A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan

Brandhorst S, Choi IY, Wei M, Cheng CW, Sedrakyan S, Navarrete G, Dubeau L, Yap LP, Park R, Vinciguerra M, Di Biase S, Mirzaei H, Mirisola MG, Childress P, Ji L, Groshen S, Penna F, Odetti P, Perin L, Conti PS, Ikeno Y, Kennedy BK, Cohen P, Morgan TE, Dorff TB, Longo VD · 2015 · Cell Metabolism

DOI: 10.1016/j.cmet.2015.05.012View source ↗

“Three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects.”

Summary

This Cell Metabolism paper from Valter Longo's USC group introduced the fasting-mimicking diet (FMD) — a 5-day periodic dietary protocol designed to deliver fasting's molecular benefits while keeping participants able to consume modest amounts of plant-based food. The paper has two parts. In aged mice, monthly FMD cycles for several months produced multi-system regeneration: hippocampal neurogenesis rose, IGF-1 dropped, PKA activity decreased, NeuroD1 expression increased, and cognitive performance improved on standard mouse cognition tests. In a 38-participant pilot human RCT, three monthly FMD cycles (each 5 days) produced reductions in body weight, body fat, blood pressure, fasting glucose, and IGF-1 without significant adverse events. The paper is foundational because it bridged rodent CR research and practical human protocol design — providing a structured, safe framework for delivering fasting benefits without continuous calorie restriction. Longo subsequently commercialized the protocol as ProLon, a packaged 5-day FMD product. The paper's data quality is solid but the commercial development complicates how it should be cited.

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References cited by this entry

ExtendsLow protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older populationLevine ME et al. · 2014
Levine/Longo 2014 made the case for protein-restriction effects on IGF-1 and mortality; Brandhorst/Longo 2015 tested a structured periodic intervention (the fasting-mimicking diet, FMD) designed to engage those mechanisms safely.
ExtendsLong-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humansFontana L et al. · 2008
Fontana 2008 documented that protein restriction lowers IGF-1 in long-term human practitioners; Brandhorst/Longo 2015 demonstrated that 5-day periodic FMD cycles can produce similar IGF-1 effects in a structured, time-limited format.

Entries that reference this one

ExtendsFasting alters the gut microbiome reducing blood pressure and body weight in metabolic syndrome patientsMaifeld A et al. · 2021
Brandhorst & Longo characterized the fasting-mimicking-diet model; Maifeld 2021 provides one of the cleaner human RCT readouts of a multi-day fast effect on the gut microbiome alongside cardiometabolic endpoints.
ExtendsCancer as a metabolic diseaseSeyfried TN & Shelton LM · 2010
Brandhorst & Longo's fasting-mimicking-diet work explores adjacent terrain — caloric/protein-restriction effects relevant to the metabolic-theory-of-cancer framework.