Tag Archives: biology

Blueprint 1.0 Review

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I spent $343 for one month of blueprint. this post shares what I got and what my thoughts on it are!

overall I’m a fan of most ingredients and the overall composition. I came up with many of them on my own a few years ago, many of which are listed here. the doses are pretty reasonable and I trust the sourcing to at least be above average

this post is not sponsored or paid for in any way, but I’ve met BJ and think he is reasonably smart and funny. below I include images, nutritional information, and plenty of links and side notes to share what I’ve learned!

Apr 13 2024 edit: added response comments from Blueprint: ctrl+F “BP” to find them

Everything I got for one month at a cost of $343

Nutty pudding

The nutty pudding mix
After being mixed with whole milk
Ingredients for the nutty pudding mix
  • mostly plant protein, giving you 26g of protein per serving
  • allulose as a sweetener is great and I’m happy to see it becoming more common (see my post on allulose for why). may want to note to consumers what it does and why they might notice it
  • cinnamon and grape seed both great inclusions
  • no opinion on pomegranate and monk fruit extract. I’m assuming the latter is as a sweetener and flavor enhancer (BP: pomegranite included to improve metabolic panel markers)
  • the taste is… alright. some people definitely like it more than I do, but I’d probably only rate it a 5/10 myself. I substituted whole milk in instead of nut milk as suggested and added the blueberry mix (below) to it to finish it. it tastes like a rather bland pudding, but a bit more dense and with little sugar or fat (BP: adding EVOO for taste may help)

Blueberry mix

Blueberry mix!
  • it’s literally just dried blueberries, macadamia nuts, and walnuts
  • tastes great no matter what do you with it really. I’d suggest adding it to the above pudding or combining it with some milk
  • blueberries are great for you and a good snack to have around
  • with that said, this mix is so simple that I’m not sure I gain much from having someone else prepare it for me (BP: mix replaces 2kg of berries and helps not having to acquire them frequently)

Longevity mix

Longevity mix powder
Longevity mix powder mixed with water and encased by glass
Nutrition info for the longevity mix
  • simple mix that you add to water
  • creatine, glucosamine, taurine, glycine, the gang’s all here
  • allulose again chosen as the primary sweetener
  • I’d increase the amount of glycine (1.5g), especially due to this being earlier in the day so it’s unlikely to be too much to disrupt sleep (this dose would be fine before bed and likely benefit sleep but the instructions online suggest to have this mix in the morning). for more information on why I’m in favor of macrodosing glycine check out the glycine section on my supplements page (hint: it extends lifespan in mice!)
  • sodium hyaluronate is an interesting choice and I wonder why they chose it + this form of it (BP: intended to reduce inflammation and restore HA levels which decline with age)
  • i’m a big fan of ashwagandha, with the note that it can cause digestive distress for some. great for lipid profile and often improves anxiety too
  • there could be a bit more creatine (2.5g) for those lifting, especially since calcium alpha-ketoglutarate was added (BP: amount chosen to be tolerable for mass market while covering omnivores average diet intake)
  • the taste is decent and comparable to most ‘vitamin’ drink mixes that you add to water. I’d probably rate it a 6.5/10, nothing to complain about but not particularly exciting

Pills!

The four bottles that I got along with what the pills from each look like. The daily suggested dosage is 3 pills from each of the larger bottles and 1 from each of the smaller, for a daily total of 8. Certainly not as bad as what was featured on my supplements page!

NAC, ginger, curcumin

Nutrition info for the NAC, ginger, and curcumin capsules
  • NAC is reasonably popular in the longevity community and pretty interesting
  • not 100% sure what the reasoning behind ginger was – I wonder if it was due to its ability to ameliorate potential gastrointestinal side effects of other supplements? (BP: intention is to improve metabolic panel, reduce inflammation, improve mood)
  • circumin is generally a good choice, although I have concerns about lower bioavailability here. does one of the other supplements included notably modify this? (BP: curcumin bioavailability 4x higher in this case due to being bio-enhanced)

Essential capsules

Nutrition info for the essential capsules
  • not going to list all the vitamins as they’re all reasonable choices
  • glad to see a higher amount of vitamin D (2,000 IU). could go even higher but the average blueprint consumer probably gets more sunlight than I do
  • I don’t know what the benefits of including e.g. iodine, calcium, manganese, and selenium are. would these be missed at all if excluded? feel free to enlighten me if you’re a reader! (BP: these deficienties are moderately common so worth including, calcium as excipient of CaAKG)
  • lithium is interesting at 1mg but I’m not sure that’s high enough to do very much (although perhaps this is the intention to keep it on the safe side)
  • I didn’t know that the body converts glucoraphanin into sulforaphane via myrosinase. good supplement!
  • fisetin at100mg daily is an interesting choice. curious how they decided daily was the correct increment and 100mg was the correct dose – I found this one hard to decide on myself (BP: dosage most studied wrt fisetin)
  • spermidine 10mg is perhaps one of the most promising supplements here due to directly improving lifespan in mice! how did they source this? see more info in the spermadine section on my supplements page
  • genistein is an interesting choice as it is pretty estrogenic. there are a lot of gender-ambiguous benefits to this, but i’m curious what the specific reasoning was and how the dose of 300mg was decided. it has affinity for α estrogen receptors, but not as much as β. if it was easier to source and include 17α-estradiol, would that have been included instead? was this included for entirely different reasons, of which there could be many? see also: does 17α-estradiol/estrogen extend male human lifespan? (BP: genistein does not increase blood estrogen levels in men, 17α generally requires Rx)

Essential softgel

Nutrition info from the essential softgels
  • nothing particularly exciting here, nice to see the better forms of vitamin k (k1, k2 mk4, k2 mk7) all included
  • astaxanthin is a nice inclusion
  • less excited over lycopene, lutein, and zeaxanthin, but I don’t know anything bad about them. would like to research them more later

Garlic, red yeast rice

Nutrition info for the garlic and red yeast rice pills
  • unsure why these are in their own pill instead of included within one of the larger mixes (from which you take 3 daily from)
    (BP: pills were grouped to reduce amount. water soluable actives went into longevity RTM, fat soluble into softgel, bitter tasting into capsules, and small amounts into essentual. RYR and NAC were separate SKUs due to regulatory concerns.
  • garlic is great if we give them the benefit of the doubt on the 12:1 exact including enough allicin
  • does the red yeast rice (500mg) actually contain a lot of monacolin k? some countries like the US dislike this due to it being bioidentical to e.g. lovastatin (BP: no, this is why CoAs are shared)
  • interesting side note: when you research a lot of natural compounds (roots, vegetable extracts, etc), it’s very interesting how many of them are bioidentical to actual pharmaceuticals. when I was young I didn’t understand why ‘vegetables’ or such should be good for me: adults would tell me they had “vitamins and minerals” in them, but I could obviously both a) test myself for vitamin and mineral deficiencies and b) supplement them if I was deficient in them. it wasn’t until many, many years later that I learned how amazingly complex everything we eat is and how many biologically active ingredients are in dishes. think of a dish with many vegetables, spices, roots, meat, etc, as basically having 20 different drugs in it, but with all of them in very small doses. many of them are also very slightly psychoactive too! just as you can get high on nutmeg and sweet potatoes inhibit α-glucosidase and are thus anti-diabetic like the drug acarbose and red yeast rice is literally the same as a statin medication and berberine found in plants like barberry is a mimetic of the anti-diabetic drug metformin, the foods we eat on a daily basis have an astoundingly large amount of downstream effects in the body which have nothing to do with the vitamins or minerals in them. the cases we tend to know about like marajuana or opium are not rare in that they have strong biological effects, but rather are only rare in the dose response curves that are common with consumption. the present epistemic milieu we reside in with respect to nutrition doesn’t talk about this much primarily because we know so little about the topic and actually learning what is going on enough to have high confidence and rigor is extremely tedious and slow

Olive oil

  • it’s olive oil. it is made from olives
  • the branding of ‘snake oil‘ is honestly pretty funny given how most supplement marketing is basically fraudulent

Marketing

  • no cards or instructions were included in the box. this is missing out on a gigantic free lunch!
  • I’d strongly suggest adding instructions, a thank-you card, and a discount code for future purchases
  • the discount code should be notable as user retention may be more challenging than other monthly supplements due to the tediousness of consumption (8 pills, one drink mix, one pudding mix, olive oil, and another mix, every single day!)
  • given the higher price point it would be great if the bags could be redone to have a high-quality zipper on them as sealing them is annoying
  • the supplement bottles should be shinier. this will increase conversion as this product is offered at a ‘premium’ price point. I’d look into making a bespoke logo for blueprint as well or otherwise refining the font and decor around it. you will be surprised how much of a return you can get by spending $0.10 more on shiny paper and branding!
  • I would move supplements with the highest probability of causing digestive distress into their own pill so that users can modulate dosage or ablate it themselves for e.g. supplements like ashwaganda and curcumin. this should be included in the instructions as otherwise users who feel unwell may simply never try blueprint again
  • current marketing paradigm likely favors a cohort of more males than females and more adolescents than the elderly. this is reasonable and likely the correct choice to make early on, but I’d consider long-term strategies on how to improve this. encouraging gifting to the elderly (e.g. one’s parents) is likely a great idea here for obvious reasons
  • (BP: agreed on much of the above, some are already being implemented)

Research and sourcing

  • most of what is included is good, but I’m not told why it was included! if there was so much money spent on research and reviewing studies, it would be great if some of it could be shared to me as a lowly and uninformed end-user
  • why does the blueprint page advertise ‘non-gmo’, and what does ‘no artificial ingredients’ mean? generally the latter means next to nothing, but I don’t actually care if something as simple to synthesize as e.g. glycine is ‘artificial’ or not as long as it is the right chemical and without contaminants or impurities! modify labels for your intended audience accordingly
  • similarly to sharing research the website states that you “test the ingredients” yourselves. I assume this means more than just eating them and making sure you don’t die, but this seems like a great thing to share more about, especially because this is very tedious to do (BP: manufacturers are asked for CoA and then we test the individual ngredients ourselves)
  • having users share metrics before and after a few months of blueprint consumption would be great (BJ told me isn’t necessary as the individual ingredients already have sufficient evidence on their own. but if you ask me, there is never enough science being done and there is never enough data, so I’d prefer we continue to learn all that we can even if it only confirms our priors) (BP: a few thousand people are on it and sharing biomarkers, we will share this data)
  • relatedly I’m concerned that some of the supplements may inhibit various enzymes that then cause unknown and/or undesired changes of bioavailability in other supplements or drugs. both curcumin and ginger inhibit CYP3A4 and this may be suboptimal if combined with other longevity drugs like rapamycin (which, similarly, could block astaxanthin which blueprint includes as well). this is challenging as we have limited knowledge on this topic for most supplements and drugs, but is worth at least being aware of
  • fortunately i’ve written from-scratch personal tracking software that I can throw all of this data into in order to solve a few of the questions (those which are easily answerable via blood tests at least), but this is costly and tedious and I am tired of getting blood tests. I may try A/B testing all of blueprint RCT-style to see if I can notice any other variables it effects that I wouldn’t have otherwise predicted

Final thoughts

  • overall this is a decent purchase if you want to make the trade-off of spending more money for not having to perform your own research, logistics, sourcing, purchasing, etc
  • with that said, there’s secondary effects to note: a) the substitution effect of having something decent rather than what you’d have had instead (this is why most ‘diets’ are always an improvement: the typical American diet is so bad that basically anything that is not insane is likely to be a net-benefit), and b) the psychological effect of causing you to consciously think more about optimizing for your health. I would strongly bet that there is a ‘healthy user bias’ among blueprint users that results in them having e.g. better lipid and glycemic profiles than non-blueprint users even if they stopped taking blueprint as they probably get more exercise than average
  • the largest benefits in longevity may still be things that we cannot easily sell in a bag or bottle, whether that is because it is intangible like exercise, or because of excessive regulation (e.g. the revolutionary weight-loss drug semaglutide requires a prescription and often insurance, although notably can also be purchased online regardless from parties which are not fans of the US patent system. even so, clinical trials for it began 15 years ago which likely resulted in the early death of millions of americans due to obesity. other longevity drugs like rapamycin are also challenging to distribute to the average consumer for similar reasons (and that one is FDA-approved too!). the FDA is excessively conservative in what they allow, with drugs requiring a decade and ~$600M to be later slowly distributed to the general public, and this is before we even bring in talk of gene therapies or anything newer
  • alpha in longevity (both personal and scientific) still remains in copious quantities for those who are willing to search for it!
  • I haven’t yet decided if I’ll purchase another month of blueprint. I’ll try it for a bit longer and see how I feel, but I think it’s a reasonable product overall and I’m glad it exists
  • If you enjoyed this post you might like my website (see also: supplements) or my twitter
  • feedback (especially any potential corrections) is very welcome! DM me on twitter or submit anonymously here

Pascalian Longevity: Why not?

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Scott Alexander of SlateStarCodex / AstralCodexTen recently wrote Pascalian Medicine, in which he looks at various substances purported to improve covid outcomes, but which have relatively low amounts of evidence in their favor, likening administration of all of them to patients to a Pascal’s wager-type argument: if there is a small probability of a potential treatment helping with covid, and if it’s also very unlikely that this treatment is harmful, should we just give it to the patient regardless of if the quality of evidence is low and uncertain, as it would clearly have a positive expected outcome regardless?

The naive answer to this could simply be to attempt to calculate an expected value (note: I use the term expected value often here, but in some cases the terms hazard ratio, relative risk, or odds ratio would be more appropriate) for each treatment, and administer it if it’s positive. But there could be some unintended consequences of using this methodology over the entire set of potential treatments: we could end up suggesting treatments of 10 or 100+ pills for conditions, and apart from something just feeling off about this, it could magnify potential drug interactions, some treatments could oppose others directly, the financial cost could start to become prohibitive, and it could decrease patient confidence and have many other undesirable second-order effects.

Pascalian Longevity

There are many counter-arguments presented to the above concept which become less salient when the goal is changed from ‘find drug treatments to prescribe to all covid patients’ to ‘find personal health interventions that increase your own lifespan/longevity’.

I am fortunate enough that I am able to evaluate potential longevity interventions myself, pay for them myself, administer them myself, and review their potential effects on me myself. I might not do a perfect job of this – research is difficult, time-consuming, and lacking in rigor and quantity, and finding appropriate longevity biomarkers to quantitatively asses the effects of interventions is also difficult. But uncertainty is a given here, and that is why we incorporate it into our frameworks when deciding if something is worth doing or not by calculating an expected value. Furthermore, any harm that I may accidentally incur will only be done to myself, reducing the ethical qualms of this framework to near-zero (I would strongly oppose arguments that I should not have the right to take drugs which I think may significantly improve my own health, although some may disagree here).

My modus operandi with respect to longevity may have many uncertainties in its output, but still operates with a very strong (in my opinion) positive expected value: If a substance significantly and consistently increases the lifespan of organisms similar to humans (ideally in humans), and is also very safe in humans, then it is something that I want to take

This is how I operate personally with longevity, and it does result in me taking quite a few things (currently I’m at around 15). I do still try to minimize what I take as a meta-principle (for example, setting a minimum threshold of expected value that a substance must provide to warrant inclusion, rather than simply accepting any positive expected value) for a few reasons: firstly, to reduce potential drug interactions (which we do attempt to asses on a per-substance basis, rather than account for as an unknown, but unknowns are unfortunately a very large component of messing with biology regardless). Secondly, to keep my costs relatively sane, although I am not too worried about this as there are few ways to spend money more effectively than on trying to improve your health. Thirdly, to reduce the occurrence of interventions that may have the same or opposing mechanisms of action (taking two things with the same mechanism of action may be okay, but sometimes dose-response curves are less favorable, and taking >~2x of something will result in diminished or even negative returns). Lastly, to minimize potential secondary side-effects that could be cumulative over large classes of substances (for example, effects on the liver).

I don’t intend to promote any specific substances or interventions here as I don’t give medical advice, nor do I want anything specific to be the focus of this post, but I do want to remind us that just as we can calculate expected values in a utilitarian fashion and get effective altruism as a result, we can do the same for longevity interventions and get a very strong chance at notably increasing our lifespan/healthspan as a result. I do have a list of some of what I take here, but it is definitely not intended to promote anything specific to others.

Why Not?: Potential counter-arguments

Algernon’s Law

Algernon’s Law is sometimes brought up, suggesting that evolution has already put a lot of effort into optimizing our body, and thus we are unlikely to find improvements easily. But, as Gwern notes in the above link, there’s at least three potential ways around this reasoning: interventions may be complex (and/or too far away in the evolutionary plane) and could not have easily been found, they may be minor or only work in some individuals, or they may have a large trade-off involved and cause harm to reproductive fitness.

Although some areas of future longevity treatments may fall under exception one and be complex enough that evolution could not have found them, I would suggest that the majority of today’s potential treatments fall under exception three: evolution optimizes for reproductive fitness, not for longevity, and for this reason there are many interventions which will improve our longevity that it has not given to us already (this is part of why I am more optimistic about longevity interventions than I am about intelligence interventions/nootropics).

For an extreme example of this, it has been noted that castrated males often live longer, and that this is obviously something evolution would not be very interested in exploring. Although this has been found with median lifespan in male mice (maybe in females too?), there is also purported historical data on Korean eunuchs suggesting that they may have lived a full 14-19 years longer (there are definitely potential confounding variables and/or bad data here, but we don’t have RCTs on this in humans for obvious reasons..), and a more recent study in sheep that is also highly relevant: Castration delays epigenetic aging and feminizes DNA methylation at androgen-regulated loci, where epigenetic aging clocks that look at DNA methylation are used in castrated sheep. There are other traits that seem to improve longevity as well, for example decreased height. It seems quite plausible that there are a lot of trade-offs that optimize for strong reproductive fitness early in the lifespan of organisms, which end up costing the organism dearly in terms of longevity. These trade-offs may be involved in many areas such as testosterone, estrogen, growth hormone, IGF-1, caloric restriction, mtor activation, and many others.

Large error in estimating unknown risks

One other counter-argument here is often along the lines of “you are messing with things you don’t understand, and you could be hurting yourself but be unaware of this; the damage may also be difficult to notice, or perhaps only become noticeable at a much later time”

It is true that our understanding of biology is lacking, and therefore also that we are operating in highly uncertain environments. I would be open to evidence that suggests reasoning for why we may be systemically underestimating the unknown risks of longevity interventions, but given how strong the potential upside is, these would have to be some pretty terrible mistakes that are being made. It is often noted how curing cancer may only extend human lifespan by a few years, whereas a longevity improvement of 5% for everyone would provide much more value (and is also much easier to find in my opinion). One could make an argument here that even if I was doing something that notably increased my risk of e.g. cancer, if the expected lifespan increase of this intervention was as much as 1-5%, this could still be a huge net positive for my health! I don’t take approaches that are this extreme regardless, and I try to keep the risk side of my risk/reward ratio low independently of the level of potential reward in attempt to account for this uncertainty. I am also not aware of many interventions that seem to have very high numbers in both the numerator and denominator here, although I am pretty certain that they do exist; I don’t currently take anything that I think has notably detrimental side-effects for the time being.

Is it fair to call this approach Pascallian?

The original nature of Pascal’s wager is that of extreme probabilities resulting in positive expected values, but the numbers that we are operating with are nowhere near as extreme as they could be. It is probably not a good idea to take 10,000 supplements, each of which have a 0.1% chance of extending your lifespan by a year for many reasons (similarly, if 10,000 people that claimed to be God all offered me immortality for a small fee, I would hope to decline all of their offers unless sufficient evidence was provided by one).

As I’m not arguing in favor of taking hundreds or thousands of supplements in the hopes that I strike gold with a few of them, it may be worth noting that ‘Pascallian Longevity’ would be a poor label for my strategy. Regardless, taking just 5-10 longevity interventions with a strong upside potential seems to be significantly more than almost everyone is doing already, so I still stand by my claim that there are many free lunches (free banquets, if you ask me) in this area, and I am very optimistic about the types of longevity interventions we’ll find in the coming decades.

Open to any corrections/comments on Twitter or any medium on my about page

Links

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This page lists many of my favorite blog posts, organized by author. Much of my most-cherished knowledge is from blog posts or internet comments, so I hope to share some of that with others here. Last updated: Apr 17, 2024

Scott Alexander (Twitter): As the author behind SlateStarCodex (now AstralCodexTen) and many great LessWrong posts, Scott is among one of the best written content creators of the last decade. He writes about psychiatry, rationality, and meta-science. Here’s some writing of his that I love, with my favorites bolded:

Gwern Branwen (Twitter – currently private): Well-known for having quality deep dives in diverse areas such as statistics, technology, machine learning, genetics, psychology, and many others. Also often recognized as an amazingly aesthetic, verbose, and highly-usable website. Favorite posts:

  • About Gwern: About Gwern; who he is, what he has done, and links to other mediums
  • It Looks Like You’re Trying To Take Over The World: An eloquently-written and humorous short story about AI alignment and paperclipping, featuring our good friend Clippy alongside a multitude of entertaining references, both to Internet history and many arxiv machine learning papers
  • Generating Anime Faces: An overview of GANs in machine learning, with focus on Stylegan2 and anime art generation including ThisWaifuDoesNotExist and its follow-up ThisAnimeDoesNotExist, both trained from a large Danbooru dataset
  • Death Note Anonymity: Using information theory to quantify the magnitude of Light Yagami’s mistakes in Death Note (absolutely worth watching, even if you’re not into anime), offering insightful analysis and constructive criticism
  • The Scaling Hypothesis: Discussion of the scaling hypothesis in machine learning (essentially how much better models get with significantly more data+compute), with obligatory emphasis on GPT-2 and GPT-3
  • Melatonin: Detailed information on melatonin, a simple endogenous hormone that notably improves sleep in many individuals when supplemented just before bedtime
  • Nicotine: An analysis on the benefits of nicotine as a nootropic, with attention given to the fact that it is often incorrectly assumed to be a dangerous and addictive drug due to its inclusion in cigarettes and consequently significantly-confounded research claims
  • Modafinil: Discussion of modafinil, a prescription stimulant drug that appears to have a relatively favorable cost/benefit profile for productivity and alertness
  • Embryo Selection for Intelligence: A cost-benefit analysis of the marginal cost of IVF-based embryo selection for intelligence and other traits
  • Why Correlation Usually ≠ Causation: A meta-scientific discourse and analysis on the age-old adage that correlation does not imply causation
  • The Melancholy of Subculture Society: A brief analysis on the cultural effects of the Internet allowing niche subcultures to easily form
  • Newsletters: Links to Gwern’s past ~monthly newsletters
  • My Anime List: Gwern’s top-rated anime

Andrej Karpathy: (Twitter) A bright AI researcher who has spent time both at OpenAI and as the chief AI officer at Telsa. He has a popular Youtube channel with machiune learning content as well.

  • The Unreasonable Effectiveness of Recurrent Neural Networks: Back in 2015 Andrej trained a 10M-parameter RNN on some interesting text datasets like the source code for the Linux kernel and Shakespeare. Performance was surprisingly good!
  • Biohacking Lite: It’s always fun to read content from people from fields like computer science when they later deep dive into biology, often for their own personal health. This post has some high-SNR content on the basics of metabolism and energy in humans as well as some quantified-self demonstrations and simple dietary advice.

Scott Aaronson: A theoretical computer scientist with a focus on quantum computing and complexity theory. Although his posts on quantum computational complexity theory research go over my head, I’ve enjoyed some great content from him in other categories. Favorites:

Matt Levine (Twitter): An ex-Goldman Bloomberg opinion columnist with some wonderfully insightful and hilarious posts (offered as a free newsletter, generally ~4x a week) on the happenings in our modern yet often-insane financial world. Posts are generally centered around current events and are best read as they come out. Some examples:

Nintil (Twitter): A wonderful blog by Jose Luis Ricón with a focus on longevity, economics, and meta-science. Favorite posts:

Patrick Collison (Twitter): The CEO and co-founder of Stripe, often with focuses involving meta-science, individual and societal productivity, and economics

  • Fast: Examples of people quickly accomplishing ambitious things together
  • Questions: A short list of interesting questions
  • Advice: Advice, particularly for young and ambitious individuals
  • Book Recommendations: A well-sized list of suggested reading

Sam Altman (Twitter): The CEO of OpenAI and former president of Y Combinator, his posts often focus on startups, artificial intelligence, productivity, and science. Favorites:

  • How to be Successful: Thirteen thoughts on how to achieve long-term successful outcomes: learn a lot, compound yourself, work hard, and be ambitious
  • Productivity: Various productivity tips, such as ‘Picking the right thing to work on is the most important element of productivity and usually almost ignored. So think about it more!’
  • Advice for Ambitious 19 Year Olds: Advice for young and ambitious individuals, such as ‘The best people always seem to be building stuff and hanging around smart people’
  • How to Invest In Startups: Advice about being a good startup investor
  • Super successful companies: Notes some salient commonalities between many very successful companies
  • The Strength of Being Misunderstood: You should trade being short-term low-status for being long-term high-status

Paul Graham (Twitter): The founder of Y Combinator, with many posts focusing on startups, ideas and frameworks for everyday life, as well as advice and reflections for people that fit the founder/builder/nerd stereotype. Some favorites:

  • Do Things That Don’t Scale: An amazing tip on gaining initial traction and leverage by doing high-impact activities that won’t scale, but that will work effectively for the time being
  • What You Can’t Say: Reflections on that which exists outside of the Overton window
  • How to Make Wealth: An essay on effectively building wealth over time
  • Keep Your Identity Small: On why politics and religion yield such uniquely useless discussions due to excessive involvement with personal identity
  • Having Kids: Personal experiences and thoughts on having kids
  • It’s Charisma, Stupid: A 2004 essay arguing that charisma is the most important trait for elected politicians, using the US presidency as an example
  • What I worked on: A personal and emotional memoir on pg’s professional and personal history

Alexey Guzey (Twitter): Currently working on New Science, Alexey has some great blog posts with a focus on properly using the Internet for social leverage (reach out to people more, cold email people more, initiate conversations more, and create content more!), meta-science, productivity, biology, and more. Some favorites:

Melting Asphalt (Twitter): Written by Kevin Simler (along with Robin Hanson (Twitter), co-author of The Elephant in the Brain), Melting Asphalt has a wonderful collection of posts on evolutionary psychology, game theory, and novel and introspective takes on what makes us human. Favorites:

  • Neurons Gone Wild: A beautifully speculative post that suggests a recursively selfish model of biological neurons which enables selfish sub-agents and networks to co-exist in an evolutionary semi-competitive environment within our own minds. Probably my favorite post on this blog for several reasons. Also see Hallucinated Gods
  • Music in Human Evolution: A great book review of Why Do People Sing?: Music in Human Evolution by Joseph Jordania, involving predatory defense mechanisms, disposition of the dead, battle trances, and the audio-visual intimidation display
  • Crony Beliefs: On beliefs that stick around when they shouldn’t
  • Personality: The Body in Society:
    What is personality? ‘Nature and nurture work together to create a prototype, which then negotiates with the external world. The result is a strategy for getting along and getting ahead — a strategy we call “personality”, in other words, ‘Personality is a strategy for making the most of one’s particular lot in life.’ See also: part two and part three
  • Ads Don’t Work That Way: On ‘cultural imprinting’ and signaling in advertising
  • Doesn’t Matter, Warm Fuzzies: Discusses many interesting aspects of human ecology and society, with a focus on rituals, culture, confabulation, mimicry, and more
  • Social Status: Down the Rabbit Hole: On social status in humans, including an analysis of two proposed separate status systems: dominance/submission and prestige/admiration. See also: Social Status II: Cults and Loyalty
  • Border Stories: Borders are a necessary precondition for agency within a hostile ecosystem

Telescopic Turnip: Reads like type of cross-over between scott alexander and gwern, which means it’s good

Qualia Computing: With a subtitle of ‘revealing the computational properties of consciousness’, Qualia Computing is a great blog for anyone interested in the neurology, phenomenology, and interesting attempts at quantifications and explanations behind our own conscious experiences (qualia)

Patrick Mckenzie (Twitter): An entrepreneur and writer that lives in Japan and currently works at Stripe with a focus on startups and outreach, Patrick has many invaluable posts about finance, startups, marketing and professional communication, and highly-regarded SaaS and entrepreneurial advice. Favorite posts:

Nat Friedman (Twitter): Great personal website!

Fantastic Anachronism (Twitter): todo, see Recommended Reading

Applied Divinity Studies: todo

Peter Attia (Twitter): todo

Vitalik Buterin (Twitter): todo, see The bulldozer vs vetocracy political axis

Lesswrong: todo

Overcoming Bias: todo, ‘This is a blog on why we believe and do what we do, why we pretend otherwise, how we might do better, and what our descendants might do, if they don’t all die’, from Robin Hanson.

Tim Ferris: 11 Reasons Not to Become Famous

Dynomight (Twitter): todo, see Better air is the easiest way not to die by The impact of air pollution on health is often significantly underrepresented, and working on improving the quality of air in your dwelling can result in a very high ROI for your health

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Does 17α-estradiol/estrogen extend male human lifespan?

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17α-estradiol is a relatively (or completely) non-feminizing form of estradiol (E2), or estrogen. It is a naturally occurring enantiomer of 17β-estradiol (the much more common form of estradiol, usually just referred to as ‘estradiol’) which is found in both male and female humans. This post a a brief essay that discusses the prospect of it extending lifespan in humans. There are two primary types of estrogen receptors, ERα and Erβ, and as you may expect, 17α-estradiol appears to show a stronger binding affinity for ERα. It has a very low binding affinity in locations that generally induce feminization (which appear to be sometimes be both ERα and ERβ), so it’s also possible to take as a male without significantly altering one’s appearance towards the opposite gender. Although we can definitively point to a plethora of effects of regular estrogen, it is difficult to tell what the true purpose of 17α-estradiol is in humans, with Stout et al. (2016) stating “the physiological functions of endogenous 17α-E2 are unclear”. There is evidence it has neuroprotective properties, can help treat Parkinson’s disease, cerebrovascular disease, and much more. This likely involves ER-X, which in turn activates MAPK/ERK and many, many other things down the line (as usual..), but it’s difficult to know for certain. Although these reasons were among the reasons that researchers took into account when deciding to dedicate funding to testing 17α-estradiol in mice for longevity effects, subsequent papers have found more exciting mechanisms of action which are elaborated upon below. For some interesting further reading on this topic that goes into more detail exploring possible mechanisms of action here I’d also suggest reading the following papers: Castration delays epigenetic aging and feminizes DNA methylation at androgen-regulated loci, Hypermethylation of estrogen receptor-alpha gene in atheromatosis patients and its correlation with homocysteine.

17α-estradiol has been found to consistently and significantly extend the median lifespan of male mice, including by the NIH’s Intervention Testing Program, the closest thing we have to a gold standard of longevity RCT experimentation in mice, where three studies are rigorously performed at three separate locations, allowing the results to be instantly compared and reproduced by the two other parties and locations upon completion. Strong et al. (2016) find that 17α-estradiol extends median lifespan of male mice by an average of 19% (26%, 23%, and 9% from the three independent testing sites), and increased the maximum age by an average of 12% (21%, 8%, and 8% from the three testing sites, using the 90th percentile). Harrison et al. (2014) similarly find that median male lifespan was increased by 12%, but did not find an increase in maximum lifespan, and these results have been replicated even more in recent years.

These are some impressive results for such a common and simple endogenous substance! One of the first things we notice is that this effect only applies to males, with female lifespan (both median and maximum) being unaffected. As the substance in question is an estrogen, we can assume that this is either due to female mice already having this benefit, as they already have a sufficient level of it, or that something more complex is at play, and there is a different downstream pathway that is only being activated in males for some reason (more on this later). I had initially assumed the former hypothesis was at least a partial explanation, having known that females consistently live longer than males when it comes to humans, and that this was obviously biological in nature. However, it’s much more complicated in mice as females do not always outlive males, and in fact many times the opposite is true. One meta-analysis (good overview, original book source) finds 65 studies where males lived longer and 51 where females lived longer, with this often depending on the strain of mice used, which varies greatly depending on the type of reseasrch and time period. Regardless, it’s clear there is much more at play in this scenario, and perhaps something special about 17α-estradiol in particular.

Although the ITP studies initially included 17α-estradiol due to the reasons mentioned in the first paragraph, later research such as Stout et al. (2016) has now found that 17α-estradiol not only increased AMPK levels (as some other notable longevity substances such as Metformin also do), but also reduced mTOR activity (complex 1!) in visceral adipose tissue, which is rather reminiscent of Rapamycin, which has extended the lifespan of every organism we have performed an RCT with thus far (and likely can in humans too, if you ask me). In a way, this is significantly more exciting, because it gives us a much more plausible way to explain the lifespan extension effects we are noticing. However, it is also partially a disappointment: if these effects are the real reasons why 17α-estradiol extends male mice lifespan, then this substance may offer us nothing that we do not already have via rapamycin and metformin, among others. The paper also noted that fasting glucose, insulin, and glycosylated hemoglobin were reduced along with inflammatory markers improving. These are similar to the types of positive side effects we would expect from a longevity agent, and the study also notes that no feminization nor cardiac dysfunction occurred.

How do these effects (such as AMPK and mTOR modulation) occur? I don’t know, and apparently neither does anyone else. As is often the unfortunate case in biology, the paper has this to say: “The signaling mechanism(s) by which 17α-E2 elicits downstream effects remains elusive despite having been investigated for several decades”. Perhaps just a few more decades to go and this section will be updated with more information, then. Mann et al (2020) find that male mice without ERα do not benefit from 17α-estradiol, which helps us narrow down the first step by excluding Erβ, ER-X and other less-predictable initial mechanisms. Interestingly, they also note that “both 17α-estradiol and 17β-estradiol elicit similar genomic binding and transcriptional activation of ERα”, which would leave us with the question of why we are focusing on 17α-estradiol specifically, if 17β-estradiol (which is much more common) suffices as well. Importantly, they also seem to think changes in the liver might be involved. Garratt et al. (2018) add that distinct sex-specific changes in the metabolomic profile of the liver and plasma were found, and also notes that the longevity benefit for males disappears post-castration. They first supplement males and females, showing many differences related to metabolism including with amino acids. Then they use castrated males and notice that their profiles are the same as the control group, and thus conclude that they are no longer being positively affected by 17α-estradiol. I am unsure if we should be focusing on the AMKP/mTOR effects (which are very relevant to longevity) or on the liver/metabolic effects (which are also very relevant), or if these are in fact just two different temporal points on the same biological pathway which we don’t yet fully understand, but this helps us connect at least a few more dots.

All of the above sounds exciting, but it’s also all in mice. Sometimes this is useful, as mice are actually quite similar to humans (more so than many may expect), but a lot of it is also less useful or outright misleading. I cannot find a way to take only 17α-estradiol in a safe way as a human, however there is a topical cream of it (alfatradiol) which is used to treat pattern hair loss.

Luckily, one thing that the ITP study found was that 17α-estradiol was among one of the substances that seems to perform well with respect to longevity (if not fully) when given later in life (this has replicated afterwards as well), contrary to some others which have the best effect when started in youth and continued until death. In theory I wouldn’t mind waiting a decade or two until we have a better idea of what is going on here, after which point I would hope we have more fruitful and actionable results (especially in humans); although at the same time there’s likely many reasonable and safe ways we can go about achieving this (hopeful) effect in human males (assigned at birth) already, either via a type of estrogen or an estrogenic drug such as a SERM.

It is worth reminding ourselves that 17α-estradiol is already present in humans, and in both sexes, with women generally having significantly higher levels, as one expects of estrogen. Similarly, regular estrogen binds to both estrogen receptors, including our target, which we now know to be the alpha receptor. Given this, is it possible that just taking regular estradiol (for example, estradiol valerate, which for most purposes ends up biologically equivalent to endogenous estradiol and thus also binds to both primary estrogen receptors) to increase the levels of estrogen is a potential longevity intervention?

This is a difficult question to answer with the data currently available, although there are millions of persons assigned male at birth that are already on various forms of estradiol for various reasons, one of them being to assist in gender transition from male to female. As the lifespan benefit only applied to male (assigned at birth) mice, there would be benefits to analyzing these cohorts for more information, especially if we were able to have DNA methylation clocks used on these groups alongside a control (although this would not be a true RCT, as which persons decide to undergo feminizing HRT would not be random, I suspect we could still get the information we’d want with a good sample size).

There are other potential avenues of statistical analysis that could be attempted here, although they prove to be difficult for various reasons. Most male to female transgender individuals decide to transition earlier in their life, and this was also a particularly uncommon choice to make many decades ago in comparison to the present, so we have very few deaths due to age-related causes that we would be able to analyze to attain a proper hazard ratio. Even if we waited a long time for this (or had this data already), it would be terribly confounded due to the lack of randomization and many potential selection effects. Even so, one of the following must be true:

  • 17α-estradiol does not extend male (assigned at birth) human lifespan
  • 17α-estradiol does extend male (assigned at birth) human lifespan, however this does not apply to most/any transgender (m->f) individuals. This could be due to insufficient dosage, insufficient affinity for the alpha receptor, the inclusion of 17β-estradiol, the common addition of other substances such as anti-androgens, or another unknown factors/confounders
  • 17α-estradiol does extend male (assigned at birth) human lifespan, and this effect therefore does apply to most transgender (m->f) individuals, however we have either failed to notice it completely, or other effects/confounding variables ablate this, for example an increased risk of blood clots from estrogen supplementation (which depends greatly on the route of administration as well as type of estrogen used) or various potential side-effects from anti-androgen usage

Option one is certainly a possibility, as it always is in longevity when all of our studies are only in mice. We could differ too much from mice for the mechanism of action to apply to us (perhaps if it is related to metabolism or some newer subset of liver functionality), or if the mechanism of action is indeed the AMPK/mTOR pathways, perhaps 17α-estradiol does not modulate these in humans as it does in mice. This could have implications for other potential longevity agents such as metformin and rapamycin in humans as well, which also heavily involve these pathways, which could cause these agents to interplay synergistically or perhaps cancel one another out, as there may be no further benefit that can be gained after one of these agents is already taken at the optimal dosage. It is worth noting that many aspects related to AMPK/mTOR and DNA methylation are heavily evolutionary conserved as well (mTOR quite strongly, which is another reason why rapamycin likely extends human lifespan). We also already know that human females have longer lifespans than males for biological reasons, and that there are quite a few reports that the lifespan of castrated males is significantly increased. If 17α-estradiol (or estradiol valerate perhaps) does not extend human male lifespan, I would have to believe there is some other similar route that likely does, and we just have to find the best way to go about pursuing it.

Option two is, in my opinion, moderately plausible. It could the case that when we do have groups that supplement estradiol, the dosage taken is nowhere near sufficient for a noticeable longevity improvement, and that if we would simply increase it by some factor, longevity benefits would become apparent. There does seem to be a dose-dependent relationship for the longevity benefits in mice, and it may be possible that estrogen receptor alpha simply isn’t being agonized nearly enough. This may depend on the type of estrogen and route of administration used, as well as other drugs that may be taken (for example, most male to female transgender individuals take an anti-androgen as well as an estrogen, and this could potentially ablate benefits). My personal conjecture would be that estrogen monotherapy via injections would have the best probability of a longevity benefit for those assigned male at birth, although modulating or combining this with SERMs may also be of interest, although much more experimental and difficult to get right (I may add more to this later as this is a pretty interesting avenue to me for multiple reasons).

As for option three, it may seem difficult at first glance to think that millions of male to female transgender individuals are all currently supplementing a substance that may increase their lifespan by 5-20%, but yet none of us (or them) have noticed this yet. However, there are no preventative reasons for why this couldn’t be the case, nor statistical evidence against this possibility. It could even be that suppressing testosterone and activating estrogen receptor alpha are additive in nature, and we end up with a particularly impressive lifespan extension effect from conventional feminizing HRT.

Although I obviously cannot be sure of any specifics, I do think there is likely some hormonal intervention that should significantly increase male (assigned at birth) human lifespan, but that we just may need another decade or two to get the optimal intervention figured out properly. It would be great to have substances like 17α-estradiol in human trials already, as the potential ROI for successful longevity interventions is massive both in terms of billions of additional QALYs and trillions of dollars saved in healthcare expenditure.

In conclusion, 17α-estradiol might notably extend human lifespan for those assigned male at birth. There are many potential mechanisms of action that could cause this, with the most interesting one perhaps being activation of the mTOR and AMPK pathways, resulting in more ‘feminine’ DNA methylation. This longevity benefit, if it exists, may apply to many male to female transgender individuals, or could also be weaker or stronger for various reasons, such as due to the common usage of anti-androgens. If this longevity benefit does not apply to these groups, there may be alternative hormonal interventions that work instead, such as supplementing 17α-estradiol directly, using a SERM with a strong binding affinity in the right areas, or other modifications to the HPG axis that reduce some potential negative longevity effects of testosterone.

Disclaimer: I’m a random person on the Internet and none of this is medical advice. I’d like to rewrite and expand on the potential mechanisms of actions in this post and talk a bit more about what I do myself in this area some time too. Feel free to mention any corrections or comments to me (see: About page).