Discusses how autophagy induction may have been an every-day phenomenon in human history.
The Natural State
One question that arises from CR studies is why the cell would not practice autophagy independent of diet if the benefits were so substantial? A good question, one that should be asked of any simple panacea. To answer the question, we need to consider the ‘natural state’ within which human evolution has operated.
Consider the case with ascorbate (vitamin C). Humans and other primates lack the ability to synthesize it and as a result are prone to scurvy and other problems when it is in short supply. It is thought that primates in the ‘natural state’ lost the necessary gene, the so-called ‘thrifty gene’ hypothesis20, since they were primarily tropical and ate lots of fruit and the loss of the gene had no immediate down side. There was no selection pressure to retain it and we now suffer the consequences.
Consider then the benefits of exercise to human health. Again in the ‘natural state’ vigorous exercise was probably a given for all individuals. There was no selection pressure to provide its benefit in its absence.
Similarly there was probably little selection pressure to promote autophagy independent of diet since being on the edge of starvation is so common in the natural state. Animals generally reproduce until their numbers match the available food supply, which is more-or-less the definition of being on the edge of starvation. In the natural state, an animal crosses that edge many times in its life, inducing autophagy each time.
Nor would they be eating ‘balanced’ meals. When a fruit was ripe, they would eat that until it was gone. Similarly with any other scavenged food source. There would be times of low protein intake as well as times of high with days or weeks between. Even when fed to satiation, our genetic ancestors could have been protein cycling.
We cosmopolitan humans have ‘progressed’ beyond the natural state and must consciously compensate by exercising, taking vitamins, and dieting. protein cycling may then be just one more activity to add to that list.
Before we managed fire, our days were governed by the sun. In the tropics, the sun is down for 12 hours every day. Without fire, there is little to do in the dark but sleep. So our ancestors likely fasted at least 12 hours every night even if they ate continually throughout the day. A 12 hours fast with our ancestors’ diet may have been sufficient to induce autophagy and perhaps they were already protein cycling. Even today the conventional American diet is three meals a day in one 12 hour interval and two 6 hour intervals. The English language even recognizes the overnight as a fast and calls the morning meal ‘breakfast.’ On a low protein diet, the overnight interval may be sufficient to induce autophagy and perhaps protein cycling is routine for most people of the world. Indeed the traditional breakfast in many cultures is notably lacking in protein and perhaps there are 18 hours of protein fasting when that is the case. In parts of the Amazon, for instance, breakfast is often just coffee and a piece of casabe, a no-protein bread made from cassava. The ‘traditional’ breakfast in most countries is coffee or tea and bread with sugar in some form. Again protein is notably lacking. Interestingly, caffeine and similar substances, as found in coffee or tea, are also promotors of autophagy. They inhibit the same enzyme known as ‘mammalian target of rapamycin’ (mTOR) just as does rapamycin, the standard research drug for inducing autophagy21.
Perhaps the health problems peculiar to modern culture, the increasing incidence of AD and especially of diabetes22, are a consequence of the extinguishing of the overnight protein fast. Many people now eat protein-laden snacks well into the evening and have ‘balanced’ high protein breakfasts the next morning. This, together with a high protein diet generally, may be enough so that routine autophagy that the cell may depend on for aggregate clearance fails to occur. If this speculation were true, and it is just a speculation, then protein cycling could be achieved merely by not snacking in the evening and eating a low protein breakfast with coffee or tea!