Prolonged Intermittent Fasting Remodels Immunometabolic Pathways Without Systemic Inflammation in Healthy Men

The precise mechanisms by which prolonged intermittent fasting (IF) induces metabolic and immune adaptations remain incompletely understood. Specifically, the translation of transcriptional immune responses into systemic inflammatory changes, and their interplay with key cellular processes like autophagy, senescence-associated signaling, and inflammasome regulation, represents a significant knowledge gap. Current understanding often oversimplifies IF's impact on inflammation, necessitating a deeper look into the molecular dissociation between gene expression and circulating cytokine levels.

This study conducted a secondary integrative analysis of a previously characterized cohort of healthy young men undergoing Ramadan fasting. Longitudinal data were collected across four time points (T1-T4), allowing for a comprehensive re-analysis. Researchers integrated targeted mRNA profiling of autophagy- (ULK1, ATG5), senescence- (p53, p21), and inflammasome-related genes (NLRP3, IL1B) with measurements of circulating cytokines and standard clinical parameters. Baseline-stratified regression and exploratory clustering were applied to assess inter-individual variability in responses.

Prolonged intermittent fasting was associated with modest but significant reductions in body weight (-1.78 ± 1.44 kg, FDR < 0.001) and BMI (-0.56 ± 0.47 kg/m2, FDR < 0.001), without any observed hemodynamic instability. At the transcriptional level, autophagy-related transcripts (ULK1, ATG5) were consistently upregulated, indicating enhanced cellular recycling. Senescence markers showed divergent regulation, with p53 increasing while p21 decreased. Inflammasome-related genes, including NLRP3 and IL1B, also increased transcriptionally. However, this transcriptional priming did not translate into systemic inflammatory escalation: circulating IL-1β and IL-6 remained stable, and TNFα actually decreased (FDR < 0.001).