Mitophagy Activation by Rapamycin Enhances Mitochondrial Function and Cognition (New Study)

Alzheimer’s disease (AD) is the most prevalent form of dementia, characterized by severe mitochondrial dysfunction, which is an intracellular process that is significantly compromised in the early stages of AD. Mitophagy, the selective removal of damaged mitochondria, is a potential therapeutic strategy for AD. Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, augmented autophagy and mitigated cognitive impairment. Our study revealed that rapamycin enhances cognitive function by activating mitophagy, alleviating neuronal loss, and improving mitochondrial dysfunction in 5×FAD mice. Interestingly, the neuroprotective effect of rapamycin in AD were negated by treatment with 3-MA, a mitophagy inhibitor. Overall, our findings suggest that rapamycin ameliorates cognitive impairment in 5×FAD mice via mitophagy activation and its downstream PINK1-Parkin pathway, which aids in the clearance of amyloid-β (Aβ) and damaged mitochondria. This study reveals a novel mechanism involving mitophagy regulation underlying the therapeutic effect of rapamycin in AD. This study provides new insights and therapeutic targets for rapamycin in the treatment of AD. However, there are still some shortcomings in this topic; if we can further knock out the PINK1/Parkin gene in animals or use siRNA technology, we can further confirm the experimental results.

Full Paper (open access):

More about the Mouse Model used:


I wish i could reconcile studies like this, and frankly all the reports of sleep disturbance etc. in people who take rapamycin with the evidence that it barely gets through the Blood brain barrier. Perhaps just a little is needed, or perhaps it affects the brain via secondary pathways that don’t require rapamycin to cross the BBB. Interesting and welcome results though. It will be interesting to see what the human clinical trial shows for AD. Apparently the trial ends in Aug of this year.


Matt Kaeberlein thinks that the brain’s peripheral blood vessels and inflammation reduction might be enough to show improvement without crossing the BBB.

Also, he says as we age the BBB is not as effective at keeping out substances. So older folks get more BBB benefits.

Just now took my zydus 2mg dose and a fresh squeezed red grapefruit. I get a blood rush… can feel my heartbeat and ears start ringing… like tinnitus. That’s what potentially makes my sleep more fretful on rapamycin night.

Also, made a fresh batch of hair tonic… was sure to add 4 pills of Metformin… with zydus pills… and the rest…

I am definitely getting fine hair growth. And, some coloring of the grey… rich, natural color.


Sleep disruption (which i also get) is AIUI a symptom of autophagy which will be more likely on higher serum levels of Rapa.


John - can you remember where you saw a reference to this (that sleep disruption is a symptom of autophagy?)

All I can find is the research that shows sleep disruption disregulates autophagy… Short-Term Sleep Fragmentation Dysregulates Autophagy in a Brain Region-Specific Manner - PMC


I saw something about autophagy causing problems for circadian proteins and it is in many ways people’s experiences. I need to walk my son to school in a few minutes. I will try to find the reference either later today or tomorrow.


AFAIK, people with AD have blood-brain barriers (BBB) that resemble a sieve.
It has been shown that their brains are riddled with fungi, bacteria and viruses, all of which would have gained entry to the brain via a defective BBB. So I don’t think we should have any concerns about rapamycin crossing. Whether it would do any good by that late stage is anybody’s guess.
If I was a clinician I would try hitting them with antibiotics, anti fungal and antivirals, THEN rapa.
Just my 5c worth.


I found a reference to this in my notes: