Can statins be pro-healthspan/longevity even if they don't increase mice lifespan? Interaction with metformin / rapamycin/ etc?

[BeatTheOdds]

How statins might affect brain cholesterol synthesis and cognitive function | Tom Dayspring

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.

[DrFraser]

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

[A_User]

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.

[AlexKChen]

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

[relaxedmeatball]

@tj_long

Is Praluent better than Repatha? 150mg of Praluent once a month seems to be an off-label use, right? Does anyone have experience with whether the effectiveness declines too much during the last week?

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)

[PYM]

“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

[AlexKChen]

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.

[AlexKChen]

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). (考研)

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.	(考研)
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.	(考研)
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.	(考研)

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. (考研)

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.

[nikney]

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.