17-Alpha Estradiol - Another Top Anti-Aging Drug

@RapAdmin

Re Apollo, drilled down into their stable of companies.

Did you see this one:

“Aeovian Pharmaceuticals is a San Francisco Bay Area-based R&D-stage biopharmaceutical company developing novel and highly selective therapeutics modulating the mTORC1 pathway.

Addressing the mTORC1 pathway has been challenging to-date however, because chronic treatment with conventional, non-selective mTOR inhibitors, such as rapamycin and Everolimus, leads to off-target inhibition of mTORC2 which results in dose-limiting deleterious effects on metabolic health and immune function. The associated toxicity leads to severe clinical adverse events that significantly reduce treatment safety, decrease compliance, and compromise therapeutic efficacy.

In contrast, by virtue of their selectivity, our compounds potently inhibit mTORC1, but avoid inhibition of mTORC2, and therefore are not expected to cause the mTORC2-related side effects that limit the conventional non-selective mTOR inhibitors. We believe that the exquisite selectivity of our compounds for mTORC1 will enable a significantly improved safety profile resulting in improved tolerability, patient compliance, and ultimately improved efficacy in treating mTORC1-mediated rare and age-related diseases.

Our proprietary platform is supported by an extensive intellectual property portfolio, part of which has been obtained by assignment from the Buck Institute of Novato, California, the nation’s first independent research facility focused solely on understanding the connection between aging and chronic disease.”

Lamming is a scientific advisor.

Yes - its listed in my summary of all the different types of rapamycin and rapalogs on the market: Rapamycin Naming Conventions (part 2)

I think this is a bit of an issue for Dudley Lamming as publicly he’s quite “cool” on rapamycin (generally speaking) and I suspect it could be because he stands to make a lot of money off Aeovian stock if they are successful with their mTOR inhibitor (a direct competitor to rapamycin).

Ultimately - the more effective drugs for aging, the better for all of us, though I wonder what the cost will be of these new mTOR inhibitors if they come to market. Everolimus was about $6K per month prior to going off patent (if you didn’t have coverage by insurance)… Will the Aeovian mTOR inhibitor be $6K a month better than rapamycin… we’ll see.

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Lamming is highly conflicted, but I’m ok with that, as long as his science is above reproach and truly moves the longevity needle. I fear you are right re eventual cost for a new mTOR inhibitor. These folks are not running a charity.

This quite the interesting molecule, apparently not working predominantly via mTOR (although it does signal), but major liver gene expression.

“In alignment with our previous reports, 17a-E2 reduced calorie intake, body mass, adiposity, and obesity-related metabolic perturbations in male WT mice. These studies, coupled with our current findings, led us to speculate that 17a-E2 may be signaling through ERa in the liver to reverse metabolic disease and potentially extend healthspan and/or lifespan in males. We found that 17a-E2 dramatically reduced liver mass and lipid content”

I found the male/female selective responses quite profoundly interesting, especially as it relates to some further confirmations of the loss of most likely protective estrogen in post menopausal women and elevated aging chronic disease risk.

“The loss of endogenous estrogen action due to menopause in humans or ovariectomy (OVX) in rodents eliminates these beneficial effects and elicits metabolic perturbations. Moreover, OVX following sexual maturation has also been shown to reduce lifespan in female mice, indicating that endogenous estrogens regulate lifespan in females; which we surmise is at least partially mediated through ERalpha” This is pretty profound stuff if translatable to human female aging.

There’s a huge stack of smoking gun literature, especially for neurodegeneration in females associated with loss of estrogen late life.

And fundamentally, castrating male mice (blocking testosterone) completely ABLATED the effects of this molecule…wow.

“Despite these contrasting observations, the studies by Garratt et al. do provide important insights into the interconnected and under appreciated relationship between androgen- and estrogen-signaling pathways and their roles in metabolism and aging.”

“Notably, it is plausible that 17a-E2 could be inducing metabolic benefits and lifespan-extending effects through several distinct mechanisms, including direct actions through ERa, suppression of DHT production, and/or aromatization of testosterone”

https://www.sciencedirect.com/topics/medicine-and-dentistry/17alpha-estradiol

“17-α Estradiol is a weak estrogen and a potent 5-α reductase inhibitor” Another fascinating connection.

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Quick question - why 60 mg instead of the original 2mg/day as planned?