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 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 are very relevant to longevity) or on the liver/metabolic effects (which are also very relevant), or if these are in fact just two different temporal points on the same biological pathway which we don’t yet fully understand, but this helps us connect at least a few more dots.
All of the above sounds exciting, but it’s also all in mice. Sometimes this is useful, as mice are actually quite similar to humans (more so than many may expect), but a lot of it is also less useful or outright misleading. I cannot find a way to take only 17α-estradiol in a safe way as a human, however there is a topical cream of it (alfatradiol) which is used to treat pattern hair loss.
Luckily, one thing that the ITP study found was that 17α-estradiol was among one of the substances that seems to 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).