Could we get by with only essential amino acids in food?

The content of individual specific amino acids in proteins seems to be key to maintaining a healthy metabolism. A change in composition by restricting certain amino acids leads to overeating, but also to greater wasting of energy as heat, so weight gain does not occur. Recent studies in mouse models clearly show that branched-chain (BCAA) and sulfur amino acids (SAA) play an interesting role here. While the mechanism for branched-chain ones is still very unclear, for sulfur amino acids the most likely mechanism of action appears to be sulfhydration of enzymes. For branched-chain acids, I would guess that the mechanism could be transamination to glutamate, which is metabolized in the TCA cycle in two different ways depending on the metabolic state. Either it is further processed via oxaloacetate into glucose, and then everything works normally, or it is processed by reverse run of IDH2 into citrate and then into fat. And that is the essential difference, which however is not described in studies, because there is no mouse model that would allow to study it. It is always assumed only that standard metabolism of glutamate into oxaloacetate occurs.

From study findings, it follows that the composition of proteins itself has a fundamental influence on food intake and longevity. Take for example this interesting study, where mice were fed a diet containing either only nonessential amino acids, only essential amino acids, casein, or a casein equivalent as a mixture of amino acids. In all cases the same equivalent amount, 20% by weight in the diet, was given.

Lifespan of mice with different protein compositions in the diet. StD – standard diet, EAA – essential amino acids, Casein-AA – amino acid mixture corresponding to casein, Casein-Prot – as protein, NEAA – nonessential amino acids.

Lifespan tells us which diet covered the needs best. We see that only nonessential amino acids cannot sustain mice. Essential amino acids simply must be obtained from food; the body cannot produce them. Not even milk protein casein, which contains almost 50% essential amino acids, is an optimal protein. A mixture of amino acids with the same composition as casein looks slightly better. Why? Probably because part of casein reaches the large intestine, where bacteria metabolize it according to their needs, so the body lacks it. But if we mix an amino acid mixture, it does not reach the large intestine, and more essential amino acids enter the body.

A lack of essential amino acids turns nonessential amino acids into merely an energy source. To make proteins, the body needs all amino acids; if the essential ones run out, nothing further can be made and they must be burned as unnecessary waste. This is clearly visible. But if mice were given only essential amino acids, they could easily produce the other nonessential amino acids. It seems that an excess of essential amino acids causes no fundamental problems, quite the opposite. However, an excess of nonessential amino acids can be a problem.

Let’s recall that a deficiency of essential amino acids has in some situations shown to be beneficial. It is somewhat of a paradox. How is that possible? Probably not as a lifelong method, but it can stimulate the organism to greater activity. We already know this is mainly due to the hormone FGF21, which activates the PPP pathway and restores NADPH levels by using glucose to produce it. That increases metabolic activity in fat tissues, activates senescent stem cells, increases heat production, and signals to the brain a shortage of amino acids, leading to increased food consumption. If we switch off FGF21 production, then everything depends purely on the ratio of essential to nonessential amino acids in proteins. A lack of essential amino acids allows nonessential amino acids to be converted into glycogen, reducing the need to replenish glycogen by eating food, but without activating thermogenesis, this can mean weight loss. But sufficient liver glycogen may also promote new fat production, which in turn may increase food consumption and mean weight gain. These situations occur if the diet contains a lot of protein.

Switching off FGF21 production (Fgf21 KO) suppresses the effect of reducing protein (LP) in the diet. EE – energy expenditure as heat, BW Change – body weight change

A lack of essential amino acids is therefore a fairly fundamental modulator of metabolism. How is amino acid intake regulated? Studies tell us it is the hormone FGF21, which signals essential amino acid deficiency. The brain evaluates the level of FGF21 and promotes higher consumption, preferentially of protein. Mice in protein deficiency can evaluate which diet contains more essential amino acids and prefer it. Adipose tissue reacts to FGF21 with increased activity in storing and burning by thermogenesis, especially brown fat. That increases energy expenditure, reflected in higher consumption and thus higher intake of essential amino acids. The increase in burning raises the ratio of essential amino acids to other energy macronutrients. That seems to be the point.

In the first weeks, food intake is almost the same across groups, severe essential amino acid deficiency lowers weight but shortens life, their sufficiency ensures growth.

Exclusively essential amino acids instead of a mixture of all amino acids ensure the lowest food intake, low body weight, and the longest lifespan, without loss of size (length).

Let us now continue freely in the series…

Who tells us we’ve eaten enough food? (3)

…this time about proteins…

How could we arrange it so we can easily tell whether we have enough or not enough material and fuel for energy production? Quite simply, I would do it like this: wait to see what the body processes, and convert the excess into one substance—guess which? I already mentioned it once—liver glycogen. Excess materials, where possible, can be converted like carbohydrates into oxaloacetate and subsequently into glucose and glycogen. A lack of glycogen activates enzymes needed for gluconeogenesis, while an excess activates new fat production and storage. So if, for example, some nonessential amino acids are in excess with no use, they will replenish liver glycogen and reduce food intake, or start converting directly into fats. With fats it is different, as de novo lipogenesis is inversely counted into liver glycogen.

Does this model also work for protein intake? Essentially yes, if in the mouse model FGF21 production is switched off (FGF21 KO). The difference in body weight when changing the content of all amino acids (proteins) in the diet is then minimal. If the ratio between essential and nonessential amino acids does not change, glycogen must be replenished from carbohydrates; in the case of a high-fat mouse diet, fat intake also rises. Reducing protein slightly increases fat storage and slightly increases body weight.

It is different with active FGF21. High protein activates muscle and fat production, but protein restriction activates FGF21 and thermogenesis. All unnecessary material is burned and the ratio between essential amino acids and the rest of the unnecessary material improves significantly. True, muscles do not grow that way, but metabolism reaches optimal values and lifespan is extended.

Effect of alternating a standard protein diet (normal protein) and a low-protein diet for normal mice (C57BL6J) and for FGF21 knockout mice (FGF21-KO).

Essential amino acids therefore have their own independent regulation of dietary sufficiency. That regulation is the liver hormone FGF21. It adjusts metabolism so that more unnecessary nonessential amino acids are burned in brown fat, heat is released, and excess energy does not have to be stored as fat. It also directs the organism to seek amino acid sources—for example, mice somehow detect they lack protein and then prefer water with casein (milk protein). This is remarkable, since they probably cannot distinguish this by taste. If FGF21 production is switched off in mice, food intake is then normally controlled by liver glycogen, i.e., by the body’s energy consumption regardless of essential amino acid content. If there are surpluses, they are converted into liver glycogen; if not, more must be eaten from whatever is available—a mixture of carbohydrates, fats, and proteins. The body adjusts the ratios metabolically as needed. If essential amino acids are missing in this situation, the body stops functioning, does not eat more food, does not seek proteins, and dies prematurely. FGF21 is simply vital for survival on a diet containing little protein.

I think this is exactly the effect we see in diets with exclusively nonessential amino acids or with their large dominance (NEAA100%, EAA30%). The body lacks material for FGF21 production or simply does not switch it on. It does not detect the deficiency of essential amino acids. The result is malnutrition and early death.

In the case of a high casein diet, FGF21 is not activated, even though casein contains about 50% essential amino acids. As a direct ratio that is too little, but for FGF21 activation probably the total amino acid amount is too high. Fat production is activated. Food consumption rises and lifespan shortens. I think simply lowering the percentage of casein in the diet would significantly extend mouse lifespan. There would be fewer essential as well as surplus amino acids, and perhaps FGF21 could be activated. That would burn off excess fuel. But glucose is required for that.

What would a low-carbohydrate, low-protein diet do? That is, a high-fat diet. Even more FGF21. We have results from another study. But the question is whether this activates thermogenesis (UCP1). In the following figure we see that it does not much. Thermogenesis is mainly activated by a relatively low-fat diet with reduced protein. For thermogenesis, glucose is needed.

CON – standard diet (20% casein), LP – standard diet with reduced protein (5% casein), HFCON – high-fat diet (60% fat), HFLP – high-fat diet with reduced protein. UCP1 activates energy wasting, Acc1/Scd1/Fas/Pparg activate fat production.

As I have shown many times here, with an energy surplus the body has two options. Either activate thermogenesis, or instead trigger new fat production and cellular senescence. This is always the case—the body simply has two options for dealing with surpluses, switching depending on whether it has enough NADPH molecules for GSH recycling and thus for antioxidant protection of increased metabolism. If not, it cannot activate increased metabolism and switches to fat production and cellular senescence. The hormone FGF21 apparently helps the body make the choice toward thermogenesis, limiting fat and senescence formation. It seems that activating FGF21 is relatively easy, just reduce protein amounts at least in some meals. Alternating protein and low-protein meals may be the key we are looking for. Thinking about eating habits around 100 or more years ago, protein meals were “festive”, served only on Sundays. On weekdays, meals contained little protein.