lactate

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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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Episode Description:

Iñigo San-Millán is an internationally renowned applied physiologist and a previous guest on The Drive. His research and clinical work focuses on exercise-related metabolism, metabolic health, diabetes, cancer metabolism, nutrition, sports performance, and critical care. In this episode, Iñigo describes how his work with Tour de France winner Tadej Pogačar has provided insights into the amazing potential of elite athletes from a performance and metabolic perspective. He speaks specifically about lactate levels, fat oxidation, how carbohydrates in food can affect our lactate and how equal lactate outputs between an athlete and a metabolically unhealthy individual can mean different things. Next, he discusses how Zone 2 training boosts mitochondrial function and impacts longevity. He explains the different metrics for assessing one’s Zone 2 threshold and describes the optimal dose, frequency, duration, and type of exercise for Zone 2. Additionally, he offers his thoughts on how to incorporate high intensity training (Zone 5) to optimize health, as well as the potential of metformin and NAD to boost mitochondrial health. Finally, he discusses insights he’s gathered from studying the mitochondria of long COVID patients in the ICU.

We discuss:

• The amazing potential of cyclist Tadej Pogačar [3:00];
• Metrics for assessing athletic performance in cyclists and how that impacts race strategy [8:30];
• The impact of performance-enhancing drugs and the potential for transparency into athletes’ data during competition [17:00];
• Tadej Pogačar’s race strategy and mindset at the Tour de France [24:00];
• Defining Zone 2, fat oxidation, and how they are measured [26:45];
• Using fat and carbohydrate utilization to calculate mitochondrial function and metabolic flexibility [35:45];
• Lactate levels and fat oxidation as it relates to Zone 2 exercise [40:00];
• How moderately active individuals should train to improve metabolic function and maximize mitochondrial performance [51:45];
• Bioenergetics of the cell and what is different in elite athletes [57:30];
• How the level of carbohydrate in the diet affects fuel utilization and power output during exercise [1:08:30];
• Glutamine as a source for making glycogen—insights from studying the altered metabolism of ICU patients [1:15:00];
• How exercise mobilizes glucose transporters—an important factor in diabetic patients [1:21:00];
• Metrics for finding Zone 2 threshold—lactate, heart rate, and more [1:25:00];
• Optimal Zone 2 training: dose, frequency, duration, and type of exercise [1:41:15];
• How to incorporate high intensity training (Zone 5) to increase VO2 max and optimize fitness [1:51:15];
• Compounding benefits of Zone 2 exercise and how we can improve metabolic health into old age [2:01:45];
• The effects of metformin, NAD, and supplements on mitochondrial function [2:05:15];
• The role of lactate and exercise in cancer [2:13:30];
• How assessing metabolic parameters in long COVID patients provides insights into this disease [2:19:00];
• The advantages of using cellular surrogates of metabolism instead of VO2 max for prescribing exercise [2:25:45];
• Metabolomics reveals how cellular metabolism is altered in sedentary individuals [2:33:45];
• Cellular changes in the metabolism of people with diabetes and metabolic syndrome [2:39:15]; and
• More.

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Today’s episode of The Drive is a rebroadcast of the conversation with Iñigo San Millán, (released on December 23rd, 2019). This episode with Iñigo was one of the most popular discussions to date and is a prelude to an upcoming follow-up discussion in 2022.

In this episode, Dr. Iñigo San Millán, Assistant Professor at the University of Colorado School of Medicine, explains the crucial role of mitochondrial function in everything from metabolic health to elite exercise performance. Iñigo provides a masterclass into the many different energy system pathways, the various fuel sources (including the misunderstood lactate), the six zones of exercise training, and the parameters he uses to measure metabolic health. Additionally, he highlights the power of zone 2 training as both an effective diagnostic tool and, perhaps more importantly, as a treatment for mitochondrial and metabolic dysfunction.

We discuss:

• Iñigo’s background in sports and decision to focus on education [3:45];
  
• The various energy systems and fuels used during exercise [11:15];
  
• Iñigo’s qualification of energy systems into six training zones [19:30];
  
• Lactate as an important fuel source [29:30];
  
• Zone 2 training—physiologic characteristics, fuel sources, lactate, and the transition into zone 3 [37:00];
  
• Using blood lactate levels (and zone-2 threshold) to assess mitochondrial function [43:30];
  
• Accessing mitochondrial function by testing one’s ability to utilize fat as fuel [51:30];
  
• Athletes vs. metabolically ill patients—mitochondria, fat oxidation, muscle glycogen capacity, “fat droplets”, and more [56:30];
  
• Physiologic characteristics of zone 3, zone 4, and the lactate threshold [1:16:30];
  
• Fueling exercise—dietary implications on glycolytic function [1:27:00];
  
• Relationship between exercise and insulin sensitivity (and what we can learn from studying patients with type 1 diabetes) [1:43:00];
  
• Metformin’s impact on mitochondrial function, lactate production, and how this affects the benefits of exercise [2:00:45];
  
• Raising awareness of the risk of “double diabetes” [2:11:30];
  
• How to dose zone 2 training, and balancing exercise with nutrition [2:14:30];
  
• Proposed explanation of the Warburg Effect: Role of lactate in carcinogenesis [2:23:30];
  
• Doping in cycling, and the trend towards altitude training [2:35:45] and;
  
• More.

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