with everything we know about aging. I would go as far as to say that the disease-based approach may be actively harmful because it takes away resources from genuine aging research.
While aging probably has thousands of causes, or even more*, this does not preclude the existence of major causes that limit lifespan in the near term. This idea has been popularized by Aubrey de Grey a long time ago and now has reached the scientific mainstream with an emerging consensus about the Hallmarks of Aging (several key pathways and sequelae of aging). We also know that this view is decently well supported in mice and have known so since the late 1990s when Holly Brown-Borg and Andrzej Bartke introduced the Ames dwarf mouse to gerontology. If aging was strictly multifactorial and polygenetic there would be no hope to identify single genes that lead to pronounced lifespan extension, as they did with the long-lived Ames mouse, which is long-lived because of an underdeveloped pituitary and reduced growth hormone levels. This means one simple change to a single pathway can extend lifespan.
Of course, I am biased, since as a biogerontologist I think the biggest gains are to be had from targeting aging directly, although we can have a discussion how well the mouse data translates to humans. (Not well, IMHO, but it is the best we have.)
Sizable lifespan extension we have seen in mice has come, without exception, from interventions that target aging directly through the above discussed “hallmarks”. Just to give three famous examples of life extending treatments: We have Rapamycin, an inhibitor of the mTOR pathway, that became a plausible candidate after this pathway had been implicated in the aging of yeast. Then we have caloric restriction, which was discovered by accident and not by the disease-based approach, but is now known to target a global pathway that promotes tissue maintenance under nutrient stress. Finally, we also have senolytics, drugs that were developed to kill senescent cells, that had been linked with aging after decades of biogerontologic research.
In contrast, drugs like Aspirin, Simvastatin, Enalapril and many others were tested in mice with no clear biogerontologic rationale behind them and predictably failed to extend lifespan, even though they are obviously amazing from a disease-prevention point of view.
However, I do agree that biogerontology depends on the existence of a strong biomedical ecosystem. Rapamycin was initially discovered as an immunosuppressant and if not for that, it would have taken longer to find inhibitors of the mTOR pathway (but eventually it would have happened by standard medicinal chemistry). Working in the 1930s Clive McKay, the discoverer of caloric restriction, was perhaps more interested in the basic biology of starvation and malnutrition than finding treatments for aging, etc.
Nothing about age-related multimorbidity makes sense if it not viewed through the lens of biogerontology.
Notes
* for example, you may be able to get 10-30% of lifespan extension by targeting the top 10 causes of aging, then eventually as you want to extend lifespan more and more, other causes of aging would take the spotlight
Actually, they all do include it, but is is subsumed under stem cell aging, loss of cells and reduced regenerative capacity. Also to clarify what I would consider a misunderstanding. Not everything has to fit. There are probably infintely many causes of aging or at least quite a lot. Most of these fall into the rough categories or "hallmarks" we have come up with like reduced stem cell functioning or damage to biomolecules. Many of these causes are not relevant to immediate life extension which is why they can be ignored for now. Other categories or "hallmarks" will be discovered as we go along.
Having said that, dysfunction of the neurmuscular junction is probably the most important type of muscle aging, much more so than cell loss, and, being so complex, I do not think the hallmarks do it much justice. Many of the hallmarks are so vague as to be almost useless anyway.
Does not make that much intuitive sense to me because there are a lot of random mutations happening. If the first dose first (or first dose only) strategy reduces the size of the whole SARS-CoV-2 viriome, there will be fewer viruses and less genetic variation in total. More infections in total means more genetic diversity. More infections means that a vaccinated person will be exposed to more sources of infection, more virions, more different genomes over time, thus also increasing the likelihood of mutants able to escape the immunologic response.