Recent Research on Fasting and Calorie Restriction (February 2024)

1/ Fasting-mimicking diet caused changes indicating reduced biological age

Fasting mimicking diets (FMD) are back in the spotlight with a recent study from Dr. Valter Longo involving collaboration between his team and Dr. Morgane Levin, an expert in estimating biological age from standard blood tests.?

In humans, three cycles of FMD decrease insulin resistance and pre-diabetes markers, reduce liver fat, and rejuvenate the immune system, equivalent to a 2.5-year decrease in biological age, as shown in two clinical trials.

It's yet uncertain if this translates to a genuine reversal of biological age. Biological aging typically can't be swiftly reversed by short interventions. Real rejuvenation remains speculative; the findings likely indicates benefits on aging-related markers. Nonetheless, the study underscores therapeutic fasting's potential as a remarkable public health asset.

2/ mTOR signalling guides intestinal stem cell destiny to adapt between cycles of feeding and fasting

New research suggests in flies that the adult intestine adjusts its size and cell composition based on nutrient availability. Activation of mTORC1 influences cell fate, favoring absorptive cells over secretory ones. In aged flies, mTORC1 activity remains high but age-related decline can be mitigated through lifelong intermittent fasting. This is a complex study bringing more fundamental knowledge than clinical implications, but nonetheless shows that our intestine ages better when it is subjected to intermittent fasting. We are not meant to eat and digest all the time. Our gut needs pauses to regenerate.

3/ Adipose tissue inflammation limits the effectiveness of weight loss interventions, including fasting

In overweight individuals, ongoing inflammation in fat tissue creates a sort of "memory" that makes it harder for weight loss efforts to succeed. However, the effects of fasting routines on how the immune system interacts with fat tissue are still not fully understood.

Research shows that when mice with obesity follow intermittent fasting, certain immune cells called lipid-associated macrophages increase in their fat tissue. This happens alongside the death of fat cells and the activation of a signaling pathway involving a protein called p53. In the end, this limits the effects of fasting.

When researchers removed p53 specifically from fat cells in mice, it reduced inflammation and cell death while increasing the breakdown of fat cells. As a result, these mice lost more weight when they followed intermittent fasting routines, which improved their metabolic health. Evidence from studies involving people also suggests that p53 plays a role in weight loss in real-world situations.

4/ Periodic calorie restriction elicits health benefits with sex dimorphic persistence in primate intervention

A study on rhesus macaques found that a 4:10 diet cycle (4 days of low-calorie intake followed by 10 days of regular eating) led to weight and fat loss, with significant metabolic changes. These phenotypes were paralleled by changes in the gut microbiome. This in turn was associated with long-term benefits. There were interesting sex dimorphic responses, with males maintaining better the lower body weight for many months following the study’s conclusion in comparison to females. The authors propose that this fasting approach could offer easier adherence and potential anti-aging benefits for humans.

5/ Intermittent fasting protects β-cell identity and function in a type-2 diabetes model

A study on mice investigated the effects of intermittent fasting (IF) on type 2 diabetes (T2DM). Mice subjected to IF showed improved blood glucose levels, reduced insulin resistance, and lower body weight gain. This was already demonstrated in previous studies. The key novelty from this study is that the scientists also looked at how glucose stimulated insulin secretion directly in pancreas islets. The pancreatic cells also displayed enhanced function and protection from deterioration, demonstrating improved β-cell function.

6/ Metabolomics of Ramadan fasting and associated risk of chronic diseases

A study examined Ramadan fasting's impact on health. Researchers collected blood samples before and after Ramadan from 72 participants. They found changes in 14 metabolites linked to inflammation, amino acids, glycolysis, ketone bodies, triglycerides, and lipoproteins. Additionally, they assessed metabolic scores for chronic diseases, finding lower scores for lung, colorectal, and breast cancers post-Ramadan. This suggests potential health benefits associated with fasting, independent of body composition changes.

7/ Ketone flux through the enzyme beta-hydroxybutyrate dehydrogenase 1 (BDH1) supports metabolic remodeling of skeletal and cardiac muscles in response to time-restricted feeding

This study investigated whether intermittent time-restricted feeding (iTRF) benefits hinge on ketone activity in muscles. They found a key enzyme, beta-hydroxybutyrate dehydrogenase 1 (BDH1), abundant in heart and oxidative muscles, crucial for fatty acid oxidation (FAO). Mice lacking BDH1 in muscles showed reduced FAO efficiency and exercise tolerance during fasting. iTRF prompted significant muscle changes, with BDH1 supporting benefits like lean mass increase and improved metabolism. Overall, ketone activity boosts muscle energy and enhances iTRF effects on muscle and heart. These mechanisms appear to promote energy stability during fasting while also supporting the bioenergetic demands of tissue and organelle remodeling in response to cyclic periods of famine and feasting.

8/ Gut microbiota and metabolites exhibit different profiles after very-low-caloric restriction in patients with type 2 diabetes

Fourteen T2D patients underwent a 9-day Very Low-Calorie Diet (VLCR) of 300-600 kcal/d. Significant reductions were observed in weight, blood pressure, glucose, insulin, and triglyceride levels. Bacteroidetes increased in gut microbiota. This is in line with what we know about calorie restriction effects on the gut microbiota. Parabacteroides distasonis abundance notably rose. Plasma L-arginine increased, while lipid metabolites such as LysoPC (18:1) decreased. LysoPC (18:1) and Parabacteroides distasonis could be VLCR indicators in T2D management.

I find the proposal of Parabacteroides distasonis as a marker of very-low-caloric restriction quite speculative. This study is underpowered because of the low number of subjects and the relatively imprecise gut microbiota profiling method, and thus the level of understanding which can be achieved is not high enough to reasonably propose Parabacteroides distasonis as a marker of very-low-caloric restriction. Read the study

9/ The yin-yang effect of calorie restriction on calorie restriction-responsive tumors

Research indicates caloric restriction (CR) holds promise against cancer, including Acute Myeloid Leukemia (AML), though its exact workings are unclear. A new study was done to understand this in a laboratory animal model. In mouse models, CR initially restrains tumors by altering cell cycles and signaling pathways. However, AML eventually returns due to selection of resistant cells and decreased immune signaling genes. The authors call this a yin-yang effect of CR on CR-responsive tumors: despite eliciting short-term tumor growth inhibition, CR favors survival of cells with stem-cell features that cause the delayed emergence of a more aggressive disease.

Combining CR with LSD1 inhibition triggers potent anti-leukemic effects, suggesting potential for novel treatments across various cancers. These findings advocate for exploring epi-metabolic therapies in cancer management. However, it underscores the need for cautious exploration due to circulating hopeful yet unvalidated claims about fasting and CR in cancer treatment. Desperate patients may resort to risky practices based on social media messages, but it's crucial to reiterate that cancer isn't yet confirmed as a suitable indication for therapeutic fasting.

10/ Alterations in anthropometric, inflammatory and mental health parameters during Ramadan intermittent fasting in a group of healthy people

Ramadan intermittent fasting (RIF), a common form of religious fasting, affects body composition and mental health. This study examined its impact on various biological markers related to mental health and inflammation. Fasting participants (n = 25) were compared with non-fasting (n = 25) at different time points. Significant changes were observed in fasting participants for several markers including ?-NGF, GDNF, IL-8, TNF-α, and MMP-9. Looking at the effect sizes and the amplitude of error bars, I am not sure this study brings convincing evidences for an anti-inflammatory effect of Ramadan fasting.

Data visualisation is the key to good communication, and to convince readers. I wrote a post about why last year if you want to know more.

Other published studies included an evaluation of the impact of caloric restriction on oxidative stress and key glycolytic enzymes in the cerebral cortex, liver and kidney of old and middle-aged mice (link), the discovery that mitochondrial Ca2+ extrusion pathway through the mitochondrial calcium uniporters and efflux by Na+ /Ca2+ exchanger (NCLX) is an important regulatory node linking nutrient restriction and autophagy regulation (link), a study on how long-term calorie restriction prevented memory impairment in middle-aged male mice and increased a marker of dna oxidative stress in hippocampal dentate gyrus (link), a study on a swine model which showed that caloric restriction during pregnancy was associated with impaired inflammatory and DNA methylation markers in the offspring's adipose tissue (link).