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Peter Attia MD#31 – Navdeep Chandel, Ph.D.: metabolism, mitochondria, and metformin in health and disease
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CHAPTERS
- 0:04 – 5:23
Episode Preview and Introducing Nav Chandel
Peter Attia introduces his guest Nav Chandel, a Northwestern professor and author of Navigating Metabolism, and previews topics from ROS and mitochondrial DNA to cortisol, metformin, cancer and NAD. The two then banter before starting the interview.
- •Nav Chandel studies mitochondria and metabolism and wrote Navigating Metabolism
- •Episode topics include ROS, antioxidants, mitochondrial DNA, cortisol, metformin, cancer and NAD
- •Nav turns the tables at the end with the "what should I eat?" question
- 5:23 – 12:39
From Math and Organ Preservation to Mitochondria: Glycolysis, the TCA Cycle and ATP
Nav describes how a math background and transplant lab work led him to metabolism and enzyme kinetics. Peter then asks for a refresher on glucose, pyruvate, the TCA cycle and the electron transport chain as a battery that makes ATP.
- •Nav's path from math to organ preservation to a PhD on cytochrome c oxidase kinetics
- •Pyruvate can become lactate in the cytoplasm or enter the mitochondria via the pyruvate carrier
- •The TCA cycle generates NADH and FADH that feed the electron transport chain
- •Oxygen is the final electron acceptor, and the traditional view was that mitochondria were about ATP
- 12:39 – 19:42
Cytochrome c, Apoptosis and Mitochondria as Signaling Organelles
Nav explains the 1996 discovery that cytochrome c released from mitochondria triggers cell death, which broke the ATP-only view. He describes how this led him to propose that mitochondria signal through hydrogen peroxide and other molecules.
- •Cytochrome c has a day job in making ATP and a moonlighting role in triggering apoptosis
- •Mitochondria were seen as releasing ROS only when damaged, but Nav's group showed physiological H2O2 can be beneficial
- •Immune function and the exercise response may depend on mitochondrial H2O2 signaling
- •Bax and Bak pores release cytochrome c, and drugs targeting anti-apoptotic proteins are used in cancer
- 19:42 – 28:43
Antioxidants, Ferroptosis and ROS Balance
The discussion turns to whether antioxidants are beneficial. Nav cites failed antioxidant trials in sepsis and lung cancer and high-dose antioxidants blunting exercise benefits, and describes ferroptosis as a case where ROS become lethal.
- •Antioxidant trials in ICU sepsis and a vitamin E lung cancer trial failed or made things worse
- •High-dose antioxidants may turn off the beneficial gene response to exercise
- •Ferroptosis combines H2O2, iron and polyunsaturated lipids into toxic lipid hydroperoxides
- •The body has at least 30 enzymes, including GPX4, that keep ROS low
- 28:43 – 45:08
Mitochondrial DNA, Its Vulnerability and Maternal Inheritance
Peter and Nav discuss the 37 genes of mitochondrial DNA, its bacterial origin, and why it is odd that such critical genes sit in a vulnerable spot. Nav admits no good explanation exists for why the genes were retained or why they pass maternally, and discusses what mitochondria release for signaling.
- •Mitochondrial DNA has 37 genes, 13 of them essential for the respiratory chain
- •Mitochondria descend from an alphaproteobacterium, with the host from an archaeon
- •The mitochondrial matrix is rich in antioxidants that protect the exposed DNA
- •Why the genes remain and why inheritance is maternal are still open questions
- •Mitochondria may release ATP, H2O2 and metabolites like citrate for signaling
- 45:08 – 50:12
Mitochondrial Decline in Aging: Adaptive or Rate-Limiting?
Nav argues that although maximal mitochondrial capacity declines with age, it may never be rate limiting, since halving a mitochondrial protein causes no pathology. He proposes the decline could be adaptive, which challenges the idea of boosting mitochondria with supplements.
- •Mitochondrial DNA decreases, accumulates deletions and maximal ATP capacity falls with age
- •People use only about 10 to 20% of maximal capacity, even in exercise perhaps 40 to 50%
- •Knocking out a mitochondrial protein by 50% does not cause pathology, so function may not be rate limiting
- •Nav says he sees no evidence supporting mitochondrial-boosting supplements
- 50:12 – 1:06:02
How Metformin Works: Complex I, AMPK and the NAD/NADH Ratio
Nav and Peter explain that metformin is a weak complex I inhibitor with antidiabetic, anticancer and anti-inflammatory effects. They cover how this lowers the battery charge, activates AMPK and shifts the NAD to NADH ratio, which curbs liver gluconeogenesis.
- •Metformin is used by hundreds of millions and acts on the liver, kidney, gut and likely immune cells
- •Complex I inhibition lowers ATP, activates AMPK and promotes autophagy
- •A shifted NAD to NADH ratio slows lactate to pyruvate conversion and gluconeogenesis
- •Declining mitochondrial function with age seems paradoxical next to metformin's benefits if mitochondria were rate limiting
- 1:06:02 – 1:16:08
Proving Metformin's Anticancer Mechanism with Yeast Complex I
Nav describes his lab's experiment replacing complex I with a metformin-resistant yeast enzyme, showing the anticancer effect requires complex I inhibition. They discuss supporting human tumor metabolomics and the interplay with systemic insulin and IGF effects.
- •Yeast NDI1 catalyzes NADH to NAD without proton pumping and is not bound by metformin
- •With yeast complex I present, metformin no longer reduces tumor burden
- •Nav says the anticancer effect is not thought to be due to AMPK and that NAD/NADH ratio matters
- •Jason Locasale's patient biopsies showed altered TCA metabolites after metformin
- •Both systemic and tumor-cell mechanisms likely work together, and many tumors lack metformin transporters
- 1:16:08 – 1:26:58
Mitochondria Are Necessary for Tumorigenesis: Beyond Warburg
Nav explains the Warburg dogma that cancer suppresses mitochondria and relies on glycolysis, and how his genetic experiment in lung cancer showed that respiration is required for tumors. The conversation also covers necessary versus sufficient causes and the difficulty publishing the finding.
- •Warburg observed high lactate production in cancer cells, leading to the idea that mitochondria are suppressed
- •Knocking out the respiratory chain in mouse lung tumors produced much smaller tumors
- •Mitochondria supply the building blocks for nucleotides, so glycolysis and mitochondria are both necessary but neither is sufficient
- •The paper was rejected by many journals before PNAS published it
- •Correlation versus causation and adaptive versus maladaptive interpretations are stressed
- 1:26:58 – 1:38:15
Targeting Mitochondria in Cancer Therapy and Nav's Contrarian Positions
Nav describes drugs in development that target mitochondria, including a complex I inhibitor at MD Anderson and a TCA cycle drug, and discusses toxicity and combination strategies. He then recaps his contrarian views on antioxidants, aging and cancer and addresses whether mitochondrial dysfunction or nuclear mutations come first.
- •A strong complex I inhibitor is in an AML trial, with a therapeutic window the key question
- •A TCA cycle enzyme-targeting drug had a Phase I pancreatic cancer safety trial
- •Combining mitochondrial inhibitors with chemotherapy, BRAF inhibitors or immunotherapy is being considered
- •Nav sides with nuclear mutations driving mitochondrial changes in cancer
- •Rare TCA cycle mutation cancers are exceptions, and oncocytomas with complex I loss are benign
- 1:38:15 – 1:45:56
Supplements, Vitamin C and Whether Nav Takes Metformin
Peter asks about dietary antioxidants, supplements and cancer patients, and why Nav does not take metformin himself. Nav says vitamin C from about an orange a day supports gene-regulating enzymes, and that he waits for rigorous trials while he sees metformin's best proven benefit as antidiabetic.
- •Natural vitamin C intake supports enzymes controlling DNA methylation, unrelated to antioxidant activity
- •Nav does not take supplements and avoids any drug without a rigorous clinical trial
- •His reasoning is that exercise already mimics metformin's AMPK effects
- •Metformin's possible anti-inflammatory benefit over decades is something he is rethinking, with CANTOS cited as support for targeting inflammation
- •Evidence for metformin's immune-modulating effects is still thin
- 1:45:56 – 1:55:25
NAD Precursors and MitoQ
They discuss NAD precursors such as NR and NMN, the sirtuin rationale, and Josh Rabinowitz's finding that these go heavily to the liver. Nav speculates about immune cells and notes the antioxidant tradeoffs of MitoQ and CoQ10.
- •NAD precursors are meant to boost sirtuin activity, which is thought to decline with age
- •Rabinowitz's work suggests orally taken NR is taken up heavily by the liver
- •Nav speculates NAD supplements might act on liver and immune cells, with CD38 an NAD-degrading enzyme on immune cells
- •MitoQ is a mitochondria-targeted CoQ with a narrow therapeutic window because it removes beneficial ROS signaling
- •Nav sees metformin as having more potential than most antioxidants but still doesn't take it
- 1:55:25 – 2:02:05
Metabolite Toxicity and L2-Hydroxyglutarate Hypothesis
Nav lays out a new idea that metabolites, not only misfolded proteins, could cause neurodegeneration. He focuses on L2-hydroxyglutarate, which rises when NADH increases and NAD falls in severe mitochondrial dysfunction such as hypoxia.
- •Proteotoxicity is the dominant theory, but metabolite toxicity may be complementary
- •Inborn errors of metabolism show metabolites can cause pathology at high levels
- •L2HG is triggered when the NADH/NAD ratio rises due to respiratory chain failure
- •Weak inhibition by metformin would not shift the ratio enough, and the process would take days in cell culture
- 2:02:05 – 2:09:35
Cortisol, Stress and the Alcohol Tangent
Nav pitches cortisol as an overlooked variable in longevity circles, wondering whether regimented high achievers stress themselves. Peter agrees hypercortisolemia matters, notes measurement difficulty and the lack of pharmacologic targets, and mentions meditation and alcohol.
- •Nav wonders if stress via cortisol affects mitochondria much like insulin does
- •Peter notes only free cortisol matters and it is measured in saliva or urine
- •Peter says response to stress matters more than the stressful situation itself and finds meditation most helpful
- •Peter's view on alcohol is that toxicity builds slowly and enjoyment can offset some downside
- •Nav suggests tracking liver enzymes such as ALT
- 2:09:35 – 2:22:36
What Should I Eat? Mediterranean Diet, PREDIMED and Fasting
Nav asks Peter the dreaded diet question, and they joke about party small talk. They go through PREDIMED and its limitations, macronutrient preferences, mouse versus human data, ketogenic diets and insulin resistance, and Peter's growing interest in fasting.
- •Nav favors a Mediterranean-style diet and dislikes high-protein, high-carb or high-fat extremes
- •Peter explains PREDIMED's performance bias and randomization irregularities, which he thinks did not change the results
- •Peter distrusts mouse studies for human nutrition and separates short- from long-term insulin resistance on keto
- •Nav eats roughly a third each of fat, carbs and protein and fasts about 15 hours daily
- •Peter focuses more on prolonged calorie deprivation than on exact macronutrient amounts
