And Those Proteins Again — Limit Them or Not?

Although all nutrition experts keep convincing us that we eat too little protein—because we supposedly need all essential amino acids to build muscle—things may be far more complicated. I’d say this view of metabolism comes from findings based on studying athletes. But I’m definitely not an athlete. I understand that top athletes need to regenerate muscle with enough branched-chain amino acids (BCAAs), for example. However, the general population doesn’t wear down their muscles very much and probably recycles amino acids to a greater extent without needing to supply new ones. Mice in studies are active, but they don’t undergo any special performance training. So they may be a good model for the general population.

I’ve already written here about how protein affects mouse longevity. Now let’s discuss one study that examined the short-term effects of lower protein intake on the organism using a mouse model. The study lasted only one week. Yet the changes are very striking. I increasingly recall the eating habits of our ancestors, specifically their weekly cycle. We no longer have anything like that—we eat basically the same every day. That really wasn’t typical. Sundays were exceptional; they were days for replenishing protein. The other weekdays probably resembled a protein intake somewhere between 5 and 10% of calories. This study may help us understand what happens in the body during a week of limited protein intake.

Here we see six groups with different protein intakes ranging from 0% to 18% of total caloric intake. Casein, a milk protein, was used as the protein source. It’s not ideal, because from other studies we know that when standard chow is replaced with a casein-based mix, it shortens the lifespan of mice. The changing protein content was replaced with sugar. So this is also somewhat a study on replacing protein with sugar. The mice had free access to food—there were no restrictions.

At first glance it’s clear that some parameters change nonlinearly: they first rise with increasing protein intake to some optimal value and then fall, e.g., body fat. Others have a minimum, or are linear, e.g., insulin and glucose levels. We’re talking about healthy mice here, with no metabolic issues.

The finding? It’s 6%! So roughly 6% or more protein seems to be above the threshold, while less than 5% protein (casein) likely causes problems, triggering defense programs. We can see this in the FGF21 hormone graph. I could stop here—we know what we needed to know. If we cycle protein intake between 6 and 20%, we’ll be in the same zone. If we want to kick a disrupted system into action, less than 5% protein may trigger it.

By limiting protein, fat storage can be shut down—this is clearly visible in the analysis of the enzymes required for fat production (FASN, SCD1). Detoxification enzymes (ALDH2) and anti-senescent activity (FGF21) can also be activated.

What mechanism causes this? I’d say that activation of protein production under mild protein shortage also activates gluconeogenesis—the production of glucose in the liver, for example from glycerol. Evidence for this is increased aspartate production from glycerol.

As we’ve seen, aspartate is part of the malate–aspartate shuttle, which transports NADH between mitochondria and the cytosol, thereby regulating glycolysis as needed. The activity of this shuttle tends to be disrupted by a fatty diet. Increased glycerol use likely leads to the release of glycerol from fat stores and could be the cause of rapid weight loss as well as significantly reduced insulin levels when protein intake is low. Fats are stored in fat droplets as triglycerides—three fatty acids bound to glycerol via ester bonds. Overall, limiting protein may address problems that arise from a fatty diet as a consequence of peroxidation of vulnerable omega-6 polyunsaturated oils. It may restore glycolysis regulation and activate detoxification, preventing poisoning by toxins such as HNE and MDA.

Increased demand for glycerol leads to reduced insulin production, increased lipolysis, and glycerol release. Along with it, free fatty acids are released, which reduces glucose oxidation because it forces the organism to burn more fat. Glycerol and glucose can therefore serve to produce non-essential amino acids to replenish the amino-acid spectrum. I assume that essential amino acids are preferentially obtained by breaking down unnecessary structures.

Older people have many of these senescent, non-functional cells, so there is plenty to recycle. That’s why I see a big difference in protein requirements between young, growing individuals and older people with a high proportion of senescent cells. I think determining the optimal content and composition of protein depending on metabolic state and the proportion of senescent cells would be highly desirable. I hope researchers will emerge who bring new information to this issue and conduct studies that take these additional parameters into account.

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References:

Multiomics assessment of dietary protein titration reveals altered hepatic glucose utilization