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Prolonged fasting promotes systemic inflammation and platelet activation in humans: a medically supervised, water-only fasting and refeeding study

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Prolonged fasting promotes systemic inflammation and platelet activation in humans

Commissati S, Cagigas ML, Masedunskas A, … Rocca B, Fiorito G, Fontana L · Molecular Metabolism 2025; article 102152 · DOI: 10.1016/j.molmet.2025.102152

A SOMAScan plasma-proteomics study of a medically supervised ~10-day water-only fast + ~5-day guided refeeding (Fontana group; samples from TrueNorth Health Center). It is the most important counterpoint to Pietzner 2024: it replicates Pietzner’s muscle/bone and lipid signatures with no discrepancies, but its primary finding is that prolonged fasting (PF) is acutely pro-inflammatory and activates platelets — sharpening the cardiometabolic-safety picture rather than the geroprotective one. See prolonged-fasting for the intervention-level synthesis.

Design

  • n = 20 middle-aged volunteers (11 women, 9 men; mean age 52.2 ± 11.8 yr; BMI 28.8 ± 6.4 — i.e., overweight, older, and more diverse than Pietzner’s lean young cohort).
  • Intervention: medically supervised water-only fast, mean 9.8 ± 3.1 days, followed by 5.3 ± 2.4 days of guided plant-based refeeding. Blood/urine 6–8 am, before/during/after.
  • Proteomics: untargeted SOMAScan, 1,317 proteins (note: the proteomics volcano analysis used a N=15 subset); plus targeted mass spectrometry (amyloid-β, by C2N Diagnostics) and ELISAs (CRP, urinary 11-dehydro-TXB2) for orthogonal validation.
  • External validation cohorts: retrospective data from 1,422 individuals undergoing modified fasting at the Buchinger-Wilhelmi Clinic (Germany; mean fast 8.2 ± 0.1 d) for the CRP finding, plus comparison to Pietzner 2024 and Wilhelmi de Toledo 2019.
  • Single-arm, uncontrolled, variable fasting/refeeding durations (volunteer-decided) — the key design limitation.

Physiological response

  • Weight loss 7.7% mean (women −6.3 ± 1.7 kg / 7.6%; men −6.9 ± 2.2 kg / 7.8%; p<0.0001); BMI −2.2 ± 0.5; waist −6% — all persisting through refeeding.
  • Adherence confirmed by significantly elevated serum β-hydroxybutyrate (p<0.0001), normalizing on refeeding.
  • Glucose fell 85.7 → 70.3 mg/dL (−18%); during refeeding glucose and HOMA-IR rose significantly (transient insulin resistance on reintroduction of food).

Proteome overview and convergence with Pietzner 2024

  • 6.6% of proteins (86/1,317) changed (adj p<0.05; 74 down, 12 up); <1% (12 proteins) remained altered after refeeding → the response is largely transient. (Pietzner’s 35.9% figure is higher partly because of the larger 3,072-plex Olink panel and 7-day-only window vs this ~10-day fast + refeeding analysis.)
  • Muscle/bone preservation (TGF-β superfamily): INHBA −3.3 fold (p=9.07×10⁻⁵), myostatin −2 fold (p=4.66×10⁻⁴), GDF11/8 −1.6 fold (p=7.57×10⁻⁴); PTH −2.1 fold (p=0.0045, a compensatory bone-sparing signal); adiponectin 5,643 → 4,275 ng/mL (p<0.0001).
  • Energy/lipid/autophagy: PPARα signaling activated; CLEAR lysosomal-biogenesis network up (autophagy/exocytosis); FGF19 +1.8 fold (p=0.048); soluble leptin receptor +2.2 fold (p=0.002).
  • Direct replication: the FGF19 and soluble-leptin-receptor increases were previously reported by Pietzner 2024; comparative analysis at the 7-day endpoint found an overlap of 44 decreased + 5 increased proteins with no discrepancies between studies, despite different platforms (SOMAScan vs Olink). Common Reactome pathways: neutrophil + platelet degranulation, interleukin, MAPK, PI3K/AKT. → the water-only-PF proteome signature is highly conserved.

Primary finding — PF is pro-inflammatory

Contrary to the authors’ hypothesis (and to the chronic-CR anti-inflammatory literature):

  • Significant increases in hepcidin, ferritin, midkine, MMP9, IL-8, and PAFAH (PLA2G7).
  • hsCRP rose +129% (Wilcoxon p=0.0004, ANOVA p=0.0070), normalizing after refeeding in all but one participant. CRP rise associated with TGF-β signaling and the complement/coagulation cascade.
  • Validation cohort (n=1,422, Buchinger-Wilhelmi): 66.6% had a significant CRP increase (2.8 → 4.3 mg/L), regardless of fasting duration (5/10/15/20 days) — confirming the acute-phase response is a general feature of PF.
  • Liver enzymes: AST +65%, ALT +64%, remaining elevated during refeeding (hepatic stress; also seen in the validation cohort).

Platelet activation

  • Reactome enrichment for platelet degranulation; vWF and soluble glycoprotein Ibα (GP1Bα) mildly increased; prothrombin unchanged (1-fold, p=0.85).
  • Urinary 11-dehydro-TXB2 (a gold-standard biomarker of in vivo platelet activation and cardiovascular risk; predictive in Framingham and ASCEND) rose +21% during fasting and +36% post-refeeding, with no change in platelet count → driven by degranulation, not increased platelet production.
  • Interpretation: a PF-induced phenotype of interconnected inflammation + platelet activation, potentially raising thrombotic risk in individuals with pre-existing conditions / unstable atherosclerotic plaques.

Cardiometabolic and other findings

  • Lipids: total cholesterol, non-HDL, LDL, and TC/HDL ratio all rose during fasting (reversed after refeeding); triglycerides rose steadily, +32% post-refeeding. PCSK9 fell −1.49 fold (p=0.008) — decreased, consistent with low-insulin/SREBP-2 biology (see PCSK9 note on the Pietzner page).
  • Chemerin −1.7 fold (p=0.0002), fetuin-B −1.8 fold (p=6.05×10⁻⁵).
  • Amyloid-β: PF significantly reduced plasma Aβ40 and Aβ42 (mass spec), returning to baseline after refeeding; the clinically validated Aβ42/Aβ40 ratio was unchanged. First report of PF lowering circulating amyloid-β; reduced synaptogenesis + amyloid-fibril-formation pathways; BDNF +1.32 fold (p=0.18, non-significant trend).
  • Oxidative status: no systemic antioxidant effect — extracellular SOD3 fell (−1.3 fold, p=0.003) and urinary 8-iso-PGF2α was heterogeneous → PF does not universally reduce oxidative stress in humans.

Adverse events

Mild AEs common (headaches, weakness, fatigue, insomnia, dry mouth, orthostatic hypotension) — prompting transition to broth/juice in 6 participants. Severe AEs: severe abdominal pain + diarrhea (n=1), hypokalemia (n=1), arrhythmias (n=1), dizziness + palpitations (n=1). Underscores the need for medical supervision.

Limitations and conflicts

  • Single-arm, no control group; small n; volunteer-decided (variable) fasting and refeeding durations.
  • COI: A. Goldhamer is founder of TrueNorth Health Center (the supervised-fasting facility supplying participants); K.M. Kirmess and M.R. Meyer are employed by C2N Diagnostics (amyloid-β assay vendor).

Cross-references

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