Nuanced Benefits of Fasting-Mimicking Diets: High Protein vs. Low Protein

A recent study published in Clinical Nutrition sheds new light on the physiological impacts of Fasting-Mimicking Diets (FMDs), revealing that while both low-protein and high-protein versions offer significant health advantages, their specific benefits can differ notably. This randomized controlled trial explored the effects of a 7-day plant-based FMD with either a low protein/high fat (LP-FMD) or high protein/low fat (HP-FMD) composition in healthy humans.

Both FMD approaches demonstrated remarkable shared benefits, proving effective in promoting cardiometabolic health and initiating the crucial cellular recycling process known as autophagy.
Regardless of macronutrient ratios, participants on both FMDs experienced similar reductions in body weight and overall fat mass, underscoring that calorie restriction is a primary driver for these changes. Furthermore, both LP-FMD and HP-FMD led to a comparable decrease of approximately 10% in fasting plasma glucose concentrations and a significant 35% reduction in IGF-1 levels, a key growth factor associated with aging. The study also confirmed that both diets effectively induced autophagy at a molecular level, upregulating several genes involved in this protective cellular mechanism, such as MAP1LC3A, GABARAPL1, and ZFPM1. Levels of plasma branched-chain amino acids (BCAAs) also saw a similar increase in both FMD groups, potentially serving as a marker for tissue autophagy activation.

However, the research revealed distinct advantages unique to each macronutrient composition.

The High Protein FMD (HP-FMD) emerged as particularly potent in several key areas. It was the only diet to significantly reduce visceral fat mass compared to the control group, a crucial benefit given visceral fat’s strong association with metabolic risk. HP-FMD also delivered selective improvements in cardiovascular function, specifically enhancing heart rate variability (RMSSD), a measure of autonomic nervous system health. Additionally, this higher protein version significantly reduced circulating triglycerides (TAG) and total saturated fatty acids (SFA), alongside other fatty acids like MFA and OFA, offering a more favorable lipid profile. Perhaps most notably, only the HP-FMD group experienced significant increases in gut microbiome diversity, as measured by the number of faecal species and the Shannon Index. The percentage of the phylum Firmicutes also increased in the HP-FMD group relative to LP-FMD. In terms of molecular responses, HP-FMD uniquely increased ULK1 expression, an autophagy-activating kinase, and showed a tendency to decrease ER stress-related gene ATF6, a reduction not observed with LP-FMD.

In contrast, the Low Protein FMD (LP-FMD) demonstrated its own specific strengths. While both FMDs induced ketogenesis, the increase in serum hydroxybutyrate (ketone) levels was notably higher in the LP-FMD group than in the HP-FMD group, indicating a more pronounced metabolic shift towards ketone production. At the molecular level, LP-FMD showed distinct upregulation of specific autophagy-related genes, including BNIP3 and a tendency for ATG4B expression to increase, resulting in a significant difference when compared to the HP-FMD group. Furthermore, LP-FMD showed a tendency for SIRT1 expression to increase, an anti-aging gene, a response not seen with HP-FMD. It also led to an increase in FOXO1 expression, whereas HP-FMD showed a reduction in this gene, resulting in a significant difference between the two FMD groups. Lastly, LP-FMD exhibited a greater response in GABPB1 expression compared to the HP-FMD group.

These findings suggest that while calorie restriction is fundamental to the broad benefits of FMDs, customizing the macronutrient composition can offer targeted advantages to align with specific health objectives and individual preferences, without compromising the core benefits like autophagy induction. Future studies will need to further explore these nuances, potentially by varying fat and carbohydrate content independently to precisely isolate the role of protein in these observed outcomes.

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