Using 10-month-old APOE3 or APOE4 targeted replacement male mice maintained on normal chow with and without 14.4 ppm 17aE2 for 20 weeks, our initial results indicate genotype differences in the efficacy of 17αE2 across multiple outcomes.
APOE4 mice exhibited an aged phenotype compared to APOE3, with APOE4 mice having a higher frailty index; however, 17αE2 treatment reduced the frailty index most strongly in APOE4 mice. APOE4 mice were impaired across multiple metabolic measures including body weight, plasma leptin, and hepatic steatosis. 17αE2 significantly attenuated the APOE4 metabolic phenotype. These data confirm and extend prior findings that APOE4 is linked to progeroid effects both peripheral and neural outcomes associated with AD risk. Importantly, 17αE2 significantly improved a range of measures, but showed the strongest effects in the APOE4 genotype.
Improvement in frailty is nice, but sadly where is the cognitive data for these mice? They would have only pursued this work in apoe4 mice for AD implications.
This is the problem with ITP…it’s purely a mouse and cancer model, but we humans die of multiple other causes.
Perhaps we need to be making skin cream with rapamycin and 17-alpha estradiol?
A patent application that looks to be from Johnson and Johnson’s China office.
Patent Application: Use of 17-‘alpha’-estradiol for treatment of aged or sundamaged skin and./or skin atrophy
Abstract
The present invention relates to a method for treatment of mammalian skin conditions where stimulated connective tissue synthesis is beneficial, comprising treating skin in need of such treatment with a safe and effective amount of 17-alpha-estradiol.
Description: The 17-alpha-estradiol is in the application on aging or sun damage skin and/or the atrophoderma
skin responds to some estrogen that comprise 17-.Fibroblast in the estrogen chafe, the level of increase connective tissue matrix molecule.When whole body or local approach give estrogen, the synthetic increase of non-protein moleculars such as collagen, elastin laminin and hyaluronic acid.As a result, skin keeps or increase thickness and integrity.These skin appearances are better, and that can resist environment on function stress.When making Local treatment with 17-, the Local treatment of women’s skin of estrogen deficiency also shows the increase of the disappearance of wrinkle, water content and the improvement of skin elasticity.In addition, when injured, can to expect under the estrogenic situation that skin healing gets faster having, because fibroblast is in state of activation.
Well, it sounds interesting. My reading of the patent information gives me the impression that research for this may have started in the late 1990s. If so, I wonder why it hasn’t come to fruition yet?
In one of the papers they mix the powder in distilled water for the clinical study. Different levels of dilution of the solution with distilled water will result in different quantities of 17-alpha estradiol being consumed for a given quantity. Not too hard to figure out…
17α-estradiol does not adversely affect sperm parameters or fertility in male mice: implications for reproduction-longevity trade-offs
Despite an abundance of data indicating that 17α-E2 attenuates several hallmarks of aging in male rodents, very little is known with regard to its effects on feminization and fertility. In these studies, we evaluated the effects of 17α-E2 on several markers of male reproductive health in two independent cohorts of mice. In alignment with our previous reports, chronic 17α-E2 treatment prevented gains in body mass, but did not adversely affect testes mass or seminiferous tubule morphology. We subsequently determined that chronic 17α-E2 treatment also did not alter plasma 17β-estradiol or estrone concentrations, while mildly increasing plasma testosterone levels.
We conclude that chronic treatment with 17α-E2 at the dose most commonly employed in aging research does not adversely affect reproductive fitness in male mice, which suggests 17α-E2 does not extend lifespan or curtail disease parameters through tradeoff effects with reproduction.
17α-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice
Estrogen signaling is protective against chronic liver diseases…We sought to determine if 17α-estradiol (17α-E2), a naturally-occurring diastereomer of 17β-E2, could attenuate liver fibrosis.
Findings: We found that 17α-E2 significantly reduced collagen synthesis rates and increased collagen degradation rates, which was mirrored by declines in transforming growth factor β1 (TGF-β1) and lysyl oxidase-like 2 (LOXL2) protein content in liver. These improvements were associated with increased matrix metalloproteinase 2 (MMP2) activity and suppressed stearoyl-coenzyme A desaturase 1 (SCD1) protein levels, the latter of which has been linked to the resolution of liver fibrosis. We also found that 17α-E2 increased liver fetuin-A protein, a strong inhibitor of TGF-β1 signaling, and reduced pro-inflammatory macrophage activation and cytokines expression in the liver.
Interpretation: We conclude that 17α-E2 reduces fibrotic burden by suppressing HSC activation and enhancing collagen degradation mechanisms. Future studies will be needed to determine if 17α-E2 acts directly in hepatocytes, HSCs, and/or immune cells to elicit these benefits
Seems like 17 alpha-estradiol might be a good match for a keto diet…
17α-Estradiol Mitigates the Negative Effects of High-Fat Feeding in Both Male and Female Mice
Although the effects of 17α-E2 on liver and adipose tissue are well described, potential benefits in skeletal muscle are unknown. The objective of this study was to determine if 17α-E2 can mitigate the negative effects of a high-fat diet (HFD) on skeletal muscle metabolism. In addition, we sought to determine if there were sex differences in these responses.
17α-E2 reduced insulin resistance in males and females. 17α-E2 reduced the expression of IL-6 and TNFα in males, but 17α-E2 did not change cytokine expression in females. There was no difference in gastrocnemius ORO staining in the males or females. 17α-E2 supplementation did not change quadricep triglycerides in males. However, females on 17α-E2 had significantly lower quadricep triglycerides compared to HFD. These results suggest that long term 17α-E2 supplementation ameliorates the effects of a HFD on skeletal muscle in both males and females but in a sex dimorphic manner.
17α-E2 is definitely up there with acarbose as next on my anti-aging list. I wanted to give rapamycin a full year before adding another major intervention. I am on the keto diet, so this might be the key factor in deciding to try 17α-E2.
I would not risk feminization features. But I have an idea for this as Alzheimer’s was my white whale previously.
There is a completely different alternative to pretty much completely avoid the feminizing effects of 17-beta-estradiol “contamination” using a brain-selective pro-drug that crosses the BBB. The downside is it won’t have desired 17-alpha estradiol systemic effects, but I suspect it has promise for decreasing age-related amyloid-beta and pro-cognitive effects with neuroprotective/decreased neuroinflammatory properties. That memory boost in mice seemed pretty decent.
@tongMD Re DHED, brain ONLY pathway, very interesting molecule.
Do you have other “white whale” thoughts other than summary below, or your original meaning?
I see no clinical trials registered.
Here is a summary of DHED/AD (2016)
One notable comment: "Roberta Diaz Brinton, PhD, has proposed the “healthy cell bias” hypothesis of estrogen actions in the brain, which suggests that estrogens are protective in healthy cells but may be harmful in diseased states. For example, in cell culture, 17β-estradiol is protective when applied prior to or during Aβ42 insult. It is not protective if applied after—and exacerbates Aβ42-induced apoptosis. If this theory is true, DHED may only be protective at an early stage of AD (or before the appearance of neuropathology).
A more recent 2019 paper, transgenic AND ovariectomized mice (female Tg2576 transgenic AD mice were ovariectomized and then treated by implanting Alzet osmotic mini pumps containing DHED or vehicle subcutaneously for 8 weeks):
" Evidence showed that AD is not restricted to neurodegenerative process but strongly interacts with immunological mechanisms in the brain (Zhang et al. 2013). Cytokines including TNF-α, IL-6, and IL-1β are associated with increased Aβ in aging Tg2576 mice, so we analyzed the RNA and protein levels of TNF-α, IL-6, and IL-1β. We observed a significantly decreasing of TNF-α, IL-6, and IL-1β in the hippocampus. These data demonstrate that DHED might involve in inhibiting the inflammatory pathway to influence Aβ level in hippocampus. Taken together, our findings uncovered a new mechanism for DHED to improve the cognitive function of AD mice and may provide a viable therapy to treat AD."
One thing that’s puzzling about the potential translatability of 17 alpha is that we have a lot (relatively) of people who were assigned male at birth (AMAB) who are taking 17 beta estradiol for gender affirming therapy without any sign of life extension in this population. There’s even some mixed evidence that 17 beta estradiol increases CVD risk in those AMAB.
Blagosklonny raised similar questions in a couple of tweets:
If these TM2Fs were assigned biological males at birth and got tons of 17 beta-E2 at the level intended for females (and androgen blockers ie spirinolactone), I would assume applicability is extremely slim. Not to mention, there are a bunch of confounders like obesity/medical conditions (pre hormone therapy), stress, HIV/other STI (seen enough advanced HIV induced cardiomyopathies), and drug use.
There are huge estrogenic potency differences (17alpha E2 is very weak “feminizer”) and massive differences in binding affinities for ER-alpha receptors (17alpha E2 is 2-3x stronger) vs ER-beta receptors.
ER-alpha and ER-beta tend to antagonize each other. The most obvious example is the bone. Based on the studies on the mechanisms in rats - long-term consequences of high 17-beta-E2 with ER-alpha resistance should show much higher CV and bone disorder risk. We know ER-alpha is far more cardioprotective than ER-beta, and ER-beta is pro-arrhythmia. This seems to mostly explain why 17-alpha-E2 in male rats live longer.
We already have a case report of a man in 20s with ER-alpha insensitivity (rare):
He had normal testosterone, early onset of osteoporosis (think unopposed ER-beta activation) in his 20s, insulin resistance, continued slow linear growth in height, and signs of potential infertility (low sperm count). Seems to fit what we expect based on rat studies.
Men all have 17 alpha E2 and 17 beta E2 in the system, more than a postmenopausal woman. Male fetuses have higher brain 17 beta E2 than female fetuses and are responsible for “masculinizing” gene epigenetic activation via demethylation. Best to not think of estrogen=female hormone, because there are different male specific “masculinity” effects, positive libido effects, pro-spermatogenesis effects, anti-obesity effects, and some “anti-estrogenic” effects depending on the estrogen dose, type, and where.
There are no trials partly because of very conflicting messages and exactly when estradiol can be useful as a protective factor against “aging”. But I can see why Dr. Miller felt 17 alpha estradiol specifically was totally worth the shot over a lot of other interventions that didn’t make the cut in the NIH NIA ITP to clear the field and subsequent further confirmation since the first run had some moderate anomalies in a few control groups. I initially had some hesitancy myself but the second run definitely put 17-alpha estradiol higher up on my priority to investigate with unneutered male dogs vs neutered male dogs prone to canine cognitive dysfunction because the effect size is way too large to ignore as opposed to say aspirin.
This review has a pretty deep dive, includes what I mean by conflicting messaging, and influenced a lot of what I thought about how 17-beta-estradiol vs 17-alpha-estradiol works for “anti-cognitive aging”. It includes what the evidence is for that proposed “healthy cell bias” hypothesis you mentioned.
