14 replies to this topic

[Adam Karlovsky]

Obesity kills - if it doesn't reduce healthspan, then it increases the aggressiveness of the development of cancer and other diseases. This study shows that rapamycin, one of our favourite anti-aging drugs, may help reduce obesity by reducing food intake, effectively 'resetting' the body weight set-point.

 

https://www.ncbi.nlm...les/PMC4008417/

 

 

 

Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy.

 

 

If anyone is struggling to maintain a restricted calorie diet, perhaps a single course of rapamycin will make all future efforts much easier? As well, we'd expect longevity benefits from the rapamycin itself via the manipulation of mTOR inhibition. I'm no doctor, so it's not medical advice, but I advocate for most people to take at least one course of rapamycin in their lifetime. 

[Exception]

Hey Adam, I didn't know you were on here. In my research on rapamycin, I saw that it causes diabetes. My immediate reaction was that it's probably too dangerous to take. What do you have to say about this issue?

[Adam Karlovsky]

It does progress insulin resistance, which could be a problem for diabetics and pre-diabetics. This only occurs after sustained inhibition of mTOR, so short-courses of rapamycin are less likely to be a problem.

Meanwhile, losing weight will improve insulin resistance in most cases (though losing weight is harder when you're insulin resistant). If I was obese and at risk of diabetes I might still give rapamycin a try for weight loss, I'd just be careful by monitoring insulin sensitivity, and not go overboard. People have talked about pairing rapamycin with metformin, or using rapamycin analogues like everolimus. I prefer berberine to metformin - it might make sense to first start with an AMPK activator, and then introduce a short course of rapamycin once one knows insulin sensitivity is under control.

[VP.]

I've been taking rapa since late January with no effect on my weight.  N=1

[Adam Karlovsky]

What dose are you taking? Are you overweight as it is, or normal weight? Any effects on hunger/cravings? Pairing rapamycin with some fasting or not?

[VP.]

What dose are you taking? Are you overweight as it is, or normal weight? Any effects on hunger/cravings? Pairing rapamycin with some fasting or not?

2 mg once every two weeks with about 10 oz of grapefruit juice a day for a week. It's enough to cause a mouth sore for a few days. I am in my late 50's and normal weight (BMI 23.6). No effects except the mouth sore and increasing strength and stamina (maybe training effect). No fasting. 

Edited by VP., 03 April 2017 - 03:21 PM.

[Skyguy2005]

What does taking rapamycin feel like? Good?

[SearchingForAnswers]

Taking 3mg a week. I'll report if I see any results in this area.

 

Edit: No grapefruit juice. Also taking metformin 500mg x1.

Edited by SearchingForAnswers, 12 September 2017 - 02:01 PM.

[VP.]

Update. Had my worst cold in 25 years in April 2017. Cut back to every other week of rapa/grapefruit juice (1-2mg). I am now back to every week 1-2 mg with GF juice. As of today I feel great and lost 11-12 pounds with no change in diet or exercise. I would characterize the weight loss as effortless. Only side effects is a mouth sore if I drink too much GF juice. This is rare. I also take 1000mg metformin and NAD+.  

[RWhigham]

 

 

 I prefer berberine to metformin 

Berberine is a strong inhibitor of the P450 family ref1 and will interfere with rapamycin clearance ref2.

 

For longevity, we want to intermittently inhibit mTORC1, and leave mTORC2 alone. If rapamycin does not clear quickly, mTORC2 will have time to become inhibited, and mTORC1 will stay inhibited too long. This will create an anti-rejection scenario instead of the desired longevity effects.

[poonja]

Is there a similar concern with metformin as rapamycin plus metformin is the cornerstone of a promising anti-aging protocol?

[RWhigham]

Is there a similar concern with metformin as rapamycin plus metformin is the cornerstone of a promising anti-aging protocol?

No concern with metformin + rapamycin. Metformin is not an inhibitor or a promoter of the P450 family.

 

Caveat: the following is from my notes.   When I quickly browse the web and make notes with my antiquated text-based system I seldom retain sources. I cannot spend all day today documenting these notes. Consider this post  a cautionary note and a guide for study, not a scientific treatise.

 

Most phytochemicals (plant chemicals) and pharmaceuticals affect the P450 system. One of the strongest pharmaceutical inhibitors is clarithromycin (Biaxin). Potent phytochemical inhibitors include grapefruit juice, berberine, naringenin, and St John's Wort. Phytochemicals that only inhibit 25% of an enzyme are considered weak because there is more genetic variability between people than that.

 

Taking one or two of the weak inhibitors may not be a problem (including Echinacea, Ginkgo, garlic, goldenseal, milk thistle, Green-tea, Grape-SE, and many others), but combining a lot of them with rapamycin I would consider unwise.

 

To the best of my knowledge the following have no appreciable effect on P450 system and safe to combine

 PQQ

 Metformin

 Curcumin

 Ashwagandha

 Icariin-Horny Goat Weed

 Eleuthero senticosus - Siberian Eleuthero

 Astragalus

 Nettle Root

 

To be more scientific, one would have to know precisely which P450 family members might contribute to metabolising what you are interested in, and then find out which supplements of interest are promoters and inhibitors for those.  Examples of this kind of information (with my comment added) are as follows:  (I show 3A4 in bold because it metabolizes about half of all toxins and is considered the most important)

 

Fisetin showed potent inhibitory effects on CYP2C9, CYP2C19, and CYP1A2. - a potent inhibitor for metabolizing some things.

Fisetin showed moderate inhibition of CYP2D6 and weak inhibition of CYP3A4.  - a weak inhibitor for most things

 

Schizandra increased CYP2E1 and CYP3A1/2 in vivo  - a promoter increases the elimination speed of anything metabolized by these

Schizandra inhibited CYP2D2 in vivo - an inhibitor decreases the elimination speed of anything metabolized by these.

 

Resveratrol inhibited the activities of CYP3A4, CYP2D6, and CYP2C9 - I think this was in vivo but I'm not sure

 

Edited by RWhigham, 25 October 2017 - 06:19 PM.

[eighthman]

Been doing the 5mg once a week regimen (dissolved in alcohol, mostly) and I noticed something.  In my youth, I was very thin because I had a limited appetite which would shut down firmly in the midst of modest meals. Trying to go beyond that, would make me feel a bit sick.

 

Anyhow, this faded away with aging and keeping weight off is more difficult.   After a month of weekly doses, I noticed this feeling has returned after many years absence.  And weight loss is somewhat easier again.

 

Now if you guys could fix the wrinkles and grey hair, I would appreciate it.  That would be the 'whole deal and a bag of chips'.   !

[to age or not to age]

We have taken rapamycin - 5 mg once a week - for 10 + months.  My wife had recurring mouth sores and stopped 2 months ago. But has been super fit since.

I caught a nasty flu 3 weeks ago after not having had any kind of cold for 10 years (we also take NR, Resveratrol and Curcumin daily). I have stopped taking rapamycin 

and will see. I caught the cold a day after taking a dose, which is suspicious.

[eighthman]

I didn't want to say anything yet because it's too early.  No mouth sores but immune system seems solid.  I will see ........