Blocking cortisol extends lifespan more than rapamycin, by improving mitochondrial function
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Yet another confirmation that cortisol, while being life-saving in acute stress situations, can shorten lifespan if chronically elevated. In fact, according to the study below, antagonizing the effects of even normal cortisol levels may extend lifespan. This corroborates Ray’s statement that all the symptoms of aging (and thus every chronic disease) can be reliably reproduced in even youthful organisms by the administration of sufficiently high doses of cortisol. An interesting finding of the study was that the anti-aging effects was due to improved mitochondrial function, so this suggests (again) that any benefit or risk from a specific substance is likely ultimately due to its effects on metabolism/mitochondria. And it just so happens that cortisol does suppress mitochondrial function, while simultaneously enhancing both fatty acid synthesis and fatty acid oxidation, as well as lipolysis. Finally, the study compared the effects of cortisol blocking to the effects of the well-known life-extension drug rapamycin, which works by blocking the mTOR protein. In fact, blocking cortisol extended lifespan by 40%+ more, compared to rapamycin and without the known (and very dangerous) side effects of rapamycin (immunosuppression). The two drugs were not synergistic when used together, suggesting they work through the same pathway.
The anti-cortisol drug the study used was the well-known Mifepristone/RU486. However, there is plenty of evidence that progesterone, DHEA, testosterone, DHT, etc are also capable of antagonizing the effects of cortisol. As a curious example, I would point to both Elon Musk and (especially) Jeff Bezos, who are some of the most well-known users of testosterone (TRT). Both have had doctors and the general public commenting that since starting TRT they have able to “age in reverse” and that is readily visible by comparing pictures from their younger years (20s and 30s) to recent ones. While medicine will probably attribute those beneficial effects on testosterone (T) being an “anabolic” steroid, in reality most of the “anabolism” stems from the anti-catabolic effects of T (it is a cortisol blocker at the receptor level, just like RU486). As such, OTC alternatives with known anti-cortisol effects such as progesterone/DHEA or pregnenolone may also be able to achieve the same effect.
https://doi.org/10.1080/19336934.2024.2419151
“…The University of Southern California scientists directly compared the effects of mifepristone on female fruit flies with another drug that has shown anti-aging potential, the immunosuppressant rapamycin. They found that both drugs taken separately improved the flies’ longevity, though mifepristone performed a bit better, extending the flies’ lifespan by a median 114% compared to 81% for rapamycin. However, when both drugs were used together on the flies, the flies actually went on to have a slightly lower lifespan than normal—indicating that the drugs work in a very similar way to boost longevity, the researchers said. The team’s other experiments suggest that both drugs do this by improving the cells’ ability to clean up their damaged or dysfunctional mitochondria…”
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@haidut Now that you mention it, there are some pretty wild changes in Elon's appearance. At one point he seemed to be aging rapidly with very marked wrinkles, grey hair, and a very unhealthy looking hue. Few weeks later he looks like a vibrant 30 year old. Has he himself ever commented on what he's taking?
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@haidut
Even though I agree with everything you said, unfortunately we have no evidence of it from this study. As you may guess from my name, I know some things about fruitflies and their hormones. Basically, flies do not have a cortisol analogue, so in this case mifepristone acts as a progesterone antagonist. Flies change a lot their guts with reproduction to maximise egg production at the cost of their fitness/lifespan decrease. Basically, mifepristone blocks flies' progesterone (called juvenile hormone) and this prevents the remodelling of their intestine (which involves a reduction in mitochondrial efficiency). So blocking flies' progesterone or mTor has no additive effect as they both go towards the same direction reducing gut growth and turning flies into sterile.
Anyway, I hope this kind of studies will come soon in mice even though we know already the outcome ;). I hope that within a couple of years I will be able to start my own research group and I will get in touch with you! I'd love to think together new ways to test Peat 's principles or your compounds with my fruitflies! -
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@fruitfly Good reply. Thanks for sharing.
I was thinking I want to see this replicated with a series of mammals and then we'll see. As opposed to RU486 we actually have this data on rapamycin and it does increase lifespan significantly in all of those species.And calling rapamycin very dangerous is a stretch. The immune suppression is more towards excessive inflammatory cytokines.
Dare to think.
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@Mauritio what is the difference between the immunosuppressive effect of cortisol and that of rapamycin?
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@Epik this guy gives a great answer at 51:22
Rapamycin dampens excessive sterile inflammation that is often present unnecessarily in old age.
While cortisol has a strong short term anti-inflammatory effect as well, it is disastrous for the body in the long run.
Dare to think.
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This makes the case stronger that a carnivorous diet makes us age more, doesn't it?
Temporal thinking is the faculty that’s
engaged by an enriched environment, but it’s
wrong to call it “thinking,” because it’s simply
the way organisms exist... - Ray Peat Nov 2017 Newsletter -
@yerrag definitely. I think it has benefits because of endotoxin reduction and reduction of toxic chemicals.
But the mTOR activation and high amounts of methionine and cysteine are definitely an issue.
Large amounts of gelatin might protect to some degree. But the studies on rapamycin and methionine restriction are so obvious and many that I don't think theres a way around this.
It always leads back to a high carb diet.Dare to think.
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@Mauritio And not only that, but cortisol destroys the thymus gland and the thymus gland is where t-lymphocytes mature, and this has the effect of lowering immunity.
Temporal thinking is the faculty that’s
engaged by an enriched environment, but it’s
wrong to call it “thinking,” because it’s simply
the way organisms exist... - Ray Peat Nov 2017 Newsletter -
@yerrag
Yes, although this study shows rapamycin has thymus weight lowering effect in mice. Although there was clearly a dose dependant effect and the HEDs were like 15-60mg per day which is really high, so I'm not sure if there would be any such effect if you were to take just 1-5mg / week .
So the weekly dose of this study was about 30-100 times higher than what most humans take.
