本期节目邀请了普林斯顿大学的化学和整合基因组学教授Josh Rabinowitz，深入探讨了代谢组学、NAD及其前体，以及癌症代谢这三个核心主题。节目首先介绍了代谢的基本概念，然后详细阐述了葡萄糖代谢、乳酸作为燃料、电子传递链和Krebs循环，以及NAD在能量产生中的关键作用。此外，节目还讨论了与年龄相关的NAD水平下降问题，以及通过静脉或口服补充NMN和NR来增加NAD的效果。最后，Josh分享了关于癌症代谢和免疫疗法的最新研究进展，为未来的癌症治疗带来了新的希望。

🍎 **代谢组学基础**: 节目首先定义了代谢、代谢物和通量组学。代谢是指细胞内发生的化学反应总和，而代谢物是这些反应的中间产物或最终产物。通量组学则关注代谢物在细胞内的流动和转化，帮助理解代谢系统的工作方式。

💡 **NAD与能量产生**: 节目深入探讨了NAD（烟酰胺腺嘌呤二核苷酸）在能量产生中的核心作用。NAD是细胞内重要的辅酶，参与电子传递链和Krebs循环，这些过程对于产生细胞能量至关重要。节目还解释了NAD如何影响细胞的氧化还原反应，从而影响细胞的健康和功能。

👴 **NAD与衰老**: 随着年龄的增长，人体内的NAD水平会下降。节目讨论了通过静脉或口服补充NAD前体（如NMN和NR）来提高NAD水平的尝试。虽然一些研究表明补充NAD可能对健康有益，但节目也强调了当前研究的局限性，以及进一步研究的必要性。

🎗️ **癌症代谢与免疫疗法**: 节目最后探讨了癌症代谢，以及其与免疫疗法的交叉点。癌细胞的代谢方式与正常细胞不同，这为治疗癌症提供了新的靶点。节目讨论了如何利用癌细胞的代谢特性，结合免疫疗法，有望将癌症转化为慢性疾病，为癌症治疗带来新的希望。

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Josh Rabinowitz is a Professor of Chemistry and Integrative Genomics at Princeton University, where his research focuses on developing a quantitative, comprehensive understanding of cellular metabolism through the study of metabolites and their fluxes. In this episode, Josh focuses the discussion on three main topics: metabolomics, NAD (and its precursors), and cancer metabolism. The metabolomics discussion starts with a broad definition of metabolism, metabolites, and fluxomics before diving deep into glucose metabolism, lactate as a fuel, movement of lactate, and the regulation of these substrates. He then gives a detailed explanation of the electron transport chain and Krebs cycle and their implications with respect to both drugs and nutrition while also explaining how NAD is central to the process of energy generation. He then discusses the age-related decline in NAD and what current literature says about efforts to increase NAD through intravenous or oral supplementation with the precursors NMN and NR, including whether doing so provides any advantage to lifespan or healthspan. Finally, Josh ends the conversation talking about cancer metabolism and how one particular intersection between cancer metabolism and immunotherapy might provide a hopeful outlook on the future of cancer treatment.

We discuss:

Josh’s background and unique path to becoming a research scientist at Princeton [3:30]; What sparked Josh’s early interest in metabolism [11:15]; Metabolomics 101: defining metabolites and how they are regulated [16:30]; Fluxomics: metabolism as a system in action [26:00]; The Randle Hypothesis: glucose and fatty acids compete as substrates for oxidation [33:30]; The important role of lactate as an alternate fuel [36:30]; Fasting lactate levels as a potential early indicator of metabolic dysfunction [48:00]; The beauty of the Krebs cycle and the role of NAD in energy production [53:15]; How the drug metformin acts on complex I of the electron transport chain [1:05:00]; The difference between NADH and NADPH [1:08:45]; NAD levels with age, and the efficacy of supplementing with intravenous NAD [1:10:45]; The usefulness of restoring NAD levels and efficacy of oral supplementation with NAD precursors NR and NMN [1:22:15]; Exploring the hypothesis that boosting NAD levels is beneficial [1:32:30]; Cancer metabolism and the intersection with immunotherapy [1:39:00]; Making cancer a chronic disease: exploiting the metabolic quirks of cancer, augmenting the immune system, and more [1:46:15]; The challenge of treating pancreatic cancer [1:50:30]; Epithelial cancers that might respond to metabolic approaches to therapy [1:56:30]; Josh’s hopeful outlook on the future of cancer treatment [1:59:00]; Nutritional approaches to cancer attenuation [2:00:15]; What makes Princeton University special [2:06:15]; More.

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