Is Ketosis Normal?

Humans are born into ketosis and will remain in ketosis while breastfeeding, whether or not the mother is in ketosis. For hunter-gatherers, breastfeeding commonly lasts for the first couple of years, the most important time for growth and development, especially the brain. So, evolution has created ketosis as a protected state for infancy. But it goes far beyond that.

Unlike other carnivores, evidence indicates humans remain in ketosis even while eating higher amounts of protein. We are capable of gluconeogenesis, a necessary function turning protein into glucose, but we don’t so heavily rely upon it. Under normal evolutionary conditions, humans would spend much, probably most, of their time in ketosis. No other species so easily goes into and remains in ketosis. The human brain, in fact, preferentially uses ketones. And it is probably because of our large, energy-hungry brains that we are so ketosis-prone in the first place. That is likely why babies are born so fat, so that they can have a ready supply of ketones.

It was a trade-off of the human brain growing larger as the gut grew smaller, as it requires a lot of energy to digest plant matter and that energy was needed for the evolutionary development of a larger brain. So, humans turned to eating fat from animals, to replace a digestive system needed to break down fibrous plants to produce fat. Herbivores are forced to spend all day eating vast amounts of plant matter and it is energy intensive work. Ketosis freed humans from this activity and simultaneously freed up immense energy to be used for other purposes, specifically greater neurocognitive functioning and higher thought.

The benefits and advantages of ketosis are amazingly numerous. It protects against or improves epilepsy, along with other neurocognitive disorders and mental illnesses, from bipolar disorder to ADHD, not to mention much more serious diseases such as Alzheimer’s. It also shows benefit for autoimmune disorders, cancer, and trauma. There is no health condition I can think of, besides type 1 diabetes, that would be worsened by ketosis. And if one were on a ketogenic diet in the first place, one would be unlikely to develop type 1 diabetes and so that is moot.

One would be forgiven for thinking that ketosis might be the natural state of the human species. Still, whatever one thinks of evolutionary arguments, no one can deny that ketosis is a far healthier state to be in, or at least there is no evidence to the contrary. That said, one doesn’t have to be in constant ketosis to see many of these benefits. Even in epilepsy, after a period of healing, some patients can stop a ketogenic diet and stay free of seizures. There are many mechanisms for this healing power of ketosis, such as the related autophagy, but the general anti-inflammatory effect might be more important considering inflammation is found in so many diseases.

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By Amber L. O’Hearn:

Babies thrive under a ketogenic metabolism

Optimal Weaning from an Evolutionary Perspective

Ketosis Without Starvation: the human advantage

I’d love to see this question approached systematically, but the survey does at least suggest that protein levels above our minimum needs based on positive nitrogen balance still support ketosis. […]

Obligate carnivores are always on very low carb diets, so you might think they are always in ketosis, but that’s not at all the case. In fact they are specialised at gluconeogenesis, that is, getting all their energy needs met by converting protein into glucose. Protein needs tend to be high.

Cats have much higher protein needs than omnivores and surprisingly, they don’t adapt well to reduced protein or fasting [Cen2002]. They don’t seem to have good mechanisms to compensate for the various amino acid and vitamin deficiencies that develop, so they suffer from ammonia toxicity, methylation problems, and oxidative stress. They do produce ketones fasted, but they don’t seem to use them in a productive way. and they actually accumulate fatty acids in the liver when fasted; the opposite of what humans do, Because they are still producing glucose, they become like human type two diabetics.

Dolphins are particularly interesting because they have really large brains, and they eat a diet that would be expected to be ketogenic if fed to humans. However, they don’t seem to even generate ketone at all, not even when fasting. Instead, they ramp up gluconeogenesis [Rid2013].

They keep their bodies and their brains going by increased glucose.

When faced with this observation that humans use ketosis even when they don’t have to for glucose production, one obviously wonders how this happens from a mechanistic standpoint. I have never seen the question raised in the literature, let alone answered. If I were to take a guess, I’d say it probably happens somewhere in this process.

CPT1A is a kind of gatekeeper, transporting fatty acids into the mitochondria for oxidation. This is normally a necessary step in the creation of ketone bodies. The coenzyme malonyl-CoA inhibits CPT1A [Fos2004]. The functional reason it does that is because malonyl-CoA is a direct result of glucose oxidation and is on the path to de novo lipogenesis. It could be inefficient to be both generating fat and oxidizing it. So this is a convenient signal to slow entry of fat into the mitochondria.

However, its action is not stictly linear. It uses hysteresis. Hysteresis is a way of preventing thrashing back and forth between two states at the threshold of their switch. For example, if you set your thermostat to 20°C, you would not want the heater to be turned on when the temperature drops to 19.999 and turned off again at 20. This would result in constant switching. Instead, a thermostat waits until the temperature drops a little lower before activating the heater, and heats it a little more than required before deactivating it.

Hysteresis is implemented in CPT1A by its becoming insensitive to malonyl-CoA when levels of it are low [Ont1980], [Bre1981], [Gra1988], [Gre2009], [Akk2009]. That means that once CPT1A becomes very active in transporting fatty acids, it takes time before the presence of malonyl-CoA will inhibit CPT1A at full strength again. That means that fluxuations in glucose oxidation, or small, transient increases in glucose oxidation don’t disturb the burning of fatty acids or the production of ketones.

It could be the case that humans develop more insensitivity to malonyl-CoA under ketosis than other species do, allowing them to metabolise more protein without disturbing ketosis. Among humans, this is case in populations such as some Inuit with the Artic variant of CPT1A. That mutation slows down CPT1A activity immensely. This was permitted by their diet which was very high in polyunsaturated fats from sea mammals. Polyunsaturated fats upregulate fatty acid oxidation by a large proportion compared to saturated fats [Cun2002], [Fra2003], [Fue2004], so this mutation would not necessarily have been disruptive of ketosis in that population when eating their natural diet [Lem2012]. But a second effect of the same gene further decreases the sensitivity of CPT1A to inhibition by malonyl-CoA. That means they are less likely to be knocked out of ketosis by high protein intake. […]

But it’s not just epilepsy that ketosis is good for. Epilepsy is just the condition with the most research, and the widest acknowledgment.

Other conditions for which at least some evidence supports improvement via a ketogenic diet include neurological disabilities in cognition and motor control [Sta2012]; the benefit here may have to do with the proper maintenance of brain structures such as myelination (Recall phases: tear down damage, rebuild)

Survival after brain damage, the hypoxia of stroke or blows to the head is improved in animal models [Sta2012]. There is even animal evidence that brain damage due to nerve gas is largely mitigated by being in a state of ketosis during the insult [Lan2011]. Again, this suggests a structural support and resilience provided by a ketogenic metabolism. Resilience comes in part from not being as susceptible to damage in the first place, and that could be from reduced oxidative stress when using ketones for fuel.

Ketogenic diets as a treatment for cancer are controversial, but some of the best evidence in support of it comes from glioblastomas. See e.g. [Zuc2010], [Sch2012]. This could be due mostly to the hypoglycemia stalling the rate of tumour development.

And to venture into an area less well studied, but of critical importance given the epidemic that would be more apparent were it less taboo, there is preliminary evidence in the form of case studies that ketogenic diets may be promising treatments for many psychiatric illnesses too, for example, [Kra2009], [Phe2012]. Given that anticonvulsants are also used to treat bipolar, and the solid results of ketogenic diets on epilepsy, this may not be surprising. Additionally, the enhanced availability of AA and DHA may play a crucial role Because these fatty acids are critical for the brain, and dysregulation in their flux has been associated with bipolar disorder and schizophrenia. See e.g. [McN2008] and [Pee1996].

I would almost like to call a ketogenic diet a brain-growth mimicking diet.

The question of how and why humans are so ketosis prone may lead to interesting new insights about us as a species. We seem to avoid giving up ketosis as long as possible. only halting it when we take in so much glucose exogenously that we have to store it.

It seems likely that it facilitated the evolution of our brains, that organ that makes us so different from other animals that we sometimes forget we are animals.