Insomnia / 2 AM Wakeups Related to mTOR Suppression & Autophagy? (N=1)

#1

I wanted to throw my recent N=1 out to the group to see if anyone else has this specific phenotype or experiences severe sleep disruption from Rapamycin and other metabolic stressors.

It seems my nervous system reacts aggressively to any major metabolic shift, mTOR suppression, or upregulation of autophagy/mitophagy. It feels like exactly the same as the severe insomnia I would get from an extended fast or a really deep caloric cut – essentially no problem falling asleep - but after ~4 hrs of sleep I am wide awake (probably tied to a cortisol and adrenaline surge triggered by metabolic stress)

Here is exactly how my N=1 played out:

  • Phase 1 (Winter Diet + UA): Started taking Urolithin A (UA) during the winter while I was at the bottom of a pretty hard diet/cut. I experienced severe sleep destruction, but at the time, I just blamed it on the aggressive caloric deficit.
  • Phase 2 (Maintenance + Rapa): Stopped the UA. About 3-4 weeks later, I hit maintenance calories and decided to start Rapamycin, tapering the dose up. I almost immediately started seeing sleep destruction as the dose ramped up. I was getting exactly 4 solid hours of sleep, and then I’d be wide awake at 2–3 AM. I tried every sleep supplement and trick in the book, and nothing worked consistently.
  • Phase 3 (Washout): Paused the Rapamycin for about 4 weeks. My sleep dramatically improved and went back to normal. Like 8-9 hours felt great.
  • Phase 4 (The Rapa Test): Took a single one-time dose of Rapa to test it. My sleep immediately deteriorated back to those exact 2 AM wakeups, and it lasted for about 6 days before clearing.
  • Phase 5 (The UA Test): Figured Rapamycin was the culprit and maybe just wasn’t for me, so I decided to try UA again. I took it and immediately got the exact same result: wide awake at 2 AM. After a week, i began thinking its the UA. Stopped it and within ~48 hours my sleep was significantly better.

It feels like my brain interprets these cellular cleanup signals (mTOR inhibition from Rapa, mitophagy from UA) as a starvation/survival event, triggering a stress response that completely wrecks my sleep architecture. This is what AI created to explain this, but unclear how accurate it is.

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A few questions for the community:

  1. Has anyone else experienced this exact pattern of 2 AM wakeups with Rapa, UA, or fasting?
  2. Did lowering the dose significantly or extending the interval resolve the sleep disruption for you, or did it still hit you just as hard?
  3. Has anyone found a way to blunt this specific fasting-mimicking stress response without ruining the autophagic benefits, or is this just a sign that my biology isn’t compatible with these compounds?
#2

I have this issue - fall asleep very easily, but wake up soon, and then awake until early morning and another spell of sleep. But it’s not conneted to rapamycin in my case.

In my case it’s connected to generally lowish calories. I was a full on, pretty severe CR practitioner for 8 years (1300-1450 cal/day), no longer so, but retained lowish calories (1800 or so).

When the CR site was still active (RIP- CRSociety.org), there were almost universal reports of much shorter sleep duration on CR (but still fully restful!), and for some it was also this pattern of falling asleep and waking up.

In animals on CR this is a well-known phenomenon. It’s connected to sharply increased exploratory activity. Evolutionarily you can see the sense of it - the animal must be active and search out food, so this is definitely something that happens. This is such strong an effect, that if you put in a wheel into a cage of a mouse on CR, the mouse will run on that wheel obsessively, much more than ad-lib mice, and in fact to the point where they wear themselves out with relentless running. Interestingly, exercise in severely CR’d animals is lifespan-shortening because they expend energy they can’t spare. Longest lived CR’d animals are those that are at the highest level of CR without exercise.

In any case, this early waking might be connected to this. Basically, it’s your body saying “get up, find food”.

Does rapamycin do the same? I honestly don’t have any idea. I really don’t know.

The more interesting question for me is different. One of the big complaints on the CR site from CRONies (CR practitioners Calorie Restriction with Optimal Nutrition), was the poor applicability of studies to CRONies - those studies are all conducted in ad-lib people (except a couple like CALERIE+). But CRONies frequently have very, very different biomarkers and health responses to interventions and drugs. Consequently, health advice based on those studies is often wrong or inappropriate for CRONies. This is the light in which I wonder about sleep.

We all know about the importance of sleep, and the sound advice about optimal sleep etc. But, that is for ad-lib people. Are we sure the same applies to CR’d or low cal, (or folks on rapamycin very speculative!) - are we sure that such interrupted sleep is damaging to health exactly as it would be for ad-lib people? Well, it’s not clear. It’s not clear because animals on CR have such sleep, yet live longer and healthier than ad-lib controls. It’s like the argument about muscle size and exercise in ad-lib animals vs CR’d animals. CR’d animals have smaller muscles and exercise less, but have longer lasting muscles and a longer and healthier lives despite exercise and muscle size recommendations for ad-lib.

Fasting - well, it might trigger the exact same response of interrupted sleep based on increased need for exploratory behavior. Rapamycin? I don’t know.

Perhaps a person on rapamycin has slightly different physiology and requires slightly different recommendations for optimal health than the ad-lib person?

Bottom line: is it possible that rapamycin causes this sleep phenomenon? I don’t know. And if it does, is it health damaging? I don’t know. What I do know is that it’s not a simple question to answer and any measures taken might - again might - be counterproductive. You might just be exhibiting “normal” adaptive behavior. I don’t know one way or another, I just know it’s complicated. YMMV.

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#3

Yes, this is exactly what I am describing. I also experienced the same when I did keto + IF. And is reproducable with Rapa or UA (at least in my very small trials). I would feel shot out of cannon amazing - at 2 AM, could do work, workout, etc. However - stacking a week of days like this back to-back along with exercise obviously taxes the hell out of my body. I also would get super tired in the evenings (because of the lack of sleep).

#4

As an addendum - I can reproduce this very easily. On those occasions when I overeat - say Thanksgiving or some such occasion - I sleep like a log, 8-10 hours. I’ve observed this repeatedly. Cut calories - cut sleep. Eat more - sleep more.

But then getting back to my question - isn’t this more complicated? I mean, do I really want to eat lifespan and healthspan shortening amounts of calories just so that I can sleep “optimally” 7-8 uninterrupted hours in order to be healthier? Perhaps the 7-8 hours is a recommendation based on the damage ordinary caloric ad-lib intake (and especially SAD diet) does, and the body needs 7-8 hours to partially compenstate and repair the damage? Remember, those sleep studies and recommendations are done on ad-lib people… perhaps people who don’t have optimal caloric intake or diet.

Where does all of this net out? What’s optimal? FWIW, my tactic is not to jump out of bed at 2 am when I wake up - I just lie there thinking or commit the other crime everyone warns against, which is read (iPad, iPhone, sometimes book etc.). I eventually fall back asleep 5-6 am till 10 or so. If you put it together, I probably do get about 5-7 hours per night, but obviously it’s fragmented. Like I said repeatedly on the CRSociety site and sometimes here - I feel rested after this “terrible sleep”, almost feel guilty about it, and skeptical (maybe I’m fooling myself that I feel fine?). But really, how bad is it? Sure, it’s bad if you are ad-lib maybe on a SAD diet, but how bad for someone in my (or your) situation? I simply don’t know :man_shrugging:…

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