On saturated fat, blood cholesterol, and heart disease

Why would the body increase blood cholesterol in response to saturated fat? And how could that be bad, if evolution intended things that way?

I recently received the following question:

Okay. First saturated fat. Isn’t human body fat essentially identical to the fat on mammals and if it is, and saturated fat is bad, why would evolution or an intelligent designer design us to store excess energy in a form that’s bad for us? Second, cholesterol. I thought dietary cholesterol had very little to do with cholesterol levels. Most of it is made by us naturally. So how does consumption translate to excess cholesterol that impacts arteries? I thought that coronary disease was mostly caused by inflammation. These are truly honest questions from curiosity. I promise no stupid arguments from me though I can’t promise no follow-up. My world is language, not biology.

My answer:

First, I don't think saturated fat has a major role in cardiovascular disease. If you consider that blood pressure, diabetes, smoking, gender, age are all at least as important as LDL. My recent reading through the literature suggests that LDL is actually of lower importance than all of these. Combine this with the fact that saturated fat has a variable and modest impact on LDL cholesterol in most people, and saturated fat intake not all that important as a risk factor for cardiovascular disease. It does have an impact, but that impact is very modest.

Second, atherosclerosis affects us later in life and to my understanding is not generally a cause of death and disability in pre-modern hunter-gatherer groups. That's even if LDL cholesterol had a really large impact on atherosclerosis, which it doesn't. So for saturated fat, we are talking about a modest to marginal impact on LDL cholesterol, which has a modest to marginal impact on CVD, which has a modest to marginal impact on hunter-gatherer mortality during the vast bulk of human evolutionary history. Furthermore, while I believe the "grandmother hypothesis" is correct--that is, that older people in the community contribute to the fitness of offspring and thus evolution does "select for" human longevity--it is still also true that evolution has less of an impact at older ages than at younger ages. That is, natural selection will ensure that genes that help us to reproduce are very strongly selected for, while selection pressures for genes that marginally impact survival at older ages will be less strongly selected for. And so evolution may simply not have operated very strongly in favor of reducing LDL levels from saturated fat intake (or innate fat stores): it has a modest impact on LDL cholesterol, which has a modest impact on atherosclerosis, which has a modest impact on hunter-gatherer morbidity and mortality, which has a modest impact on evolutionary fitness. It's such a tiny piece of such a large puzzle.

Third, let's pivot to the benefits of LDL cholesterol. Two postulated benefits of blood LDL cholesterol are in muscular development and in the immune system. There are a number of studies that suggest that higher LDL cholesterol levels lead to higher muscle gain. Cholesterol is important for the synthesis of cell membranes and of new tissue. Likewise, there are a number of studies that suggest the lipoprotein system plays an important immunological role. This actually makes sense: not only are lipoprotein levels in the blood modulated by inflammatory signaling but inflammatory signaling also directly modulates atherogenesis (the generation of atherosclerotic plaques in the arterial wall, i.e. cardiovascular disease) itself. We know that, for instance from CANTOS, that by reducing IL-1b levels in the blood, we reduce the rate of heart attacks. This is because the fundamental processes of atherogenesis are oriented toward protecting the blood vessels of the body against injury and pathogen invasion, even if they can go awry and cause disease in the modern context.

Now, as far as muscle is concerned, as you pointed out, it is well-known that blood cholesterol levels rise in response to saturated fat intake. Saturated fat is predominantly present in the fat of animals, particularly large ones. Would this not make sense for a number of reasons? Eating animal fat means that one is hunting. Hunting large, fatty game either requires some amount of strength or is an activity that indicates that one is engaging in competition with one’s tribe’s fellow males. We know that large game hunting is as much of a social status signaling exercise as it is important for food, at least in the !Kung. Now, when participating in such an activity, it would be beneficial for increases in muscle mass. It is well-known that the higher muscle mass in human males is important for infraspecific sexual competition in a hunter-gatherer context. Furthermore, if blood cholesterol levels contribute to muscle gain, it should make good sense for these levels to rise when one is consuming a meal high in protein: the body is doing all it can to prepare the muscles for growth.

As far as the immune system is concerned, if saturated fat intake provides a signal of animal consumption, it would also make sense for the body to increase cholesterol lipoproteins to prepare the body immunologically. After all, animals can have many parasites and other pathogens, and if cholesterol lipoproteins are important for human immune function, then increasing their level in the blood may help the body to ward off infection that may come from consuming these organisms.

All of this just goes to show that LDL cholesterol might have certain benefits, and that those benefits may explain the prevalence of higher, “unhealthy” LDL cholesterol levels in the body in a modern context. As we saw in the first two points of this answer, saturated fat’s impact on LDL cholesterol simply isn’t going to play a large impact on human evolutionary fitness, and thus isn’t likely to be strongly selected against, and now we see that LDL cholesterol may have important evolutionary benefits, especially at younger ages. So the negative impact at older ages of causing atherosclerosis may not be all that important.

To illustrate this further, consider that there seems to be a dose-response relationship between the average blood pressure in the animals of a species and incidence of cardiovascular disease. Birds such as eagles and turkeys have extremely high blood pressures and an extremely high incidence of atherosclerosis upon dissection. This is because birds need high blood pressures to fuel their intensely metabolically demanding activities like flying. Humans have among the highest blood pressures of mammals, and this is because we are upright and require blood to flow against gravity to reach the brain. (Giraffes also have very high blood pressures.) And correspondingly, humans have a relatively high rate of atherosclerosis compared to other mammals. Compare humans and birds to many mammals and reptiles and amphibians with lower blood pressures. Many of these almost never get atherosclerosis.

This illustrates the concept that there are certain important adaptations that take precedence over the prevention of atherosclerosis. Evolution, in other words, does not optimize every biological outcome but often needs to balance different biological outcomes depending upon the anatomy and physiology of the species. Some species get more atherosclerosis than others, but this happens because there are adaptive advantages to standing upright and flying.

The same may also be true for higher LDL cholesterol levels and other biological benefits that we do not understand clearly. We know this more clearly for blood pressure, but I would like to use that example in particular to show that the same principle may apply to lipoproteins.

Finally, desaturates do cause saturated fat to become unsaturated before it enters the circulation, but all of this is secondary to what we have written above!

I would like the above considerations to illustrate just why I am often so averse to evolutionary explanations for optimal nutrition or lifestyle: evolution is very complex and does not optimize every variable but sometimes needs to make tradeoffs.

As to your second question, for most people, dietary cholesterol does not have an impact on blood cholesterol, and this was shown as far back as Ancel Keys, who published on this subject. However, for a certain subset of the population, maybe about 20%, dietary cholesterol does impact blood cholesterol. I am in that subset of the population. My blood cholesterol levels skyrocket when I consume dietary cholesterol. Now, most people do not know whether they are in this subset of the population or not, so I think it is still important for people to understand that this problem exists. Furthermore, for most people, there is likely a threshold for cholesterol consumption and blood cholesterol: just a little bit of dietary cholesterol causes blood cholesterol levels to rise, and any higher intake does not cause any further increase in blood cholesterol. This is why vegans often have markedly lower blood cholesterol levels: because they do not meet this threshold because they do not consume any dietary cholesterol. Now, again, in dietary cholesterol hyper responders, more dietary cholesterol seems to lead to a linear increase in cholesterol, but for most people, this is not the case, and they respond to dietary cholesterol in the more thresholded manner that I have just described.

I hope that answers your questions. If it doesn’t, I hope you can put this text on your nightstand and at least use it to help you fall asleep on more difficult nights.

Now, to readers, the context of this question was partly my claim online that I take a statin and reduce my blood cholesterol to lower my cardiovascular disease risk. It turns out that biology and medicine are very complicated. I hope you enjoyed reading or at least can use this text the same way I recommended to my reader!