#122

Dayspring mentions here that both types of statin get into the brain eventually, so it doesn’t matter which one uses. I stopped Atorvastatin but I’m probably going to be starting a baby dose of Rosuvastatin again following your advice as Dayspring also mentions “baby statins” in this clip and it looks like Rosuvustatin is the most bang for buck in small doses.

I just “liked and subscribed” to your youtube channel btw. Look forward to seeing more.

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#123

Yes I’ve seen that episode with Dayspring. He’s almost certainly wrong on this. Atorvastatin (lipophilic) does get into the brain readily, whereas rosuvastatin (hydrophilic), if it gets in will be a much smaller amount.

Thanks for supporting the channel - and I’ll have better quality and detailed materials upcoming.

Vera-Health.ai says on this:
Rosuvastatin’s ability to cross the blood-brain barrier (BBB) is a topic of interest due to its potential implications for treating neurological conditions. The BBB is a selective barrier that regulates the passage of substances from the bloodstream into the central nervous system (CNS) 6.

A study by Sierra et al. compared various statins, including rosuvastatin, for their potential to penetrate the BBB and their neuroprotective effects. The study found that rosuvastatin has a lower potential for BBB penetration compared to more lipophilic statins like simvastatin 1. This is consistent with the general understanding that lipophilicity is a key factor in a drug’s ability to cross the BBB.

However, another study suggests that rosuvastatin may still have therapeutic potential in the CNS. It was shown to mitigate BBB disruption in sepsis-associated encephalopathy by restoring occludin levels, a tight junction protein critical for BBB integrity 2. This indicates that while rosuvastatin may not readily cross the BBB, it can influence BBB function and integrity.

Additionally, the role of transporters like organic anion transporting polypeptide 1a4 (Oatp1a4) at the BBB is crucial for the CNS disposition of statins. The regulation of these transporters by signaling pathways, such as the TGF-β/ALK1 pathway, can affect the distribution of statins like rosuvastatin in different brain regions 3.

In summary, while rosuvastatin may not have high BBB penetration due to its lower lipophilicity, it can still impact BBB function and potentially exert effects on the CNS through mechanisms involving BBB integrity and transporter regulation. This makes it a candidate for further research in neurological applications, despite its limited direct penetration into the brain. (ASHP Drug Compendium [Rosuvastatin; Statins

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#124

I wonder what evidence Thomas Dayspring uses!
I think I looked at this previously and that he actually was correct that rosuvastatin also crosses the BBB.

#125

Screenshot 2025-09-07 at 7.16.41 PM
Screenshot 2025-09-07 at 7.16.41 PM1064×486 32.2 KB

https://x.com/davidasinclair/status/1964464220906672197

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#126

I do a once-monthly, and I’m sad enough to actually plot my LDL-C levels at various time points after injections.

Just note, this graph is a composite of around 2 years worth of separate injections and testing. The X axis shows the interval between the last 140mg Repatha injection and my current LDL-C. (It’s not me taking one injection, then a whole bunch of blood draws. So basically, it will be noisier).

However, I think the data are pretty clear. For me, PCSK9i kicks in fairly quickly, by day 10 there’s a huge reduction, and it hits baseline somewhere between day 36 and 42. Thus, if I inject every 30 days, it isn’t wearing off. The dotted line on the X axis shows my baseline (Crestor + Ezetimibe only) of 75mg/dl.

Obviously an injection every 2 weeks would definitely keep things lower, which I am considering.

Time since PCSK9i.pdf (18.1 KB)

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#127

“Here, we revealed that ApoE4 astrocytes could regulate neuronal APP metabolism to induce amyloidosis through cholesterol oversupply. This study provides new insight into the contribution of ApoE4 and astrocytes to amyloidosis in AD, as well as the importance of regulating astrocytic APOE isotypes and its cholesterol oversupply for disease intervention.”

https://www.sciencedirect.com/science/article/pii/S2213671121003830

It appears that part of the problem in apoE4 carriers may be an oversupply of cholesterol, and so statins by reducing cholesterol production helps blunt this influence on amyloid production

And have a look at this too:
https://www.alzheimers.gov/news/alzheimers-tied-cholesterol-abnormal-nerve-insulation

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#128

I got my Mitome mitochondria report, and I have a blockage at the Q-junction (or complex II/III), which means statins are NOT good for me.

AGI timelines are short, so short-term energy matters more. Nexlizet is stil important.

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#129

Short answer you probably want: pravastatin tends to have the least smack on mitochondrial complex III, with rosuvastatin usually next least. The usual troublemakers are the lipophilic crew, especially when they flip into their lactone forms (that’s when CIII gets grumpy). (PubMed )

Here’s the side-by-side you asked for:

Statin Hydro/Lipophilic What’s reported for Complex III Read this if you like receipts
Pravastatin Hydrophilic Consistently the least mitochondrial impact in cell models; did not impair β-cell mitochondrial function vs atorvastatin. (Nature)
Rosuvastatin Hydrophilic Lower off-target mitochondrial exposure than lipophilic statins by distribution; high doses can still ding liver mitochondrial respiration in mice. (PubMed )
Atorvastatin Lipophilic Impairs β-cell mitochondrial function; lipophilicity raises nonhepatic exposure, which correlates with more mitochondrial mischief. (Nature)
Simvastatin (esp. lactone) Lipophilic Lactone form is a strong CIII inhibitor at the Qₒ site; robust in vitro inhibition, large drops in respiration. Acid form less so. (PubMed )
Lovastatin (lactone) Lipophilic Same story: lactone forms are much more myotoxic and inhibit CIII. (ScienceDirect)
Fluvastatin / Pitavastatin Lipophilic Direct head-to-head CIII data are thinner, but class effect: lipophilic statins penetrate muscle more, and lactone species are the usual CIII hitters. (PubMed )

Why this pattern shows up

  • Hydrophilicity vs lipophilicity: hydrophilic statins hang out in the liver more and wander into muscle less, which means fewer chances to annoy mitochondrial CIII outside the liver. Lipophilic statins slip into extrahepatic cells easily. (PMC)
  • Lactone forms: several statins interconvert to lactones that bind the Qₒ site of complex III and can knock activity down hard in vitro. That’s been tied to myopathy signals. (PubMed )

Practical take

If Complex III is your personal villain, the rank order from gentlest to spiciest (very roughly, across studies) is:
pravastatin ≲ rosuvastatin < pitavastatin/fluva-zone < atorvastatin < simvastatin/lovastatin (lactone forms worst). Evidence is strongest for “pravastatin least,” “simvastatin/lovastatin lactones most.” Human data are patchier than cell/animal work, so treat this as directional, not gospel. (Nature)

If you’re discussing a switch with your clinician, the boring but useful checklist is: pick a hydrophilic option, lowest effective dose, watch for myopathy symptoms, and consider interactions that jack up lactone exposure. Yes, it’s annoying. No, your mitochondria don’t care about our feelings.

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#130

Humans have the highest cholesterol levels among primates. This likely occurred during evolutionary development for brain development. But today, cholesterol is the primary source of atherosclerosis. Therefore, I believe it should be lowered to a reasonable level for cardiovascular health.

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#131

The high cholesterol levels I think have more to do with our diet and lifestyle, than evolutionary requirements. We see this even when you compare wild and captive apes: Cholesterol values in free-ranging gorillas (Gorilla gorilla gorilla and Gorilla beringei) and Bornean orangutans (Pongo pygmaeus) - PubMed

Which is another reason why it is a fallacy to think that serum cholesterol levels have anything to do with brain size or cognitive abilities.

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#132

I assume you’ve had a cervical spine MRI? I only ask because I had episodes - every 3 months or so for 2-3 weeks where I had sudden severe all day all night pain (impossible to sleep) that seemed motivated by nothing (movement, posture etc) out of the clear blue sky and ameliorated by nothing. OTC painkillers completely ineffective and vicodin too. The pain was located between the spine and scapula.

Eventually the episodes became more frequent until constant, joined by pain spreading to my shoulder, then arm, forearm, hand on one side. After several different wrong diagnoses and ineffective treatments, PT etc, I was diagnosed through MRI as having cervical spine stenosis at several joints with myelopathy with hyperintensities between C5-C6 and osteophytes plus a few other neurological issues. What finally pushed the neurologist to do an MRI on the spine was the development of numbness, tingling and loss of feeling in my fingers in the affected hand. Previously they were concentrating on the shoulder in imaging (MRI, X-rays, US). Corticosteroid injections were somewhat effective in diminishing the pain to the point I could snatch a few hours of sleep nightly. Still experiencing radiculopathy pain.

Scheduled for ACDF surgery at the end of December.

The thing about cervical spine nerve issues is that the pain in other areas (traps, scapula, shoulder etc) is nerve pain that’s not at the site of the pathology (neck joints). I never had any neck pain. All the pain was in areas that were referred. The distribution of osteophytes impingement can determine where the pain refers to (such as face) through knock on effects including muscle spasms (I had spasms in my delts, pecs, bicep).

Anyhow, this seems so obvious a thing to check, I assume they already did that for you… except it took them months in my case while trying to diagnose me with frozen shoulder, impingement, rotator cuff degeneration, arthritis and so on. When I developed numbness it finally put them on the right path. So I thought I’d mention this just in case. Hope you find some resolution soon!

#133

Hi Cronos. Thanks for the detailed reply and sorry for the belated response. I’m glad you finally got a clearer diagnosis and you’re on the right path, even though it’s taken you to surgery.

Yes, I’ve had multiple MRIs, including several of my spine. There were some minor findings on the left side of my neck (the same side as the facial pain), but multiple doctors I saw didn’t consider it clinically significant.

I did also have my scans reviewed independently by the MSK neurology guy who immediately said it was “obvious” I had left sided cervical herniations, and that a cervical spine surgeon would want to operate straight away. I took the same scans to two cervical spine specialists, and both essentially said he was talking rubbish and that the herniations weren’t near the range where surgery would be considered. That left me feeling he wasn’t reliable, and I did get a slightly arrogant, off vibe from him on the video call tbh. (Oddly, I’ve since seen him pop up in Bryan Johnson content where Bryan was getting advice from him to correct his forward head posture)

So at this point my cervical imaging has been treated as broadly normal, and the only clear structural issue has been my lower back, which I’ve already had two surgeries for.

I have considered an upright cervical MRI with flexion/extension, but it would involve travel, is very expensive. I was also advised it would likely be a waste of money. I’m still tempted, just because the symptoms are so stubborn and it’s the only obvious imaging route i haven’t taken yet.

Right now the NHS is offering psychiatry input for coping with the mental side of constant pain. I’m not opposed to that in principle, but it’s tricky because talking itself can trigger the pain, and the cognitive behavioural therapy they suggest involves a lot of talking. I’ve had a couple of appointments and I’m seeing where it goes.

Since my second lower back operation over a year ago, I’ve been clawing back upright time very slowly, basically adding minutes of walking time over months. I do as much as I can each day, but progress is very incremental.

I’m 44, so I haven’t given up hope of meaningful improvement yet, even if the timescale is painfully slow. I’m trying to stay as healthy as possible to give myself the best chance.

Anyway, thank you again for flagging the cervical route. I agree, it’s an essential box to tick. Best wishes for your ACDF surgery, btw. I hope it goes smoothly and it sets you up nicely for a better year.

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#134

Oof, that’s tough. Chronic unpredictable pain is truly debilitating, so I’m entirely sympathetic. When my pain was intense days and nights on end, and I couldn’t sleep, I literally couldn’t concentrate on anything, no work, no play, couldn’t even passively watch videos, movies etc. I told my wife, that this is what “debilitating condition” feels like. I actually couldn’t leave the house. I once went for a walk with my wife to the neighborhood food store and as I walked the pain kept increasing to the point I was contemplating just sitting down right there on the pavement so as not to pass out and hit my head, I was going to wait for her to fetch the car as uber made no sense for a couple of blocks. I managed to turn around and hobble back home, and collapse on the couch. That was it for leaving the house. For medical appointments, strictly couch/bed–>car–>doc’s office.

There were some hours where the pain would drop by half, truly felt like luxury. But it’s no way to live. That’s why I found the fumbling diagnosis process depressing. Anyhow, I figured you must have had all the MRIs as it’s such an obvious diagnostic. It’s important to have a good interpreter of the imaging though. Some bone spurs in that space can be subtle, so any stenosis area needs going over with a fine tooth comb - I assume all that was done in your case. And beware of snappy diagnosis where they want to march you straight to the operating room, because “it’s obvious”, always get a second (and third) opinion - I had one young guy want to operate on my shoulder to decompress the joint based on a faulty diagnosis of frozen shoulder, he was already telling his assistant to look where he can fit me in his schedule. I had to tell him to hold his horses, he was surprised that I wanted to drag this out being in so much pain. To a man with a hammer everything looks like a nail. When you are tired, in a lot of pain and a confident surgeon assures you that relief is within sight it can be very tempting, especially if you’re not aware of the volume of misdiagnosis out there. “S/he’s a professional, they know!”… alas, no, they do not, necessarily.

Funnily enough, when I was 14 I had a couple of trigeminal pain episodes in my face, both happened at school, I had no idea what was going on. My parents took me to a neurologist who recommended waiting it out as I was “probably in a growth spurt”. I don’t know if that was right, but fortunately that was the last of it. Nerve pain is the worst.

Anyhow, thank you for your well wishes. I am better painwise with the nerve block shots, so now I just have to survive the surgery. My thoughts are with you, hoping for a diagnosis that sticks for you and a treatment plan.

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#135

I’ve heard good things, and it looks good to me, about the book Back Mechanic for all things related to the back if you haven’t heard about it: Lower back pain: causes, treatment and prevention

It has a system of rehab and diagnosing injury in the book that might be worth a try.

#136

Hi. Sorry to hear about your facial pain. I’m guessing one of the many neurologists you’ve seen has worked you up for trigeminal neuralgia? I’m a neuroradiologist and we see a fair number of MRI brain studies looking for neurovascular compression of the trigeminal nerve, which is one of the causes of trigeminal neuralgia. It’s a long shot but wanted to make sure you haven’t left any stones unturned.

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