Looking at the causal processes, triglycerides (also one part of apoB), have robust evidence for DSH/suicide and depression, LDL has weak evidence for an inverse relationship (meaning lower LDL higher risk) for the former. HDL also causally associated with depressive symptoms and MD.
So basically triglycerides and HDL-c have strong and moderate evidence respectively, while LDL for an inverse relationship has weak evidence.
There was consistent evidence that triglyceride (TG) is causally associated with DS (MR-IVW Ī² for one-s.d. increase in TG = 0.0346, 95% CI 0.0114ā0.0578), supported by MR-IVW and GSMR and multiple r2 clumping thresholds. We also observed relatively consistent associations of TG with DSH/suicide (MR-Egger OR = 2.514, CI 1.579ā4.003). There was moderate evidence for positive associations of TG with MD and the number of episodes of low mood. For HDL-c, we observed moderate evidence for causal associations with DS and MD. LDL-c and TC did not show robust causal relationships with depression phenotypes, except for weak evidence that LDL-c is inversely related to DSH/suicide. We did not detect significant associations when depression phenotypes were treated as exposures.
Statins may improve depression based on their lipophilicity (able to cross the blood-brain barrier). If you search for it, studies seems to be more in favor of statins in reducing depression than the reverse.
We retrieved five randomized controlled trials meeting our inclusion criteria: four used a statin in addition to an antidepressant and compared it to placebo plus antidepressant, and one compared two statins alone. and one comparing one statin with another. Statins compared to placebo in addition to antidepressants were efficacious at 8 weeks (N = 255, SMD = -0.48, 95% CI = -0.74 to -0. 22) and 12 weeks (N = 134, SMD = -0.47, 95% CI = -0.89 to -0.05, moderate certainty) with no difference for acceptability, tolerability, and safety (low certainty). An exploratory network meta-analysis suggested that the most lipophilic statins, especially simvastatin, could be more efficacious than less lipophilic or hydrophilic molecules.
So we are back to lifestyle, food, exercise, stress, caloric surplus, lack of exerciseā¦
I was not referring to depression directly, but mainly to aggression, which may present as hetero or auto aggressive behaviorā¦
LDL-C also has a role in immunity, low levels may be associated with neurodegenerative diseases or even some autoimmune processes and diseases, but unfortunately as it acts as primary immunity defense activator it also has the capacity to trigger sterile inflammation that progresses/causes ASCVD.
And I am referring to all this just to open some space for discussion. Tom Dayspring, Peter Attia et al. propagate this idea, that lower the better, which IMO should be taken with a grain of salt since there is so much we donāt know about human biologyā¦
Systemic levels donāt influence brain levels of cholesterol, so I donāt see how it would increase aggression. Brain levels of cholesterol are separate from the rest of the body, the brain synthesizes all it needs, separated with the blood-brain barrier. Hydrophilic statins have a hard time crossing the BBB also. Aggression should have been picked up in any of the trials of PCSK9i, statins, as well, or in the genetic studies. As a side effect.
Can I ask which provider you use for your weekly blood test? I have one scheduled for next week that covers 56 or so biomarkers but it is quite expensive.
I am in the UK. I have used a range of labs. Normally now it is a mixture of London Medical, Randox and Nationwide Pathology. All are in the range of GBP 150-200.
Annually, of course that is in the territory of GBP 10K note exactly Bryan Jones territory, but still not petty cash.
Incidentally I have used Medicheks, but because they are a postal service rather than a courier service there are metabolism issues.
Thanks John. Medichecks give me the option to get the blood draw done at a local pharmacy where the sample is couriered same day and I usually get my result with 48-72hrs. Iāve been on 5mg rapa for 3 months. Will be interesting to see any changes from baseline.
The problem is that these studies actually tell us how much there is to know. If there is a treatment that lowers risk for a disease by 96%, that means there is little room for anything else.
āI use that term [ignorance] purposely to be a little provocative. But I donāt mean stupidity. I donāt mean dumb. I donāt mean a callow indifference to facts or data or any of thatā - Firestein
To be clear, I am not advocating very low LDL levels
It was amusing to me, that way back in the day when I took a forensics (debate) class, it did not matter which side of the debate I was on, I could find plenty of ammo for my cause.
I think we have debated this issue many times in this and other threads in this forum.
My stance is: High LDC is not acceptable, rapamycin notwithstanding.
On average, there was a 20% drop in CVD risk seen for every 39 mg/dL drop in LDL cholesterol. In other words, a drop in LDL from 70 mg/dL down to 31 mg/dL was associated with 20% fewer CVD events such as heart attack or stroke.
āVery low cholesterol levels may be a sign of an underlying disease. Some potential causes of low overall or LDL cholesterol include chronic infections, inflammation, and malnourishmentā
I found this study earlier which is a bit interesting, showing the causal relationship of apoB and lifespan:
Amount of apoB studied
Every 1 SD (standard deviation) of increase of apoB, at 0.24 g/L or 24 mg/dl was studied:
Estimates were inferred causal effects per 1 SD elevated lipoprotein trait (for apoB, 1 SD=0Ā·24 g/L).
Effects of every increase of 24 mg/dl of apoB
For every 24 mg/dl (1 SD) increase in apoB, there was a 60% less chance of reaching the 90th percentile of lifespan:
(odds ratio [OR] of surviving to the 90th centile of lifespan: 0Ā·38 per 1 SD higher apoB in offspring, 95% CI 0Ā·22ā0Ā·65).
Our findings support apoB as being the major lipoprotein entity implicated in the aetiology of coronary heart disease and stroke and identify that higher apoB decreases lifespan and increases the risk of type 2 diabetes. These findings highlight the crucial role of apoB in causing cardiometabolic disease, which collectively shortens the lifespan.
Not surprising, and very significant considering rapamycin increases apoB, and by a lot higher than 24 mg/dl. Tell me if I missed something with this study.
The real magnitudes of effect, in terms of duration of life lost due to elevated apoB, are likely to be greater, as indicated in the effect estimates from the GWAS of 90th centile of survival. Our findings further strengthen the suggestion that it is the number of circulating apoB particles, rather than their lipid content, that is the critical element for atherogenesis, manifested as coronary heart disease and ischaemic stroke.5, 6, 8 The cholesterol within LDL particles does play a causal role in atherogenesis but it is within the physiological framework of the trapping of apoB particles within the arterial wall.
Consistently lost in the wash of this debate is whether rapamycin can protect against CAD despite an increase in lipids. As Iāve pointed out numerous times, thereās considerable evidence that this is the case.
In a rabbit study, rapamycin resulted in zero plaque rupture and a decrease in plaque burden while increasing lipids. This was in contrast to a 56% incidence of plaque rupture in the control group. The mechanism seems to be an increase in the thickening and stability of the fibrous cap. A similar effect has been seen with gotu kola.
So again, is there evidence that the low risk person with elevated lipids from rapamycin needs to resort to statin therapy? If concerned , thereās statin alternatives. A good therapeutic target seems to be an ApoB to ApoA ratio < 0.8. Iām very close to that with just adding citrus bergamot at 1000 mg per day. Iām going to see if pantethine 600 mg is additive. Best of both worlds without the risk of diabetes or cognitive impairment.
I donāt know if I have to say this but obviously rabbit studies are near useless as well, except for oneās pet rabbit.
I find it unlikely that we will ever know whether rapamycin can offset the extreme risks from elevated apoB, or another mTOR inhibitor. In the meanwhile I donāt see the problem in trying to alleviate that with supplements as you do, or medications that lower apoB. If apoB goes down all is well.
You seem to be very confident that MR studies imply that any treatment that changes {LDL, APO-B} must correspondingly change [AS]CVD risk, even when, in the case of rapamycin, this is not supported by animal studies. Why are you so confident in this one line of evidence?
In the end Humans are not all the same, but studies on mammals are not IMO ānear uselessā. I am into n~8 biohacking studies with humans which are useful because we have some vague idea as to what happens with Homo Sapiens, but ānear uselessā is not a conclusion I agree with.
Because it is a different animal, you are not a rabbit, which is an entirely different complex system. What works in one tend to not work in another because there are so many different moving, causal parts.
Hereās some examples and a good article on this topic:
Approximately 100 vaccines have been shown effective against an HIV-like virus in animal models, however, none have prevented HIV in humans.
Likewise, up to one-thousand drugs have been shown effective for neuroprotection in animal models but none have been effective for humans.
Along the same lines, of twenty two drugs tested on animals and shown to be therapeutic in spinal cord injury, none were effective in humans.
The success of the animal model in basic research can also be questioned based on the fact that, according to one report, only 0.004% of basic research papers in leading journals led to a new class of drugs.
For example, in part because the targets derived from animal models are not predictive for humans, the percentage of new drugs in development, after initial evaluation, that ultimately make it to market is somewhere in the area of 0.0002%.
Mendelian randomization is done on humans, also with a study design that eliminates most confounders due to the natural randomization of gene variants. Those same gene variants that in many cases only do one thing, for example increase apoB a little.
