Role of Estrogen Receptor α in Aging and Chronic Disease
We also discuss how 17α-estradiol administration elicits health benefits in an ERα-dependent manner, which provides proof-of-concept that ERα may be a druggable target for attenuating aging and age-related disease burden.
HEALTH BENEFITS OF AGONIZING ERα WITH 17α-ESTRADIOL
Although estrogen replacement therapies improve a variety of comorbid conditions and likely elicit benefits on aging processes [136-139], chronic administration has been linked with greater cancer and cardiovascular risks in some female populations [140,141]. Additionally, elevated serum 17β-E2 in males is associated with stroke risk [142], prostate cancer development [143], and feminization [144]. Therefore, the challenge remains of determining how best to exploit the beneficial effects of systemic estrogen therapies while circumventing adverse biological consequences. We and others have begun to address this biological challenge through the use of 17α-estradiol (17α-E2). 17α-E2 is a naturally-occurring diastereomer of 17β-E2 [145,146] that is present in both mammalian sexes [147-149], although circulating levels are quite low. 17α-E2 is also a minor constituent of estrogen replacement therapies [150] but only possesses about 3%–4% of the binding affinity to ERα that 17β-E2 does [151]. 17α-E2 has predominantly been studied as a neuroprotective hormone with mild to moderate efficacy in both male and female models of ischemia, Alzheimer’s, and Parkinson’s diseases [147,150,152-155]. It was not until recently that the effects of 17α-E2 on systemic aging, longevity, and conditions that promote aging (e.g., obesity) were evaluated. The National Institute on Aging Interventions Testing Program has shown that 17α-E2 extends lifespan in male mice when treatment is initiated in mid-life [156,157] and late-life [158]. The magnitude of lifespan extension with 17α-E2 treatment in male mice is similar to that of calorie restriction [159] and rapamycin administration [160], which indicates 17α-E2 elicits potent effects that could conceivably be translated to men.
Our previous work has established that 17α-E2 administration reduces calorie intake and adiposity in conjunction with dramatic improvements in metabolic parameters (e.g., glucose tolerance, insulin sensitivity, ectopic lipid deposition) in obese and/or aged male mice [161-165]. We surmise these benefits underly the lifespan-extending effects of 17α-E2. Others have also reported that 17α-E2 treatment elicits benefits on glucose tolerance, mTORC2 signaling, hepatic urea cycling, markers of neuroinflammation, and sarcopenia [166-170]. Importantly, male-specific benefits occur without overt feminization of sex hormone profiles [161] or reproductive function [171]. Female mice are generally unresponsive to 17α-E2 treatment [166-170,172,173], unless subjected to chronic high-fat feeding over several months (unpublished observation) or following OVX [174]. Until recently the receptor(s) that mediate the actions of 17α-E2 were believed to be uncharacterized [146,148,154,175], although our recent report clearly demonstrated that the majority of health benefits attributed to 17α-E2 treatment are ERα-dependent [163]. This report also established that the hypothalamus and liver are the primary organ systems where 17α-E2 signals to regulate metabolic homeostasis in male rodents. Additional studies are needed to determine if 17α-E2 acts predominantly through ERα in a cell-type-specific manner in the hypothalamus and/or liver to modulate not only systemic metabolic homeostasis, but also aging and longevity. Although not definitive, the data generated thus far indicates that ERα agonism by 17α-E2 in hypothalamic neurons and/or hepatocytes may hold therapeutic potential for attenuating mechanisms that promote aging and chronic disease burden in men.
This situation is still a little uncertain for me. You’re right, on his website it states he is taking 4g per week but on the 8/22 tweet he says he is taking 4mg per week. And it looks like a typo because 4g is 1000x more than 4mg and would be a very big increase in dose. And also if you look at the standard womens dose of 17-Beta estradiol .625 mg per day it equals 4.3mg per week. However… in a July 2023 YT Short
Bryan says “I apply this cream to my body, 4gm per week”. This could be referring to the quantity of cream and not the concentration of 17α-E2. But stating the amount of cream and not the drug is of no use to the viewers. The other thing to keep in mind is that 17α-E2 is 100 times less effective than 17β-estradiol, which makes 4gm per week of 17α-E2 incomparable to the 17-Beta estradiol doses for women. And the final thing is that in the 8/22 Tweet he does say “May trial higher dose”. Look, the 4gm per week dose does make more sense than 4g per week, but shit, that would be a huge mistake on the website where is saying “17aE2, 4g wk transdermal”. Thats unintentionally misleading followers to take 1000x more than he is taking!! (the “17aE2, 4g wk transdermal” was added to his website on the 28th April 2023 and has remained unchanged). I am taking 4mg of 17aE2 transdermal per week, but if its meant to be 4g per week, I’m wasting my time. And if it is 4mg, the uncertainty minimises the placebo effect
Hi All. I emailed Bryan Johnson’s team and they confirmed it was a typo on the website which has now been updated. He is taking 4mg per week not 4g per week.
17α-Estradiol Signals Primarily Through Nongenomic Mechanisms: Implications For Its Beneficial Longevity Effects
Recent work indicates that exogenous 17α-estradiol (17α-E2), a stereoisomer of 17β-E2, increases longevity 20% in male mice, despite previous literature that 17α-E2 is a weak estrogen with low affinity for nuclear (n)ESR1. This study aimed to obtain mechanistic insights into uterine 17α-E2 actions in vivo. We hypothesized that 17α-E2 signals preferentially through membrane (m)ESR1 to affect target tissues and promote longevity. To test this, we treated pre-pubertal (postnatal day 20) female CD-1 mice with 3 daily ip injections of vehicle or 10 mg/kg of 17α-E2 or 17β-E2. 17α-E2 treatment did not significantly increase uterine weight - a marker of nuclear (n)ESR1 signaling (20.3 ± 2.1 vs. vehicle 15.7 ± 2.0, p>0.05, n=4), while 17β-E2 strongly increased it to 41.4 + 1.1 mg; p<0.05). Accordingly, histological analysis revealed reduced cell proliferation in 17α-E2- vs. 17β-E2-treated uteri. Both 17α-E2 and 17β-E2 produced robust and similar epithelial p-ERK and p-AKT expression, the active phosphorylated forms of these protein kinases. Western blotting and immunofluorescence showed that 17α-E2 and 17β-E2 stimulated a strong and comparable stimulation of EZH2, a critical mediator of estrogen’s epigenetic effects linked to mESR1 signaling, as well as increases in NRF2 and CBP signaling. Progesterone pre-treatment blocks both the 17α-E2- and 17β-E2-mediated increases in p-ERK. In conclusion, despite limited actions through nESR1, 17α-E2 robustly signals through mESR1 to activate uterine protein kinase cascades and epigenetic effects. Thus, 17α-E2 acts preferentially through mESR1, which may explain its powerful longevity effects despite limited effects on classical markers of estrogen action such as uterine weight.
17α-estradiol Alleviates High-Fat Diet-Induced Inflammatory and Metabolic Dysfunction in Skeletal Muscle of Male and Female Mice
We hypothesized that male, but not female, mice, would benefit from 17α-E2 treatment during a HFD with changes in the mitochondrial proteome to support lipid oxidation and subsequent reductions in DAG and ceramide content. To test this hypothesis, we used a multi-omics approach to determine changes in lipotoxic lipid intermediates, metabolites, and proteins related to metabolic homeostasis. Unexpectedly, we found that 17α-E2 had marked but different beneficial effects within each sex. In male mice, we show that 17α-E2 alleviates HFD-induced metabolic detriments of skeletal muscle by reducing the accumulation of diacylglycerol (DAGs) and ceramides, inflammatory cytokine levels, and altered the abundance of most of the proteins related to lipolysis and beta-oxidation. Similar to male mice, 17α-E2 treatment reduced fat mass while protecting muscle mass in female mice but had little muscle inflammatory cytokine levels. While female mice were resistant to HFD induced changes in DAGs, 17α-E2 treatment induced the upregulation six DAG species. In female mice, 17α-E2 treatment changed the relative abundance of proteins involved in lipolysis, beta-oxidation, as well as structural and contractile proteins but to a smaller extent than male mice. These data demonstrate metabolic benefits of 17α-E2 in skeletal muscle of male and female mice and contribute to the growing literature of the use of 17α-E2 for multi-tissue healthspan benefits.
They tested a bunch of compounds in female B6C3F1hybrid mice, which is a long-lived strain. The compound which reduced mean lifespan most was 17beta-E2 (-21%). I couldn’t find the exact doses used.
They tested 1033 different compounds, and when the compounds were grouped by pharmacology, the only class which significanlty reduced lifespan was the estrogen agonists. In contrast, SERMs (which act as estrogen antagonists in tissues like breast and uterus, while acting as estrogen agonists in many other tissues) as a group extended lifespan.
17beta-E2 may damage DNA independent of its ER-binding activity, which might partially explain the above results.
We have demonstrated that E2 can bind to DNA directly and that binding not only occurs at the centre of the ERE half site but can also bind to random DNA sequences. E2 is shown to intercalate between base pairs, forming aromatic interactions with these base pairs…We predict that this intercalation will alter the structure of the DNA duplex, and therefore have the potential to affect the biological functions of DNA including the inhibition of transcription, replication, and DNA repair processes [40]. Therefore, excess E2 has the potential to exert some serious side effects such as disruption of ER-DNA binding, DNA damage and possibly the initiation of cancer. Molecular Mechanism of Binding between 17β-Estradiol and DNA
Mendelian randomization suggests that estrogen is causal for ER-positive breast cancer and endometrial cancer, so this could also be contributing to the above results. Obviously this would be an issue specific to female mice.
Another MR study suggests 17beta-E2 supports kidney function in men:
Our two-sample MR analysis based on the instruments assessing estradiol levels below vs. above the detection limit revealed a significant causal effect in males with a positive effect direction, implying that higher levels of estradiol could lead to higher eGFRs. This association was validated in the one-sample MR using continuous levels of estradiol above the detection limit. Mendelian randomization indicates causal effects of estradiol levels on kidney function in males
Now as for why the female mice don’t benefit in ITP, I think due to higher levels of endogenous estrogen, they already possess the ERalpha and ERbeta-mediated benefits (as studies suggest male benefits occur through these receptors).
We can estimate in women the amount of bound ERalpha using equation: %bound receptor=1/(Kd/[L])+1. Using 17beta-E2’s 115pM Kd @ ERalpha, we can see that going from 200pg/mL to 300pg/mL only increases bound receptor by about 4%. In contrast, going from 10pg/mL to 100pg/mL leads to 314% increase in bound receptor!
In essence, due to the nonlinear nature of the occupancy equation, raising a woman’s estrogen levels will produce a relatively small increase in ERalpha signaling, whereas an equivalent increase in a man’s estrogen levels will produce a much greater increase in ERalpha signaling.
If adding more 17beta-E2 has a relatively small effect in women, then this will especially be the case with 17alpha-E2—due to it’s much weaker affinity at ERalpha. On the other hand, since men would be expected to see a much greater effect from an equivalent increase in 17beta-E2, similar reasoning suggests they would see a much greater effect from an increase in 17alpha-E2.
You can do similar analysis with ERbeta (where 17beta-E2 has a similar Kd), just keep in mind that this is an approximation. Serum levels don’t necessarily reflect tissue or intracellular levels, where the relevant signaling is taking place. Additionally, I used human 17alpha-E2 Kd and serum levels, so this relationship would need to also hold with mouse values.
You’re fine - you’re using the 17 alpha estradiol version, thats not what he’s talking about. I’m not sure why he’s bring up the 17 beta estradiol test results, they are different molecules.
Yes - but the ITP tested 17-alpha E2 on mice and while the female mice did not see any lifespan increase (and no decrease), we saw very good lifespan increase in the male mice. Given the very different effects of 17-alpha E2 on male mice and male humans, I don’t think the effect of the feminizing hormone (17 beta-E2) in a mouse study is of much concern.
The non-feminizing claim I’m extremely skeptical of, and actually the study in post you linked even suggests that 17alpha-E2 (or one of its metabolites) is feminizing in macaques. Mouse studies have shown basically identical transcriptional profiles for both 17alpha-E2 and 17beta-E2 in liver, which further suggests that 17beta-E2 would be feminizing at high doses.
Like I said, if you plan on taking an estrogen agonist, you should be aware that estrogen agonists decrease lifespan in female mice. Obviously 17alpha-E2 increased male mice lifespan, which suggests the effects of estrogen agonists are biphasic, so you should be aware so you don’t overshoot the dose. If anyone knows any RCTs or MR studies relating to ER signaling please link them.
My 17alpha-E2 just came in actually, but I’m not sure on dose or ROA yet.
This video convinced me that 17-alfa estradiol is a substance that I should add to my health extending efforts. As well as keep taking sildenafil or other PDE5 inhibitors.
I wonder how well the 17eA in pantostin is absorbed through the skin and if some amounts of 17aE will reach systemic circulation.
I consider using 17aE in the form of (Pantostin) on my face. There are indications that topical 17aE might be beneficial to skin health, and since I don’t focus on my scalp, it might be an attractive ingredient to use topically on my face.
And since some products on the market already contain estriol and methyl estradiolpropanoate (MEP) etc, I think it is reasonable to think that it might be beneficial to my face as well as possibly being a tiny bit beneficial to the rest of my body.
This is what I will do till I find a way to get my hands on 17aE for oral ingestion.
As DSMO is more potent, I am using a 10:2 ratio. Essentially, I add about 20% of DSMO directly in the bottle and I use the bottle to dispense substance. I use it on my inner thigh.
