Is the effect of rapamycin actually due to caloric restriction?

I’m hoping the answer is no.

I was reading this: Rapamycin prolongs female reproductive lifespan - PMC

In addition, it is worth noting that rapamycin induced a decrease of food intake by ~33.9%. The rapamycin-treated rats were lean and smaller than the control rats, although their calorie intake per gram of body weight was comparable to that of the control rats at the end of treatment.

When reading an ITP article for rapa + acarbose I did not find any information about food intake being measured, but they did find lower body weight raac16 and even lower in raac9, basically linearly correlating with lifespan gain…


What if it was by reducing cancer in mice (which is the leading cause of death for them, not CVD like for humans)?

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Sure - but is it due to eating less or an effect of rapamycin besides eating less? Would rapamycin help in combination with some amount of CR?

Eating less is anticancer and longevity increasing in wild mice Does caloric restriction extend life in wild mice? - PMC

Generally in humans they have not seen the same weight loss when taking rapamycin that they see in mice.

While there is no question that since mTOR is the nutrient sensing pathway and rapamycin inhibits this pathway, that there is going to be some significant overlap in the mechanisms with caloric restriction (i.e. reduction of nutrients).

But there are many reasons to believe that there are also significant separate and discrete differences in how they convey their benefits…

Caloric restriction does not increase lifespan much when started later in life, as rapamycin does (for example, in mice).

Also - Even with calorie restriction, rapamycin slows muscle aging

Thats off the top of my head… I’ll see if I can find some other quick references on this topic.


Is the effect of rapamycin actually due to caloric retriction?

I hope not, as I’m eating the same or more than before I started taking rapa, with my weight not changing significantly. It does seem possible that CR and rapa have some common pathways to life extension.

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It’s my understanding that it is a caloric restriction mimetic. So it mimics those effects in the body independent of your actual caloric intake.


It has some similarities (like mTorC1 is inhibited by both Rapamycin and CR) but it is not the same - for example there are studies that compare CR and Rapamycin for different types of mice (progeria mice, diabetes mice, short telomeres mice) - and effects are sometimes different (one can extend lifespan and other shorten and vice versa - based on type of mice)

– For example:

    1. Rapamycin works stronger in female mice, but CR works the same for both sexes
    1. Rapamycin increases blood sugar levels, CR decreases it
    1. CR usually also requires intermittent fasting to work fully

I did a search and couldn’t find evidence for this. All I could find was here:
" Three randomized controlled trials have compared the benefits of adding TRE with a CR diet in adults with obesity. TRE did not add to CR-induced improvements in body composition, blood lipids or glucose parameters."

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It may not affect parameters, but most research from mice tells that IF is important for lifespan extension of CR.
Also, the second thing that many research papers doesn’t take into account is that when mice are given less food, they eat all of this because they are hungry, and they are automatically doing IF even if they don’t know this


it seems that De Gray concluded otherwise in his recent update? “the all-treatments group is still taking roughly twice as long as the all-controls group (starting from 19 months old, when the experiment began) to get down to a given survival percentage in males, albeit only about 50% longer than controls in females.”

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It probably depends on the strain of mice - Aubrey De Gray uses B6 mice in RMR, NIA ITP used Het3

In Het3 mice Rapamycin works stronger in female mice (partly because female mice have 3x more Rapamycin in blood after the same dose of Rapamycin) but CR works equally in both sexes

Almost all other drugs beyond Rapamycin work much stronger in male mice in Het3 (17 alfa estradiol, Canagliflozin, Acarbose, Protandim)


Related research:

Ultraviolet B acts as a dietary restriction mimetic by targeting mitochondrial bioenergetics.

Asya Martirosyan, Yuting Li, Yvonne Woitzat, Seunghye Lee, Li Fu and Maria Ermolaeva

bioRxiv. posted 6 March 2024, 10.1101/2024.03.05.583543


Interesting will be interesting to see where it ends up when published