The Selfish Brain Theory

The unique position of the brain as a body organ is characterized by:

1. its chemical isolation from the rest of the body by the blood-bran barrier

2. its high energy consumption: though weighing as little as 2% of the body mass the brain consumes above 20% of all available energy

3. its low energy depot capacity,

4. its energy substrate selectivity,

5. its plasticity - ability to adjust reactions to circumstances and learn how to anticipate the consequences,

6. its ability to record information from both peripheral organs and its own environment.

So how these peculiarities of the brain's energy demands are being satisfied by the entire organism and how do they influence the way organism works?

Researchers from University of Luebeck and Universite de Lausanne proposed a new framework for describing the regulation of energy flow in the organism. In the article "The selfish brain: competition for energy resources" they wrote:

"The brain prioritizes adjustment of its own ATP concentration. For this reason it activates its stress system and in so doing competes for energy resources with the rest of the organism (allocation). The brain then alters the appetite (food intake) so that it can alleviate the stress system and return it to a state of rest."

Important points of the process of restoration of homeostatic balancing of energy supply are the following:

1. When there's a shortage of of glucose-based energy supply in the body, glucose allocation to the brain is provided anyway, even if the rest of the body is energy-starving.
2. Alternative substrates than can provide a portion of the brains energy supply, such as ketones, lead to a "disburdening" of the regulatory system.
3. This "disburdening" of the regulatory system works through ketogenesis, to ensure which the lipolysis starts leading to body mass reduction.
4. Replenishment of the stores can be later possible due to glucose allocation to the muscle and adipose tissue leading to normalization of body mass.
5. Return of the system of glucose sensors in the brain to a state of balance (setpoint).

Source: Neuroscience and Biobehavioral Reviews 28 (2004) 143-180

Pyruvate protects neurons against A-beta peptides characteristic for Alzheimer's

Pyruvate is one of major energy carriers in the brain, it is shown to be protective against damaging consequences of neurotoxins, such as hydrogen peroxide, glutamate, zinc, and copper/cysteine (1). Pyruvate plus another energy substrate, malate, in addition to standard glucose concentrations, protects embryonic neurons in the brain region such as hippocampus and cortex against glutamate excitotoxicity (2). These pyruvate and malate effects promoting neuronal survival were preferential over over glucose suggested that glucose-derived pyruvate from glucose may be limited in neurons studied in vitro, especially under conditions of elevated energy demands. neurons.

Supplementation of glucose-containing culture media with energy substrates, pyruvate plus malate (P/M), protected rat primary neurons from degeneration and death caused by A-beta peptides characteristic for Alzheimer's disease (3).

References

1. Eimerl and Schramm 1995; Desagher et al., 1997; Ruiz et al., 1998; Sheline et al., 2000; Wang and Cynader, 2001
2. Ruiz et al., 1998
3. Alvarez et al., 2003

Source: Pyruvate Protection Against -Amyloid-Induced Neuronal Death: Role of Mitochondrial Redox State. Gema Alvarez, Milagros Ramos, Francisca Ruiz, Jorgina Satrustegui, and Elena Bogonez. Journal of Neuroscience Research 73:260-269 (2003)

On the mechanisms of brain protection by ketones.

The interest to ketones remains high for almost a century because they are produced during the ketogenic diet, which is famous for many beneficial health effects. Notwithstanding its high clinical efficacy for treatment of drug-resistant childhood epilepsy, how exactly it worked, remained poorly understood. It's been known for a long time that early in life (as well as on a high-fat, low carbohydrate diet), glucose alone cannot meet the brain's energy needs and other energy carrying chemicals should take part. What's not been know, was how basic brain traits changed depending on available fuels.

Researchers studied how naturally occurring ketones influenced activity of brain cells during development. They showed that a shortage of ketones caused pathological changes in brain cells resulting in abnormal behavior of GABA, the principal brain chemical helping to resist hyperactivity. It was repeatedly reported earlier that, normally working as a "break pedal", GABA did not do the job in the immature brain and acted as a "gas pedal" instead. To imagine the devastating consequences, picture a car having two gas pedals and no brakes.

To make things worse, the energy deficit during hyperactivity is usually combined with increased energy demands thus starting a vicious circle -- demands/deficit/demands -- a well known feature of many neurodegenerative diseases including Alzheimer's, Parkinson's, epilepsy, encephalopathies, dementia, or multiple sclerosis. For many of them, the ketogenic diet was shown to be of a significant help. In the new article, the French and UK researchers offered an explanation. When there was enough of ketone bodies, GABA displayed its natural "break" properties and parameters of brain cells were also normal -- as it happens in real life, in real animals and babies.

Researchers suggest that sufficient supply of appropriate brain fuels can break the vicious circle and prevent brain's hyper-excitation. They now look into other natural energy substrates possibly having greater potential as a "diet in a bottle" than the costly ketones while being as efficient as the overly-stringent ketogenic diet.

Source: J Neurochem. 2009 Aug;110(4):1330-8. Epub 2009 Jun 22.
GABA action in immature neocortical neurons directly depends on the availability of ketone bodies. Rheims S, Holmgren CD, Chazal G, Mulder J, Harkany T, Zilberter T, Zilberter Y.

Toxic glycolysis and brain aging

The intermittent glycolysis during fasting, physical exercise, and stress may delay senescence by lowering intracellular concentration of methylglyoxal, a common intermediate in the Maillard reaction (glycation).

A simple logic allows to imagine that a situation when food is available to an animal at all times and in any quantities should be very seldom. In real life, there are seasons when food is abundant and seasons when it's scarce. To smoothen the energy delivery to vital organs, there all kind of depots, most famous (or rather infamous for us human beings in Western societies) is the fat depot, having practically unlimited capacity. There is clinical evidence that a human body can save in this depot enough energy to feed itself for a year. Vitamins and electrolyte fluids should be adequately supplied of course, but no calories enter the body - and it survives!

The opposite situation, when animals are allowed to eat as much as they can, as often as they can, is called ad libitum (AL). In experiments on beneficial effects of calorie restriction (CR), the food intake in the AL situation is taken for 100% and then different percentages of restrictions are applied to see CR effectiveness to slow down the process of aging, especially brain aging.

In an early study of the energy metabolism McCarter and Palmer (1) interesting differences were revealed, between rats fed CR diets and those fed the same food but AL. Although in both groups energy metabolism was mostly glycolytic, taping in carbohydrate metabolic way, CR very soon after feeding switched to using their bodies' fat reserves with their glycolysis suppressed, while the AL group maintained practically non-stop glycolysis.

So it's been suggested that that the beneficial effects of CR could be due to suppression of glycolysis and in experiments of Walker et al. (2) and Partridge and Brand (3) the question of whether the shortened life-span of AL animals results from some metabolic toxicity, specifically whether glycolysis is deleterious but possibly hormetic (4)

The hormesis hypotheses by Masoro (5) and Sinclair (6) suggests that intermittent stress may induce synthesis of long-term protective functions. Glycolytic intermediates dihydroxyacetone- and glyceraldehyde-3-phosphates are form methylglyoxal (MG), which is potentially toxic.

Hipkiss (7) suggested that non-stop glycolysis is deleterious due to the generation of MG, but periods of glycolysis interruption could be hormetic. MG damages mitochondria and induces a pro-oxidant state characteristics to cellular aging. The decreased glycolysis during CR may delay senescence by lowering intracellular MG concentration compared to AL animals.

Sources

1. Am. J. Physiol. 1992 263, E448-E452

2. Mech. Ageing Dev. 2005 126, 929-937

3. Mech. Ageing Dev. 2005 126, 911-912

4. Hormesis - An effect in which a toxic substance acts like a stimulant in small doses, but it is an inhibitor in large doses.

5. Mech. Ageing Dev. 2005 126, 913-922

6. Mech. Ageing Dev. 2005 126, 987-1002.

7. Mech. Ageing Dev. 2006 127 8-15

Is ketosis natural?

"Repeat after me three times, ketones are not evil, ketones are not evil, ketones are not evil... OK, now that we have gotten that out of the way..."

-- Jeffrey Paul Krabb, MD

In general medical literature, ketosis is often defined as abnormally high levels of ketone bodies in the blood.

Meanwhile, ketosis -- but not ketoacidosis! -- naturally occurs:

• Every morning after the night fast
• During fasting and calorie restriction
• After intensive prolonged exercise
• As a result of a diet significantly higher in fat comparing tha in carbohydrates
• Early in ontogenesis

Ketogenic diet is more efficient than antiepileptic drugs

• The ketogenic diet's success rate greatly exceeds that of the medications.

• Its side effects, both cognitive and allergic, appear fewer than most available medications.

• Understand why changing from a glucose energy to a ketone energy is anticonvulsant can help in developing a pharmacological approach simulating the biochemical effects of the ketogenic diet.

Source : “The Ketogenic diet. Advances in Pediatrics”, 1997.

Anticonvulsant action of the ketogenig diet

HYPOTHESES:

Ketogenic diet reduces seizures by:

a) promoting inhibitory action of GABA

b) reducing cellular consequences of energy deficiency by supplying an alternative and 40 % more efficient fuel

c) eliminating damaging consequences of excessive glycolysis

Question: what does work in this case -- ketone bodies or glycolysis exclusion?

Physiological effects of ketone bodies

Ketone bodies dynamics in neonatal rats

• Ketone bodies are produced from fatty acids in liver mitochondria in response to low availability of carbohydrate fuel (in the blood plus stored as glycogen)

• Ketone bodies enter the cells by simple diffusion (beta-hydroxybutirate) or are carried by transporters (acetoacetate) thus supplying energy source that is 40% more efficient than glucose

(Glucose enter the cells being carried by transporters that are under the influence of insulin)

Two energy sources: carbohydrates vs fatty acids

Read when and why glycolysis is harmful --> click here

The choice of an energy pathway is dictated by the law of substrate along-term vailability in food

The utilization of an energy source depends on short-term substrate availability to cells

Differences:

• The fatty acids pathway is more energy efficient by 40%
• Ketone bodies enter the cells by simple diffusion or are carried by transporters
• Glucose enter the cells being carried by transporters that are under influence of insulin
• The carbohydrate pathway includes the state of glycolysis, which is shown to potentially impose oxidative damage

Ketone bodies dynamics in neonatal rats

Energy substrates availability in milk

We calculated the ketogenic potential of different kinds of milk using the standard Wilder's formula (Wilder, 1921)

Ketogenic to Anti-Ketogenic Macronutrient Ratio

K:A=(0.9 fat +0.46 protein) : (1.0 carb +0.1 fat+0.54 protein)

This formula essentially reflects the rate of utilization of either carbohydrate or lipid substrates depending of their availability

The numbers in front of nutrient names are coefficients that are calculated based on nutrient ability to cause or resist ketosis.

1) Carbohydrate is assigned the coefficient 1.0 because it is an absolutely anti-ketogenic nutrient. The more carbohydrate grams contained in a diet, the less KB the body can produce

2) Fat is a 90-percent ketogenic nutrient

3) Protein can participate in the process of gluconeogenesis.

Here are K:A ratios of milk of some species.

Human milk - 0,568

Cow milk - 0,663

Goat milk - 0,779

Rat milk - 1,628

Mouse milk - 2,846

(Clinical data: out of 21,000 human neonates, 47 were in ketosis)

Ketosis dynamics in human newborns

Blood glucose concentration falls rapidly after birth, reaching its minimal level by 1 h of age and then rising to stabilize by 3 h of age even without feeding

During the first 8 h, newborns have low plasma ketone body concentrations despite adequate levels of precursor free fatty acids

Newborn brain potentially can utilize ketone bodies at a rate that is up to 40-fold greater than that of infant or adult brain

• Starting from 12 h of age, newborns show high ketone body turnover rates approaching those in adults after several days of fasting
• By the 6th postnatal day, breast-fed infants have lower blood glucose concentrations than formula-fed newborns but significantly higher ketone body concentrations and lower insulin responses

These findings suggest:

1. ketogenic properties of breast milk, e.g., lipase content allowing delivery of fatty acids to the liver
2. anti-ketogenic properties of protein, fat and energy load in the formula-fed infant

Sources: Denne, Kalhan, 1986; Kraus et. al, 1974, Bougneres et al., 1986, Hawdon et al., 1992; Persson B, Settergren, 1972; Stanley et al., 1979; Lucas et al., 1981

How well is ketogenic diet researched?

Research into the effects of ketone bodies: references

Ketogenic diet research, selected references