Nov 2018: Dr. Peat Talks About Cholesterol Esters Causing Aging

[ecstatichamster]

I never knew anything about them. He says that the buildup of cholesterol esters is what is tied to aging and brain aging, and that even reversing this to create more free cholesterol may help the brain and the body. It is a fascinating newsletter.

I never knew anything about cholesterol esters. What do you know?

 

[lampofred]

It's an extremely interesting newsletter and has a lot of info he has never talked about before. Definitely going to be reading it several more times because there are so many ideas in there about nerve excitation and nerve degeneration that are completely new to me. Also love the quotes about how those who have knowledge have the duty to act.

 

[Hugh Johnson]

If esterificion is bad, perhaps there are ways promote de-esterification.

 

[YourUniverse]

eliminate PUFA, supplement with progesterone, and use Lidocaine to block cholesterol ester formation

 

[yerrag]

I never knew anything about them. He says that the buildup of cholesterol esters is what is tied to aging and brain aging, and that even reversing this to create more free cholesterol may help the brain and the body. It is a fascinating newsletter.
I never knew anything about cholesterol esters. What do you know?

I just read the newsletter. Was there mention of reducing the accumulated cholesterol ester in our bodies? Or is it implied that making our body go back to producing cholesterol adequately (or profusely) would reduce the amount of cholesterol ester in our bodies? I feel good that we're off to a right start by avoiding PUFAs. As well as statins.

What can be done/taken to facilitate the removal or breakdown of cholesterol esters from our body?

Also interesting to learn that LDL is needed for the production of progesterone, and that the amount of progesterone produced is dependent on the availability of LDL in the blood.

In a study of several hundred people in the seventies, it was found that in those whose baseline total cholesterol was 195-244 mg/dL, "...each 10-mg/dL increase in the 1988-1991 change in non-HDL-C was associated with an adjusted mortality odds ratio (OR) of 0.67..." (Karlamangla et al, 2004)

This means that higher LDL is associated with higher survival rates.

 

[Hugh Johnson]

https://www.sciencedirect.com/topics/medicine-and-dentistry/cholesteryl-ester-storage-disease

I would look here. I'll see if I have the time to read all that later.

 

[ecstatichamster]

I just read the newsletter. Was there mention of reducing the accumulated cholesterol ester in our bodies? Or is it implied that making our body go back to producing cholesterol adequately (or profusely) would reduce the amount of cholesterol ester in our bodies? I feel good that we're off to a right start by avoiding PUFAs. As well as statins.

Possibly more free cholesterol can reverse the problem.

The characteristic opacity of aged skin is the result of an accumulation of layers of dead cells on the surface. While the vital underlying skin cells contain much less cholesterol than normal, the inert cells contain an increased amount of choles- terol sulfate. When the skin’s free cholesterol content is increased experimentally, the skin regains its ability to shed the dead superficial cells. When it’s lowered experimentally, as with a statin, the skin takes on the structure and appearance of old skin. Aging seems to be a state of cholesterol starvation.​

and

In the brain, the accumulation of cholesterol esters (at the expense of free cholesterol) increases with age and contributes to neurodegeneration. Intervention to liberate cholesterol from the fatty acids has a nerve-protecting effect in a worm model of Parkinson’s disease (Zhang, et al., 2017).


Here is Zhang 2017:
NCEH-1 modulates cholesterol metabolism and protects against α-synuclein toxicity in a C. elegans model of Parkinson’s disease

Parkinson’s disease (PD) is an aging-associated neurodegenerative disease affecting millions worldwide. Misfolding, oligomerization and accumulation of the human α-synuclein protein is a key pathological hallmark of PD and is associated with the progressive loss of dopaminergic neurons over the course of aging.

Lifespan extension via the suppression of IGF-1/insulin-like signaling (IIS) offers a possibility to retard disease onset through induction of metabolic changes that provide neuroprotection.

The nceh-1 gene of Caenorhabditis elegans encodes an ortholog of neutral cholesterol ester hydrolase 1 (NCEH-1), an IIS downstream protein that was identified in a screen as a modulator of α-synuclein accumulation in vivo. The mechanism whereby cholesterol metabolism functionally impacts neurodegeneration induced by α-synuclein is undefined.

Here we report that NCEH-1 protects dopaminergic neurons from α-synuclein-dependent neurotoxicity in C. elegans via a mechanism that is independent of lifespan extension.

We discovered that the presence of cholesterol, LDLR-mediated cholesterol endocytosis, and cholesterol efflux are all essential to NCEH-1-mediated neuroprotection.

In protecting from α-synuclein neurotoxicity, NCEH-1 also stimulates cholesterol-derived neurosteroid formation and lowers cellular reactive oxygen species in mitochondria. Collectively, this study augments our understanding of how cholesterol metabolism can modulate a neuroprotective mechanism that attenuates α-synuclein neurotoxicity, thereby pointing toward regulation of neuronal cholesterol turnover as a potential therapeutic avenue for PD.​

It would seem that pregnenolone and progesterone would be very protective, yes?

 

[ecstatichamster]

and this:
https://www.sciencedirect.com/science/article/abs/pii/S0960076016303338

To this aim, by liquid chromatography–tandem mass spectrometry we observed that in the experimental model of the rat raised diabetic by streptozotocin injection, one month of pathology induced changes in the levels of several neuroactive steroids, such as pregnenolone, progesterone and its metabolites (i.e., tetrahydroprogesterone and isopregnanolone) and testosterone and its metabolites (i.e., dihydrotestosterone and 3α-diol). Interestingly these brain changes were not fully reflected by the plasma level changes, suggesting that early phase of diabetes directly affects steroidogenesis and/or steroid metabolism in the hippocampus.​

Any energetic issues in the body including those resulting in "prediabetes" mean that this is going on in the brain...

 

[ecstatichamster]

this is a pretty good review by an investigator:
https://www.sciencedirect.com/science/article/pii/S0016648018304805

The brain has traditionally been considered to be a target site of peripheral steroid hormones.

On the other hand, extensive studies over the past thirty years have demonstrated that the brain is a site of biosynthesis of several steroids.

Such steroids synthesized de novo from cholesterol in the brain are called neurosteroids.

To investigate the biosynthesis and biological actions of neurosteroids in the brain, data on the regio- and temporal-specific synthesis of neurosteroids are needed.

In the mid 1990s, the Purkinje cell, an important cerebellar neuron, was discovered as a major cell producing neurosteroids in the brain of vertebrates.

It was the first demonstration of de novo neuronal biosynthesis of neurosteroids in the brain. Subsequently, neuronal biosynthesis of neurosteroids and biological actions of neurosteroids have become clear by the follow-up studies using the Purkinje cell as an excellent cellular model.

Progesterone and estradiol, which are known as sex steroid hormones, are actively synthesized de novo from cholesterol in the Purkinje cell during development, when cerebellar neuronal circuit formation occurs.

Importantly, progesterone and estradiol synthesized in the Purkinje cell promote dendritic growth, spinogenesis and synaptogenesis via their cognate nuclear receptors in the Purkinje cell.

Neurotrophic factors may mediate these neurosteroid actions. Futhermore, allopregnanolone (3α,5α-tetrahydroprogesterone), a progesterone metabolite, is also synthesized in the cerebellum and acts on the survival of Purkinje cells. On the other hand, at the beginning of 2010s, the pineal gland, an endocrine organ located close to the cerebellum, was discovered as an important site of the biosynthesis of neurosteroids.

Allopregnanolone, a major pineal neurosteroid, acts on the Purkinje cell for the survival of Purkinje cells by suppressing the expression of caspase-3, a crucial mediator of apoptosis.

I as a recipient of Kobayashi Award from the Japan Society for Comparative Endocrinology in 2016 summarize the discovery of cerebellar and pineal neurosteroids and their biological actions on the growth and survival of Purkinje cells during development

 

[Whichway?]

Where can we find the latest newsletter? Searched the forum but can’t seem to locate it.

 

[Mito]

Where can we find the latest newsletter? Searched the forum but can’t seem to locate it.

You can send an email to [email protected]. It’s $28 for 12 newsletters.

 

[yerrag]

Possibly more free cholesterol can reverse the problem.

The characteristic opacity of aged skin is the result of an accumulation of layers of dead cells on the surface. While the vital underlying skin cells contain much less cholesterol than normal, the inert cells contain an increased amount of choles- terol sulfate. When the skin’s free cholesterol content is increased experimentally, the skin regains its ability to shed the dead superficial cells. When it’s lowered experimentally, as with a statin, the skin takes on the structure and appearance of old skin. Aging seems to be a state of cholesterol starvation.
and

In the brain, the accumulation of cholesterol esters (at the expense of free cholesterol) increases with age and contributes to neurodegeneration. Intervention to liberate cholesterol from the fatty acids has a nerve-protecting effect in a worm model of Parkinson’s disease (Zhang, et al., 2017).

Thanks. More free cholesterol being the answer. I still wonder what happens to the cholesterol esters in the presence of more free cholesterol. Do they breakdown into free cholesterol in the presence of an abundance of free cholesterol? Or would their effect be marginalized as free cholesterol predominates over cholesteryl esters simply as the ratio of cholesterol ester/free cholesterol become infinitesimal?

In the newsletter, Ray gives the impression that cholesterol ester accumulation in our lifetime is a preordained reality, as if resistance is futile:

The polyunsaturated fatty acids, that accumulate with age, have been known for about 80 years to be the main source of this material. These fatty acids inhibit the synthesis of cholesterol (Kuroda and Endo, 1976), and increase its conversion to cholesterol esters (Spector, et al, 1980). At birth, there is a very low concentration of cholesterol ester, and the proportion remains low until about the age of 20, when growth slows, and beyond the age of 20, the cholesterol esters become the main component of the lipids of blood vessels (Smith, 1974). The accumulation generally increases with age in other tissues, and the proportion seems to correlate with loss of function in viral disease and cancer as well as in aging. An increase of the esterification rate in the serum is a predictor of heart disease and sudden death (Tanaka et al, 2013).

But maybe Ray is saying that in the context of the general population, which is intoxicated generally by PUFAs.

 

[tankasnowgod]

Thanks. More free cholesterol being the answer. I still wonder what happens to the cholesterol esters in the presence of more free cholesterol. Do they breakdown into free cholesterol in the presence of an abundance of free cholesterol? Or would their effect be marginalized as free cholesterol predominates over cholesteryl esters simply as the ratio of cholesterol ester/free cholesterol become infinitesimal?

In the newsletter, Ray gives the impression that cholesterol ester accumulation in our lifetime is a preordained reality, as if resistance is futile:

The polyunsaturated fatty acids, that accumulate with age, have been known for about 80 years to be the main source of this material. These fatty acids inhibit the synthesis of cholesterol (Kuroda and Endo, 1976), and increase its conversion to cholesterol esters (Spector, et al, 1980). At birth, there is a very low concentration of cholesterol ester, and the proportion remains low until about the age of 20, when growth slows, and beyond the age of 20, the cholesterol esters become the main component of the lipids of blood vessels (Smith, 1974). The accumulation generally increases with age in other tissues, and the proportion seems to correlate with loss of function in viral disease and cancer as well as in aging. An increase of the esterification rate in the serum is a predictor of heart disease and sudden death (Tanaka et al, 2013).

But maybe Ray is saying that in the context of the general population, which is intoxicated generally by PUFAs.

If he was referencing a 1974 study, there was already a fair amount of extra PUFA in the average diet, thanks to "Vegetable" Oils. Although it would be a lot higher today.

 

[Sourdoughbanana]

Masterjohn has a piece somewhere on PUFAs lowering blood cholesterol the “wrong” way since they lead to more esters.

The only way to go is to improve thyroid function, keep LH function high, eat large amounts of potassium, fast, all of this decreasing blood cholesterol so that it yields more pregnenolone, Progesterone and other downstream protective hormones. That’s what a natural healthy individual does.

Artificially tweaking lipoproteins (via PUFAs, fish oil, niacin what have you) is about as bad as letting cholesterol go high

 

[Mito]

Masterjohn has a piece somewhere on PUFAs lowering blood cholesterol the “wrong” way since they lead to more esters.

And in the liver, if the cholesterol gets esterified, then the liver perceives that as a decrease in the cholesterol content because the liver is judging its available cholesterol by the size of the pool of free cholesterol. So when you consume polyunsaturated fatty acids, they are more effective at esterifying cholesterol then other fatty acids. They shift the pool of cholesterol from free to bound. The liver looks at the pool of free cholesterol, says, “Hey, where did all my cholesterol go?,” makes more LDL receptor, brings LDL particles from the blood into the liver.

Now, notably polyunsaturated fatty acids differ from cholesterol-lowering drugs in the sense that they haven’t changed the amount of cholesterol. They’ve just shifted it into the bound fraction. And so one of the things that animal experiments have shown is that when you lower blood cholesterol with polyunsaturated fatty acids, you don’t alter total body cholesterol. You just move cholesterol from the blood into all the other tissues, where it gets stuck as cholesteryl esters.

Now, I’m focusing on the liver because the liver is the main controller of blood cholesterol, but polyunsaturated fatty acids will increase cholesteryl esters in adipose tissues and in the other internal organs and pretty much everywhere. So all of these interventions fall under the category of number one, the liver takes in more cholesterol when it needs more cholesterol.

https://chrismasterjohnphd.com/2017/03/19/what-to-do-about-high-cholesterol/

 

[yerrag]

And in the liver, if the cholesterol gets esterified, then the liver perceives that as a decrease in the cholesterol content because the liver is judging its available cholesterol by the size of the pool of free cholesterol. So when you consume polyunsaturated fatty acids, they are more effective at esterifying cholesterol then other fatty acids. They shift the pool of cholesterol from free to bound. The liver looks at the pool of free cholesterol, says, “Hey, where did all my cholesterol go?,” makes more LDL receptor, brings LDL particles from the blood into the liver.

Now, notably polyunsaturated fatty acids differ from cholesterol-lowering drugs in the sense that they haven’t changed the amount of cholesterol. They’ve just shifted it into the bound fraction. And so one of the things that animal experiments have shown is that when you lower blood cholesterol with polyunsaturated fatty acids, you don’t alter total body cholesterol. You just move cholesterol from the blood into all the other tissues, where it gets stuck as cholesteryl esters.

Now, I’m focusing on the liver because the liver is the main controller of blood cholesterol, but polyunsaturated fatty acids will increase cholesteryl esters in adipose tissues and in the other internal organs and pretty much everywhere. So all of these interventions fall under the category of number one, the liver takes in more cholesterol when it needs more cholesterol.

https://chrismasterjohnphd.com/2017/03/19/what-to-do-about-high-cholesterol/

What's the implication then with the liver taking in more cholesterol? Will that cause free cholesterol in the blood to go low, the so-called "good effect" of PUFAs?

And what happens to the cholesteryl esters in the internal organs? In the liver, is that what's causing fatty liver disease?

Are cholesteryl esters included in total cholesterol in blood tests? Had to ask. Just doesn't seem so to me.

 

[High_Prob]

Masterjohn has a piece somewhere on PUFAs lowering blood cholesterol the “wrong” way since they lead to more esters.

The only way to go is to improve thyroid function, keep LH function high, eat large amounts of potassium, fast, all of this decreasing blood cholesterol so that it yields more pregnenolone, Progesterone and other downstream protective hormones. That’s what a natural healthy individual does.

Artificially tweaking lipoproteins (via PUFAs, fish oil, niacin what have you) is about as bad as letting cholesterol go high

And also push it toward bile acid production - vitamin C

http://orthomolecular.org/library/jom/1991/pdf/1991-v06n03&04-p166.pdf

 

[haidut]

https://www.sciencedirect.com/topics/medicine-and-dentistry/cholesteryl-ester-storage-disease

I would look here. I'll see if I have the time to read all that later.

That link suggests allopregnanolone, progesterone, pregnenolone, magnesium, GABA, etc (GABA agonists) and niacinamide, butyric acid (HDAC inhibitors) as two possible approaches to treatment. Even alcohol (up to 2 drinks daily) as it is a GABA agonist and has been shown to dissolve lipofuscin, which is a similar issue. Tocopherol may also help due to its GABA effect and ester dissolving effects.
@ecstatichamster

"...In Npc1-deficient mice, the neurosteroid allopregnanolone (ALLO), delivered complexed with hydroxypropyl-β-cyclodextrin (HPBCD), increased Purkinje cell survival, reduced accumulation of gangliosides, slowed the progression of neurodegeneration, and doubled lifespan, in comparison to NPC mice treated with HPBCD alone [102,103]. The neuroprotective actions of ALLO include activation of GABA receptors [102], pregnane X receptors [104], reduction of the accumulation of reactive oxygen species [105]."

"...Inhibitors of histone deacetylases reduce the accumulation of cholesterol in two human fibroblast cell lines carrying mutations in NPC1 but not in a cell line carrying a mutation in NPC2 [109]. None of these studies have addressed potential effects on steroidogenesis."

 

[Sourdoughbanana]

Are cholesteryl esters included in total cholesterol in blood tests? Had to ask. Just doesn't seem so to me.

I doubt that, as esters are found in tissues, not in the blood

 

[Mito]

What's the implication then with the liver taking in more cholesterol? Will that cause free cholesterol in the blood to go low, the so-called "good effect" of PUFAs?

Yes that’s how PUFA lowers serum LDL.

Are cholesteryl esters included in total cholesterol in blood tests? Had to ask. Just doesn't seem so to me.

I don’t think so but it can be measured. Biomarker Menu - Pacific Biomarkers