How can we "stimulate" mTOR?

[adreno]

There is a product on Amazon called Myo-X Myostatin Inhibitor. The company claims huge reductions in circulating Myostatin and similar increases in circulating Follistatin. Haven't been able to verify these claims yet.

Yeah I saw that. Couldn't find anything published to support their claims.

 

[Gondwanaland]

bathing a bit less than my skin temperature, and working down gradually

Not sure if it is appropriate to ask this here, but...

• for how long have you been cold showering?
• how often?
• did you catch a cold / flu when you started?
• what results did you get?
• I am weighting 45kg (my healthy weight is 52kg), would you say I can benefit from it?
• would this practice worsen lower back (intervertebral disk dehydration) and sciatica pain?
• what hormonal effects did you notice? thyroid, estrogen, testosterone, cortisol etc

 

[eljefe19]

I found pure Follistatin sold here;
https://www.peptidesciences.com/follistatin-315

Expense aside what do you guys think??

 

[Gondwanaland]

Please discuss more about Follistatin so I can better understand it. My FSH is very high and lowered a bit since I started estrogen replacement. I am experiencing huge benefits from it, but unfortunately there had already been enormous damage to my body (collagen/joint problems).

 

[anne_likes_red]

Not sure if it is appropriate to ask this here, but...

• for how long have you been cold showering?
• how often?
• did you catch a cold / flu when you started?
• what results did you get?
• I am weighting 45kg (my healthy weight is 52kg), would you say I can benefit from it?
• would this practice worsen lower back (intervertebral disk dehydration) and sciatica pain?
• what hormonal effects did you notice? thyroid, estrogen, testosterone, cortisol etc

5 years cool -> cold -> ice bathing. 4 or 5 times a week initially then 2 or 3 once I was well acclimatised. (Except the last 3 summers where I've taken a break.)
Body temp normalised. Other improvements were with exercise capacity, lessening of viral symptoms ie: swollen spleen and glands. Body weight stayed the same but composition altered...ie a bit more muscle.
Will PM you later re yr other questions. It's partially on topic lol - cold exposure does stimulate mtorc1 but by a different (PKA) pathway than the one discussed here.
Anne.
PS No cold or flu when I started (in Autumn) but I have heard of others experiencing a cold. I started with a low body temperature - low for decades - and low stress tolerance, so I approached it very conservatively.

 

[eljefe19]

Found a very interesting agent called YK-11. It's a SARM (partial androgen receptor agonist) without androgenic side effects and it inhibits Myostatin by inducing Follistatin (Reference). It can be bought at nootropicsource.com
I've just bought it and will experiment with it.

 

[necessary8]

I just found out that mTOR promotes NK cell cytotoxicity. Could inhibited mTOR explain low NK cytotoxicity in ME/CFS patients?

http://www.nature.com/ni/journal/v15/n8/full/ni.2936.html
https://www.ncbi.nlm.nih.gov/pubmed/24795729

The mTORC1 inhibitor rapamycin inhibited NK cell cytotoxicity both in mice and humans

 

[Tunguska]

Someone posted this article on uridine on another forum (2017):
https://www.sciencedaily.com/releases/2017/03/170317131617.htm

"Biology textbooks indicate that the liver produces uridine for the circulatory system," said Dr. Scherer, also Professor of Internal Medicine and Cell Biology. "But what we found is that the liver serves as the primary producer of this metabolite only in the fed state. In the fasted state, the body's fat cells take over the production of uridine." [...] These findings were replicated in human, mouse, and rat studies. [...] blood uridine levels go up during fasting and down when feeding. During feeding, the liver reduces uridine levels by secreting uridine into bile, which is transferred to the gallbladder and then sent to the gut, where it helps in the absorption of nutrients. "It turns out that having uridine in your gut helps you absorb glucose; therefore uridine helps in glucose regulation," Dr. Scherer said. [...] The uridine in the blood works through the hypothalamus in the brain to affect another tightly regulated system -- body temperature, Dr. Scherer added. It appears that only uridine made by fat cells reduces body temperature, he said. [...]
* Blood uridine levels are elevated during fasting and drop rapidly during feeding. Excess uridine is released through the bile.
* The liver is the predominant uridine biosynthesis organ, contributing to blood uridine levels in the fed state.
* The fat cells dominate uridine biosynthesis and blood levels in the fasted state.
* The fasting-induced rise in uridine is linked to a drop in core body temperature driven by a reduction in the metabolic rate.

http://science.sciencemag.org/content/355/6330/eaaf5375

Fasting causes an adipocyte-mediated rise in plasma uridine, which triggers a lowering of body temperature. Feeding causes a bile-mediated drop in plasma uridine, which enhances insulin sensitivity in a leptin-dependent manner. Thus, uridine is part of a complex regulatory loop that affects energy balance and potentially contributes to metabolic disease.

Abstract
Uridine, a pyrimidine nucleoside present at high levels in the plasma of rodents and humans, is critical for RNA synthesis, glycogen deposition, and many other essential cellular processes. It also contributes to systemic metabolism, but the underlying mechanisms remain unclear. We found that plasma uridine levels are regulated by fasting and refeeding in mice, rats, and humans. Fasting increases plasma uridine levels, and this increase relies largely on adipocytes. In contrast, refeeding reduces plasma uridine levels through biliary clearance. Elevation of plasma uridine is required for the drop in body temperature that occurs during fasting. Further, feeding-induced clearance of plasma uridine improves glucose metabolism. We also present findings that implicate leptin signaling in uridine homeostasis and consequent metabolic control and thermoregulation. Our results indicate that plasma uridine governs energy homeostasis and thermoregulation in a mechanism involving adipocyte-dependent uridine biosynthesis and leptin signaling.

So clearly some oral uridine can help with glucose processing, and glycogen (no surprise there - must pair well with fructose for liver).

But on the other hand, forcing high blood levels (sublingual UMP protocol) relative to lower ATP appears to promote the fasting state, which is not the hallmark of an mTor promoter. Seems like a bad idea now unless you've addressed all other limiting factors (esp. ATP; methylation must not be broken) or if not taken with food/carbs. Deficiency less a concern.

@eljefe19 There's plenty I keep my eye on. The first question is always if it crosses the BBB. But for myself it's a matter of survival so I can't rock the boat and need reliable substances first. Let us know how it goes but try to give them a good run...

 

[Sidereal]

I haven't read the whole thread so apologies if this has already been posted but as someone who has marked improvements in ME symptoms in the summer (vs winter) I thought these comments by Naviaux on AMPK and mTOR were very interesting. In my case, the spring/summer improvements have nothing whatsoever to do with sun exposure or vitamin D because even during the years when I was housebound and not exposed to the sun ever it still happened like clockwork.

From: http://www.sciencedirect.com/science/article/pii/S1567724913002390

3.2. Summer and winter metabolism
Large trends in the seasonal variation of metabolism can be placed in context by considering the evolutionary forces that have acted on our ancestors. Seasonal changes in calorie availability were the rule. Summer was a time of plenty, when the environment provided abundant calories, which were harvested with physical exercise. This was a natural time for cell growth, during which building blocks were polymerized to produce new cells and increase biomass. Physical exercise ensured that the added biomass was functionally efficient. The master fuel sensor in the cell during summer is mTOR (mammalian target of rapamycin) (Yang and Ming, 2012). mTOR facilitates protein synthesis and growth using new materials taken in from the environment. mTOR inhibits the internal recycling of used or damaged cellular resources by autophagy. The pathways supported by mTOR are Janus faced. In cells capable of dividing, mTOR promotes rapid growth with net polymer synthesis, without inflammation. Used or damaged proteins, lipids, glycans, RNA, and DNA are diluted by new synthesis from fresh building blocks obtained from rich summer ecosystems. In differentiated cells that cannot dispose of excess calories without hypertrophy, mTOR excess results in the accumulation of old and damaged macromolecules like oxidized or aggregated proteins, and produces chronic inflammation—oxidizing conditions that act as a thermodynamic break on the inexorable accumulation of intracellular polymers like lipids, proteins, glycogen, and nucleic acids from their monomer building blocks.

Winter was a time of caloric restriction and a time when resources stored in the summer and fall had to be used with great efficiency if survival was to be assured. The master fuel sensor in the winter is AMPK (AMP activated protein kinase) (Salminen and Kaarniranta, 2012). AMPK optimizes energy efficiency and stimulates the recycling of cellular materials in autophagy. This cycle occurs to a lesser extent each night and during fasting. The pathways activated by AMPK support regeneration and are anti-inflammatory because they work to break down damaged proteins, lipids, glycans, RNA, and DNA. AMPK facilitates the resynthesis of these macromolecules from newly synthesized monomers and refreshed building blocks. Monomer synthesis and polymer synthesis are balanced for winter maintenance. Historically, before the 1980s, most human nutrition research was focused on disorders of deficiency. After the 1980s, much of human nutrition research has been redirected to disorders of caloric excess. Indeed many of the genes that have been found to guard against age-related diseases like diabetes, cancer, and heart disease are found to be “winter genes” coordinated by AMPK, while the “summer genes” coordinated by mTOR lead to chronic disease and inflammation when combined with caloric excess and physical inactivity. Technological progress and industrial scale farming practices have been a double-edge sword for the health of populations around the world. Many developed nations now experience an “endless summer” of calorie availability, decreased physical exercise, and an absence of the historical norm of winter caloric restriction. This has led to modern epidemics of obesity in both adults and children, and to a growing tide of chronic disease traceable to cellular inflammation.

 

[adreno]

I haven't read the whole thread so apologies if this has already been posted but as someone who has marked improvements in ME symptoms in the summer (vs winter) I thought these comments by Naviaux on AMPK and mTOR were very interesting. In my case, the spring/summer improvements have nothing whatsoever to do with sun exposure or vitamin D because even during the years when I was housebound and not exposed to the sun ever it still happened like clockwork.

From: http://www.sciencedirect.com/science/article/pii/S1567724913002390

Interesting. Could this be why we see lower prevalence of ME in non-white (black, asian) populations?

 

[Murph]

Just thinking about the winter metabolism.

Bears probably hibernate because they feel awful. We have this vision of them all cosy and snuggled up. It's from the cartoons though. I bet they feel like I feel.

 

[Tunguska]

I haven't read the whole thread so apologies if this has already been posted but as someone who has marked improvements in ME symptoms in the summer (vs winter) I thought these comments by Naviaux on AMPK and mTOR were very interesting. In my case, the spring/summer improvements have nothing whatsoever to do with sun exposure or vitamin D because even during the years when I was housebound and not exposed to the sun ever it still happened like clockwork.

From: http://www.sciencedirect.com/science/article/pii/S1567724913002390

He talks in the past evolutionary sense of europeans. The idea of that translating to attenuated mTor responses in winter in most people still today through seasonal clock is pretty tenuous. I think it would be a weak effect or something solved pretty easily. It needs a lot more explanation.

 

[Jesse2233]

He talks in the past evolutionary sense of europeans. The idea of that translating to attenuated mTor responses in winter in most people still today through seasonal clock is pretty tenuous. I think it would be a weak effect or something solved pretty easily. It needs a lot more explanation.

If true one could alternate between the northern and southern hemispheres to compensate

 

[Tunguska]

If true one could alternate between the northern and southern hemispheres to compensate

Hah doubt you'd have to go that far. As far as I'm aware the seasonal clock responds to strong light entrainment, retinoic acid, thyroid, and tons more... no airplanes required. (Edit: I wonder about the glucocorticoids...)

 

[helen1]

5 years cool -> cold -> ice bathing. 4 or 5 times a week initially then 2 or 3 once I was well acclimatised. (Except the last 3 summers where I've taken a break.)
Body temp normalised. Other improvements were with exercise capacity, lessening of viral symptoms ie: swollen spleen and glands. Body weight stayed the same but composition altered...ie a bit more muscle.
Will PM you later re yr other questions. It's partially on topic lol - cold exposure does stimulate mtorc1 but by a different (PKA) pathway than the one discussed here.
Anne.
PS No cold or flu when I started (in Autumn) but I have heard of others experiencing a cold. I started with a low body temperature - low for decades - and low stress tolerance, so I approached it very conservatively.

I've tried cold baths and swims off and on for two years due to @anne_likes_red and @Asklipia's experiences. And that they stimulate mTOR!

Am back to doing them and had forgotten how helpful they are for mood, energy and temperature regulation. It's hard when you start though. If anyone's going to give it a try I've found a trick that helps make it much more bearable: wear water shoes (wetsuit or kayaking footwear) in the bath, as feet get painfully cold otherwise.

Question: Does anyone know how cold therapy affects hormones especially estrogen? And how mTOR activation generally affect hormones esp estrogen?

Edit: forgot the best thing about cold baths - reduction of PEM symptoms and duration.

 

[CFS_for_19_years]

Regarding cold bathing: I did this a long time ago and I wonder if it's similar to what you cold-bathers are doing:
1. Draw cold bath with enough water so that the water covers your hips.
2. Wear a sweater in the bath so that at least your upper part stays warm.
3. Stay in the bath 10 - 15 minutes.
4. When you get out of the bath, wrap yourself in a wool blanket and get into bed for an hour until you are warm again.
Are there any modifications anyone can recommend?

 

[Gondwanaland]

Question: Does anyone know how cold therapy affects hormones especially estrogen? And how mTOR activation generally affect hormones esp estrogen?

Are you interested in lowering or increasing it?

 

[Sushi]

Regarding cold bathing:

How about continuing this discussion in one of the existing threads on the subject unless it is directly related to mTOR?

 

[helen1]

Are you interested in lowering or increasing it?

need to increase it

 

[helen1]

Regarding cold bathing: I did this a long time ago and I wonder if it's similar to what you cold-bathers are doing:
1. Draw cold bath with enough water so that the water covers your hips.
2. Wear a sweater in the bath so that at least your upper part stays warm.
3. Stay in the bath 10 - 15 minutes.
4. When you get out of the bath, wrap yourself in a wool blanket and get into bed for an hour until you are warm again.
Are there any modifications anyone can recommend?

As mentioned above, keep your feet from hypothermia by wearing water shoes. And 5 mins has a notable effect on me. I wouldn't try 10-15 mins the first few times, it would crash most of us.