Autophagy – the secret of cell renewal by Dr. Ohsumi

In 2016, the Nobel Prize in Physiology or Medicine was awarded to Dr. Yoshinori Ohsumi of the Tokyo Institute of Technology for identifying the mechanisms underlying autophagy. Autophagy (a term derived from the Greek words auto-, meaning “alone,” and phagein, meaning “to feed”) is a vital function in which intracellular proteins are broken down to be reused to generate the amino acids needed to sustain life. This function is also known as the “intracellular recycling system”.

Dr. Yoshinori Ohsumi first observed and documented autophagy in yeast cells in 1988, when he observed the encapsulation of proteins from the vacuole and their degradation to amino acids, after which they were returned to the cytoplasm of the cell. The scientist subsequently devoted himself to studying the process of autophagy and discovered and identified 14 of the genes mediating the process. The equivalent of the yeast vacuole in mammalian cells is the lysosome. Cells also use the mechanism of autophagy to eliminate damaged organelles and proteins, a quality control mechanism by which they combat the negative effects of aging.

How does fasting stimulate autophagy?

Subsequently, there is a trend of searching for mechanisms promoting autophagy. It is becoming clear that different types of food restriction are a very successful means to this end. Broadly speaking, the main mechanism by which fasting promotes autophagy is by suppressing so-called nutrient-sensing pathways – cellular pathways that sense the availability of nutrients and energy. Restricted food intake reduces glucose, amino acid, insulin and IGF-1 levels, resulting in decreased activity of the IGF-1/PI3K/AKT and mTOR/S6K signaling axes. Since mTOR is one of the major negative regulators of autophagy, its suppression removes the brake on this process and allows activation of cellular “self-cleaning”.

In parallel, the energy deficit during fasting also activates adaptive cellular programs related to stress resistance and survival. As a result, the cell transitions from a state of growth and synthesis to a state of maintenance and recycling in which damaged proteins, aggregates, and dysfunctional organelles are degraded and reused. This is what autophagy is, an evolutionarily conserved mechanism of intracellular clearance and metabolic adaptation.

Therefore, starvation does not stimulate autophagy directly but through a metabolic deficiency signal that inhibits pro-growth pathways and activates cell survival, repair and recycling programs.

Research shows that fasting also increases the amount of the substance spermidine. It plays an important role because it helps to activate processes in cells that stimulate autophagy. When there is more spermidine, the cells more easily “clean themselves” and work more efficiently.

This is one of the reasons scientists believe that fasting or calorie restriction can have a positive effect on health and longevity. However, it is still not completely clear exactly how all these processes work in the human body and more research is needed.

The relationship between fasting, spermidine and autophagy

Recent studies have shown that fasting and calorie restriction lead to increased levels of the polyamine spermidine in a variety of organisms, including yeast, insects, mammals, and humans. This increase is due to increased metabolic flux through the polyamine synthetic pathway, which is activated upon nutritional deficiency. Spermidine , in turn, directly regulates autophagy by stimulating hypusination of eIF5A, a specific posttranslational modification of the translational factor eIF5A that is required for the activation of autophagic processes. Experimental data show that blocking spermidine synthesis or eIF5A hypusination significantly reduces the autophagic response to starvation, indicating that spermidine is a key mediator of nutritional deficiency-induced autophagy.

Sources used:

1. GOVERNMENT OF JAPAN, 2017. Autophagy Research Opens New Medical Frontiers. Available at: https://www.japan.go.jp/tomodachi/2017/autumn2017/autophagy_research.html
2. Intermittent and periodic fasting, longevity and disease, doi: 10.1038/s43587-020-00013-3
3. HOFER, S. J., DASKALAKI, I., BERGMANN, M., FRIŠČIĆ, J., ZIMMERMANN, A., MUELLER, M. I., ABDELLATIF, M., NICASTRO, R., MASSER, S., DURAND, S., et al. 2024. Spermidine is essential for fasting-mediated autophagy and longevity. Nature Cell Biology. 26(9), 1571-1584. Available at: https://doi.org/10.1038/s41556-024-01468-x
4. NOBEL FOUNDATION, 2016. The Nobel Prize in Physiology or Medicine 2016 – Press Release. Available at: https://www.nobelprize.org/prizes/medicine/2016/press-release/