Human fasting modulates macrophage function and upregulates multiple bioactive metabolites that extend lifespan in Caenorhabditis elegans: a pilot clinical study.
Human fasting modulates macrophage function and upregulates multiple bioactive metabolites that extend lifespan in Caenorhabditis elegans: a pilot clinical study.
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DOI：
10.1016/j.ajcnut.2022.10.015
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发表时间：
2023-02
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--
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定期延长禁食（PF）可以延长模型生物体的寿命，并在临床和实验上改善多种疾病状态，部分原因在于其调节免疫系统的能力。然而，PF 期间代谢因素、免疫力和寿命之间的关系仍不清楚，尤其是在人类中。本研究旨在观察人类受试者中 PF 对代谢和免疫健康的临床和实验标志物的影响，并揭示可能导致这些影响的潜在血浆传播因素。在这项严格控制的试点研究（ClinicalTrial.gov 标识符，NCT03487679）中，20 名年轻男性和女性参与了 3 d 研究方案，包括对 4 种不同代谢状态的评估：1）隔夜禁食基线状态，2）餐后 2 小时禁食状态，3）36 小时禁食状态，以及 4）餐后 12 小时后最后 2 小时餐后重新进食状态36小时禁食期。对每个状态的免疫和代谢健康的临床和实验标志物以及参与者血浆的综合代谢组学分析进行了评估。然后评估禁食 36 小时后在循环中上调的生物活性代谢物在分离的人类巨噬细胞中模拟禁食效果的能力以及延长秀丽隐杆线虫寿命的能力。我们发现 PF 强烈改变血浆代谢组并对人类巨噬细胞产生有益的免疫调节作用。我们还鉴定了 4 种在 PF 期间上调的生物活性代谢物（亚精胺、1-甲基烟酰胺、棕榈酰乙醇酰胺和油酰乙醇酰胺），它们可以复制这些免疫调节作用。此外，我们发现这些代谢物及其组合显着延长了秀丽隐杆线虫的中位寿命高达 96%。这项研究的结果揭示了人类受 PF 影响的多种功能和免疫途径，确定了开发禁食模拟化合物的候选化合物，并揭示了长寿研究的研究目标。
Periodic prolonged fasting (PF) extends lifespan in model organisms and ameliorates multiple disease states both clinically and experimentally owing, in part, to its ability to modulate the immune system. However, the relationship between metabolic factors, immunity, and longevity during PF remains poorly characterized especially in humans. This study aimed to observe the effects of PF in human subjects on the clinical and experimental markers of metabolic and immune health and uncover underlying plasma-borne factors that may be responsible for these effects. In this rigorously controlled pilot study (ClinicalTrial.gov identifier, NCT03487679), 20 young males and females participated in a 3-d study protocol including assessments of 4 distinct metabolic states: 1) overnight fasted baseline state, 2) 2-h postprandial fed state, 3) 36-h fasted state, and 4) final 2-h postprandial re-fed state 12 h after the 36-h fasting period. Clinical and experimental markers of immune and metabolic health were assessed for each state along with comprehensive metabolomic profiling of participant plasma. Bioactive metabolites identified to be upregulated in circulation after 36 h of fasting were then assessed for their ability to mimic the effects of fasting in isolated human macrophage as well as the ability to extend lifespan in Caenorhabditis elegans. We showed that PF robustly altered the plasma metabolome and conferred beneficial immunomodulatory effects on human macrophages. We also identified 4 bioactive metabolites that were upregulated during PF (spermidine, 1-methylnicotinamide, palmitoylethanolamide, and oleoylethanolamide) that could replicate these immunomodulatory effects. Furthermore, we found that these metabolites and their combination significantly extended the median lifespan of C. elegans by as much as 96%. The results of this study reveal multiple functionalities and immunological pathways affected by PF in humans, identify candidates for the development of fasting mimetic compounds, and uncover targets for investigation in longevity research.
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