Could "alternate-day fasting" make you healthier?

Scientists have discovered a possible reason why this extreme form of intermittent fasting works.

Alternate day fasting is a deprivation diet that may be as challenging as it is beneficial for health. Studies on humans and animals suggest that eating just every other day could be a sound way of preventing metabolic conditions like high blood pressure and cholesterol, both of which can cause heart disease.

But scientists are just starting to get to grips with why this extreme form of intermittent fasting seems to work to our advantage.

In a new study published Tuesday in the journal Cell Reports, scientists show alternate day fasting’s profound effect on liver proteins and the metabolism of fatty acids in the liver. The results point to the reason why fasting positively affects metabolic health, suggesting that it is the act of repeated fasting itself — and not any accompanying weight loss — that underlies the benefits.

Why does alternate day fasting boost health?

The results add to a growing pile of evidence suggesting the diet holds hidden health benefits, although it doesn't necessarily help you lose weight.

In a September 2019 study published in the journal Cell Metabolism, researchers declared that a strict, alternate day fasting diet was “safe” for healthy adults. The largest study of its kind, the results linked the diet to lower cholesterol levels, less belly fat, and reduced levels of sICAM-1 — a biomarker linked to age-associated disease and inflammation.

And in other studies in mice, alternate day fasting is linked to increased lifespan, improved insulin sensitivity, decreased total blood cholesterol levels, and reduced fasting-glucose levels — but in the absence of any weight loss. A 2017 study on 100 humans similarly found that alternate day fasting did not affect weight loss.

The new mouse study moves the science forward by investigating how fasting drives these positive effects without affecting weight.

Mice on the alternate day fasting diet were allowed to eat however much they want for one day, and then given no food the next day. This regime was kept up for 12 days. Meanwhile, control mice could eat however much chow they wanted every day.

The fasting mice ate almost twice as much on their feeding day compared to the control mice, but they showed no significant body weight differences.

But their bodies did change in other ways: They were significantly more glucose tolerant compared to the control group mice, and they had lower insulin levels.

The changes in the fasting mice led the researchers to analyze their liver tissue to see if anything had changed in the way the organ processed sugar. The liver is known to be a key fasting-responsive organ. They discovered that fasting “reprograms” the HNF-4(alpha) protein, which regulates a number of liver genes. Fasting inhibited the protein's production, which the researchers link to downstream consequences in the mice, including lower abundance of blood proteins linked to inflammation.

The analysis also reveals that fasting changes the metabolism of fatty acids in the liver.

Although the study is in mice, there is hope that the findings will be translated to humans. Mice have a "complex response to fasting" that the researchers argue. Ultimately, the team hopes that further examination of the pathways identified in this study may enable the development of “small molecule interventions” — therapies that can induce the diet's beneficial effects “without the need to fast.”

That could be the win-win people are looking for. Fasting comes with serious downsides — it is incredibly difficult to stick with it, and it can send people with a history of eating issues down a dangerous path. Ultimately, exercise, nutritious foods, and sleep are the holy trinity of good health — but fasting is a more novel approach that may pay out some of the same dividends... fast.

Summary: Every-other-day fasting (EODF) is an effective intervention for the treatment of metabolic disease, including improvements in liver health. But how the liver proteome is reprogrammed by EODF is currently unknown. Here, we use EODF in mice and multi-omics analysis to identify regulated pathways. Many changes to the liver proteome are distinct after EODF and absent after a single fasting bout. Key among these is the simultaneous induction by EODF of de novo lipogenesis and fatty acid oxidative enzymes. Together with the activation of oxidative stress defenses, this contributes to the improvements in glucose tolerance and lifespan after EODF. Enrichment analysis shows unexpected downregulation of HNF4 targets by EODF, and we confirm HNF4 inhibition. Suppressed HNF4 targets include bile synthetic enzymes and secreted proteins, such a 1-antitrypsin or inflammatory factors, which reflect EODF phenotypes. Interactive online access is provided to a data resource (https://www.larancelab.com/eodf), which provides a global view of fasting-induced mechanisms in mice.
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