Rapamycin is Fantastic and Worth Trying

[Tarmander]

@Immanency I eat around 250-300g of raw red meat every other day. Otherwise its usually cooked or raw chicken
@peatmoss I would rather not go into what I do publicly. You should be able to figure it out from what I have shared.
@Badger Awesome links. Dr. Green's experience was definitely part of the motivation for me to try it
@joaquin It should. Any kind of fasting or protein restriction should lower mTOR. Haven't read the literature on it

 

[frannybananny]

@frannybananny It is definitely not good to suppress mTOR all the time, and doing so would lead to very bad things happening. But perhaps, spiking its suppression here and there, turns on anti aging effects. I has definitely done me good, and I have built muscle.

@Peater To add on to what was said in the podcast, if you just want to try it, alldaychemist is good, but if you are going to take it long term, going to India Mart online and contacting a pharmacy over there directly is going to be less expensive. However you have to wire them money, so it is a bit riskier.

So, any opinion on HMB?

 

[Tarmander]

So, any opinion on HMB?

No opinions

 

[yerrag]

Ray Peat Q1, 2022:

An important factor in creating functional and metabolic inertia is a phosphate transfer enzyme that creates a general pattern of activation, the kinase called mTOR (mechanistic target of rapamycin).
A bacterial fungicidal antibiotic, rapamycin, originally used to treat candidiasis, was found to be immunosuppressive, and is used to prevent rejection of kidney transplants. The mTOR enzyme inhibited by rapamycin has been found to promote growth, inflammation, fibrosis, and cancer growth, and to accelerate aging. Lactate
promotes the activation of mTOR, and mTOR activates aerobic glycolysis, the defining feature of cancer.

Interrupting the vicious circles of cancerization is essential for the survival of the organism. There are many substances that can inhibit the
inflammatory, degenerative processes acting at multiple levels, and these substances tend to be synergistic, so that a great number of substances
can be safely used at the same time. This kind of supportive therapy has nothing in common with the ruling paradigm of cancer treatment—it is reinforcing the organism’s state of health, rather
than attacking the disease of cancer.
Things that favor the production of CO2 rather than lactate include CO2, sodium bicarbonate and acetazolamide, flavonoids such as apigenin and
fisetin (Constantin, et al., 2010; Shan, et al., 2017;
Zhao, et al., 2021), thyroid hormone,
progesterone, and lidocaine (Karniel and Beitner, 2000),

Some of the things that inhibit mTOR include caffeine (Zhou, et al., 2010), aspirin (Din, et al.,2012), lidocaine (Zhang, et al., 2021), vitamin D (Al-Hendy, et al., 2016), and flavonoids.

Things that increase intracellular calcium tend to increase mTOR (Amemiya, et al., 2021). Radiation (ultraviolet and ionizing radiation) increases mTOR, and this effect can be reduced by flavonoids (Bridgeman, et al., 2016). mTOR is
one of the factors in the radiation bystander effect, which is responsible for prolonged damage of other unirradiated cells in the organism (Verma
and Tiku, 2022).

Many of the flavonoids are known as “antioxidants,” but, like ascorbic acid/dehydroascorbate, inside the functioning cell they become beneficial
oxidative catalysts. In excessive doses they might act as reducing agents. Ascorbic acid itself in some situations increases mTOR (Moretti, et al.,4
2014). It’s safest to get the flavonoids from food, rather than supplements.

 

[GTW]

What is metabolic inertia?
"Stress is life, life is stress, the absence of stress is death." Hans Seelye
Life is not static equilibrium, it's dynamic.
About HMB, I have several bottles given to me by a Polish veterinarian who researched on dogs when patented and studied with University Iowa Âmes development.
Seelye also recognized that chronic stress was often maladaptive.
In theory HMB, resembling ketone bodies hydroxybutyrate and acetoacetate, signals feedback that energy is good, no need to catabolize muscle in stress conditions.
I did not use HMB preferring to manage stress catabolism by avoiding hypoglycemia/blood glucose roller coaster.
My nephew says HMB was great for recovery from muscle soreness when he worked at the sawmill.

 

[GTW]

Fisetin and other senolytic agents...

 

[frannybananny]

What is metabolic inertia?
"Stress is life, life is stress, the absence of stress is death." Hans Seelye
Life is not static equilibrium, it's dynamic.
About HMB, I have several bottles given to me by a Polish veterinarian who researched on dogs when patented and studied with University Iowa Âmes development.
Seelye also recognized that chronic stress was often maladaptive.
In theory HMB, resembling ketone bodies hydroxybutyrate and acetoacetate, signals feedback that energy is good, no need to catabolize muscle in stress conditions.
I did not use HMB preferring to manage stress catabolism by avoiding hypoglycemia/blood glucose roller coaster.
My nephew says HMB was great for recovery from muscle soreness when he worked at the sawmill.

Thanks for that!

 

[frannybananny]

No opinions

Ok, thanks anyway.

 

[Makrosky]

@Tarmander thank you so so much for sharing this man. Very happy to hear you are doing so good.

I will give it a try.

Btw, I think you should try molecular hydrogen pills. You might be very positively surprised.

 

[ecstatichamster]

@Tarmander thank you so so much for sharing this man. Very happy to hear you are doing so good.

I will give it a try.

Btw, I think you should try molecular hydrogen pills. You might be very positively surprised.

Hydrogen makes so much difference for me. But after listening to @Tarmander podcast, not as much difference as he indicates for rapamycin.

 

[Makrosky]

Hydrogen makes so much difference for me. But after listening to @tarmender podcast, not as much difference as he indicates for rapamycin.

Definitely, my reasoning is the following:
- He already has a good stack. And from his words, no need to complicate or try new things or risk messing up with what already works fantastic
BUT
Molecular Hydrogen doesn't add anything. It doesn't add effects, doesn't change anything, it just removes what blocks energy. It is subtle. Myself and others have described it this way in other threads.

That"s why I think it is a good addition for Tarmander, not because it produces such dramatic effects as rapamycin but because it can complement without modifying what already works for him.

 

[Tarmander]

@Makrosky That is interesting man. Are you taking a specific one you like?

 

[Makrosky]

@Makrosky That is interesting man. Are you taking a specific one you like?

I use Amazon product ASIN B07D7RD7VTView: https://www.amazon.com/-/es/Active-Ultra-Hydrogen-Water-Tablet/dp/B07D7RD7VT
but others like the Dr Mercola ones I believe are the same.

But you know what? Forget about it. Sorry. Sounds like you don't need anything else, really. We always fall on the trap.

Cheers

 

[Blaine]

Thanks for sharing your experience, @Tarmander. After listening to your podcast and perusing some rapamycin forums, I went ahead and ordered some "rapa" (generic Rapamune from AllDayChemist). Unfortunately, the tablets contain titanium dioxide, but I wasn't able to find a source that didn't.

I'll report back on my experience in a few months. I'm about your same age, and have greatly improved my health through peating, but still have fairly low energy levels which I would love to bring up.

 

[Blossom]

Unfortunately, the tablets contain titanium dioxide, but I wasn't able to find a source that didn't.

May I ask how you were able to figure out the products additives/inactive ingredients? I’ve never been able to see that on the ADC’s site.

 

[Blaine]

May I ask how you were able to figure out the products additives/inactive ingredients? I’ve never been able to see that on the ADC’s site.

I just did a google image search for the product name + “label” and found some images showing the back of the box.

Yesterday I came across a comment on a rapamycin form claiming that the same manufacturer produces a 2mg tablet without titanium dioxide, but I wasn’t readily able to find it.

Fortunately, you apparently only need to take rapamycin occasionally, given its long half-life, so at least you don’t have to consume harmful additives on a daily basis. Some people also take a lower dose alongside grapefruit juice (which evidently greatly potentiates it), so this could further lower the excipients ingested. I still wish ADC had a cleaner product though.

 

[Blossom]

I just did a google image search for the product name + “label” and found some images showing the back of the box.

Yesterday I came across a comment on a rapamycin form claiming that the same manufacturer produces a 2mg tablet without titanium dioxide, but I wasn’t readily able to find it.

Fortunately, you apparently only need to take rapamycin occasionally, given its long half-life, so at least you don’t have to consume harmful additives on a daily basis. Some people also take a lower dose alongside grapefruit juice (which evidently greatly potentiates it), so this could further lower the excipients ingested. I still wish ADC had a cleaner product though.

Thank you!

 

[Blossom]

This is quite the intriguing rabbit hole. I just read about people making a diy skin cream with rapamycin which is right up my alley.

 

[Limon9]

I started experimenting with it around March and April of this year. At first, it made me tired, hungry, and gave me some mental boosts. I thought it might be giving me energy but I wasn’t sure. As time went on, I realized it was a massive game changer, but in a very subtle way.

5-HT6 Receptor: A New Player Controlling the Development of Neural Circuits​

ACS Chem Neurosci. 2015 Jul 15;6(7):951-60. Dayer AG, Jacobshagen M, Chaumont-Dubel S, Marine P.

"5-HT6R is able to engage key developmental signaling pathways controlling neuronal circuit formation, neuronal connectivity, and psychiatric-relevant behaviors. For example, at early stages of neuronal development, expression of 5-HT6R constitutively regulates the activity of the cyclin-dependent kinase (Cdk)5 and, through this mechanism, controls cellular processes involved in circuit formation, including neuronal migration and neurite outgrowth."

"... Pharmacological manipulation has led to interesting new therapeutic perspectives in the field of psychiatric-related disorders. Indeed, 5-HT6R blockade can rescue a pathological overactivation of the mTOR pathway induced by early life insults in rodents and normalizes the associated social and episodic memory deficits."

"Further supporting the ability of 5-HT6Rs to engage the mTOR pathway, a recent study showed a concomitant increase in 5-HT6R expression and mTOR activation in the hippocampus of rats treated with pilocarpine, a model of temporal lobe epilepsy, and mTOR activation was strongly reduced by a pretreatment with a 5-HT6 antagonist (SB399885) for 3 days prior to pilocarpine administration. Moreover, the 5-HT6 antagonist increased latency of seizures and reduced their severity, suggesting a role for the 5-HT6R/mTOR pathway in epileptogenesis. [38] Experiments performed in cell cultures showed that mTOR activation by 5-HT6Rs depends on both the physical interaction of mTOR with the receptor’s Cterminal domain and the canonical PI3K/Akt pathway classically involved in mTOR activation by growth factor receptors. [11]"

"Interestingly, monoamine oxidase isoform A (MAO-A), the main enzyme controlling the degradation of serotonin, is expressed during the process of neurulation (E7.5−E10.5). [60] SiRNA-mediated knockdown of MAO-A in whole embryonic cultures from E7.5 to E10.5 leads to excessive amounts of serotonin in embryos and to severe brain growth defects. [60] Microinjections in the amniotic cavity of an excess of serotonin mimics the brain retardation phenotype caused by MAO-A knockdown."

"5-HT6R knockdown fully rescued the severe brain alterations caused by MAO-A knockdown or microinjections of exogenous serotonin. [60] The cellular processes controlled by 5-HT6R during neurulation remain to be fully characterized but are likely to involve a decrease in apoptosis and proliferation of neuroepithelial cells."

"Besides their influence upon IN migration, [17] 5-HT6Rs have emerged as a promising target for the treatment of cognitive symptoms of schizophrenia. [85−87] 5-HT6 antagonists improve cognition in a broad range of cognitive decline paradigms in rodents, including neurodevelopmental models of schizophrenia, such as neonatal treatment with phencyclidine (PCP) or rearing in social isolation after weaning, which recapitulates in adult animals the cognitive and other behavioral changes characteristic of schizophrenia. [88,89] Furthermore, several antagonists successfully passed phase II of clinical trials for the treatment of cognitive impairment, especially in schizophrenia and Alzheimer’s disease, and some of them have been nominated for further development. [90] The nature of signaling mechanisms mediating the influence of 5-HT6Rs on cognition has long remained unsolved. As outlined above, given the positive influence of the Gs-adenylyl cyclase pathway upon cognition, [18] it was unlikely that the inactivation of this pathway would transduce procognitive effects of 5-HT6 antagonists. The discovery of 5-HT6R coupling to the mTOR pathway [10] was an important step to solve this issue. Indeed, deregulation of mTOR signaling (mostly, but not systematically, its excessive activation) is increasingly recognized as one key signaling event underlying cognitive impairment in various pathological situations, including rare genetic forms of autism spectrum disorder (ASD) such as tuberous sclerosis [24,25,33,34] and Fragile X syndrome (FXS) [91,92], syndromes caused by the disruption of PTEN such as Llermitte-Duclos disease and Cowden syndrome [26,32,54,93], as well as Down’s syndrome. [93] Likewise, memory deficits induced by cannabis consumption are mediated by mTOR activation, [94] and, correspondingly, blocking cannabinoid CB1 receptors rescued behavioral deficits and normalized mTOR activity in a mouse model of FXS. [91] Finally, a recent study showed that a nonphysiological increase in mTOR signaling mediates cognitive and affective deficits caused by the knockdown of Disc1, a major gene implicated in schizophrenia, in adult-born dentate granule neurons. [95]"

"... an increase in mTOR activity was detected in the prefrontal cortex of adult rats treated at the neonatal stage with phencyclidine or reared in social isolation. [11] Furthermore, this enhanced mTOR signaling was abolished by 5-HT6 antagonists, and rapamycin, like 5-HT6 antagonists, rescued the deficits in social cognition and episodic memory observed in these developmental models of schizophrenia. [11]"

Several hypotheses have to be explored, such as an increase in 5-HT release in PFC resulting from changes in network connectivity occurring at critical periods of postnatal brain development and persisting in adulthood, as well as the alteration of 5-HT6R functional status and of its coupling properties. It is also important to establish in these models the temporal patterns of 5-HT6R elicited mTOR activation and, in the case of early onset, its involvement in aberrant developmental processes occurring during childhood and adolescence in schizophrenia.

This enzyme would be fundamentally involved in neuronal development, but appears to be chronically over-activated in psychiatric conditions. I know that a lot of CFS-related practitioners promote various "brain rewiring" courses, with focused breathing and gentle movements, so perhaps your use of the antibiotic has correctively nudged something. Sorry if I'm just recapitulating your podcast, I haven't had the quiet to listen yet. Ergot derivatives appear to act on 5-HT6, and those drugs are sometimes associated with long-term effects from brief usage. @haidut sells a few of them, and probably has much more well-researched insight on this.

"The way these regulators of energy and aging interact is holistic, and it’s necessary to understand that organisms make generalizations about their problems. Things that inhibit mTOR will increase adaptation and organization with expansion of the time horizon, while things that activate it (methionine, estrogen, radiation) will accelerate cell growth and inflammation and activate terminal processes. Progesterone and estrogen relate to the degree of mTOR activity through the body as a whole, not just through a series of receptor intermediates."

- Ray Peat's Newsletter, Q2 2022, Aging, Energy, Progesterone.

 

[Tarmander]

This is quite the intriguing rabbit hole. I just read about people making a diy skin cream with rapamycin which is right up my alley.

A lot of people doing this. If you make one let me know!

5-HT6 Receptor: A New Player Controlling the Development of Neural Circuits​

ACS Chem Neurosci. 2015 Jul 15;6(7):951-60. Dayer AG, Jacobshagen M, Chaumont-Dubel S, Marine P.








This enzyme would be fundamentally involved in neuronal development, but appears to be chronically over-activated in psychiatric conditions. I know that a lot of CFS-related practitioners promote various "brain rewiring" courses, with focused breathing and gentle movements, so perhaps your use of the antibiotic has correctively nudged something. Sorry if I'm just recapitulating your podcast, I haven't had the quiet to listen yet. Ergot derivatives appear to act on 5-HT6, and those drugs are sometimes associated with long-term effects from brief usage. @haidut sells a few of them, and probably has much more well-researched insight on this.

Really interesting, and a nice way to tie it back into Peat.