There are three main nutrient sensors of the human body which are also shared with our mammal cousins. These are mTOR, AMPK and insulin, each of which modulate significant biochemical pathways. Most of these sensors affect multiple pathways. Blocking or inhibiting mTOR for example improves protein handling, increases autophagy and enhances stem cell function. (Source) Contrarily to the Government’s ideologically-driven Conventional Medicine and even to most of integrative medicine, Holistic Science recommends fewer nutrients as well as better quality nutrients. This is why caloric restriction and holistic vegan diets extend lifespans. Hence the rationale for decreasing and optimizing the above mentioned nutrient sensors.
In this perspective, AMPK induces mitochondrial biogenesis (creation of new mitochondrion) as well as regulates mitochondrial metabolism and dynamics. In the 2017 study, Weir et al showed that AMPK can maintain youthful mitochondrial network morphology even with aging. When they exposed animals to Dietary restriction and Intermittent Fasting, there was a striking change in mitochondrial networks..(1) If this holds true for humans, then dietary interventions are the key to longevity. This has refocused attention to meal quality, frequency, timing and intermittent fasting.
During our evolutionary history, most large animals and humans ate only intermittently. Long periods of starvation were normal, whether due to seasonal changes or due to episodic weather events. Many animals developed forms of quiescence in response to the onset of food shortages. If food was not available, then most of the cells in our body stop growing. Importantly, the same genes that control quiescence also control lifespan. In rodents, fasting for 24 hours every other day or twice weekly extends lifespan up to 30%. Chronic caloric restriction may also have similar benefits. Fasting may promote mitochondrial function, trigger autophagy and DNA repair pathways.
But what is more controversial is whether the benefits relate to caloric restriction in general, or whether it relates to specific nutrients. Original studies from 1985 suggested that it was calories, rather than protein. However, a point overlooked originally was that these animals were not food restricted. Subsequent studies, (eg. Grandison et al, 2009,) Solon-Biet 2014, Nakagawa 2012 and others pointed specifically to protein restriction as the key to longevity in these animal studies. Most believe this is due to dietary protein’s key regulatory effect on mTOR and IGF1. In humans, unlike rodents, severe calorie restriction does not reduce serum iGF-1 concentration unless protein intake is also reduced.
So the main question becomes what types of proteins ? Is it all protein or certain amino acids? At this juncture, the answer is not completely known. In animal studies the specific amino acid that is critical differs between species. In humans, branched chain amino acids seem to be a particularly strong activatory of mTOR.
Decreased Nutrients Sensors
Compared to other dietary interventions, intermittent fasting appears to be far more powerful because alone has the ability to affect all 3 nutrient sensors simultaneously, as well as stimulate autophagy and mitophagy. mTOR is sensitive to dietary protein. Insulin is sensitive to proteins and carbohydrates. So eating a pure fat diet may lower mTOR and insulin, but will not be able to raise AMPK, since that senses the energy status of the cells. Other problems will also be produced by a high fat diet.
Different nutrient sensors are sensitive to different time durations. That is, it would be useful for our body to know whether nutrients were restricted in the short term (overnight) in the medium durations (days) or long durations (weeks – months, seasons). You can see that our human body has evolved exactly those same capabilities in our nutrient sensors. Insulin (short term) mTOR (days) AMPK (weeks).
Insulin spikes quickly after a meal, but falls just as quickly during an overnight fast. It responds primarily to carbohydrates and proteins. While protein does not raise blood glucose, it raises insulin quite a bit. It also raises glucagon, so that blood glucose stays stable. mTOR is mostly sensitive to protein and particularly branched chain amino acids. It does not fall as quickly and takes somewhere from 18-30 hours to activate. AMPK is the reverse fuel gauge of the cell (AMPK goes up as cellular energy stores of ATP deplete) and only increases with prolonged energy deprivation. All macronutrients can contribute to ATP production, so AMPK is sensitive to all macronutrients.
These nutrient sensors overlap somewhat in their sensitivities and functions but each is also unique. In this manner, our cells are able to gain exquisite information about the particular macronutrient availability of the outside world.
Crafted by millions of years of evolution, the biochemical fine-tuning of our nutrient sensors is part of the holistic & happiness optimal longevity protocol.
Reference and Precision Notes
(1). Weir et al’s work highlights the key role that dietary restriction may increase lifespan by affecting mitochondrial networks. Mitochondrion are part of networks that can fuse together (fusion) or break apart (fission) in constant remodeling. A dysregulation of these mitochondrial dynamics and abnormal morphology (shape) of these mitochondrion are hallmarks of aging and thought to contribute to many degenerative diseases such as Alzheimers and Parkinsons. With age, many studies report increased swollem fragmented mitochondria. Mitophagy, a process of degrading damaged mitochondrion and recycling, plays an important role in keeping the dynamics normal.
(2) Most omnivorous mammals eat only intermittently, since we tend not to live on a Petri dish where nutrients are constantly available. Carnivores like lions and tigers often eat once a week or less. Ancestral humans tend to eat intermittently depending on food availability. Being able to function at a high level, both physically and intellectually, for extended fasting periods was fundamentally important to survival. This explains our well developed systems for food storage (glycogen in the liver, and body fat), and also our highly conserved nutrient sensors to slow cellular growth during a period of low nutrient availability. Things changed somewhat with the agricultural revolution approximately 10,000 years ago. From a hunter-gatherer society, agriculture allowed populations of humans to stay in one area and resulted in more stable food availability. However, there would still be seasonal variation and possibly long weeks or months where food is less available. There would also be shorter periods of time, days – weeks, where food was restricted.