Autophagy and Fasting: 10 Years After the Nobel Prize

On 3 October 2016, the Nobel Assembly at Karolinska Institutet awarded the Nobel Prize in Physiology or Medicine to Yoshinori Ohsumi "for his discoveries of mechanisms for autophagy". Ten years on, autophagy is one of the most quoted words in fasting. The prize itself was for basic cell biology done in baker's yeast in the 1990s, and it says nothing about how many hours a person needs to fast.

What autophagy is

The press release describes autophagy as "a fundamental process for degrading and recycling cellular components". The word comes from the Greek auto- ("self") and phagein ("to eat"), so it literally means self eating.

The mechanics, as the Nobel Assembly sets them out:

1. A membrane forms inside the cell and wraps around some of the cell's own contents, such as damaged proteins and organelles. This sack-like vesicle is called an autophagosome.
2. The autophagosome travels to the lysosome, a compartment filled with digestive enzymes.
3. The two fuse, and the contents are broken down into smaller constituents.
4. Those constituents give the cell nutrients and building blocks for renewal.

The idea was not new in 2016. According to the press release, the concept emerged during the 1960s, when researchers first saw that a cell could destroy its own contents this way. Christian de Duve, who received the Nobel Prize in 1974 for discovering the lysosome, coined the term autophagy. But the process was hard to study, and little was known about how it worked.

What the prize was actually for

Ohsumi started his own lab in 1988 and turned to protein degradation in the yeast vacuole, the yeast counterpart of the lysosome in human cells. Yeast is easy to grow and good for finding genes, but its cells are small, and at the time it was not even certain that autophagy existed in yeast.

His key experiment was a piece of clear reasoning. If autophagy was happening, autophagosomes should be arriving at the vacuole and being destroyed too quickly to see. So he took mutated yeast that lacked the vacuole's degradation enzymes and starved the cells to stimulate autophagy. Within hours, the vacuoles filled with small vesicles that had not been degraded. Those were autophagosomes. The result, published in 1992, showed that autophagy exists in yeast and, more importantly, gave him a way to see when it was working and when it was not.

From there the path was genetic. Ohsumi exposed yeast cells to a chemical that introduced random mutations, then induced autophagy and looked for cells in which the vesicles failed to accumulate. Within a year of the first discovery he had identified the first genes essential for autophagy. The press release credits him with studying thousands of yeast mutants and identifying 15 genes essential for the process, then working out what the proteins they encode do: a cascade of proteins and protein complexes, each regulating a distinct stage of how an autophagosome starts and forms.

The final step mattered most for medicine. In the Assembly's words, "virtually identical mechanisms operate in our own cells". That gave researchers the tools to study autophagy in humans.

What the Nobel Assembly said about starvation

Here is where fasting enters, and where care is needed.

The press release says that autophagy "can rapidly provide fuel for energy and building blocks for renewal of cellular components, and is therefore essential for the cellular response to starvation and other types of stress". It lists "adaptation to starvation" among the physiological processes in which autophagy is important.

It also links autophagy to much more than food: eliminating invading bacteria and viruses after infection, embryo development and cell differentiation, and clearing damaged proteins and organelles, which it calls a quality control mechanism "critical for counteracting the negative consequences of aging". Disrupted autophagy, it notes, has been linked to Parkinson's disease, type 2 diabetes, cancer and other disorders, and mutations in autophagy genes can cause genetic disease.

Notice what kind of statements those are. They are about cells. The starvation in Ohsumi's experiment was yeast cells deprived of nutrients in a lab culture.

What that does and does not tell you about fasting

What it supports. Nutrient deprivation is a trigger for autophagy at the level of the cell, and the machinery Ohsumi found in yeast has close counterparts in human cells. It is reasonable to say that autophagy is part of how cells respond when nutrients run short.

What it does not show.

• No human timing. The press release contains no number of hours at which autophagy starts or peaks in a fasting person. "Within hours" describes yeast with a disabled vacuole under a microscope, not a human body.
• No fasting trial. The prize was not awarded for a study of people fasting, and the press release cites none.
• No health promise. Links between disrupted autophagy and disease do not mean that fasting to increase autophagy prevents or treats those diseases. The press release describes research toward drugs that target autophagy as ongoing in 2016, not as finished.
• More is not automatically better. The document describes autophagy as a regulated process with many roles. It does not say that pushing it higher is always desirable.

So when you read that a fast of a particular length "activates autophagy", ask what the source is. The 2016 Nobel Prize is not that source. On the evidence of this document, the timing of autophagy during a human fast is not established.

That is also how to read the autophagy marker in a fasting app. In QoFast, the hour at which the timer shows the autophagy phase is the app's estimate based on hours fasted. It is a guide to where you are in a fast, not a measurement of what your cells are doing. Our autophagy page and the fasting stages overview explain how the app presents these phases, and the science of ketosis and fasting covers the neighboring stage.

Fasting content is general information, not medical advice. If you are pregnant or breastfeeding, have diabetes or take blood-sugar medication, have a history of eating disorders, take other regular medication, or are under 18, talk to a doctor before fasting. Do not fast to treat or prevent a disease on the strength of autophagy research.

QoFast is a fasting tracker app for iPhone and Android, for intermittent fasting and multi-day extended fasts. It shows in real time which phase the app estimates you are in (fat burning, ketosis, autophagy) based on hours fasted. It gives general information, not medical advice. It is free to download, with an optional Pro subscription: App Store and Google Play.

FAQ

Who won the Nobel Prize for autophagy? Yoshinori Ohsumi received the 2016 Nobel Prize in Physiology or Medicine, announced on 3 October 2016, for his discoveries of mechanisms for autophagy.

Did the Nobel Prize show that fasting causes autophagy in humans? No. The prize recognized experiments in yeast that identified the genes and mechanisms of autophagy. The press release says autophagy is essential for the cellular response to starvation, but it reports no human fasting study.

How many hours of fasting does it take to start autophagy? The Nobel press release gives no such figure, and human timing is not established by it. Hour markers in apps, including QoFast, are estimates.

Sources

• The Nobel Assembly at Karolinska Institutet. "The Nobel Prize in Physiology or Medicine 2016: Press release." 3 October 2016. nobelprize.org/prizes/medicine/2016/press-release