Protein Restriction as a Possible Accelerator of Autophagy

There seems to be a growing consensus that prolonged fasting—perhaps somewhere between 48 and 72 hours—is required to produce substantial autophagy. The longer the fast continues, the greater the presumed level of autophagy, although the exact timing in humans remains uncertain.

But this raises an interesting question.

We know that eating protein can suppress autophagy, at least in part because amino acids activate pathways such as mTOR that signal the body that nutrients are available. That makes biological sense. If amino acids are readily available from food, the body has less reason to break down and recycle its own cellular components to obtain them.

But what about the opposite situation?

Could severely restricting dietary protein cause autophagy to increase sooner than it would during a normal diet?

The logic seems straightforward. The body is constantly breaking down and rebuilding proteins. I've read that the amount of protein involved in daily protein turnover may be roughly 300 grams or more. Of course, that does not mean the body needs to consume 300 grams of protein every day, because most of the amino acids released through protein breakdown are recycled.

Still, suppose a person normally consumes 100 grams of protein per day. Now suppose that intake is reduced to only 15 grams.

That creates a much greater shortage of incoming amino acids.

Wouldn't that greater shortage provide a stronger signal to the body that amino acids are scarce? And if amino-acid scarcity suppresses mTOR and promotes autophagy, wouldn't severe protein restriction potentially cause autophagy to become active sooner than it would otherwise?

In other words, perhaps the relevant question isn't simply how many hours have passed since the last meal, but also how much protein and how many amino acids are being supplied during that period.

The question becomes even more interesting if the severe protein restriction continues for several days.

If 15 grams of protein is consumed on the first day, and then another 15 grams on the second day, and another 15 grams on the third, would the continued shortage of dietary amino acids progressively increase the body's reliance on its own internal recycling mechanisms?

Could this potentially produce some of the cellular effects associated with prolonged fasting without requiring a complete fast?

I realize there is an important distinction between protein turnover and autophagy. The body does not simply calculate its daily protein requirement, subtract the amount eaten, and obtain the difference by destroying old cells. Most protein turnover involves continuous recycling of amino acids within the body's existing protein pool.

Nevertheless, the underlying question seems legitimate:

Could severe protein restriction create a sufficiently low-amino-acid environment to activate autophagy earlier, or more strongly, than would occur with normal protein intake?

And if so, is there a point at which progressively lower protein intake produces progressively greater autophagy—or does the body simply adapt through other mechanisms?

These seem like questions that could be tested experimentally in humans. Ideally, researchers could keep calories relatively constant while progressively reducing protein intake and then directly measure autophagic flux over time.

I'm particularly interested in whether anyone has actually performed that kind of human experiment.

The idea seems biologically logical, but I'm not sure whether the science has established it—or whether we've simply assumed that the duration of a complete fast is the primary determinant of autophagy.