Calorie restriction, Autophagy, Longevity, and Muscle loss

We want to have muscle mass as much as possible and a fast metabolism as much as we can so that we can eat more and don’t gain weight but evolutionary biology will again tell us what is healthy and it is not constant overeating on food. Animals in nature have a hard time finding food so a basic level of existence is an increased level of autophagy with intermittent fasting and calorie restriction. I am going to use a quote from the U.S. Department of Health & Human Services National Institute on Aging website:

“Since the 1930s, investigators have consistently found that laboratory rats and mice live up to 40 percent longer than usual and also appear to be more resistant to age-related diseases when fed a diet that has at least 30 percent fewer calories than they would normally consume. Now researchers are exploring whether and how caloric restriction will affect aging in monkeys and other nonhuman primates.”

We have a large number of human studies now (Fernández-Ruiz, 2017). The calorie restriction response exists in nearly all of the species tested to date and probably had evolved very early in the history of life on Earth as a mechanism to increase the chances of surviving periodic shortages. There is a difference between fasting and prolonged calorie restriction but the underlining mechanism is the same, and caloric restriction will prolong life expectancy much more than fasting periodically although even fasting periodically will have beneficial effects on longevity.

The benefits come from two main reasons. There are other benefits like:

1. improved insulin sensitivity
2. regulating inflammatory conditions in the body
3. starving off cancer cell formation
4. detoxifying
5. improving eating patterns
6. hormonal balancing.

However, there are two main reasons on a cellular level that underlines all of the other benefits that sprout out of these two.

Firstly, when we fast blood levels of insulin drop significantly, and blood levels of growth hormone may increase as much as 5-fold. Insulin and growth hormone play antagonistic roles against one another. When one is elevated, the other will be low. When we go to sleep we fast for 10 hours, insulin drops and HGH (human growth hormone) rises. When HGH rises we grow, especially if you are in puberty. HGH stimulates growth, cell reproduction, and cell regeneration. It is thus essential in human development.

Secondly, when we fast our cells initiate important cellular repair processes and change in which genes they express. We start to regenerate and allow for cleansing and detoxification of the body. One of the reasons why sick people have a low appetite is that there are in the process of intensive regeneration. In medical terms that regeneration is called autophagy.

In the ancient Greek word, “phagy” means eating and the word “auto” means self, so autophagy means literary self-eating. You self-eat yourself every day. When any cell in our body dies, it will not go to waste. What happens is recycling. Autophagy is a completely natural physiological method in the body that deals with the destruction of cells. It controls homeostasis or regular functioning by protein degradation and destruction and turnover of the destroyed cell organelles for new cell formation. During cellular stress (deprivation of nutrients) the process of autophagy is increased.

Autophagy has the ability to likewise also destroy the cells under certain conditions. There is a form of programmed cell death and there is autophagy-induced cell death. Two different types. Programmed cell death is commonly termed apoptosis. Autophagy is termed as non-apoptotic programmed cell death with different pathways and mediators from apoptosis. Also, this is the key to calorie restriction and fasting. If the cell is precancerous for example or damaged or mutated in any way autophagy cell death will help our body to clean itself.

After glycogen depletion, we will go into increased autophagy, and our body will lean heavily on amino acids and protein catabolism for energy creation. Amino acids will be used, and some of the muscle mass will be lost.

Moreover, it is a good thing.

Our organism is much smarter than we think. Our heart is the muscle too, but it would not be touched. First goes glycogen, then fat, then muscle then vital organs, and then we die from malnutrition. It is a brilliant plan to sustain life throughout hunger. If there is a “bad” cell and a “good” cell and some of the cells need to “go” for energy, first on the line is the bad cell. First on the line to get rid of are the parts of the system that might be damaged or old. The inefficient parts. The absence of autophagy is believed to be one of the main reasons for the accumulation of damaged cells, and this can lead to serious health complications. If we start severely damaged by chemotherapy or other toxins, fasting cycles can generate, literally, an entirely new immune system.

Exercise by itself is able to increase autophagy in a situation where autophagy already happens. The more intensive the exercise is, the more effective it will be. However, if we eat and work out the exercise alone would not be beneficial.

The fastest way to shut down autophagy is to eat high amounts of complete protein. What this will do is stimulate IGF-1 (Insulin-like growth factor 1) and mTOR (rapamycin), which are potent inhibitors of autophagy. IGF-1 (Insulin Growth Factor) is somewhat responsible for muscle growth. However, IGF-1 catastrophic side effect is cancer. It is best to limit protein to about 50 to 70 grams per day, depending on lean body mass. When we ingest large amounts of protein, our liver detects it, and the response is:

”Hey let’s grow stuff, we have all essential amino acids now.”

It starts pumping IGF-1. In the fasting state liver, GH (growth hormone) binding is decreased, so more of the GH is left in the bloodstream. In protein restriction, GH receptors are maintained but not for IGF-1.

To avoid loss of muscle during calorie restriction and dieting and to increase the benefit of calorie restriction the way to go is to do moderate resistance training. This will not prevent muscle loss but will be beneficial to some extent (Cava et al., 2017).

Another way is to avoid non-vegan food or in other words sources of “complete” protein in high amounts.

When we ingest an incomplete source of protein, meaning it lacks some of the essential amino acids, it will not signal the IGF-1 release at the same level. It is not just about the overall amount of protein consumed but also the source (Allen et al., 2002).

If you are vegan and you eat complete sources of protein like soy, you will negate the benefit. It is because of the protein profile. Vegans for instance that eat 7 to 18 servings of soy meals a day may end up with circulating IGF-1 levels that are relative to those who eat meat. That is because soy has complete protein. Some other plants have high-quality proteins too. The high consumption level of protein in the diet has other negative effects regardless. Also if your only goal is to prevent muscle mass loss during dieting and are not interested in longevity you will want to increase your protein intake.

The good news is that we can use autophagy to clean our genetic base, the bad news is that we do not do it anymore. In the past nature forced us by not providing enough resources. Today we eat regularly and even if we go hungry that will not last enough to deplete our glycogen stores.

References:

1. Fernández-Ruiz I. (2017). Metabolism: Calorie restriction for healthy ageing. Nature reviews. Cardiology, 14(4), 190. https://doi.org/10.1038/nrcardio.2017.26
2. Cava, E., Yeat, N. C., & Mittendorfer, B. (2017). Preserving Healthy Muscle during Weight Loss. Advances in Nutrition, 8(3), 511-519. https://doi.org/10.3945/an.116.014506
3. Allen, N. E., Appleby, P. N., Davey, G. K., Kaaks, R., Rinaldi, S., & Key, T. J. (2002). The associations of diet with serum insulin-like growth factor I and its main binding proteins in 292 women meat-eaters, vegetarians, and vegans. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 11(11), 1441–1448.[PubMed]
4. Welton, S., Minty, R., O’Driscoll, T., Willms, H., Poirier, D., Madden, S., & Kelly, L. (2020). Intermittent fasting and weight loss: Systematic review. Canadian family physician Medecin de famille canadien, 66(2), 117–125.[PubMed]
5. Zouhal, H., Saeidi, A., Salhi, A., Li, H., Essop, M. F., Laher, I., Rhibi, F., Amani-Shalamzari, S., & Ben Abderrahman, A. (2020). Exercise Training and Fasting: Current Insights. Open access journal of sports medicine, 11, 1–28. https://doi.org/10.2147/OAJSM.S224919
6. Denduluri, S. K., Idowu, O., Wang, Z., Liao, Z., Yan, Z., Mohammed, M. K., Ye, J., Wei, Q., Wang, J., Zhao, L., & Luu, H. H. (2015). Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance. Genes & diseases, 2(1), 13–25. https://doi.org/10.1016/j.gendis.2014.10.004