Dear Mark: Grok’s Terrible Genes; Fasting, Starvation, and Metabolism

Neanderthal skullFor today’s edition of Dear Mark, I’m answering two questions from readers. The first one concerns a study I linked to in this week’s Weekend Link Love. It appears to suggest that ancient humans had worse genes than modern humans have, that they were at greater risk for many different disorders and diseases. How can this be? Last but not least, Pierre expresses skepticism at the notion of fasting or starvation causing metabolic slowdowns. I agree, but only to a point, and I explain why.

Let’s go:

Mark, what’s your take on the ancient human gene study you mentioned in weekend link love today? This one:

I found it really interesting.


The paper has a lot going on.

First, we find that the genetic disease load has not been increasing in modern humans. Many have proposed the opposite: That the rise of modern medicine and technology has relaxed the selective pressures of everyday living and allowed genetically “unfit” people to survive and reproduce, thereby increasing the rate of deleterious mutations. This paper seems to contradict that.

We find that the genetic load in certain disease categories was higher in ancient humans. Looking at individual samples, we find that the Altai Neaderthal and Otzk the Iceman had some issues. The Neanderthal had a higher genetic risk for neurological disease, immune issues, cancers, gut disorders, and metabolic disorders. The Iceman had a higher genetic risk for cardiovascular, immune, gut, and metabolic disorders.

There are several ways to interpret the results. The most common interpretation will probably be that the genetic disease load was greater in ancient humans because they weren’t living long enough for the diseases to take root and impact reproductive fitness. I think that’s part of it, but my take is different.

Maybe ancient humans carry more genes that in modern environments increase risk of diseases, but in ancestral environments were neutral or even increased fitness. Heart disease wasn’t an issue because he wasn’t chowing down on packaged cupcakes, Panda Express, and Pepsi. 

If you transported Otzi the Iceman or the Altai Neanderthal to the present day, set them up with an apartment on the Las Vegas Strip with neon signs blaring into their room at all hours of the night and ensured they spent their days hanging out at the slots and pigging out on the buffets, they’d be fat, diabetic, and feeble more quickly than most modern humans in the same position.

This is why traditional people get hit so hard by modernity. It’s perhaps why the Pacific Island nations are among the fattest in the world. It’s why native peoples all over the world, when influenced by industrial food cultures and modern sedentary lifestyles, tend to be fatter and sicker than the broader population of their countries, whether it’s Canada, the US, or Australia.

Consider the genetic predisposition to alcoholism. It’s far higher in American Indians than Americans of European descent due to a lack of protective genetic factors and higher incidence of deleterious genetic factors (and, of course, environmental factors). If you dug up some American Indian graves from the 1400s and ran DNA tests on the remains, they’d show up as having a high risk of alcohol dependence. But back then, when they weren’t exposed to alcohol, those “deleterious” genes weren’t actually deleterious. 

I suspect the same thing applies to the Neanderthal and Otzi. They had the genes for cardiovascular disease and irritable bowel syndrome. Media headlines say “Otzi had heart disease.” I’d say “Otzi had the genetic predisposition that increases heart disease risk in modern people living in modern environments.”

What’s really fun to think about is if these “deleterious” genetic variants offered protective or beneficial effects in other areas. What do you think?

Next, Pierre comments:

Not sure about the statement that metabolism slows down when you are starving. That doesn’t really square with my fasting results and it doesn’t make sense from an evolutionary standpoint. Seems that slowing down when you need to chase down some food would lead to your extinction.

I agree with your thinking. Fasting as most people practice it does not slow the metabolic rate. It takes at least 3 days of pure fasting for minor slowdowns to the metabolic rate to occur. Some studies even find that short-term fasting (48 hours) boosts metabolic rate by almost 4%. Others find similar results. This jibes with your results and hypothesis—”slowing down when you need to chase down some food would lead to your extinction.” It seems you’ve got about 3 days of full (or even extra) energy to acquire food before energy starts dropping. That should be plenty.

At some point, though, things break down. It doesn’t make sense from an evolutionary standpoint for humans to die when a European cave bear eats their face, since that leads to the human’s extinction, but die they do. There’s only so much the body can handle. Evolution can’t contend with a giant bear mouth chomping down on your head, nor can it contend well with a lack of food for six days straight. You just run out of juice.

That’s it for today, folks. Thanks for reading. Take care, and be sure to add your own comments, questions, and answers down below!


About the Author

Mark Sisson is the founder of Mark’s Daily Apple, godfather to the Primal food and lifestyle movement, and the New York Times bestselling author of The Keto Reset Diet. His latest book is Keto for Life, where he discusses how he combines the keto diet with a Primal lifestyle for optimal health and longevity. Mark is the author of numerous other books as well, including The Primal Blueprint, which was credited with turbocharging the growth of the primal/paleo movement back in 2009. After spending three decades researching and educating folks on why food is the key component to achieving and maintaining optimal wellness, Mark launched Primal Kitchen, a real-food company that creates Primal/paleo, keto, and Whole30-friendly kitchen staples.

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22 thoughts on “Dear Mark: Grok’s Terrible Genes; Fasting, Starvation, and Metabolism”

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  1. I suppose it’s possible that “deleterious” genes carried some advantages. My understanding is that this is in fact the case with sickle cell anemia – it became so prevalent in West Africa because it had protective effects against malaria, so in a time when malaria was deadly and untreatable, sickle-cell could actually be considered beneficial rather than deleterious.

    1. Half way. Malaria was a killer, and people with both alleles for sickle cell didn’t usually last long. Those who were carriers of the sickle cell (only one allele) had the best chance of survival, and thus often passed that on to further survivors. They were malaria resistant and didn’t have terrible sickle cell issues.

      1. Okay. Still true that the gene was generally beneficial, right? But my informant –
        a West African friend whose family has the gene says her one brother who has sickle cell symptoms was also, in fact, the only one in the family who was resistant to malaria. Is she mistaken about that?

  2. Interesting take on the “deleterious” genes!

    It seems like your take on fasting disagrees with the work done by Dr. Jason Fung, whom you have discussed in the past. He suggests that your BMR increases during fasting, even into extended fasts of over 14 days. Do you think he is mistaken?

    1. Dr, Fung’s work is with people with plenty of body fat, extended fasts are not recommended for lean people.

      1. I would agree, but it would depend on the definition of lean. BMI under 20? Maybe?

        I would say a 7 day fast for someone who doesn’t have 5 pounds to spare is unsafe. However, I think most people still have that last 10 or 15 or even 20 pounds of excess fat they could lose.

  3. You’ve nailed it with the “deleterious gene” interpretation. I had independently noticed the same thing and was excited to see you reaching similar conclusions.

    One potential example of how the “deleterious gene” might actually be beneficial:

    Populations inclined to diabetes in modern environments are finely tuned to an insulin-sparing evolutionary environment. In their ancestral context, they not only managed glucose more efficiently, but hormones such as IGF-1. This would have provided a lean mass advantage appropriate to apex predators. But in a modern environment, obesity and diabetes are only the tip of the iceberg of disregulated growth for these populations. We might also expect them to demonstrate a higher incidence of cancer and neuropathy.

    Conversely we might expect populations that are resistant to the novel stresses of modernity to have traded away adaptations to the ancestral environment. The agricultural genotype, therefore, might have less potential to develop lean mass, leading to a dramatic reduction in fitness potential as hunter-gatherers.

    This seems to be borne out by the available evidence. If true, this might lead to materially different “paleo” recommendations for each population.

    Unfortunately, studying differences in phenotype among different “races” is politically controversial, so I don’t think we can expect this topic to receive the scientific attention it deserves.

    This is regrettable, because a major future improvement in paleo wellness would be moving beyond the generic “Grok” model to a model of each individual’s specific genetic heritage.

    1. Insightful — thank you. I appreciate what you put into your comments.

      I don’t know if you’ve noticed lately but all the trendy books of today like “Fat For Fuel” and “Wired To Eat” focus on a paleo model with individualization based on glucose testing and tolerance to certain foods. These certain foods almost never belong that of the generic “Grok” model.

      Going out on a limb here but I’d say that most of humanity, from all walks of life, would do really well on diet that consisted of liver, marrow, heart, kidney, pancreas, spleen, brain, muscle, bone soup, the whole foul, the whole fish, the whole egg and varied fruits and veggies. I’d bet that even the Inuit would do pretty dam fine if we introduced them to some seasonal starches just as long they continued to move in a way that resembled early ancestral living.

      I’m not so sure that there’s a whole lot of room to improve upon the generic “Grok” model. In the modern world, everybody wants more… stating the obvious, sometimes less is more.

      By the way, I started reading war memoirs starting with life of Frederick Russell Burnham. Enjoying. Thank you for the recommendations.

      1. Always grateful for your thoughtful perspective LK.

        The difficulty with personal blood glucose measurement is that, like bathroom scale weight, there are so many confounding inputs besides genetic predisposition. If I understand correctly, it’s even worse — different measurement devices give dramatically different readings for the same sample (Kearns).

        There does seem to be dramatic individual variation in response to specific carbohydrate-rich foods (Wolf in Wired to Eat) but whether this is due to genetics, microbiome composition, hormonal entrainment, or even epigenetic changes is not clear (almost certainly it is some baffling combination of all those and more).

        It is so difficult to work backwards from biological measurements, especially in the context of epigenetic flexibility, that we may as well try working forwards from assumptions about ancestral adaptations.

        I agree with you that organ meats are a universal gold standard of nutrition for all populations. They are by far the most nutrient-dense foods available, and in light of human adaptations such as shortened gut, cooking, tool use for hunting and food prep — in addition to the observed behavior of extant hunter-gatherers — we can safely assume organ meats have been the mainstay of hominin nutrition for hundreds of thousands, if not millions, of years.

        In fact the more I study this, the more it seems that humans should be considered carnivorous facultative omnivores rather than true omnivores. We simply do best on a diet of animal bits (including digestive contents).

        It’s the adaptations to omnivory that seem to show the largest individual variation. As we would expect for a facultative adaptation.

        To your point, why not just eat nose-to-tail? That’s the 1,000,000-year-old-Grok diet. It’s the 10,000-year-old-Grok diets that get us wrapped around the axle. But if we get the primary diet right, the supplemental diet becomes mostly a matter of taste.

        All over that Burnham book. That’ll be two great reads I owe you for…

  4. I certainly don’t feel like my metabolism slows down after a day of fasting. Quite the opposite: I feel slightly manic, a bit fidgety, on edge. I suppose that’s cortisol at work. I don’t feel sick but I don’t enjoy the feeling, either. But after my normal dinner-to-lunch 17-hour fast, I feel just fine. I guess my tolerance is somewhere just under a day for fasting.

    A man’s gotta know his limits.

    1. A daily 15 to 17 hour dinner-to-lunch fast works well for me. Some people apparently like long fasts but I’ve never been convinced that there’s a physical or psychological reason for it.

      1. It becomes a natural rhythm after a while. I’ve never been a breakfast person, anyway, and I enjoy my lunch since it’s a true breaking of a fast. But it’s never heavy which is why six hours later I’m interested in a substantial dinner.

  5. So fasting does not slow down metabolism, at least up to a point. Do you agree though that chronic undereating (as in the classic “eat less, move more” diets) does slow down one’s metabolism? If so, does it happen right away or does it take a few days or weeks for metabolism to slow down?

  6. Regarding the idea that humans have roughly 3 days or so before they experience deleterious effects to their energy levels, I would think that would depend upon the amount of stored energy from the get go…there is an account of a morbidly obese Scottsman who became determined to lose weight and do so steadily. Well, under medical supervision and a battery of salt pills, the guy ended his total fast in just over a year! I found that account difficult to believe but apparently, it’s verifiable.

    1. He actually lasted 382 days, IIRC. He supplemented his diet of nothing with boullion and a daily multivitamin.

    2. A slowing metabolism is not just about perceived energy levels, though… my concern is also about “what happens when I start eating again?” If I understand at all correctly, once your body is below its set point (no matter how much stored energy you have left), your metabolism will slow if you are eating fewer calories than what would be required for maintenance. I’m not sure how long this takes and I wonder if a cyclical pattern would be good–a couple low-calorie days, a “day of plenty,” then low calorie again.

      1. your metabolism doesn’t slow if you don’t eat anything. Quite the opposite, your body increases its metabolism for at least 3 days to encourage you to go out and seek food .
        Most people don’t feel tired when they fast. You may feel hungry but not tired. When no calories are consumed your body will start using its own fat reserves and produce ketones as alternative fuel which prevent breaking down of muscle mass and feeds your brain ( the brain can’t utilize fat as it doesn’t cross blood-brain barrier ).

        The production of ketones is prevented if you ingest carbohydrates or too much protein. you also miss out on autophagy which is deactivated by ingesting food, even if it’s as little as 500 calories.
        Eating fewer calories a couple of days a week is certainly better than eating 3 meals a day all the time but you miss out on benefits of fasting and risk losing muscle mass along fat. I also believe it’s harder to eat a little than not eat at all for a day or so.

        1. I don’t know…when I fast, even for just under 24 hours, I am not hungry at all, but I am VERY fatigued and can barely get myself out of a chair. My thought processes are sharper, but my body is barely functional. Not sure what to make of that.

  7. As a woman (and I think this is one of those rare instances where gender actually matters), I feel like fasting even for 3 days is plenty to make a mess of my whole system. Might be the cortisol being released or something, but even when I was well into low carb diet and most likely very “fat adapted”, I felt horrible if I skipped breakfast/went too long without food. I get stressed as hell, angry, desperate for food, and certainly haven’t noticed any increase in energy. Maybe the increase in stress hormones (which apparently affect women more) meddles with metabolism, and that’s why some studies (?) have found fasting to work in disfavor for weight loss (and even health)?

  8. I can’t help but laugh at the question about metabolism slowing down with fasting. You will starve to death if you fast long enough. Your metabolism would be nothing. Obviously, there are no stupid questions but this one makes me scratch my head haha

    1. Ha, that’s funny! What makes me scratch my head is someone who reads a post and about several days of fasting, with links to studies on the effects on metabolism, and then comments about how starving to death = no metabolism.
      To each her own, I guess.