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 this paper: Castration delays epigenetic aging and feminizes DNA methylation at androgen-regulated loci.
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 orgasm 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 glycostlated 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 work decently (if not fully) when given later in life, contrary to some others which have the best effect when started in youth and continued until death. As such, I don’t mind waiting 5-20 years for this research to hopefully pan out into a more fruitful and actionable path until I start experimenting with it (although if anyone has more to say on this, please get in contact with me as I’d love to hear about you experience with 17α-estradiol).
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 normal estradiol and increasing the levels of all types of estrogen is a potential longevity treatment? This is a difficult question to answer, although there are millions of people that are already on 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 this target demographic for more information, however this turns out to be quite difficult. We have few deaths due to aging to analyze, as most individuals that transition decide to do so during an earlier period of their life. Of those, we have little data on the entirety of their life, as transitioning has increased significantly in the past few decades, so most of the relevant group is still quite young. Lastly, even if we did have this, the data would be terribly confounded in a large number of ways, and is definitely very far from the type of human RCT we would prefer.
Even so, one of the following must be true:
17α-estradiol does not extend male 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 factor
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 or various potential side-effects from anti-androgen usage
Option one is certainly a possibility, but if the AMPK/mTOR pathways are indeed the mechanism of action (and are still somehow modulated in humans by 17α-estradiol), this would imply that other potential human longevity agents such as rapamycin and metformin, which use these same pathways, will in fact, not work. If the pathway is related more to the metabolism of food, then this is easier to believe, as this is one of the areas where mice (which are herbivores) differ from us notably. On the other hand, there are enough differences between humans and mice that it’s very feasible the stars simply do not align for us here, and some critical part of this pathway has been modified past being useful (although do keep in mind that a large amount of important and interesting pathways have been evolutionary conserved for exceptionally long periods, of which mTOR is definitely included amongst).
Option two is, in my opinion, moderately plausible. It could the case that when we do have 17α-estradiol, the dosage is nowhere near sufficient for a noticeable longevity effect, and that if we would simply increase it by 10x or 50x, then we would very quickly notice something big. If not, there is a second sub-explanation here as well. Most male→female transgender individuals don’t just take an estrogen to increase estrogen, but also an anti-androgen to decrease testosterone. As we saw in mice however, castrated males did not experience the improvements as regular males did, although we cannot point specifically as to why. It seems quite possible that since most transgender (m->f) individuals take both an estrogen and an anti-androgen, they may be missing out on the potential opportunity of longevity benefits due to something the anti-androgen is doing. But again I have to add that this is pure speculation, and is just one of many guesses built on top of other guesses (we have only seen the original lifespan extension in mice).
I would like it if we were doing human trials on this right now, but I doubt we’ll get them for far too long, as is generally the case for anything that would significantly extend human lifespan and save us trillions of dollars (even if you think the chance this works is only 1%, multiply that by what we would get – billions of additional human years and trillions in less healthcare spending, and realize the massive expected value that all potential longevity interventions have).
As for option three, it would seem difficult to think that male→female transgender individuals are all supplementing a substance that may increase their lifespan by 5-20%, but yet none of us (or them) are aware of it. There is little useful data on this and we have no good reason to currently believe that this is the case, as we already are making quite a few leaps by first jumping from mice to humans, and secondly moving from 17α-estradiol to estradiol. I’d like to add a lot more to this later, but for now I’ll briefly summarize all of the above in one final paragraphs.
In conclusion, 17α-estradiol might notably extend human lifespan for those assigned male at birth. It may do this by modifying the liver and altering subsequent metabolic properties and processes, and this may also be related to its potential effects on key areas related to longevity such as AMPK and mTOR. If the former is the case, its lifespan effects are likely not additive with other drugs such as metformin or rapamycin, which although disappointing, could still offer other improvements in areas such as safety. If 17α-estradiol does extend human lifespan in this manner, some transgender individuals either do experience the benefits, but we have not yet noticed, or they do not experience the benefits, likely due to either having insufficient levels of 17α-estradiol, or due to the inclusion of an anti-androgen attenuating possible benefits. Further research, including direct human RCTs of 17α-estradiol supplementation itself, is required.
Disclaimer: I’m a random person on the Internet, and also not even a doctor. I have little formal background in biology and just click links on the Internet, read them, and then type things about them for fun. Please mention any corrections or comments to me (see: Contact section of About paget).
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.
Supplements I take daily
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.
Information: Vitamin B12 [Examine, webmd, Wikipedia] (vitamin B3). Often useful to supplement if one is taken metformin.
Name: Vitamin C
(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
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, and 3) increase my supplementation of high-quality omega 3s (fish oil) when I think I’ve had more omega 6s. 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.
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.
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.
Name: Vitamin K2
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.
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.
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.
Dosage: 0-1500mg (varies, rarely taken)
Cost/day: $0-3.80 (varies)
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.
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 spermine 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. Although I need to spend more time on this, 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, which it definitely could be, as some Mediterranean, Japanese, and other diets have a decent amount of it already. It may also 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.
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: 0mg (unable to find a suitable source for human consumption)
Description: 17-α-estradiol significantly extends male mice, and it might apply to humans as well. This section turned long so I turned it into its own post.
Dosage: 3-6g (schedule and doses vary, taken at most once a week, many other factors)
Information: Rapamycin is currently perhaps the most interesting substance on this blog post if you ask me. This section is currently unfinished, but there is a plethora of posts and literature on the substance. 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). What follows are some great papers on it, presented without additional context:
I’m currently messing around with some other substances such as acarbose and rapamycin (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 in order to properly assess its affects on blood glucose levels with specific meals. Rapamycin is a bit trickier, but has some of the greatest potential out of everything in this post.
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 taking
them because I have more doubts about their usefulness to me
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
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.
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.