(P02-022-23) A 36h Water-Only Fast Profoundly Alters the Plasma Lipidome Consistent With Benefits on Cardiometabolic Health

Objectives: Periodic prolonged fasting (PF), defined as caloric restriction for ≥ 24h, has emerged as a nutritional strategy to improve lifespan and promote healthy aging. Previously, we showed that a single bout of 36h water-only fasting in humans revealed a distinct metabolomic signature in plasma and increased the concentrations of bioactive metabolites which together enhanced both macrophage function and lifespan in C.elegans. Despite the clinical relevance of PF in health and aging, little is known about how PF acutely affects the plasma lipidome. This secondary outcome analysis aimed to investigate changes in the plasma lipidome associated with PF and whether these changes are related to markers of cardiometabolic health.

Methods: In this controlled study, 20 males and females (age, 27.5 ± 4.35 y; BMI, 24.1 ± 2.66 kg/m²) were assessed in 4 metabolic states: 1) overnight fasted (baseline), 2) 2h postprandial fed state (fed), 3) 36h fasted state (fasted), and a 4) 2h postprandial refed state 12h after the 36h fast (refed). Participants’ plasma lipidomic profiles were analyzed by liquid chromatography, electrospray ionization mass spectrometry.

Results: We identified several lipid classes, including lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), phosphatidylethanolamine (PE), and triacylglycerol that were reduced in the fasted state, whereas ceramides, sphingomyelin, and free fatty acids were increased in the fasted state. Compared to baseline, 245 out of 832 lipid species were significantly altered in the fasted state after correction for multiple testing (P ≤ 0.05). Random forest models revealed several fatty acid lipid species, PC(18:2/18:3) and LPE(18:1) as features important in discriminating fasted from baseline with a prediction accuracy of 98%.

Conclusions: PF changed the plasma lipidome and markedly altered several lipids classes that have been reported to be associated with cardiometabolic diseases, such as LPC, a major component of oxidized low-density lipoproteins. Our findings provide several biomarkers of PF and highlight specific lipid species that may be important indicators of overfeeding, which can be explored and validated for future studies on health and aging.

Funding Sources: National Institutes of Health and National Institute on Aging of the National Institute of Health