Insulin and Triglycerides

Every time I review someone’s blood test results, and then discuss with them what they mean and what they should do to improve their numbers, there’s something I almost always have to explain. And this was the relationship between fasting insulin and triglyceride levels.

Take a look at this plot:

trigs_vs_insulin_gb

Plot showing ten pairs of measurements of insulin and triglycerides, made from the same blood samples. They were collected between 2011 and 2017, and all are from my own blood tests.

It shows measurements of insulin concentration on the horizontal axis in mili units per millilitre (mIU/ml), and triglyceride levels on the vertical axis in milligrammes per decilitre (mg/dl). This is a correlation plot in which independent measurements of one variable are plotted against independent measurements of another in an attempt to see if there is a relationship between them.

Is there an order in the way the dots are organized? They are clearly not randomly distributed as a circular cloud of dots—it would mean that there is no relationship. Instead, we see what looks like a linear relationship in which lower values of insulin correspond to lower values of triglycerides, and higher values of insulin correspond to higher values of triglycerides. It’s not a straight line, but it’s definitely a clear linear relationship, and the value of the correlation coefficient, which quantifies how tight the relationship actually is, of just under 0.9 is pretty close to 1. In other words, it’s a pretty tight linear relationship.

Triglyceride is a fancy word for fat or lipid, because fat molecules are composed of three fatty acids held together by a glycerol structure. This is what triglyceride refers to. The amount of fat in the blood is affected by the amount of fat we eat, and the amount of body fat we have. Naturally, after a fatty meal, triglyceride levels will increase as the fat goes from the digestive system into the blood, they will reach a maximum, and then start to go down. The longer we wait before we eat again, the lower they will go. But there’s a few complications.

The first is that depending on the amount of insulin, one of whose jobs it is to transport nutrients into cells, whatever is circulating in the blood—and this includes glucose, of course, but also protein and fat—will in general be stored away faster if insulin is higher, and slower if insulin is lower. This means that if you eat fat together with sugar or starch, the whole lot will be packed away, and mostly as fat, minus the little bit of glucose your muscles and liver have room to store up as glycogen.

The second is that depending on the state of insulin sensitivity—the fundamental parameter that determines how well or poorly cells can use fat for fuel—triglycerides will in general be used up faster if we are more insulin sensitive and slower if we are more insulin resistant. This means that in the morning, twelve to fourteen hours after having had the exact same meal, the more insulin sensitive person will have lower triglyceride levels than the more insulin resistant.

And in fact, no matter if we have a measure of fasting insulin or not, and no matter how little we know about the person’s overall health, fasting triglyceride concentration is probably the best general marker of insulin sensitivity. Nevertheless, because their levels fluctuate quite a lot over the course of each day as a function of what we eat and drink, it is true for triglyceride levels as it is true for many other blood tests that are affected by the kind and amount of food and drink we’ve had over the last days, and most importantly by the amount of sweet or starchy carbohydrates.

Now, take a look at this second plot:

trigs_vs_insulin_final

Plot showing, in addition to the 10 points shown in the first plot (in red), another 20 pairs of measurements of insulin and triglycerides, also all from the same blood samples, but from seven other persons.

It shows the same 10 data points shown in the first plot from my own results, but with another 20 pairs of measurements taken from other people that I’ve coached and helped with the interpretation of their results. You can see that the relationship is better defined because of the additional points that now together cover a wider range of values on both axes.

However, you can also see that, the relationship is not as tight. In particular, there are a few points that are quite far off the main trend—mostly those at the top of the plot with high triglyceride and low insulin values. We see how these off-trend points affect the tightness of the relationship seen in the initial data set when we compare the values of the correlation coefficients. These off-trend points lead us to the third complication I wanted to bring up.

But first, please take a minute to consider the matter: What could lead to having low insulin and at the same time high triglycerides? What could be the cause of the difference between my numbers, which did contain some very low insulin levels, but all of which were paired with equally low triglyceride values, and this other person’s numbers? What causes insulin to go down? What happens when insulin is low? What could cause triglycerides to go up while insulin is low?

Insulin, no matter how high it is, will start to go down when we stop eating. The longer we fast, the lower it will go. Each person’s baseline will be a little different depending mainly on their metabolic health and their body fat stores. The more efficient the metabolism is at using fat for fuel—the more insulin sensitive, the lower insulin will go. But also the lower the body fat stores are, the lower insulin will go. On the flip side, the more insulin resistant and the fatter we are, the longer it will take for insulin to drop and the higher it will stay at baseline.

This is pretty shitty. I mean, as we develop insulin resistance, average insulin levels will become higher and higher. As a result we’ll store calories into our growing fat cells more and more easily, and will therefore become fatter and fatter, faster and faster. But fat cells also secrete insulin! So, the more fat cells there are, the higher the insulin levels will be, and the harder it will be to lower our basal insulin. To burn fat, we need to lower insulin levels. The fatter we are, the higher the insulin levels will tend to be. And the fatter we are, the harder it will be to lower insulin levels.

It’s a bit of a catch, but in the end, it’s not such a big deal because basically everyone who is overweight and who starts to fast and restrict carbohydrates melts their fat stores away very well. It works incrementally: insulin goes down a little, insulin resistance is reduced a little, fat-burning starts; insulin goes down a little lower, insulin resistance is further reduced, fat-burning increases; and on it goes, until we have lost all those extra kilos of fat that we were carrying on our body, be it 5, 15, 20, 35, 60 or even 100 kg of fat! It’s just a matter of time.

Now, after this little tangent on insulin and fat stores, we can come back to those anomalous points in the plot, the most conspicuous of which is the one just below 120 mg/dl of triglycerides but only 3 mUI/ml of insulin. Have you come up with an explanation? Here it mine:

That point is from one of my wife’s blood tests. It is unusual because it was done after 24 hours of fasting. My 24-hour fasting blood test done a number of weeks before, and my numbers were 41 for trigs at 2.3 for insulin. The difference between her and I was that I was already very lean, whereas she wasn’t. Therefore, as she fasted, her insulin levels dropped very low, and then the body started releasing its fat stores into the bloodstream in high gear. This is why her triglyceride levels were this high while her insulin was that low. It’s almost certainly the same for the other two points up there with trigs at 110 and 90 with insulin around 4 and 2.5 (the latter one of which is also my wife’s).

Since we did many of our blood tests around the same time, there are 9 data points from her on the plot. Several are in the centre of the main trend at insulin values between 6 and 7, but I’d like draw your attention to her lowest insulin value that was measured at 1.8, and at which time her trigs were at 57, and her lowest triglyceride level of 48, at which time her insulin was at 2.2. This shows that on average her values are a little further along the trend than mine are because of the small difference in body fat, but that she has good insulin sensitivity, and a well-functioning metabolism that can efficiently use fat for fuel.

The other off-trend point, but in the other direction on the right hand side, with insulin just above 10 and trigs around 65, is from my mother’s first blood test which I ordered and included insulin and trigs, before I got her off carbs. She was 82 at the time, eating a regular kind of diet, but not a very nutritious or varied diet with plenty of bread and cheese, because she had serious problems moving around and taking care of herself while still living alone. And so, it’s just the result of being older, having plenty of carbs, but not being highly insulin resistant nor highly overweight. Her baseline insulin levels were just generally higher because of her age and diet, but her trigs weren’t excessively high.

However, after just four days of intermittent fasting on a very low carb regime with most calories coming coconut oil spiked green juices and coconut milk smoothies, her insulin went from 10.3 to 4.7, and she lost 5 kilos, which, of course, were mostly from the release of water that the body was retaining to counter the effects of the chronic inflammation that immediately went down with the very-low carb regime and fasting.

Later, having sustained this strict green healing protocol for about 6 weeks, her numbers were at 2.9 for insulin and 56 for trigs. And by then she had lost another 5 kg, but this was now mostly fat. She had, at that point, recovered full insulin sensitivity, had lost most of her body fat stores, and overhauled her metabolism. She was 83 at that time, which shows that this sort of resetting of the metabolism can work at any age.

On this note, let’s conclude with these take-home messages:

First, the next time you get a blood test, request that insulin and triglycerides be measured, because it’s the only way to know what your fasting insulin actually is, and because it is very telling of your level of insulin resistance or sensitivity, overall metabolic health, as well as your average rate of ageing as we’ve seen in a previous post on insulin and the genetics of longevity.

Second, when you get the results back, you will be able to tell from your triglycerides concentration, in light of your insulin level, either how well the body is using fat for fuel—in the case you are already lean, or how fast you are burning your fat stores—in the case you still have excess body fat to burn through.

And third, resetting metabolic health can be done at any time and at any age, and is yet another thing that shows us how incredible our body is—the more we learn generally or individually, the more amazing it reveals itself to be.

Living healthy to 160 – insulin and the genetics of longevity

Of the most remarkable discoveries of the last 15 years, discoveries that might well turn out to be the most remarkable of the 21st century, are those of the telomere—a little tail at the end of our DNA whose length tells us how long we have left to live, and of the enzyme telomerase—the specialised protein whose job it is to try to repair the telomeres so that the cells (and we) can live longer and, from an evolutionary perspective, increase the probability that we’ll have more babies. This and other research into the biology of ageing and the details relating to the transcription of DNA, and the expression or suppression of genes is truly amazingly fascinating. I will turn to this in time, but think it would be jumping the gun to do so now.

What is definitely one of the most remarkable discoveries of the 20th century pertains to the hormone insulin. I am not, however, here referring to the fact that its discovery revolutionised medicine by allowing the saving of countless diabetics from highly premature and painful deaths, usually preceded by torturous amputations of their feet or legs and all the of the horror and misery brought on by these seemingly barbaric and radically extreme measures. (And don’t for one second imagine that such amputations are a thing of the past: I know for a fact—heard directly from the mouth of a practicing orthopaedic surgeon—that amputations are the reality of his everyday, performing sometimes two in a single day.) I’m not either, at least this time, talking about insulin as the master metabolic hormone that regulates the storage into cells of nutrients circulating in the bloodstream. What I am referring to as one of the 20th century’s greatest discoveries in regards to insulin is that of its role in regulating the rate of ageing.

Something that is almost as remarkable is that we hardly ever hear or read about this. For me, that’s really strange. But whatever, I’m not going to hypothesise and speculate to come up with an explanation for why this is. Insulin as regulator of the rate of ageing is what we’ll look at in this article.

Why do mice live two years but bats fifty? Why do rats live three years, but squirrels fifteen. Why do some tortoises live hundreds of year? Why do the smallest dogs, like Chihuahuas, live about twenty years, while the largest, like Great Danes, live five to seven years only? And why do we, humans, live around 80 years, rarely making it to 90, and very rarely to 100 years of age? It is this line of questioning that triggered in the late 80’s and early 90’s a geneticist working in evolutionary biology to hypothesise, for the first time, that ageing could be genetically regulated, at least to a certain extent.

It was the discovery and subsequent realisation in evolutionary biology at that time, that a large number of fundamental cellular processes and mechanisms regulated by a variety of genetic expressions were common to widely different organisms. The realisation was that because all animal life must necessarily share a common ancestor, it is not only logical that the most fundamental functions of cells and especially of how genes express themselves under the influence of hormones essential for life could be the same, but that it should be, to a great extent, expected to be that way. And even though these considerations may seem obvious in retrospect, the fact is that there was only one person with this knowledge, asking these questions, and having the means to do something about seeking an answer to some. Cynthia Kenyon, Professor at UCSF, was this person.

The subject was quick to choose: the tine worm that Kenyon had already been studying for years, C. elegans, was perfect because it is simple but nonetheless a complex animal, and because it has a short natural lifespan of about 30 days. The first step was clearly defined: find at least one long-lived individual. What seems very surprising from our current vantage point it that she couldn’t readily find one: she couldn’t convince anyone to join with her in this endeavour. Everyone was at that time convinced that ageing was something that just happened: things just wore out and deteriorated with use and with time; nothing to do with genes. But how could this be if different species—some very physically similar—are witnessed to have such widely different lifespans? It just had to be genetic at some level, Kenyon thought. Eventually, after a few years of asking around and searching, she found a young PhD student that was up to it, and set out to find a long-lived mutant.

A number of months down the road a long-lived mutant was found and immediately identified as a ‘DAF-2 mutant’. This mutation made the DAF-2 gene—a gene responsible for the function of two kinds of hormone receptors on a cell’s membrane—less active. The next step was to artificially create a population of DAF-2 mutants and see how long they live, statistically speaking, compared to normal C. elegans. It was found that the genetically ‘damaged’ worms, the ones for which they had turned down the expression of the DAF-2 gene, lived twice as long: starting with exactly the same number of worms, it took 70 days for the last one of the mutants to die compared to 30 days in the normal population.

But an additional observation was made: the curve that traced the fraction of worms remaining was stretched by a factor of two from about the start of adulthood for the mutants. They had the same relatively short childhood but then for the remainder of their lives, for every day in the life of the normal worms, the mutants would live two days. The most impressive was that they were really half their chronologically equally aged cousins in all respects: external appearance, level of activity and reproduction.

To make your appreciate this point as much as you should, this observation with respect to not just the lifespan but notably the healthspan of C. elegans would translate in human terms in someone being 80 years old but looking and acting like a 40 year old in the sense that nobody could tell that they were not 40, let alone 80 years old. Just like Aragon in the The Lord of the Rings. This person would be like a 40 year old at 80, like a 60 year old at 120, and like an 80 year old person coming to the end of their life by the time they were 160! Can you even imagine that? Hard isn’t it. But this is exactly what Kenyon and her team were looking at in these experiments with these little worms.

Now they wanted to understand the effect of the DAF-2 gene, or rather, understand the effect of suppressing its expression in the DNA of each cell’s nucleus at different developmental stages. If it was turned off completely, the worms would die: clearly, DAF-2 expression, at least in C. elegans, is essential for life. If it was suppressed immediately after birth (hatching), the little worms would enter the Dauer state in which they don’t eat, don’t grow, don’t reproduce, and basically don’t move either: they just sit and wait. Wait for what? For better times!

This Dauer state is a remarkable evolutionary adaptation seem in some species that allows the individual to survive during periods of severe environmental stress such as lack of food or water, but also high UV radiation or chemical exposure, for example, for long periods of time with respect to their normal lifespan in a very efficient kind of metabolic, physiological and reproductive hibernation. What’s really cool is that inducing worms out of the Dauer state, no matter how long they’ve been in it, they begin to live normally again, moving and eating, but also reproducing. So, in the Dauer state C. elegans literally stops ageing altogether and waits, suspending metabolic activities and physiological functions until conditions for reproduction and life become adequate once again.

celegansfasting

Taken from Worms live longer when they stop eating  (http://www.bbc.co.uk/nature/2790633)

If DAF-2 expression was turned back up to normal, then they moved out of Dauer and resumed their development stages equivalent to childhood, teenage-hood, and then adulthood, but didn’t live any longer as adults. Finally, suppressing DAF-2 expression at the onset of adulthood resulted in the extended lifespan as originally observed. The conclusion was therefore clear: DAF-2 expression is essential for life and necessary for normal and healthy growth and development in immature individuals from birth until they reach maturity, and suppressing DAF-2 expression was only effective at extending both lifespan and healthspan in mature individuals.Going further, they now wanted to understand how DAF-2 suppression actually worked to extent healthspan: what were the actual mechanisms that made the worms live longer when DAF-2 expression was turned down. For this, Kenyon’s team needed to look at all of C. elegans’s 20000 genes and figure out how they affect each other. (Note that this is also more or less how many genes we have, but C. elegans has only 3 chromosomes and is also hermaphrodite.) The sequencing of the worm’s genome was done in 1998, and what was found after analysis was very interesting:

The DAF-2 gene activate a phosphorylation chain that attaches phosphate groups onto the DAF-16 transcription factor. In normal individuals the DAF-2 gene is expressed normally, the phosphorylation chain works unimpeded, and the DAF-16 transcription factor is inactivated. In the mutants, the DAF-2 gene expression is suppressed, and as a consequence, the DAF-16 transcription factor is not inactivated and instead accumulates in the nucleus. There, DAF-16 encodes what Kenyon’s team showed to be the genetic key to health and longevity they were looking for from the start of this now decade long pursuit: the FOXO gene.

What does FOXO do? It promotes the expression of other genes, at least four other genes: one responsible for manufacturing antioxidants to neutralise free radicals the largest amount of which are produced by the mitochondria as they make energy for the cell, a second responsible for manufacturing ‘chaperons’ whose role as specialised proteins is to transport other proteins and in particular to bring damaged ones to the cell’s garbage collector and recycling facility to promote the replacement of those damaged proteins by new and well-functioning ones; a third responsible for manufacturing antimicrobial molecules that increase the cell’s resistance to bacterial and viral invaders; and the fourth that improves metabolic functions and in particular fat transport (reduce) and utilisation (increase).

It is these four genetically regulated cellular protection and repair mechanisms, the cumulative combined effects of all these increased expressions of antioxidants, chaperons, antimicrobials and metabolic efficiency—all of them at the cellular level—that allow the lucky DAF-2 suppressed mutants to live twice as long twice as healthy. Remarkable!

Now that all the cards about how the long-lived mutants actually live twice as long as expected under normal conditions are laid on the table, and that there is only one detail I left out of the story up to this point, tell me: can you guess what are the two sister hormones to which the cell’s sensitivity through the activity of its receptors for them are controlled by the DAF-2 gene? It’s a trick question because I told you half the answer in the introduction: The DAF-2 gene encodes the hormone receptors for both insulin and the primary form of insuline-like growth factor IGF-1. Surprised? It isn’t surprising, really. In fact, it all makes perfect sense:

Insulin and IGF-1 promote growth; nutrient absorption and cellular growth and reproduction are essential for life and thus common to all living organisms, including the more primitive of them like yeasts; growth in immature individuals is fundamental for health and for ensuring they reach maturity; but growth in adults, in mature individuals, just means ageing, and the more insulin and IGF-1 there is, the faster the rate of cellular damage and deterioration, the more genetic mutations from errors in transcription, the more pronounced the deterioration of the brain and the heart, of the arteries and the veins, of the muscles, the bones and the joints, and obviously, the faster the rate of ageing. Because what is ageing if it is not the word we use to describe the sum total, the multiple negative consequences, the end result of all of these deteriorations in these vital organs and systems but also everywhere else throughout the organism, all of it starting at the cellular level, in the nucleus of every cell.

About the necessity of insulin for normal growth, you should definitely not think that these observations impliy we should stimulate insulin secretion in the young in order to ensure proper growth. Totally not! The body knows exactly when and how much insulin is needed at any given time. In fact, any additional stimulation of insulin promoted by eating simple and starchy carbs actually deregulates the proper balance of hormones that the body is trying to maintain. This deregulation from a sugar laden diet in children is the very reason for many wide spread health problems in our youth most important of which is childhood obesity and the metabolic and physiological stresses this brings on. So, leave it to mother nature to know how to regulate the concentration of insulin in the bloodstream. Do not disrupt the delicate biochemical balance by ingesting refined carbohydrates: it’s the last thing anyone needs for good health and long life.

The first results were so interesting that several other groups joined in this research into the genetics of ageing. Not as much as one would think, but at least a handful of other groups began to apply and expand the techniques to other species. Unsurprisingly, the same effects, although with different magnitudes, were seen in these very different species, from an evolutionary standpoint: fruit flies and mice. In addition, the connection was made with lifespan-extending experiments using calorie-restriction, which have also been carried out on mice and other animals (we’ll look into this another time). And beyond the work around DAF-2, DAF-16 and FOXO, Kenyon’s group investigated other ways to influence lifespan and found two more.

The first was by disabling some of the little worm’s sensory neurones of which there are very few, making it easy to test and determine the influence they have separately and in combinations. They tested smell and taste neurones, found that disabling some would extend lifespan while disabling others didn’t. They also found that disabling different combinations of smell and taste neurones could have nulling effects. The second was playing with the TOR gene expression. For now, however, we will leave it at that.

As the fact that it is rare and relatively hard to come by this work without actually looking for it, there is something else I find very hard to comprehend. In Kenyon’s various lectures on this work, there is usually a mention of the biotech company she founded called Elixir Pharmaceuticals and how they aim to find one or more drugs that can suppress DAF-2 expression in humans without causing negative side-effects in order to extend lifespan and healthspan as was done in C. elegans with genetic manipulation. That’s fine, and does make sense to a certain extent, especially if we can find not chemical drugs but natural plant-derived compounds that have this effect on us.

The thing that doesn’t make sense and that is hard to understand from the naive perspective of the honest scientist looking for the simplest possible solution to a problem of inferring something we don’t know from information that relates to what we want to know: in this case this mean the simplest way to make the best use of this information and apply what we have learnt from these two and half decades of research in a way that we know would be beneficial in promoting a longer and healthier lifespan in humans without risks through the introduction of foreign substances in our body. Because they haven’t, here I offer my attempt to do this.

We have, thanks to Kenyon and others, understood in great detail how lifespan in complex organisms can be, to a great extent, genetically regulated, and which genes, transcription factors and mechanisms are involved in the process of regulating the rate of ageing in conjunction with the propensity for developing age-related degenerative diseases. In the final analysis, the main players are the DAF-2 gene that tunes up or down the sensitivity of insulin and IGF-1 receptors, the DAF-16 transcription factor that encodes the FOXO gene but is made inactive by the expression of DAF-2, and the star FOXO longevity gene that promotes the expression other genes responsible for stimulating the cell’s most powerful protection and repair mechanisms.

We have, from many decades of research on calorie-restriction and fasting in animals including humans (and which we’ll explore elsewhere), understood that this is an extremely effective way to extent both lifespan and healthspan and basically eliminate the occurrence of age-related degenerative diseases by greatly increase resistance to health disorders of all kinds. Some key observations on calorie-restricted animals include their very low blood levels of sugar, insulin and IGF-1, high metabolic efficiency and ability to utilise fat demonstrated by low blood levels of triglycerides, and their remarkably younger appearance with increased energy and activity levels.

And finally, we have, from more than a century of observations and research, concluded that diabetics, whose condition is characterised by very high levels of blood glucose, insulin and triglycerides, are plagued by a several-fold increase in rates of cancer, stroke, heart disease, kidney disease, arthritis, Alzheimer’s and dementia, basically all the age-related degenerative diseases known to us, and in addition, also a several fold increase in their rate of ageing based on the spectrum of blood markers used for this purpose, their appearance, but also on the length of their telomeres.

Is it not, therefore, obvious from these observations that high blood sugar, high insulin and high triglycerides are hallmarks of accelerated ageing and a propensity for degenerative diseases, while low blood sugar, low insulin and low triglycerides are instead necessarily related to extended lifespan, extended healthspan and increased resistance to all disease conditions including those categorised as degenerative, and this, independently of the actual mechanisms involved?

Is it not, therefore, plausible from these observations that the genetic mechanisms relating to the function of the DAF-2 gene, DAF-16 transcription factor and FOXO gene in conferring to the DAF-2 mutants twice as long a life can, in fact, be activated and enhanced epigenetically by creating an environment in the organism that is conducive to it: simply by keeping blood sugar, insulin and triglycerides as low as possible? In other words, isn’t it plausible from these observations that by manipulating the biochemistry to ensure that blood sugar, insulin and triglycerides are throughout the day and night as low as possible depending on the organisms requirements, that this will actually translate into the activation of the FOXO gene to enhance protection and repair at the cellular level and thus extend lifespan and healthspan?

And what is, not only the easiest and simplest, but also the most effective way to do this? It is to eliminate insulin-stimulating carbohydrates—sugars and starches—from the diet completely. This, within 24-48 hours, will allow sugar levels to drop to a functional minimum. The low blood sugar will allow the pancreas to reduce production and insulin levels to drop bit by bit. Lowered insulin will eventually allow the cells to start using the fat circulating in the blood, and in time, increase in efficiency, thereby dropping triglyceride levels lower and lower.

Why is it you think that Kenyon never mentions this anywhere? Do you think that this has simply not occurred to her? I honestly don’t know. But if there is a single thing to remember it is this: insulin is necessary for life; in the immature individual, insulin regulates growth; in the mature individual, insulin regulates the rate of ageing and the propensity for degenerative diseases. Hence, if you are a mature individual, and by this I mean full grown, and if you want to live long and healthy, the very first thing you need to do is to keep the concentration of insulin circulating in your blood as low as possible. Everything else that we can do to extend healthspan and lifespan is secondary to this.

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Six eggs per day for six days: cholesterol?

In What about cholesterol we saw how important cholesterol is for so many essential bodily functions and in so many important ways, that there should never have been a shadow of a doubt in anyone’s mind that cholesterol is anything but essential and vital to our health and our life. And that, therefore, it is ridiculous to even have to say that cholesterol is good for us. However, it is more than completely absurd, non-sensical, and outright dangerous to claim that it is bad for us. Let me assume you are now well convinced of this.

There is something we didn’t go into that relates to the fact that we’ve been told—and continue to be told—that we should minimise our intake of dietary cholesterol. The crazy thing about that recommendation is that the amount needed by the body of this vital substance depends solely on the body’s needs for it. And thus, the normally functioning liver, supplied with adequate amounts of the essential building blocks, produces cholesterol in the amount that is necessary for proper bodily function—whatever that amount happens to be at a particular time. What this means is that in a healthy individual, the amount of cholesterol you eat should not really affect the amount of cholesterol in the blood, estimated by the concentration of the lipoproteins that transport it to and from tissues.

Even though this obvious consequence of considering the body’s physiological function should just be accepted as a plain fact, unfortunately, most people—including health professionals—don’t. We continue to believe that cholesterol is bad, and we continue to try to minimise dietary cholesterol in order to lower lipoprotein concentrations, completely ignoring the fact that cholesterol and lipoprotein production is an exceedingly refined and well regulated mechanism that responds directly to the body’s needs.

It is certainly possible that if dietary cholesterol intake decreases, the liver produces more, and if dietary cholesterol intake increases, then the liver produces less; to what extent certainly depends on the physiological circumstances, and specific needs for cholesterol depend on many factors, all related to the state of the body. But it is pretty well established that the body produces more or less the same amount of cholesterol regardless of the dietary cholesterol intake because it much prefers to use the kind of cholesterol the liver produces, which is free or un-esterified cholesterol, rather than having to de-esterify the dietary cholesterol that comes primarily as cholesterol ester. Therefore, much of the dietary cholesterol is used in bile and excreted through the intestines.

For a lot more details, you can check out Peter Attia’s essential points to remember on his series The straight dope on cholesterol, even if I don’t really agree with the points linking LDL with atherosclerosis, simply because lipoprotein concentration, particle number, size distribution and everything else are all secondary or even further removed consequences of other dietary and metabolic factors upstream. In fact, I believe we should not even have started measuring lipoprotein concentrations and cholesterol in the first place. What we should have always focused on are uric acid levels and tracers of inflammation. And on another note, Peter is categorical that dietary cholesterol is not absorbed and all excreted. However, a couple of review papers I read about lipid absorption state that about 50% of intestinal cholesterol is, in fact, absorbed. The truth is that it is almost certainly dependent on a whole slew of factors and that, as for all things, the body absorbs and excretes in accord with its needs.

A viral infection, for example, will generally lead to the increase of lipoprotein concentration because these are the molecules that can most effectively gobble up and destroy viruses. Dehydration leads to a scarcity of water at the cellular level. As a consequence, each cell’s survival relies on producing more cholesterol in order to more effectively seal in the precious water it depends on for life that appears to be so scarce. Hence, dehydration also leads to higher cholesterol. A diet high in sugar—simple and starchy carbohydrates—naturally leads to a much greater amount of damage to cells and tissues throughout the body, but especially to the blood vessels themselves, from the highly damaging presence of insulin, the result of glycation of proteins and fats by higher concentrations of circulating glucose, and several other related factors. To repair the damaged cells, cholesterol is needed, and thus, in this case also, lipoprotein concentrations rise accordingly.

Although the fact that the amount of dietary cholesterol does not affect blood lipoprotein concentrations much is not debated by people in-the-know about issues pertaining to cholesterol, I just wanted to see this for myself what would happen. So, I devised a simple self-experiment: compare the lipoprotein concentrations in my blood when following my low-card, high-fat, high-nutrient diet, to those after eating 6 eggs per day for 6 days in a rowwhere I basically just added to my diet more eggs, usually raw in smoothies. That’s a lot of eggs… But before I present the results, I think it’s important to go through a few numbers relevant to this discussion.

lotsofeggs

Eggs: An average organic egg of 50 g supplies 70 calories, and contains 5 g of fat (all in the yolk), 6 g of protein (all in the egg white), less than 0.5 g of carbohydrates and 215 mg of cholesterol. This means that 6 eggs supply a total of 1300 mg of cholesterol. For me, 6 eggs per day is 3 times my usual consumption of 2 eggs per day on average—a 300% increase.

Blood volume: The blood in our body accounts for about 7% of its mass (Ref). For a weight of 100 kg, there is 7 kg of blood (about 7 litres); if you weight 50 kg, then there is 3.5 kg of blood or about 3.5 litres. And therefore, for a 57-58 kg person like me, this makes almost exactly 4 kg, and thus about 4 litres or 40 decilitres.

Lipoproteins: Cholesterol is not water-soluble, and thus has to be transported by lipoproteins. Different lipoproteins carry a different amount of cholesterol. The bulk of it, however, is found in LDL and HDL molecules. The percentage of cholesterol by weight in LDL is about 40%, and in HDL it is between 20 and 35% (Ref). To keep our calculation simple, we’ll take this to mean that LDL is half cholesterol by weight, and HDL is one quarter cholesterol.

Here are the results of the blood tests from December 16 and 22, 2011, both taken in the late afternoon after nearly 24 hours of fasting (I do this every week, so it was nothing unusual). And please don’t worry about the boldface: it appears automatically if the numbers are not in the “recommended” range, which for cholesterol is below 200 and for glucose 65-110 mg/dL. And don’t worry about the spelling: it’s spanish because I live in Spain.

Now, looking at the results, can you guess which one is which: which is the result of the blood test before one week of 6 eggs per day, and which one is after?

The answer is that the first table is from the blood test done on Dec 16, and the second table is from the blood test done on Dec 22:

After one week of eating 6 eggs per day, the LDL decreased from 110 to 95 mg/dL, the HDL increased from 106 to 112 mg/dL, the “total cholesterol” decreased from 224 to 213, and the triglycerides decreased from 41 to 29 mg/dL.

About the lipoprotein concentrations, you may recall from this graph I linked to in my first post on cholesterol, and in which was compiled all the available data found by its author, that included mortality rates and what is referred to as “total cholesterol” (but is in fact total lipoproteins), the ideal range for which is labelled “Colesterol total” in the above test results is 200-240 mg/dL, and the minimum all-cause mortality is found for concentrations of 220 mg/dL. That’s right where my numbers happen to be.

As for the glucose, well, you already know I try to keep it as low as possible, and by the way, I had no signs of hypoglycemia when my blood glucose was 60 mg/dL. In fact, I never do, even during three-day fasts, cycling to and from work, and doing resistance training at lunchtime. This demonstrates that the state of hypoglycemia can not be defined by a fixed threshold of glucose concentration below which we are considered to be in that state, but rather is based upon the individual’s metabolic function. This should be obvious since some people feel the consequence of hypoglycemia quite regularly and at glucose levels that would be exceptionally high for others, who on the contrary never feel them, simply because their metabolism has been trained to use fats for the body’s energy needs efficiently, and in fact, almost exclusively—to function in ketosis—as is my case. I plan to revisit this topic in greater detail in the future. But for now, let’s come back to the blood test results.

Firstly, we see that the sum of LDL and HDL compared to the “total cholesterol” is 216 vs. 224 (Dec 16) and 207 vs. 213 (Dec 22). This tells us that the VLDL (very low density lipoproteins) and CM (chylomicrons) together account for 8 mg/dL on Dec 16, and 6 mg/dL on Dec 22. They are, and we’ll not discuss these lipoproteins any further in this post.

Secondly, we note that the small difference in the very low concentrations of triglycerides (three fatty acids attached to a glycerol backbone), considered to be “normal” up to 150 mg/dL, mirrors the small difference in the lipoproteins that carry most of the triglycerides: the CM (90% triglycerides) and VLDL (62% triglycerides). Low triglyceride levels with low glucose and insulin levels equate to efficient metabolic use of fats.

And thirdly, we find that for 4 litres of blood, if we assume simple rounded figures of 100 mg/dL of LDL and 100 mg/dL of HDL, the total amount of cholesterol being carried around in the bloodstream is about 3000 mg: 40 dL*(50%*100 mg/dL + 25%*100 mg/dL). This is just 3 grams in the entire blood supply for a body weight of 58 kg! And an additional 1300 mg of cholesterol per day—almost half of the cholesterol in the bloodstream—from eating 6 eggs, and this for 6 consecutive days that supplied a total of 7800 mg of cholesterol, did not affect the lipoprotein concentration.

This leads us back to the hypothesis presented in the first paragraphs: the amount of cholesterol you eat should not really affect the amount of cholesterol in the blood. And although a quick experiment on a single person is far from being definitive proof of anything, this one clearly indicates, at least for me, that increasing intake of dietary cholesterol by an amount that is close to half of the total cholesterol circulating in the bloodstream, and doing this each day for 6 days in a row, does not raise lipoprotein concentrations (in this case, they went down slightly) when comparing the values measured at the same time in the late afternoon after a 24 hour fast once at the start of the week and 7 days later.

Furthermore, based on the sensible assumption that cholesterol synthesis by the liver is a response to the body’s needs, but also ability to manufacture it, if absorption of intestinal cholesterol is not nil but varies depending on the body’s needs, then supplying more dietary cholesterol may help ease the requirements on the liver for manufacturing the quantities needed. Therefore, this “help” to the liver can only be viewed as favourable considering the extreme importance of this organ for good health. It could also be that most or even all the additional dietary cholesterol was simply excreted in the stools. But in any case, it is absolutely certain that eating this huge amount of cholesterol every day did not affect lipoprotein concentrations in the blood after the period of fasting.

What I would like to do is to evaluate dietary cholesterol absorption on me, a 40-year old man in excellent health, by adopting an extreme diet of eating only eggs and water (this will remove the influence of other foods and nutrients and therefore reduce significantly the number of variables that can influence cholesterol synthesis and absorption), and take minimal blood samples at regular time intervals such as every hour or every couple of hours. By evaluating the changes in cholesterol transporters we would be able to estimate how much is absorbed because we know that lipids from the intestines are transported to the blood mostly by CM and VLDL, whereas HDL and LDL are mostly responsible for transport to and from the liver.

In any case, as we have seen here, but also as I mentioned in my opening sentences that we have known for a rather long time, dietary cholesterol does not influence blood cholesterol much. So please, when you hear someone say that we should avoid eating too much cholesterol because they have “high cholesterol”, you don’t need to say anything if you don’t want to, but remember at least this: cholesterol is so important and so good for us, that the liver and cells themselves will always do everything to supply the all the cholesterol that is needed, whatever that is at a particular time, and no matter how little or how much we get from our food. And maybe it is even the case that eating more cholesterol actually helps the liver and cells meet the body’s continuous demands throughout the day and night of this vital substance.