Baseline-Dependent Immunometabolic Responses During Prolonged Intermittent Fasting: A Secondary Integrative Analysis

Background: Prolonged intermittent fasting is associated with metabolic and immune adaptation; however, the extent to which transcriptional immune responses translate into systemic inflammatory changes, and how these processes relate to autophagy, senescence-associated signaling, and inflammasome regulation, remains incompletely understood. Methods: This study represents a secondary integrative analysis of a previously characterized cohort of healthy young men undergoing Ramadan fasting. Longitudinal data across four time points (T1–T4) were re-analyzed, integrating targeted mRNA profiling of autophagy-, senescence-, and inflammasome-related genes with circulating cytokines and clinical parameters. Baseline-stratified regression and exploratory clustering were applied to assess inter-individual variability. Results: Fasting was associated with modest reductions in body weight (−1.78 ± 1.44 kg, FDR < 0.001) and BMI (−0.56 ± 0.47 kg/m2, FDR < 0.001), without hemodynamic instability. Autophagy-related transcripts (ULK1, ATG5) were upregulated, while senescence markers showed divergent regulation (p53↑, p21↓). Inflammasome-related genes (NLRP3, IL1B) increased at the transcriptional level; however, circulating IL-1β and IL-6 remained stable and TNFα decreased (FDR < 0.001), indicating dissociation between transcriptional priming and systemic cytokine output. ΔNLRP3 was inversely associated with baseline expression (β = −1.88, R2 = 0.31, p = 0.0056), suggesting baseline-dependent transcriptional responsiveness. Responses followed a continuous spectrum rather than discrete subtypes. Conclusions: Prolonged intermittent fasting is associated with coordinated immunometabolic remodeling characterized by transcriptional changes in autophagy-, senescence-, and inflammasome-related pathways, without systemic inflammatory escalation. Inflammasome-related responses appear baseline-dependent, suggesting graded immunological responsiveness rather than a uniform activation. These findings are hypothesis-generating and support the interpretation of fasting as a graded immunometabolic modulator rather than a uniform pro-inflammatory stimulus within the limitations of a secondary exploratory analysis.