Prolonged Fasting May Actually Raise Inflammation, Not Lower It
A scoping review of 14 clinical trials finds fasting over 48 hours often increases CRP, IL-6, and TNF-α — challenging popular anti-inflammatory claims.
Summary
A comprehensive scoping review published in Ageing Research Reviews analyzed 14 human clinical trials to assess how prolonged fasting (48 hours or more) affects key inflammatory biomarkers including CRP, IL-6, and TNF-α. Contrary to widespread belief that extended fasting reduces inflammation, most studies reported either no change or an actual increase in these markers during fasting — particularly CRP, which rose significantly in people with overweight or obesity. Notably, CRP levels often normalized after refeeding, suggesting the inflammatory response may be transient or adaptive rather than harmful. The review highlights major inconsistencies across studies due to varying fasting durations, populations, and protocols, calling for rigorous randomized controlled trials to clarify long-term effects.
Detailed Summary
Extended fasting has gained significant popularity as a longevity and metabolic health strategy, with proponents claiming it powerfully reduces chronic inflammation — a key driver of aging and disease. However, the actual evidence base for this claim has never been rigorously synthesized, leaving clinicians and the public without reliable guidance.
This scoping review, conducted by researchers at the University of Sydney and published in Ageing Research Reviews, systematically searched five major databases and identified 14 peer-reviewed human clinical trials examining the effects of prolonged fasting (≥48 hours) on three established inflammatory biomarkers: C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). The review followed PRISMA-ScR guidelines to ensure methodological rigor.
The findings challenge the popular narrative. The majority of included studies reported either no significant change or an increase in inflammatory biomarkers during extended fasting periods. CRP — the most commonly measured marker — rose, often significantly, particularly in participants with overweight or obesity. Increases in TNF-α and IL-6 were also noted in some studies, though with less consistency across trials.
A potentially important nuance emerged: several studies observed that elevated CRP levels returned to normal or decreased following refeeding. This suggests the fasting-induced inflammatory response may be transient or represent an adaptive physiological mechanism — perhaps analogous to hormetic stress — rather than a sign of pathological inflammation.
The review cautions that the evidence remains limited and inconsistent, shaped by wide variation in fasting duration, participant health status, and study design. The authors call for well-designed randomized controlled trials with standardized protocols across diverse populations to properly evaluate prolonged fasting's long-term impact on inflammation and metabolic disease.
Key Findings
- Most of 14 clinical trials found prolonged fasting (≥48 h) caused no change or an increase in CRP, IL-6, or TNF-α.
- CRP rose significantly during fasting, especially in individuals with overweight or obesity.
- CRP often normalized after refeeding, suggesting the inflammatory response may be transient or adaptive.
- Evidence is inconsistent across studies due to differing fasting durations, populations, and protocols.
- No standard fasting protocol exists; randomized controlled trials are urgently needed.
Methodology
This is a systematic scoping review following PRISMA-ScR guidelines, searching PubMed, Medline, Web of Science, Embase, and Scopus for studies published through August 2024. Only peer-reviewed human clinical trials examining prolonged fasting effects on inflammatory markers were included, yielding 14 eligible studies.
Study Limitations
Only 14 studies met inclusion criteria, reflecting a sparse and heterogeneous evidence base. Significant variation in fasting duration, participant characteristics, and outcome measurement methods limits cross-study comparisons. No randomized controlled trials with standardized protocols currently exist, preventing definitive conclusions.
Enjoyed this summary?
Get the latest longevity research delivered to your inbox every week.