Rapamycin: Anti-aging and metabolic dream drug?

DavidPS

@Mauritio said in Rapamycin: Anti-aging and metabolic dream drug?:

Now I'm wondering what would happen if you combine selegiline or ergothioneine with rapamycin since they both have different MoA than rapamycin, targeting oxidative stress mainly.

Selegiline is another drug that I want to avoid. It has complex influences in the body. I am willing to wait. Vitamin E is surprisingly good for longevity in male mice.

Vitamin E at high doses improves survival, neurological performance and brain mitochondrial function in aging male mice

I do not know if it would be additive with rapamycin.

Mauritio

@DavidPS wow, 40% increase in median life span in male mice is pretty good!
There must be something that benefits male mice more than female mice about vitamin E.

It might be that vitamin E could at least partially substitute for selegiline. Since they're both ameliorating oxidative stress. I think there's a lot to the free radical theory of aging otherwise substances like selegiline, ergothioneine or vitamin E wouldn't be so successful in retarding death.
The oxidative stress is mostly downstream from PUFA consumption IMO, that's Why peat said there would be little use for vitamin E, if PUFA consumption was low or zero.
The above book recommendation comes to mind again.

Vitamin E seems to rescue the sickest individual, hence the increase in median life span, but has less drastic effect on maximum life span. In other words it prevents premature death first and foremost.
Which is similar to what selegiline is doing.
I talked about this on the forbidden forum in this post Post in thread 'Selegiline Experiences' https://raypeatforum.com/community/threads/selegiline-experiences.18419/post-903080

Btw selegiline has good safety record and has been used in humans for decades. So I don't see any issues with weekly dosing.

Mauritio

Another thing about that study is that they used vitamin E acetate.
There have been several studies showing vitamin E acetate as less effective or even harmful compared to vitamin E succinate.

In this case the succinate form decreases liver carcinoma by 77% and acetate actually increased it.
https://raypeatforum.com/community/threads/vitamin-e-succinate-very-effective-against-liver-carcinoma-acetate-form-increases-it.35475/

Another case: 650% lower tumor volume with vitamin E succinate and no result from acetate.
https://raypeatforum.com/community/threads/vitamin-e-succinate-decreases-melanoma-size-by-650-in-vivo.39088/

So I'm wondering how effective Vitamin E succinate would have been for life extension?!

(BTW can someone tell these people that I'm banned on the RPF I still see people asking me questions in several threads)

Ismail

@evan-hinkle

hey bud, which type of thiamine are you taking?

I had very similar benefits from B1 too (TTFD version), though they seem to have diminished (not sure if it's to do with low glutathione status etc. - https://hormonesmatter.com/paradoxical-reactions-with-ttfd-the-glutathione-connection/#:~:text=The initial phase of processing,use up” their reduced glutathione.)

I tried a B1 version which contained several different types (i.e. hcl, TTFD, Benfo), again had some great results, notably very energetic and somewhat of a pro-dopamine "state", though this diminished too after a day.

evan.hinkle

@Ismail hey man, just using regular old thiamine hcl. I’ve tried others, and they seem to work as well, but I just have to take a little more of the hcl version to get the same results.

Ismail

@evan-hinkle thanks bud

Mauritio

Rapamycin is anti-MUFA and anti-cancer.

I suspect that a significant part of rapamycins anti aging effects are similar to having a low PUFA intake. Since rapamycin mostly works through lowering excessive inflammation, which is largely caused by PUFA consumption.

In this in vitro study the authors showed a that rapamycin inhibited SCD1 via mTOR inhibition, which lead to a decrease in breast cancer size.

"In all three cell lines, we found that rapamycin significantly decreased polysome-associated mRNA for stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis. Activators of mTOR increased SCD1 protein expression, while rapamycin, LY294002 and BEZ235 decreased SCD1 protein expression. "

Also, simply increasing MUFA via SCD1 was enough to cause breast cancer growth, while lowering MUFA had the opposite effect.

"Furthermore, SCD1 siRNA knockdown inhibited breast cancer cell growth, while over-expression increased growth. "
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965451/

This is only in vitro, so take it with a grain of salt. But I think it coherently outlines a logical mechanism of action . Plus: in several other studies SCD1 has been down to be pro-cancer (and other diseases) and rapamycin has been shown to be anti-cancer. Btw this is "only" increasing MUFA and it already has such terrible effect on the organism, now imagine what increasing PUFA would do...
https://www.cell.com/trends/cancer/fulltext/S2405-8033(23)00032-8

Mauritio

Btw today was my first day taking rapamycin myself.

I started with 1mg.
And I notice that I feel very energetic. Normally I feel quite tired after a day of work but today I feel fit, especially mentally. Less brainfog. Also my mood is better.

I also notice that I'm calmer and more patient with people.

It's all very early but so far so good.

Mauritio

Day 2:
Slept really well. Better than usually . Lost 500g of body weight. Last evening I noticed my metabolism increasing and me heating up.

Today I Had a great, day . Felt engaged and interested in what I did . Maybe a little tired ,but nothing crazy.
I had some gut "detoxes" today. Less hair loss.
Motivation increased. Strength was about the same.

Mauritio

Day 8:
Last days felt hypothyroid, gained water weight.
Had rapamycin yesterday and today lost water weight. Weigh 650g less than yesterday morning, although I ate more than the days before.
Took rapamycin before work... Not a good idea. Was stressed and tired. Will return to after work.

I suspect that there might be a rebound mTOR effect after a few days of no rapa, hence the hypothyroid symptoms .

Or Maybe that's the "physiological insulin resistance" that is transient and materializes itself at the beginning of rapamycin treatment.
IIRC rapamycin caused water retention for tarmander as well but it went away.

Other than that my energy might be slightly higher but not sure yet.

jamsey

With rapamycin, I’ve always wondered how many effects are downstream of its anti fungal and anti biotic effects. Is there any studies with it in germ free animals?

jamsey

@jamsey found this, but not much else:
https://www.nature.com/articles/s41598-019-44106-5

LetTheRedeemed

@jamsey Hey, I wonder if this is the wonder drug to get bacterial infection in lymph nodes and bone???

Mauritio

Rapamycin increases klotho.

It is even more Peaty than I thought because it lowers phosphate. And phosphate activates mTOR. Rapamycin lowers phosphate and mTOR, decreasing calcification.

"Zhao et al. report that phosphate activates the mammalian target of rapamycin (mTOR) cascade in VSMCs, leading to downregulation of Klotho. Furthermore, rapamycin was shown to halt medial calcification. This effect was blunted in the absence of Klotho. Given the concomitant anti-atherosclerotic effects of the mTOR inhibitor, this agent has clinical potential as an inhibitor of intimal atherosclerosis and medial calcification."
https://pubmed.ncbi.nlm.nih.gov/26422620/

Here, it also increases klotho in aging mice. And it caused a huge increase in survival.

"All mice administered rapamycin survived the 12-week course, whereas 43% of the controls died."
https://pubmed.ncbi.nlm.nih.gov/37190667/

It decreased phosphate in humans.

"In the rapamycin group, serum phosphate was lower than in the CNI group with an increase in phosphate excretion and a reduction in its reabsorption."

Peatful

@Mauritio

I will tag you, but this question can be addressed to anyone here who is taking this “Wonder drug“

How do you reconcile that this is big Pharma:
Pfizer and Wyeth?

https://www.justice.gov/opa/pr/wyeth-pharmaceuticals-agrees-pay-4909-million-marketing-prescription-drug-rapamune-unapproved

Red flags personally for me as well as it’s catching on mainstream

https://youtu.be/8kObxwZDG30?si=JncC3zfIz568VnZD

Of course I think it has therapeutic benefits, but I would isolate those to compromised kidney patients, etc.

Mauritio

Rapamycin might help schizophrenia by lowering mTOR.

Schizophrenics have increased 5ht6 activation which in turn activates mTOR.

"Further, 5-HT(6) receptor activation increased mTOR signalling in rodent prefrontal cortex (PFC). Linking this signalling event to cognitive impairment, the mTOR inhibitor rapamycin prevented deficits in social cognition and novel object discrimination induced by 5-HT(6) agonists. In two developmental models of schizophrenia, specifically neonatal phencyclidine treatment and post-weaning isolation rearing, the activity of mTOR was enhanced in the PFC, and rapamycin, like 5-HT(6) antagonists, reversed these cognitive deficits. These observations suggest that recruitment of mTOR by prefrontal 5-HT(6) receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control."
https://pubmed.ncbi.nlm.nih.gov/23027611/