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.
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 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.
This page contains a collection of some of my favorite links (mostly blog posts), roughly categorized by author. My hope is that others similar to myself can waste enjoy countless hours of reading from recursively following some of the links here. I haven’t yet finished this post but have published it regardless.
todo (this will take me around 20-50 hours if I work well, hence not having finished it yet, maybe some day!)
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
Death Note Anonymity: Using information theory to quantify the magnitude of Light Yagami’s mistakes inDeath 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
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:
The SEC Is Baffled By GameStop Too: On the SEC’s Gamestop fiasco report, green company projects, as well as an obligatory section on Elon Musk’s tweets (which appear to be a common theme)
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
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 an: 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:
Why You Should Start a Blog Right Now: Encouragement to start your own blog. I strongly recommend this to people, as well as starting/doing many other things that involve content creation. Also attempts to argue against some common excuses made for why someone shouldn’t start a blog, which I mostly agree with
How to make friends over the Internet: ‘90% of meeting people is reaching out, so, unless you’re already very well-known, most of your network building will consist of actively initiating conversations’
Why (and How) You Should Join Twitter Right Now: A post encouraging Twitter usage. If you pick your follows wisely, you can have a wonderful time on Twitter, one that is full of smart and amazing people and with minimal political outrage. This is worth reconsidering if it is something you instantly dismissed as ‘not for you’ due to Twitter’s mainstream political reputation. Last time I traveled I met up with many people I had found on Twitter and had a great time with literally everyone single one (and also only had a few hundred followers myself).
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
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
Border Stories: Borders are a necessary precondition for agency within a hostile ecosystem
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:
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.
Allulose (sometimes D-psicose) is by-far one of the best ways to add sweetness to home-cooked meals in a healthy and low-calorie way. As an epimer of fructose, it has been steadily gaining popularity within the last few years, and not without good reason! Allulose is not only nearly calorie-free, but also decreases blood glucose levels with meals, and seems to have a wide range of potentially beneficial effects.This post is a short summary of why allulose is so appealing over sugar and other sugar substitutes.
Overview of Allulose
Allulose is found naturally in wheat, figs, raisins, maple syrup, and molasses, although in relatively trace amounts. It has around 10% the calories of traditional sucrose and can be manufactured from fructose. It’s around 70% as sweet as sucrose (regular sugar), but has a similar taste and feel, which is a large factor behind why it makes a great substitute (or partial substitute) for baking or dissolving into things. The taste of Allulose has a more natural and relaxing quality than some other sugar-replacement options such as xylitol and erythritol, which are both sugar alcohols, but generally have a ‘cooling effect’ (often likened to the aftertaste of consuming mint, which allulose conveniently lacks).
Allulose is also an actual sugar (not a sugar alcohol or other compound), and has similar browning properties to sucrose via the Maillard reaction. One downside to mention is that it does seem challenging to keep some styles of baked goods crunchy with allulose as the only sugar; while it definitely seems to be one of the best options for sweetening drinks, yogurts, ice creams, cakes, and so on, it may not be the best option for super-crunchy cookies (although can make great softer ones!). This seems to be due to allulose not crystallizing when it cools, its ability to hold more moisture, and that it is more soluble in liquids than sucrose; hence it being a great fit for drinks, sauces, and spongy baked goods.
Allulose was designated asGRAS by the FDA in 2019, so is still relatively new to the market compared to many other sugar substitutes, although has been gaining significant popularity for the short period that it has been available for general usage in foods. I’m sometimes now able to find allulose for sale in a supermarket or included in a sweet good (and it is also now being used in products such as Soylent), although its usage is still a small fraction to that of sugar and corn syrups. It can easily be purchased on Amazon for around $10 per lb (regular sugar is generally closer to $1-2 per lb, so it is quite a bit more expensive if you happen to use very large amounts of sugar).
What Sets Allulose Apart
Why might we want alternative sources of sweetness from sucrose to begin with? Although much has been said about the ways sugars are (in some cases) potentially harmful, it seems reasonable to posit that there are two qualities of a diet with high sugar content (remember, this means any typical western diet!) that are undesirable: firstly, the high caloric content of sugar, which makes over-eating significantly easier and therefore contributes to obesity, and secondly, the effects of sucrose on blood glucose levels and thus insulin resistance, which contributes to diabetes and metabolic syndrome.
As we would hope from an alternative to sucrose, allulose doesn’t cause an increase in blood sugar. The reason for this is that it is not absorbed and digested by the gastrointestinal tract, but rather processed by intestinal bacteria. For the most part this is a good thing, and is what enables allulose to both be low-calorie and to not be converted to glucose in the blood stream. The downside of this is that for some people, especially if consumed in large enough quantities, it can cause mildly discomforting side effects such as flatulence, subpar digestion, and abdominal discomfort. This is much more likely to occur if you, for example, eat an entire batch of allulose cookies by yourself (who would do such a thing..!?), rather than simply use it to sweeten a drink or a snack. While I haven’t experienced anything negative myself, everyone is certainly very different when it comes to food.
But, it gets much better than this! Allulose not only doesn’t increase your blood sugar, but actually decreases it! It does this by inhibitingalpha-glucosidase (along with several other similar enzymes), which is an enzyme that breaks down starches and disaccharides into glucose (i.e. causes carbohydrates to lead to blood glucose spikes). Other well-known inhibitors of alpha-glucosidase include acarbose, a popular and simple diabetic drug which significantly extends lifespan in mice and has the exact same potential side effect profile as large allulose doses (and in my opinion is probably very good for most people to be taking, perhaps extending human lifespan via the same mechanism of action as in mice), and sweet potatoes (source, another source). Thus, adding allulose to meals that contain carbohydrates will result in less of a blood glucose spike than if allulose had been excluded.
There’s now quite a few studies showing this in humans (and dogs and mice!), with allulose consistently attenuating the postprandial glucose levels both in diabetic and regular adults (effect sizes are often larger in pre-diabetic and diabetic individuals, as is often the case here).
In general it seems like replacing sugar with allulose will result in fewer calories consumed, a lower risk of obesity, lower blood glucose (average and area under the curve, sometimes peak) levels and thus improved insulin resistance and a lower risk of diabetes and metabolic syndrome, and potentially some other beneficial effects (which may or may not apply in humans, but if allulose improves your diet and lowers your food intake, I would not be surprised to see improved lipid profiles and a reduction in inflammation, even if entirely for indirect reasons, e.g. cooking at home with allulose instead of purchasing processed foods from the store. It’s also worth noting that while some of these benefits are a direct result of allulose consumption, many are also partially from a reduced intake of sugar and calories – similar to how cutting down on your sugar intake would offer many benefits).
It’s quite possible that if a notable fraction of other sugars in our diet were to be replaced with allulose, the amount we would gain both in QALYs and dollars saved via the resulting reduced healthcare burden would be extremely favorable. Allulose is still relatively new to the market, and as it is also much more expensive than sugar or corn syrups, its future market penetration may be relatively limited by consumer preferences. Regardless of its presence in our broader food ecosystem, you can start experimenting with it yourself today! (Amazon search results page link, in case this saves you 10 seconds)
I usually use allulose to sweeten drinks, greek yogurt, and sometimes add it to sauces or baked goods in small quantities. I’m also pretty interested in glycine and think it may be something that most of us should be having a lot more of as well (some notes on this in the glycine section on my supplements page), but consider it outside the scope of this article for now. Lastly, if the idea of significantly reducing the glycemic index of your meals is appealing, I strongly suggest looking into acarbose – it is a much stronger inhibitor of alpha-glucosidase, well-tolerated, and also relatively cheap.
If you enjoyed this article you might also enjoy my supplements page which discusses many other ingredients and drugs that I find interesting with respect to longevity. Feel free to reach out with any comments or corrections via any communication method on my about page, thanks for reading!
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 arevery 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).
This document is an updated list of the supplements/drugs that I
take daily, as well as notes on some other interesting substances. It
contains information on exactly what I take, how much of it, how much
it costs, and some information on the substance which should roughly
explain my reasons for taking it.
The first list contains supplements I take daily, with the second list containing supplements that I do not take daily but that nonetheless seem interesting, while the third list contains supplements that are interesting, but that seem less suitable for safe human consumption or speculation.
The focus of my supplementation is to find substances that are both very safe and also have a notable probability of improving health, lifespan, well-being, or productivity, with the ultimate goal being to significantly slow aging, even if it’s difficult to do at this time. I don’t take many nootropics as I don’t think there’s much room for intelligence improvements just from ingesting simple compounds (evolution has already put quite a bit of time into making us smart), with the exception of treating some deficiency or other issue, or improving productivity/concentration, which definitely possible (see: caffeine, modafinil, adderall, many others), but distinct from intelligence. It is worth noting this list is very specific to myself: if I had a perfectly optimal diet and lifestyle, I would likely take next to zero supplements. Like most mortals, my diet and lifestyle are definitely not perfect (and indeed, even knowing what a perfect diet would be for yourself can be intractable on its own), thus there’s always room for improvement.
This post is not an attempt to convince anyone of something
specific or to suggest anything specific, but I have decided to
publish it publicly in order to better keep myself accountable for my
reasoning, receive potential feedback, and to otherwise share some
potentially useful short summaries of information. Concordantly, I’m
not a doctor and this post contains no medical advice or suggestions.
Which supplements, if any, one should take, is a very personal
matter, as it is dependent upon many unique traits such as one’s
age, diet, lifestyle, genes, risk preference, finances, and more.
Notes on supplements
Although there are a lot of supplements that would be beneficial to many people, caution must be exercised both with research and purchasing. Supplements in the United States have very little regulation, with some sellers having poor quality control, fraudulent research, marketing, claims, and poor ingredient composition and sourcing. The supplement industry is worth billions of dollars and has many bad actors incentivized by profit over truth, so time and care must be exercised in order to find out what works best for you personally. Certainly, research can be found promising positive effects from thousands of various substances – but taking all of them would be impractical, expensive, and likely downright harmful.
It’s also important to pay attention to brands as well as to think logically about which supplements have quality differentials that are worth paying more for. For example, Vitamin D and Glycine are easy to synthesize, and it’s likely that cheaper versions of these supplements are just as good as more expensive versions. This may not be the case for a supplement like fish oil however, which is derived from complex living organisms that vary significantly on factors such as their environment, diet, quality controls, the types of fish used, and so on.
Concordantly, one of the strongest criteria I look for in most supplements is safety, which many times (not always!) comes alongside popularity and/or significant research affirming the safety of compounds. As many supplements offer marginal benefits at best, it would be irrational to purchase and consume them if they had a good chance of causing harm, as this would easily cause them to fail a basic cost/benefit or risk/reward analysis (there’s definitely some cool compounds that have very high coefficients in both the numerator and denominator of their risk/reward ratio too, so careful decision making is required).
Ideally one should attempt to find quantitative measures to
objectively evaluate if a substance is really helping them in the
desired manner. In some cases this is both easy and cheap to do, for
example with Vitamin D supplementation, which costs only a few cents
a day, does not need to be compared to a placebo, and can be tested
for in your blood for as little as $30. In other cases, proper
testing is difficult or impossible and may require significant effort
and time for very little benefit. Keeping one’s lifestyle, diet,
and other factors a perfect experimental constant is certainly
difficult, as is performing blind experiments on yourself, collecting
and analyzing data, and finding the proper quantitative desideratum
to test yourself on to begin with; testing if something specific has
definitively made you slightly smarter, happier, healthier, more
productive, or extended your lifespan, is certainly difficult if not
occasionally impossible to do in a scientifically rigorous manner
with a sample size of one.
Lastly, which supplements benefit an individual is a very personal matter. Vegans may want to take some supplements that are found in meat. Carnivores may want to take some supplements that are found in plants. Supplements that may benefit the elderly or those with common conditions such as hypercholesterolemia or diabetes often seem to be much less useful for otherwise healthy individuals. Indeed, for individuals that have many health conditions including the elderly, there’s significantly more that can be gained from supplementation, as there are many more problems that can be improved upon (although there are also be more risks as well). Supplements will effect someone differently depending on their weight, age, genetics, health, diet, and many other factors.
This means that it’s a bad idea to copy any individual’s routines completely, even if it’s a lot of work to do your own planning, research, and testing. It is also worth mentioning that the word ‘supplement’ is used here as a relatively generic word, simply meaning that the substance is only regulated as a food within the United States and thus requires no prescription (unless otherwise mentioned), but also offers few guarantees in terms of efficacy or consistency.
If you find this page interesting, here are some similar pages from others that you may enjoy:
The following list contains supplements that I’m currently
Name: Vitamin D3
Dosage: 4,000+ IU (100+ µg)
Information: Vitamin D3 [Examine, webmd, Wikipedia] (colecalciferol) is a vitamin made by the skin when exposed to sunlight. It’s a common deficiency and is very cheap to fix. The benefits of supplementation are generally found to be minor (it’s still a bit controversial if supplementation is beneficial at all, although I lean towards yes personally), but as I was notably deficient and it’s one of the cheapest supplements, it’s an easy choice for me. There is a lot of literature on Vitamin D, and many highly-powered studies including meta-analysis will often find only minor beneficial effects, but there are also quite a few studies that show notable benefits, including many related to covid as of late 2020. As noted above, this is also an easy supplement to receive a blood test for and ensure you’re taking the optimal dosage. I take half of my vitamin D earlier in the day without a meal, and the other half with my food, contrary to most other supplements. See also: Gwern on Vitamin D as well as on it harming sleep if taken at night
Name: Vitamin B3
Information: Vitamin B3 [Examine, webmd, Wikipedia] (niacin). I currently take this intermittently depending on my diet and may end up cycling off of it in the future. More information added here later.
Name: Vitamin B9
Information: Vitamin B9 [Examine, webmd, Wikipedia] (folic acid). I currently take this intermittently depending on my diet and may end up cycling off of it in the future. More information added here later.
Name: Vitamin B6
Dosage: 1500mg (partially discontinued)
Information: Vitamin B6 [Examine, webmd, Wikipedia]. This has been indefinitely discontinued as I am not longer on metformin and don’t seem to be deficient in it anymore.
Information: Vitamin B12 [Examine, webmd, Wikipedia] (vitamin B3). Often useful to supplement if one is taking metformin. I’m currently off of it as I’m not currently on metformin or any other agents that led to my initial choice to add this – blood tests seem to indicate I’m more than fine.
Name: Vitamin C
Dosage: 1000mg (Occasional – diet dependent)
Information: Vitamin C [Examine, webmd, Wikipedia] (ascorbic acid) has a variety of effects, and being a vitamin, is an essential part of a human diet. I supplement vitamin C in order to fix a tested deficiency.
Name: Fish Oil
Dosage: 1-3g+ (depends on diet and estimated omega-6 intake)
Cost/day: $0.10 (1g)
Information: Fish oil [Examine, webmd, Wikipedia] (omega-3 EPA+DHA) is another common and cheap supplement. Although many studies find minor or sometimes no benefits, many others find a large amount of diverse improvements, even if they are minor. It’s likelythat the ratio of omega-6/omega-3 you consume is important, with most people consuming far too much omega-6 (which won’t hurt to reduce regardless) and not enough omega-3, so dosing of fish oil should be based on your diet, which is easily more than an order of magnitude more important to begin with.
Similarly, it’s probably good advice to 1) reduce fried food intake, 2) replace oils high in linoleic acid such as safflower and sunflower oils with oils that have much less such as coconut oil and olive oil (2021 edit: I am less sure about this than I was before, although I still lean towards it myself Deciding which oils/fats (and with what / prepared in which manner) are bad for you continues to be an extremely hard problem. See A Comprehensive Rebuttal to Seed Oil Sophistry for an example of a comprehensive potential counter-argument in the great seed oil/fat debate) and 3) increase my supplementation of high-quality omega 3s (fish oil) when I think I’ve had more omega 6s. For example, if I do decide to eat a lot of fried food, I take several fish oils, compared to only 1-2g normally. I also like to note that fish oil seems to be one of the supplements worth spending a bit more money on – quality is high-variance and of higher importance, and unlike other supplements which can trivially be synthesized, the production processes of fish oil vary greatly depending on the company and product. Also see this review on pubmed and this summary on Wikipedia
Cost/day: $0.02 (1g)
Information: Garlic [Examine, webmd, Wikipedia] is another popular and cheap supplement. There’s good evidence that it improveslipidprofiles, may help with some cancerrisks, and may have other very minor benefits (may activate AMPK too?). The most desirable compound in garlic is allicin, which is diluted in garlic that is microwaved, boiled, or aged. Dosage should be based on which type of garlic is being consumed. As many people enjoy the taste of garlic, it’s a good candidate to include in meals as well (which is probably optimal for most things, resulting in notably higher bioavailability on average).
Name: Olive Leaf
Information: Olive Leaf Extract [Examine, Wikipedia] is a cheap and easy way to hopefully mimic the benefits of olive oil, as the leaves of the olive tree contain good amounts of relevant olive phenols such asoleuropein. It may still be better to consume olive oil instead, which is still a great thing to add to meals, but with such a low cost, this seems worth inclusion to me. I am not particularly excited about this supplement but have included it regardless.
Information: Magnesium [Examine, webmd, Wikipedia, Gwern] deficiencies are moderately common (up to 45-60%) and easily fixed. Fixing a magnesium deficiency is cheap and seems to offer quite a few minor general benefits, and also sleep and anxiety improvements for some. Depending on your diet, supplementation may be unnecessary. Magnesium comes in a lot of different forms so close attention is needed when purchasing. I stick to citrate as it makes dosing easier, has good bio-availability, and is unlikely to cause digestion issues. The above Gwern link is a great resource on Magnesium as well. This is also another supplement that is easy to get before and after blood tests for to see if your intervention performed as desired.
Name: Vitamin K2
Dosage: 100mcg (diet-dependent)
Information: Vitamin K [Examine, webmd, Wikipedia], like most vitamins, is primarily beneficial for those deficient in it, so it is best to examine your diet thoroughly and/or be tested. There are several forms of vitamin K, and also several forms of vitamin K2. Vitamin K2 MK-7 seemstobe one of the best forms to take in general, although K1 has decent evidence in favor of it as well, depending on one’s circumstances.
Information: Glucosamine [Examine, webmd, Wikipedia] is an amino sugar derived from shellfish that is commonly taken by the elderly to improve joint functionality and reduce pain. Glucosamine extends the lifespan of some mammals in studies, potentially in ways that are evolutionarily conserved, activating AMPK and therefore having slight similarity with metformin. Glucosamine may also induce autophagy via an mTOR-independent pathway, which may be the mechanism of action for its effects on lifespan. Due to its popularity as a supplement we can be relatively sure of its safety as well. Chondroiton is commonly included with glucosamine supplements, which appears very uninteresting for my own purposes, so I look for pure d-glucosamine/glucosamine sulfate, which is generally cheap.
Name: Lithium Orotate
Information: Lithium [webmd, Wikipedia] is a metallic element that is often found in foods such as legumes, grains, vegetables, and in some places, drinking water. Lithium is generally present in most diets in notable quantities, and in slightly larger quantities in diets such as the Mediterranean diet. For purposes such as mine, it is supplemented at low doses, which is much different (~1/100th the dose) from the doses sometimes prescribed for some psychiatric disorders. Lithium reduces mortality, stabilizes mood, and promotes longevity, likely via multiple pathways, although the specific mechanisms of action are difficult to discern and more research is needed. As I was tested for lithium and had a very low concentration in my blood, I decided it was worth it to supplement it n low doses.
Dosage: 0-15g (varies)
Information: Glycine [Examine, webmd, Wikipedia] is an amino acid that is often supplemented to improve sleep. Better sleep is formidable by itself, but some studies find that it increases lifespanin organismsvia methods that may be evolutionarily conserved. Although glycine is present in some foods and is also synthesized by your body, it may bethe case that glycine deficiencies are technically common in humans, as the amount that is able to readily be synthesized in-vivo is sub-optimal. This may be relatively asymptomatic from an individual perspective and only manifest itself via a slight probabilistic decrease in healthspan/lifespan, although users often notice quite a few improvements besides just better sleep. Glycine may improve insulin sensitivity and other similar metrics. There may be somelongevitybenefits of a diet low in methionine (meat, fish, eggs, etc) as well, which may be related to one’s effective glycine/methionine ratio. I still consume a lot of methionine from common sources such as chicken breast, so this is another potential way in which glycine could be beneficial. Glycine appears to be very safe, even in larger doses, and is relatively cheap, more so as a powder, as is the case of most substances.
I take glycine in powder form, which makes it easy to consume arbitrary doses (including the ability to add it to drinks or meals if desired), and notably cheaper than buying large amounts of pills, which are generally 1g each. On days where I consume a lot of meat such as beef, I take significantly more glycine. This is partially an attempt to optimize my diet’s methionine/glycine ratio, but also intended to do a better job at mimicking what a more traditional consumption of animal meat might have been like, from an evolutionary perspective, which would have included much more glycine than most of us receive in the common cuts of meat that consumers generally use. As a side note, glycine does taste sweet and dissolves in water, so it’s a great addition to tea or coffee.
Regardless, given glycine’s near-flawlessly safe and simple profile, there should be zero harm in having a bit too much. My larger dosage was arrived at from a combination of the papers linked above (and linked to by those links), as well as some reasoning about my diet (high in methionine) and lifestyle. Unfortunately even with a blood plasma test of amino acid concentrations, it’s difficult to know if this is the optimal dose for human longevity, or if it is even helpful at all to begin with, but the cost/benefit analysis here still seems to lean heavily into the green. As a simple and common amino acid, it seems pretty difficult to hurt yourself with glycine, so even taking 10-50g a day shouldn’t be harmful.
Dosage: 1-10g+ (varies, used as a sweetener with some meals)
Information: Allulose is an amazing alternative to sugar with 90% fewer calories and the ability to decrease your blood sugar in response to high-carbohydrate meals. I wrote a full post on Allulose here
Dosage: 445mg (sometimes discontinued)
Information: Bacopa [Examine, webmd, Wikipedia] is an herb that seems to offer reliable but likely very minor improvements to some areas of memory and generalcognition. Effects are likely difficult to notice without rigorous placebo-controlled self-testing, but it is relatively safe and cheap regardless. Digestive side-effects aren’t uncommon, as is the case with many herbal supplements. In the future I’d like to replace my bacopa with a placebo and attempt to look for differences in quantitative cognitive performance metrics such as my anki recollection, but performing this experiment well is difficult, both because the effect is very minor and because a proper experiment with n=1 is very difficult. I don’t think bacopa is likely to be a big deal, but I’ve added it for now. As of 2021 I sometimes don’t take this, as it may result in slightly poorer digestion, and the benefit was marginal at best, but I have left it on this list for now.
Dosage: 470mg (occasionally discontinued due to potential digestive side-effects)
Information: Ashwagandha [Examine, webmd, Wikipedia] is an herb that offers potential anxiety and lipid profile improvements. Some users report that it reduces anxiety and stress significantly, with some studies showing up to a 28% reductions in cortisol (in subjects with elevated levels). Lipid improvements can also be notable, with some studies showing a 10% reduction of total cholesterol, even in healthy subjects. As an uncommon herbal supplement, digestive side effects are a notable probability. Ashwagandha is likely worth trying if you feel that you have untreated anxiety, you never know when you’ll get lucky with how much of a benefit you receive from some things. Although not scientifically rigorous, it did appear like the periods during which I took ashwaganda resulted in a notably improved lipid profile, consistent with what many studies have shown. I’d like to test this on myself in an n=1 RCT both for lipids and for potential relaxation/anxiolytic effects, but haven’t gotten around to it.
Information: Fisetin [Wikipedia] is a plant flavonol that is found in several vegetables and fruits, with the highest concentration being found in strawberries. Fisetin is a sirtuin-activating compound and has extended the lifespan of yeast, worms, flies, and mice. It has been shown to be a strong senolytic agent and may induce apoptosis and other effects via the PI3K/AKT/mTOR pathway. I do not take it every day and am quite uncertain about what the right regime for supplementation should be for it, but currently take ~1,500mg of it for 4 days continually once every few months. This likely has room for improvement and may change in the future. I’d like to write more about fisetin in order to justify this, but haven’t yet found the time. Here’s a single picture of a pretty mouse instead.
Astaxanthin has increased
the life span of C. elegans by 16-30%, with the authors stating
“These results suggest that AX protects the cell organelle
mitochondria and nucleus of the nematode, resulting in a lifespan
extension via an Ins/IGF-1 signaling pathway during normal aging, at
least in part”. While this is certainly interesting, expecting such
a lifespan increase in humans is far too optimistic from this case
Astaxanthin appears to be very safe in humans and is a relatively popular dietary supplement, with a market estimated at over $500M USD annually, although the majority of this supply is used as a component in animal feed and cosmetics.
Dosage: 0-500mg (varies, often discontinued as of lately)
Cost/day: 0-$0.17 (varies)
Wikipedia] is a
pigment found in tumeric.
Curcumin’s strongest benefit seems to be the reduction
in inflammation that it offers, although there appear to be some
other areas that may be improved as well such as lipid profiles,
mental health, potentially improved digestion, and reduced pain with
some conditions such as osteoarthritis.
It may exhibit a notable anti-tumor
effect via apoptosis. It seems relatively safe, although has low
bio-availability, so is often taken with substances to increases its
availability such as piperine, or taken in an otherwise proprietary
formulation that generally has some type of oil that improves
bio-availability instead. As inflammation is important in aging and
many other diseases, it’s something that is nice to be aware of.
I only sometimes take curcumin depending on my inflammation levels, generally measured via c-reactive protein.. When it is negligibly low, I stop taking it, and if I ever see it creep up in blood test results, I resume supplementation. Curcumin can be potentially tough on the liver, and in large doses has a greater potential to cause adverse affects. Some papersshowquiteafew potential drug interactions that can occur by taking curcumin, especially in larger doses, and via a variety of mechanisms, including its affect on platelets and potential interactions with enzymes such as CYP3A4, potentially affecting the metabolism of a large amount of drugs.
Dosage: 1.2g (currently discontinued, replaced with metformin or nothing)
Information: Berberine (Examine, webmd, Wikipedia] is an extract from various plants. It appears to be a pretty strong natural mimetic of metformin, a popular drug for diabetes with many alluring potential anti-aging properties. It often improves lipid profiles and blood glucose, and thus may have many of the long-term benefits that metformin may have. Concordantly, the possibility for digestive side-effects is relatively high, and it’s sometimes taken several times a day in smaller doses as a result. Examine suggestions that it also inhibits enzymes such as CYP2D6 to some extent, which could lead to undesirable interactions with some drugs. It’s likely better to be on metformin than berberine, as drugs are kept to a significantly higher regulatory standard than supplements are and we have much more data on users of metformin.
(much higher If drinks are considered)
Information: Caffeine [Examine, webmd, Wikipedia] is something you likely don’t need an introduction to. I try to keep my dosage relatively low to avoid issues with tolerance, using a combination of coffee, tea, or caffeine pills, depending on the amount desired and my mood. When taking 100mg or more of caffeine, I generally have 100mg of L-theanine as well.
Dosage: 0-200mg, (not taken often, 100mg if taken generally)
Information: L-theanine [Examine, webmd, Wikipedia] is an amino acid that is present in tea leaves which is often combined with caffeine for supposedly synergistic effectsoncognitionandmood, improving the upsides of caffeine while helping to ameliorate some of the potential downsides. I generally only take it if I’m having more caffeine than average on a given day, since I keep my caffeine intake pretty low.
Dosage: 1mg (not taken consistently)
Gwern] is a hormone
secreted by the pineal gland with an important role in regulating
your sleep cycle. Melatonin production can be suppressed in many
individuals that are otherwise healthy, for example by exposure
to blue light from computer screens before bed (which solutions
like the program f.lux and blue-light blocking glasses attempt to
solve). The generally accepted benefits of melatonin are a reduction
in the time to fall asleep, although some individuals claim that it
reduces their need for sleep as well (often by 15-60 minutes). For
those with sleep conditions such
as insomnia or jet
lag (or just being older in many cases), melatonin can be a much
greater aid in improving sleep and quality of life.
lifespan of some mice by 18%, primarily given as a supplement
later in life in an attempt to give older mice more effective pineal
gland functionality (directly giving older mice the pineal glands of
younger mice was also performed, which also was very beneficial).
Melatonin levels similarly decline
with age in humans (as most important things do), and
supplementation may be increasingly
beneficial as one ages.
The proper dose of
melatonin to take varies between individuals and many melatonin pills
for sale are dosed too high (5-10mg), so approximate
self-experimentation can be used such as starting with 0.5mg and
increasing your dosage until benefits are noticed. The above link to
Gwern’s website on Melatonin points to a good in-depth analysis
that is worth reading as well.
I don’t always take melatonin, but it’s great to be aware of and have.
Dosage: ~1-10+mg (various sources, currently primarily wheat germ)
Dosing for spermidine is difficult. It’s obviously very safe, but 1mg is likely not enough for the level of effect that we want. The average daily nutritional intake of spermidine varies from 7 to 25mg, and we can see how much one might want to consume for blood levels of spermidine to increase by 39%: perhaps 10mg per day (calculated by multiplying the 66g of natto consumed per day by its approximate spermidine content of 150mg/kg to yield 10mg per day). Although we don’t have plasma concentrations of spermine and spermidine in humans in relation to mortality, this is available in several mice studies. I need to spend more time on this, but I think one might want to supplement as much as 5-20mg of spermadine per day, assuming that it’s not present in their diet in notable quantities already (which is quite possible, as some Mediterranean, Japanese, and other diets contain notable quantities of it).
I currently consume spermidine via wheat germ, which seems to have around 243mg/kg of spermidine in it. If I wanted 10mg a day, this would result in having to consume 41g of wheat germ per day, which although feasible, is a bit tedious, potentially unsavory depending on the method of consumption, and would also result in an additional 164 calories consumed per day. There are some spermidine supplements on amazon, but I am not sure that I trust any of them very much (with the most recent one having the most obvious fake reviews I have ever seen on a supplement), and many of them are simply wheat germ inside of a capsule, which is not only likely to be an insufficient dosage, but also much more expensive. It may be worth mentioning for some readers that spermidine is also present in human sperm, but not in enough quantities to warrant consumption unless you consume copious amounts of it (~0.1mg per ejaculation, assuming 3.5mL and 31ug/Ml).
Dosage: 0.5-1g (Currently partially discontinued for various reasons)
Information: Metformin [webmd, Wikipedia] is a prescription drug for diabetes and is one of the most popular drugs taken by those interested in longevity, often taken for this purpose by individuals without diabetes. Metformin is said to mimic some of the potential benefits of caloric restriction. It increases the lifespan of mice, increasing AMPK activity and antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Lifespans of other organisms such as silkworms and nematodes are also increased. There exists a vast literature on Metformin with respect to its mechanisms of improving longevity apart from just this; it’s currently the most popular drug taken to combat aging.
Due to the prevalence of diabetes, Metformin has over 80 million users (the vast majority taking it for diabetes), which gives us wonderful data on its safety, with its side effects rarely including anything besides minor gastrointestinal issues. Metformin is also cheap, costing only $5-$25 a month in the United States. For the above reasons and many others, Metformin appears to be one of the best candidates for an anti-aging drug, leading it to become one of the only drugs making clinical progress in this area with trials such as TAME (Targeting Aging with Metformin). Metformin deserves a larger write-up than I’ve given it here, so you’re encouraged to perform your own research on it (just as you should for anything written about on this page).
For long-term Metformin usage, be sure that you are not hypoglycemic, as well as that your levels of vitamin B6 and B12 are in acceptable ranges, as deficiencies in these are slightly associated with Metformin usage. Metformin may also diminish some health improvements from exercise, and although more research is needed, this factor should be considered for non-diabetics considering Metformin usage. See also: Gwern on metformin
Dosage: varies greatly, taken at the start of meals with high carbohydrates
Information: Acarbose is a simple diabetic drug which inhibits alpha glucosidase, causing your glucose to spike less than it normally would when ingesting carbohydrates. It is very safe and common, especially in countries such as the United States. Various studies onacarbose in mice have consistently shown it to expend lifespan, sometimes as high as 22% in males, generally much less in females. The probability this applies to humans is, in my opinion, moderately likely, although it is unlikely to be nearly as strong of an effect. Although mice have a lot of similarity with humans (more than many would expect!), their digestive system and diet are more dissimilar than most other categories. With that said, this drug is very safe and provably reduces the glucose spikes in your blood that occur when ingesting large amounts of carbohydrates, which in general seems to be a good thing. It therefore has a lot more potential when taken at the start of eating a large pizza rather than a normal meal (unless pizza is your normal meal, in which case it’s hard to blame you, but you should probably eat other things as well).
Dosage: 0 mg / various
Description: 17-α-estradiol significantly extends male mice lifespan, and this may apply to humans as well. This section turned long so I turned it into its own post. I currently micro-dose estrogen and am experimenting with some other potential solutions here myself; I’d like to write more on this and on related HPG interactions and estrogens/androgens in general.
Dosage: 4-8mg (schedule and doses vary, taken at most once a week, many other factors)
Information: Rapamycin is perhaps the most exciting substance for me in longevity right now. Rapamycin notably extends the lifespan of most organisms we have given it to thus far, but lacks proper research in humans aside from its use as an immunosuppressant. It’s a very popular drug to research in the area of longevity, and deserves a longer write-up than I’ve given it here. It’s also potentially quite dangerous and we have little data in humans (aside from those we give it to for organ transplants), so please don’t take it yourself (Jan 2021 update: mTOR Inhibitors Associated with Higher Cardiovascular Adverse Events ‐ A Large Population Database Analysis). Dosage for rapamycin is a bit tricky but it seems like the most knowledgeable persons I know in the area are currently converging onto something like 3-10mg, once a week, with various longer break periods between dosing schedules.
Out of all of the longevity agents I am interested in and/or take myself, it is likely to be the one that I have the highest hope for in humans. We have a decent understanding of the mechanism (compared to many other things, at least), it works very consistently and strongly in several other organisms, and the mechanism of action is strongly evolutionarily conserved. As for safety concerns, it seems like if taken in a low dosage and infrequently enough, the safety profile improves significantly and it may be a net-plus in many areas (this may be related to mtorc1 vs mtorc2 activation depending on the dosage and timing (it does have a pretty long half-life!), which also makes it seem like it can be taken without actually suppressing one’s immune system or causing some other undesirable effect categories).
Although I do know of many others that take rapamycin, I still don’t suggest it to anyone myself, firstly because I don’t offer medical advice of that nature regardless of my cost/benefit analysis (are there risks of potentially bad unknown side-effects with long-term usage? sure, but the risk of *not* taking longevity agents is also pretty large, and results in a much earlier likely death), and secondly because it is still likely to be higher risk than a lot of other simple things that I do often suggest to others, like glycine supplementation, which I see as close to zero risk. I’d hope that anyone that takes it themselves has blood panels done (if not much more) to ensure they’re not doing easily-observable harm to themselves as well. I’d like this section to be more comprehensive, but I’ll follow with some relevant pubmed papers for now:
I’m currently messing around with some other substances such as acarbose, rapamycin, SERMs, and some others (which now have some notes on them above and below), but don’t currently have the testing available to be able to make confident claims with them. For acarbose I’d like to us a Dexcom G6 CGM and frequentl blood panels in order to properly assess its affects on blood glucose levels (and perhaps other metrics) with specific meals. Rapamycin is a bit trickier, but has some of the greatest potential out of everything in this post, and I’d consider blood panels mandatory for anyone that takes it.
This list changes as
I encounter new evidence, test new supplements, or change other
aspects of myself such as my diet or lifestyle, but I hope to keep it
updated, even if only for myself. I’m constantly looking for
substances that have a good probability of doing a much better job at
enhancing longevity, but it’s very hard to find and test them in a
safe way – it’s unlikely many supplements such as simple vitamins
or herbs are truly going to increase out lifespan notably. The next
section has more information about some substances which are more
interesting, but that I’m currently not taking.
Currently I spend
around $1-2 a day on supplements. As my average food expenses can
easily exceed $10 per day, a 10-20% increase in this is not too bad
of a price for me to pay, even if the benefits are mostly minor.
Healthcare costs are very high, so anything that may lower them, even
if decades down the line, can turn out to be very cost-effective.
Regardless, spending money on improving my own health seems to be the
best possible use of money – it is the least fungible thing I can
spend on. This reasoning applies to improving diet and exercise as
well, which generally offer much greater returns than most
I try to keep my supplement stack very minimal and would rather dedicate research time and effort towards substances that might have significant effects on aging such as metformin and rapamycin, rather than substances that are often very difficult to determine any effects of, such as the large amount of amino acids or uncommon vitamin forms that can be taken. Keeping the amounts of supplements I take to a minimum offers much more than a financial benefit – it reduces the probability I will cause damage to my liver over time (which users of many supplements, or anything risky, should get tested for), and reduces the probability there will be any type of drug interactions caused by anything I take, for example by some substances inhibiting or inducing enzymes that then cause other substances to increase or decrease in efficacy (see CYP3A4 and CYP2D6 for some good examples).
Additional supplements I do not currently take
This section contains a list of supplements that I think might be worth taking, but that I currently don’t use. Substances in this section seem to be relatively safe, and I’m generally only not taking them because I have more doubts about their usefulness to me specifically.
Among aspirin’s more common adverse effects is an increased risk
of gastrointestinal bleeding, which is one of the reasons it’s not
suggested by most organizations for otherwise healthy individuals
with low CVD risk. Aspirin has increased
the average lifespan (although not the maximum lifespan) of mice
in some studies, but this is unlikely
to be the case in humans unless significantly more needs to be
taken, which would increase the probability of adverse effects
To summarize, it’s very likely that continual aspirin usage
reduces the risk of some types of cancer and moderately likely that
it can reduce the risk of CVD in some higher-risk groups. Although
side-effects are negligible for most individuals, it is difficult to
tell if aspirin is worth taking for healthy and young individuals.
It’s likely much more beneficial for the elderly or middle-aged, as
they’re at a much higher risk of cancers as well as CVD. As a
result of this, I don’t take aspirin regularly.
is well-known as a major component of chocolate. Although the sugar
added to most modern chocolate definitely does not benefit one’s
health, cocoa itself has many bioactive substances with potential
benefits. Among the most notable is (-)-epicatechin, which can offer
in blood flow and a corresponding reduction
in blood pressure for many individuals. As usual, the most
notable improvements in blood pressure and cholesterol occurred in
individuals with pre-existing elevated levels. Some age-related
markers improve in mice when supplemented with (-)-epicatechin,
although no direct increase in lifespan has yet been noted.
Supplementation with some form of cocoa (supplemented or consumed as ultra-dark chocolate) may be beneficial for some individuals, although consuming too much sugar with cocoa would likely offset any positive effects. Quality cocoa extract is more expensive than many of the other supplements listed on this page, coming in at $1-2 day for a proper dosage.
Also, I’d love to purchase this and test it on myself for awhile to see if the effects can easily be measured.
(Coenzyme Q10 / ubiquinone) is a substance found in meat and fish
that is primarily present in mitochondria and aids ATP production.
Although supplementation is likely safe, it’s difficult to find
convincing evidence that CoQ10 supplementation would be effective for
longevity. It may improve
lipid peroxidation, blood
flow and offer minor improvements in other areas, but in my
opinion doesn’t appear to stand out from most supplements, both
experimentally and theoretically.
Wikipedia] is an
organic compound used in the recycling of ATP
in humans. It can be found in notable amounts of muscle meat and can
also be synthesized
in humans via glycine, arginine, and methionine. Creatine is a very
popular supplement for athletes with strong evidence that it notably
power output and lean
mass, with some evidence that it can offer minor improvements in
related areas such as recovery, fatigue, and some biomarkers that are
positively associated with quality anaerobic exercise. It’s very
safe, has little potential for any side effects, and is relatively
cheap. The only reason I don’t take creatine right now is that I’m
not doing many activities to build muscle, although I’ll likely
start taking it soon, even if only alongside basic resistance
training, calisthenics, or even cardio.
Wikipedia] is a
flavanoid found in fruits and vegetables. As usual, eating the right
fruits and vegetables is good for you on its own, and may make
supplementation less beneficial, or completely irrelevant. I likely
get enough of this from my diet, although there may be benefits to
infrequent high-dose supplementation.
an ammonium compound found in notable quantities in meat such as
beef. Supplementation sometimes appears to offer some decent results,
but I’ve determined that I like already get a sufficient amount
from my diet.
Resveratrol [Examine, webmd, Wikipedia] cannot go without being mentioned, as the extract from grapes that inspired the ‘red wine is great for you’ craze many years ago, it has been a constant source of speculative benefits and is still a very popular supplement in longevity communities. Although it hasn’t quite lived up to its initial hype, there’s still a lot of research on how it may be beneficial for longevity in one way or another. I’m personally not very into resveratrol and don’t see it as that interesting by itself. A summary is currently excluded here and you’re encouraged to read the above links if interested, but to be rather blunt, I think resveratrol is very likely approximately worthless, and is just yet another case study in now media hype in no way correlates with actual efficacy.
is a compound found in vegetables such as broccoli and cabbages, with
the best sources of it being broccoli sprouts and cauliflower
sprouts. I’ve taken sulforaphane previously, but it will be
difficult to know if it had a notable effect on me or not. I’m
currently focusing more on my diet and have decided against taking
sulforaphane. I’ve excluded a research summary in favor of the
Trimethylglycine [Exmine, Wikipedia] is a betaine amino-acid derivative found in some plants. It is notable for reliably reducing homocysteine levels in healthy subjects, sometimes by as much as 10%, and as much as 10-40% in unhealthy individuals. It appears that it might have a slightly negative effect in increasing, or preventing to some extent a decrease in, LDL, which is why I’m currently not taking it. It’s a nice molecule to be aware of and might deserve a spot in my stack at a later point, but as usual it would be nice to have more research available.
A lot of supplements have been excluded from this list, including many which are very interesting. Individuals who follow nootropic or longevity communities will definitely be curious why their favorite substance may have been excluded from this page, to which my answer is mostly that there’s too many substances for me to include all of them, so I did quite a bit of picking personal favorites. Even so, there’s likely many substances I’d like to include, but which I haven’t yet heard about or done enough research on. Feel free to message me on Twitter if you have any great suggestions here.
More interesting and potentially unsafe
This section contains some brief notes and links on substances that appear to be a lot more ‘experimental’ than the above sections, but have some interesting potential. In some cases it’s impossible to find proper tests of safety, or even basic toxicity, in humans. Regardless, they’re all interesting chemicals, sometimes increasing the lifespan of organisms such as mice by large amounts. A lot of compounds have been excluded from this list as there are too many for me to list currently. The most interesting item of this list is currently rapamycin, by a large margin. Also see list of potential CRMs.
is a compound present in some cosmetics, toothpaste, shampoo,
lotions, and more, which has improved lifespan in C. elegans in
Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test: https://www.aging-us.com/article/203736/text
membranaceus contains a compound called TA-65 that may
activate telomerase, extending the lengths of the shortest
telomeres in humans. This compound is lacking in notable research,
and much of what exists is clearly for-profit.
(This section is currently copy-pasted from section #1)
notably extends the lifespan of most organisms we have given it to
thus far, but lacks proper research in humans aside from its use as
an immunosuppressant. It’s a very popular drug to research in the
area of longevity, and deserves a longer write-up than I’ve given
it here; I may even start taking it in the near future.
There’s apparently quite a few people that have been taking this themselves, buying it from less-than-reputable Internet sources and hopefully not letting it be contaminated with light, as when exposed to light it degrades and becomes very dangerous to consume. This is certainly not something I plan to touch myself in with the current state of our knowledge on it, but it does seem like a very interesting chemical nonetheless.
is an unusual and understudied drug, in some ways similar to
selegiline noted above. It has prolonged lifespan to a minor extent,
such as 4% in mice.
This section has been moved, please see this post.
is an estrogen that is significantly less feminizing (99% less so)
than normal estradiol. It appears to have some neuro-protective
benefits as many estrogens do, and has extended lifespan in mice.