216 - Metabolomics, NAD+, and cancer metabolism | Josh Rabinowitz, M.D., Ph.D.

KEYPOINTS

• 01

  Metabolism went from unfashionable to central.

  Josh Rabinowitz, an MD-PhD who runs a metabolomics lab at Princeton, recalls a mentor saying that in the late 1990s metabolism researchers felt like the bottom 10th percentile because nobody found it interesting. Tools for measuring hundreds of metabolites and their fluxes have since made it a frontier in diabetes, aging and cancer.

• 02

  Concentrations hide flux.

  Metabolomics measures levels; fluxomics measures how fast molecules are made and used. Attia's fasting glucose of 89 mg/dL represents only about 4–5 grams of glucose in the blood, roughly 20 calories and a few minutes of fuel, yet it stays in a tight 80–100 range overnight because production and consumption match. A static reading of 180 vs. 90 says little about which flux went wrong.

• 03

  Homeostasis is extraordinarily tight.

  Attia uses pH as an example: the scale runs 0–14, but humans live at about 7.4 and can barely survive outside about 7.0–7.7, a narrow window on a logarithmic scale. Glucose is similar: Attia has seen his own range from about 50 to 240–250 mg/dL, a 5x span, while lactate ranges 60-fold.

• 04

  Glucose and fat compete for oxidation (the Randle hypothesis).

  Rabinowitz thinks much of what sets blood glucose is competition between glucose and fat. In diabetes, underlying problems in fat handling mean more glucose is needed either to induce enough insulin to suppress lipolysis or to outcompete fat for burning in tissues, with ectopic fat in liver and muscle as part of the problem.

• 05

  Lactate is a fuel, not just waste.

  Back to yeast, cells run glycolysis whenever needed and 'spit out' redox-balanced waste (lactate in humans, ethanol in yeast), then pick it up and reuse it in the TCA cycle. Attia has measured his lactate from about 0.3 mmol at rest to 20 mmol after an all-out two-minute effort. Rabinowitz's work helped establish lactate as a major circulating fuel.

• 06

  Fasting lactate may flag metabolic dysfunction.

  Attia observes that insulin-resistant people often have fasting lactate approaching 2 mmol with no activity, while healthy people sit below about 0.5. Rabinowitz agrees the correlation is interesting and plausibly reflects impaired mitochondrial oxidation, though causation isn't settled.

• 07

  Metformin inhibits complex I, but that may not be the whole story.

  It's not disputed that metformin inhibits complex I of the electron transport chain, where NADH is offloaded to make NAD+. The open question is whether that's the main effect at clinical doses of around two grams a day; 'five people who study metformin will tell you five different things.'

• 08

  NAD declines only modestly with age.

  NAD+ levels fall perhaps 10–20% with aging, a percent change rather than a fold change, compared with much larger swings when tissues are stressed. NADH carries electrons for energy production, while NADPH supports biosynthesis and antioxidant defense.

• 09

  NAD supplements: plausible, unproven.

  Oral NAD is broken down in the gut, and NR (nicotinamide riboside) largely enters the body as nicotinic acid or nicotinamide. People don't flush on NR or NMN at 500 mg–1 g because that doesn't produce enough niacin to cross the threshold of a few grams. Rabinowitz isn't convinced that boosting NAD by 20% in a 50-year-old helps, and says proper trials are needed; IV NAD has little supporting evidence.

• 10

  Cancer may become a chronic disease through metabolism plus immunity.

  Rabinowitz admits he once doubted immunotherapy's promise. He now favors a 'stalemate' strategy that combines multiple modes of action, including metabolic and nucleic-acid targets, rather than hitting hard on one lever. Pancreatic cancer, his main focus, is the fourth leading cause of cancer death, with even stage 1 disease about 80–85% fatal.