Recent Research on Fasting and Calorie Restriction (December 2023)

I hope you will enjoy this new issue, including several studies on fasting and brain health, effects of dietary restriction of a single amino acid, information on lung cancer cell reprogramming during calorie restriction, and the description of a novel calorie restriction mimetic.

1/ Adult neural stem cells are resilient to intermittent fasting.

Two studies published in EMBO reports observed that intermittent fasting did not promote the growth of new brain cells nor enhance memory in mice. The scientific literature is often biased because scientific journals are less interested by negative findings. However, they are still important to highlight because they often reveal nuances which were unknown before.

In the first study, night‐time every‐other‐day intermittent fasting did not have any effect on adult hippocampal neurogenesis in mice. The fasting regimen did not increase the proliferation of adult neural stem cells, nor did it promote the differentiation of these cells into new neurons.

The second study tested the 5:2 intermittent fasting protocol in mice. They also found no induction of hippocampal neurogenesis and no improvement in learning in adolescent or adult mice of either sex. There was also no impact of intermittent fasting on spatial learning or anxiety behavior.

Both studies contradict previous findings suggesting that intermittent fasting could boost brain health and cognitive function. Even if these studies are of very high quality, we should thus not rush into concluding that it shows intermittent fasting doesn’t promote brain health. Looking at the big picture, it probably reflects that different fasting protocols are not equal in activating neurogenesis. This is not necessarily a surprise knowing that mechanisms which are responsible of cell regeneration like autophagy are only activated by long fasting protocols.

2/ Intermittent fasting effects on memory in aged mice.

In this new study on mice, intermittent fasting increased norepinephrine and dopamine in the hypothalamus, enhancing cognitive function. Anxiety-like behavior in these mice was reduced by intermittent fasting. Spatial navigation was improved in females. However, spatial object orientation was impaired. In addition, novel object recognition was impacted and this varied by gender and age. These effects are highlighting the nuanced impact of intermittent fasting on mood and cognition based on sex and age in laboratory animals. It could provide clarification as to why the studies described above did not found effects of intermittent fasting on brain health, since these effects are not only dependent on fasting protocol but also on sex and age.

3/ Fasting has analgesic effects by increasing orexin levels.

Intermittent fasting reduced pain in mice. Scientists found that this was related to increased levels of Orexin A in the spinal cord. Orexin A, also known as hypocretin-1, is a neuropeptide that plays roles in sleep-wake regulation. Blocking the action of orexin receptors reversed this pain-relieving effect, suggesting that orexin plays a key role in fasting's analgesic properties. There was already evidence for a role of orexin in pain modulation because orexin receptors are found in regions of the central nervous system associated with pain processing. Read the study.

This supports the numerous existing studies showing fasting can have beneficial effects for patients with chronic pain syndromes, already well described in a review in 2010 by the team of Pr. Andreas Michalsen.

4/ Comparison of intermittent fasting and voluntary wheel running on physical and cognitive abilities in obese rats

In this new study in laboratory rats, intermittent fasting proves superior to voluntary wheel running in curbing weight gain and preserving physical activity in obese rats. It is an interesting finding, but this should not be taken at face value because the complexity of physical exercice and fasting in humans is hardly recapitulated by this type of animal study. The conclusion from the authors of this study that one intervention is better than the other is thus highly speculative.

5/ Ghrelin is associated with an elevated mood after an overnight fast

In a study described in a preprint, involving 103 participants, including 51 with major depressive disorder, researchers found that after an overnight fast, higher levels of acyl ghrelin were associated with improved mood in individuals with depressive disorder. These findings suggest a potential role for ghrelin in explaining the antidepressant effects of fasting interventions, offering a complementary approach for individuals with melancholic depressive disorder.

6/ Phlorizin is a novel caloric restriction mimetic

Phlorizin is proposed as a new caloric restriction mimetic in a new study. This compound is inducing a cellular response to metabolic stress resembling nutrient and oxygen deprivation. By inhibiting glucose intake, it activates AMPK, triggering autophagosome production for nutrient deprivation. Simultaneously, it induces an oxygen-deprivation response activating the Hif-1α/Bnip3 axis.

Phlorizin is a naturally occurring phenol glycoside first isolated from the bark of an apple tree in 1835. It was already showed in 2010 that this compounds extend the lifespan of the yeast Saccharomyces cerevisiae. ?Apple peel contains 12 to 418 mg/ kg of it, while apple pulp contains 4 to 20 mg/kg. An apple a day keeps the doctor away!

7/ Reprogramming of cancer cells by time-restricted feeding.

The scientists who published a study showing time-restricted feeding inhibits lung cancer progression, discussed in the November issue of my newsletter, published more details on the mechanisms explaining these effects. In this new study, the authors showed that inhibition of lung cancer cell progression was due to changes in gene expressions associated with an inhibition of cell proliferation and an induction of apoptosis. This study doesn’t provide ground-breaking information, but it provides evidence that in vitro models could also be interesting approaches to understand the effects of intermittent fasting.

8/ Dietary restriction of isoleucine increases healthspan and lifespan in mice.?

Restricting the availability of single amino acids in the diet can have effects on healthy lifespan. In this new study, isoleucine restriction enhanced metabolic health and longevity in mice. This dietary intervention not only improved leanness and glycemic control in both sexes but also demonstrated a sex-specific impact on hepatic metabolism. Isoleucine restriction reduced frailty and extended lifespan, with more pronounced effects in males. The authors propose that clinical applications could include pharmaceutical mimicry. These experiments are actually impossible to translate clinically as one cannot restrict the levels of a single molecule in normal daily habits of people.

9/ Late-life shift in caloric intake extends lifespan in fruit flies

Calorie restriction slows aging and extends lifespan in fruit flies, even when implemented late in life. In contrast, shifting from low to high calories increased mortality and shortened lifespan. Transcriptomic analysis revealed that calorie restriction triggered stress response. This new study highlights the importance of dietary choices in aging. It's never too late to switch to healthier dietary choices.

10/ Time-restricted eating improves Non-Alcoholic Fatty Liver Disease

In a 12-week study on non-alcoholic fatty liver disease, time-restricted eating (16/8), without calorie restrictions, proved more effective than standard care in improving hepatic steatosis, weight, and waist circumference. Intermittent fasting is clearly one of the most effective intervention to treat fatty liver disease. Is anyone still surprised?

I hope you enjoyed this new issue. If you have any question, believe that I forgot an important study, please don't hesitate to comment or write to me.

Merry Christmas ! Now is not the time to fast, it is the time to feast !