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Mike Lustgarten

LDL: What's Optimal For Health And Longevity?

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1 hour ago, InquilineKea said:

Given cholesterol's importance in maintaining cell fluidity and in segregating lipid rafts, I would not be surprised if cholesterol improved cognition (and if low cholesterol decreased it).

But on the other side of the ledger, clogged blood vessels reduce blood flow which could predispose a person to dementia. That is what this study [1] seems to have found - i.e. higher cholesterol in mid-life was associated with higher dementia risk 3 decades later. From this discussion of the study by folks at Harvard medical school:

A large study has found that even moderately elevated cholesterol levels in middle age increase the risk of developing dementia in old age.

Researchers analyzed the health outcomes of 9,844 members of the Kaiser Permanente Northern California Medical Group, who had undergone detailed health evaluations, including cholesterol testing, at ages 40 to 45. The researchers then examined participants' medical records 30 to 35 years later.

When compared with participants with desirable cholesterol levels (defined as less than 200 mg/dL), those with moderately elevated levels (200 to 239 mg/dL) were 50% more likely to develop vascular dementia later on. They were also more likely to develop Alzheimer's disease, although the results did not reach statistical significance.

Those with high cholesterol (240 mg/dL or higher) were 57% more likely to develop Alzheimer's. They were also more likely to develop vascular dementia, but the results did not reach statistical significance.

Previous studies have shown that high cholesterol and other factors that contribute to heart disease can increase risk of dementia. But this study is notable for its size and inclusion of participants from multiple ethnic backgrounds. As such, it adds further evidence that finding ways to keep cholesterol levels in the healthy range is good for the mind as well as for the heart.

This seems like more of a reason not to worry about cholesterol being too low, especially when young / middle age.

--Dean

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[1] Solomon A, et al. "Midlife Serum Cholesterol and Increased Risk of Alzheimer's and Vascular Dementia Three Decades Later," Dementia and Geriatric Cognitive Disorders (Aug. 2009): Vol. 28, No. 1, pp. 75–80.

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3 hours ago, Dean Pomerleau said:

This seems like more of a reason not to worry about cholesterol being too low

Observational study with statistically insignificant results.  Maybe a reason for better studies but not much else.

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9 hours ago, Todd Allen said:

Observational study with statistically insignificant results.  Maybe a reason for better studies but not much else.

Fortunately more studies have been done. This 2020 meta-analysis [1] of over 100 observational studies found elevated LDL-c in particular to be associated with a 2.5x greater risk of Alzheimer's disease (RR = 2.55, 95% CI [1.25, 5.22]).

And while it isn't a randomized control trial, this meta-analysis [2] of 30 studies including over 9M people tells the same story about the link between dementia and the obvious cholesterol-lowering intervention (i. e. statins). That is, people who took statins to lower their LDL level were 31% less likely to develop Alzheimer's disease than people who didn't (RR =0.69, 95% CI [0.60–0.80], p < 0.0001). 

--Dean

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[1] Brain Sci. 2020 Jun 18;10(6):386. doi: 10.3390/brainsci10060386.

Cholesterol and Alzheimer's Disease Risk: A Meta-Meta-Analysis.

Sáiz-Vazquez O(1), Puente-Martínez A(2), Ubillos-Landa S(3), Pacheco-Bonrostro 
J(4), Santabárbara J(5)(6).

Free Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349210/

BACKGROUND: Alzheimer's disease (AD) is the most common subtype of dementia. In 
the last ten years, the relationship between cholesterol and AD has been 
investigated. Evidence suggests that cholesterol is associated with AD and 
represents promising targets for intervention. However, the causality of these 
associations is unclear. Therefore, we sought to conduct a meta-meta-analysis to 
determine the effect of cholesterol on the development AD. Then, we assessed the 
effect of serum levels of low-density lipoprotein cholesterol (LDL-C) and 
high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and 
triglycerides (TG), on AD risk.
METHODS: A systematic search of meta-analyses was conducted. Scopus, Web of 
Science, Science direct, PubMed and Google academic system databases were 
reviewed.
RESULTS: We found 100 primary studies and five meta-analyses to analyze the 
relationships between cholesterol and AD. The total effect of cholesterol on 
risk of AD was significant and heterogeneous. Subgroup analysis shows that LDL-C 
levels influence the development of AD. However, non-significant effects of 
HDL-C, TC and TG levels on AD were found.
CONCLUSIONS: These results strengthen the evidence that LDL-C cholesterol levels 
increase risk for AD.
More initiatives to investigate the relationship between 
cholesterol and AD are needed.

DOI: 10.3390/brainsci10060386
PMCID: PMC7349210
PMID: 32570800

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[2] Neuroepidemiology 2020;54:214–226
https://doi.org/10.1159/000503105

Association between Use of Statin and Risk of Dementia: A Meta-Analysis of Observational Studies
Poly T.N.a,b,g · Islam M.M.a,b,g · Walther B.A.f · Yang H.-C.a,b,g · Wu C.-C.a · Lin M.-C.a,e · Li Y.-C.a,b,c,d,g

Free full text: https://www.karger.com/Article/FullText/503105

Abstract
Background and Aims: The impact of statin on dementia risk reduction has been a subject of debate over the last decade, but the evidence remains inconclusive. Therefore, we performed a meta-analysis of relevant observational studies to quantify the magnitude of the association between statin therapy and the risk of dementia. Methods: We systematically searched for relevant studies published from January 2000 to March 2018 using EMBASE, Google, Google Scholar, PubMed, Scopus, and Web of Science. Two authors performed study selection, data abstraction, and risk of bias assessment. We then extracted data from the selected studies and performed meta-analysis of observational studies using a random-effects model. Subgroup and sensitivity analyses were also conducted. Results: A total of 30 observational studies, including 9,162,509 participants (84,101 dementia patients), met the eligibility criteria. Patients with statin had a lower all-caused dementia risk than those without statin (risk ratio [RR] 0.83, 95% CI 0.79–0.87, I2 = 57.73%). The overall pooled reduction of Alzheimer disease in patients with statin use was RR 0.69 (95% CI 0.60–0.80, p < 0.0001), and the overall pooled RR of statin use and vascular dementia risk was RR 0.93 (95% CI 0.74–1.16, p = 0.54). Conclusion: This study suggests that the use of statin is significantly associated with a decreased risk of dementia. Future studies measuring such outcomes would provide useful information to patients, clinicians, and policymakers. Until further evidence is established, clinicians need to make sure that statin use should remain restricted to the treatment of cardiovascular disease.

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3 hours ago, Dean Pomerleau said:

This 2020 meta-analysis [1] of over 100 observational studies found elevated LDL-c in particular to be associated with a 2.5x greater risk of Alzheimer's disease (RR = 2.55, 95% CI [1.25, 5.22]).

And while it isn't a randomized control trial, this meta-analysis [2] of 30 studies including over 9M people tells the same story about the link between dementia and the obvious cholesterol-lowering intervention (i. e. statins). That is, people who took statins to lower their LDL level were 31% less likely to develop Alzheimer's disease than people who didn't (RR =0.69, 95% CI [0.60–0.80], p < 0.0001). 

 

A high number of observational studies finding a similar association increases confidence the association is real.  But it doesn't speak to whether the association is causative or even meaningful.  It doesn't matter how many studies find an association between eating ice cream and drowning, until we do the tests of giving and withholding ice cream and count the bodies assuming ice cream causes drowning is ridiculous.

As for statins and Alzheimer's was it the cholesterol change that mattered?  Maybe pleiotropic effects such as the anti-inflammatory action of statins were responsible.  Or maybe a selection bias is at work such that there is less Alzheimer's among those of sufficiently robust health to tolerate ongoing statin treatment?

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Todd,

If you judge the above referenced evidence to be inconclusive or irrelevant you are of course free to continue believing high LDL is harmless or even beneficial and live accordingly. At least such a belief will only harm yourself if it turns out to be incorrect.

--Dean

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4 minutes ago, Todd Allen said:

until we do the tests of giving and withholding ice cream and count the bodies assuming ice cream causes drowning is ridiculous.

So, where are the randomized control studies showing that smoking is bad for health by making people smoke and others not smoke?  Smoking is bad, as shown by cohort studies.  Where are the randomized control studies showing that COVID causes the death of humans?

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44 minutes ago, Dean Pomerleau said:

If you judge the above referenced evidence to be inconclusive or irrelevant you are of course free to continue believing high LDL is harmless or even beneficial and live accordingly.

I believe LDL-C is a poor measure.  It ignores a tremendous amount of complexity.  The cholesterol content of LDL present in the blood is a tiny fraction of that in the body and the amount in the blood can be extremely dynamic for a wide range of reasons both good and bad still incompletely understood.  Fasting can dramatically increase LDL.  My highest ever LDL reading came near the end of a 7 day fast.  And while too much fasting is unequivocally harmful my personal experience with it suggests significant benefits.

Edited by Todd Allen

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45 minutes ago, AlPater said:

So, where are the randomized control studies showing that smoking is bad for health by making people smoke and others not smoke?

The association between smoking and lung cancer is profound something like 20 times higher rates among smokers.  Thus even if there are confounders such as increased alcohol consumption or decreased exercise among smokers we can be fairly confident of some degree of causation without RCTs.   We also have data on an extensive number of toxins found in cigarette smoke such as acrolein, formaldehyde, arsenic, cadmium, cyanide, etc. which are consistent with the assumption that smoking is harmful.  And yet it still isn't clear cut as there are tradeoffs, for example smokers apparently have lower rates of obesity and Parkinson's disease.

Edited by Todd Allen

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Everything else equal, fat consumption increases LDL/HDL/total cholesterol, but it can also help reduce carb consumption *and* the number of postprandial glucose spikes/average glucose levels (by being a substitute and promoting satiety!) that's why it's SO important to figure out WHAT is the optimal level of cholesterol, and whether a moderate level of cholesterol is better than a low level. The studies you referenced cite negative effects from having borderline high TC (> 200) or high LDL (>100), but what about levels that are just moderate and not high? I feel that glucose is *more* damaging at these levels. Also, cholesterol in itself isn't that bad - it easily gets oxidized, so cholesterol may only be bad in the organism that has unusually high ROS or metabolic syndrome.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2527634/ - also, you want your membranes to be more saturated than unsaturated

Edited by InquilineKea

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2 hours ago, Todd Allen said:

I believe LDL-C is a poor measure.  It ignores a tremendous amount of complexity.  The cholesterol content of LDL present in the blood is a tiny fraction of that in the body and the amount in the blood can be extremely dynamic for a wide range of reasons both good and bad still incompletely understood.  Fasting can dramatically increase LDL.  My highest ever LDL reading came near the end of a 7 day fast.  And while too much fasting is unequivocally harmful my personal experience with it suggests significant benefits.

What was your highest LDL reading? My highest was 100 though it's normally 70

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2 hours ago, Dean Pomerleau said:

you are of course free to continue believing high LDL is harmless or even beneficial

I'm not so interested in question of  high LDL (I think its quite risky for most people),  but rather the question if moderate-low LDL is better than very low LDL.   I'm leaning toward the  moderate side based on my research, but it's an open question.

Edited by Sibiriak

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2 hours ago, Sibiriak said:

but rather the question if moderate-low LDL is better than very low LDL

Very low by the assumption of statins of very low by dietary intervention? The latter may not even be reachable by all people (barring, perhaps, extreme, surely impractical or almost impossible low-fat diets)

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1 hour ago, mccoy said:

Very low by the assumption of statins of very low by dietary intervention? The latter may not even be reachable by all people (barring, perhaps, extreme, surely impractical or almost impossible low-fat diets)

I understand that there is controversy and that the prevailing view is often challenged, and that's good.

But in my case, five years ago my total cholesterol was just over 190 and I was about 160-165lbs. I had been a vegetarian for a long time, but ate bread, liberal quantities of EVOO, desserts, and drank red wine regularly. I did yoga one or two times a week and took hikes every other day or so. I was still considered "healthy" by most.

After I changed my diet (thanks to an extent to this forum) and started exercising more regularly. Based on such changes, my weight has dropped to 144-142lbs (64kg), my body fat is about 11% (DEXA) and my total cholesterol has dropped to less than 140, with LDL at 71. Triglycerides, usually in the 50s, are less than 30 now.

To me, this is clearly a healthier lifestyle, closer to what someone in the mid-1950s Okinawan population had, or those in most Blue Zones. I feel generally better, have a defined 6-pack (even an8-pack :) for the first time in my life, my resting heart rate is in the low 40s and my blood pressure is consistently below 115/75.

My point with this bragging is that my cholesterol has dropped dramatically based on such lifestyle changes and it seems to me that such a drop is beneficial. I am open to being convinced that I should eat more cheese and pizza, but so far I have seen nothing to convince me of it :)

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1 hour ago, Saul said:

My numbers are even better.

Yep, but many of you here have been doing this for a long time and are probably better than me at it.  For me, it's a significant improvement and kind of surprising how quickly I adapted.

But the point is that with what are generally accepted as healthy diet changes, my cholesterol dropped to levels that according to some of the population studies above should be the end of me. Perhaps so, but at least I feel healthier....

I will try some of the straw I sleep on and let you know, Sibiriak.

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6 hours ago, InquilineKea said:

Mike Lustgarten says that coconut butter reduced his inflammation

No, Alex, I said that within my data, coconut butter has the best correlation (close to significance, p=0.07) for lower CRP (see 14:14 in the video). Whether that's causative is unknown.
 

 

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12 hours ago, Ron Put said:

...my cholesterol has dropped dramatically....and it seems to me that such a drop is beneficial.  [...]  have a defined 6-pack  [...] I feel healthier


Well, that's pretty strong  scientific evidence.  Just about settles the question of optimal LDL levels.  Thanks.

Edited by Sibiriak

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The big question is, even on CR, with optimal values for most biomarkers, will the corresponding low TC and LDL be bad for longevity? At least 2 studies that I know of attempted to account for reverse causation and there was still an increased mortality risk for relatively low circulating levels of cholesterol. To me, that doesn't mean eat more pizza, candy or other junk. Within CR, is there an optimal diet composition that increases LDL, TC to further minimize mortality risk? Alternatively, making sure that the higher cholesterol levels wouldn't promote atherosclerosis or Alzheimer's disease would be a top priority.

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12 minutes ago, Mike Lustgarten said:

To me, that doesn't mean eat more pizza, candy or other junk.

Dammit-all!!    I suppose chorizo is out as well.  What about  straw? 

 

(Good post , Mike.  Sums up the issue well. )

Edited by Sibiriak

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5 hours ago, Sibiriak said:

Dammit-all!!    I suppose chorizo is out as well.  What about  straw? 

That was funny! The first time....

But it's missing the point. I changed my diet primarily because my cholesterol was inching up with age, getting too close to 200 for my comfort. Based on the preponderance of the evidence I had, I decided to make changes in accordance with such evidence. I had my annual blood panels as a baseline and have been testing a bit more frequently as I started making dietary changes. I have been pretty good at tracking nutrients with Cronometer for about three years and have made continuous adjustments to get as close to optimum as I can, including consuming higher levels of fiber (through whole foods) than I did before.

To answer Mike's question, my cholesterol and inflammation markers dropped as predicted by the theories suggesting that what is generally accepted as a better diet, plus a bit more exercise = lower cholesterol and inflammation.

To reiterate, my point is that the evidence, as I saw it, pointed to a plant-based, whole food diet as being beneficial and I expected to see lower cholesterol and lower inflammation. I did.

Most of those who frequent this forum are also practicing what are generally considered "healthy" diets, plus carrying degrees of CR. Barring genetic predispositions, such diets generally result in much lower total cholesterol and inflammation values, including TC and LDL lower than what some of the population studies cited above would suggest are optimum for longevity. The problem with such studies, as already discussed, is that there are many variables, including various diseases and metabolic issues that may account for the morbidity associated with lower TC or LDL.

But the significant drop in my TC, LDL, and inflammation values is unlikely to be because of an underlying disease or metabolic issue, and the same goes for most of the self-selected group of regular participants here. Does it settle the question for us, or for the population at large?  No, of course not. But it gives me reasonable comfort that I am doing the right thing and that my lower TC and LDL are a good thing, based on the current consensus within the majority of the medical community.

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