How does Metformin affect metabolism and aging?

Metformin primarily acts as a weak inhibitor of mitochondrial complex one. This inhibition leads to a decrease in the cell's energy charge, activating AMPK, which promotes autophagy and reduces glucose production in the liver. These effects contribute to its anti-diabetic properties. Additionally, Metformin has anti-inflammatory and anti-cancer effects, and it's being explored as a potential anti-aging therapy, possibly by inducing adaptive stress responses through mitochondrial inhibition.

What is the Warburg Effect and how is the understanding of cancer metabolism evolving?

The Warburg Effect, observed by Otto Warburg, noted that cancer cells consume a lot of glucose and produce lactate even in the presence of oxygen, suggesting reduced mitochondrial function. However, newer research, including genetic experiments, indicates that robust mitochondrial function and TCA cycle activity are necessary for tumor growth. Cancer cells use both glycolysis for building blocks and mitochondrial function for biomass production, making both pathways targets for cancer therapy.

Are antioxidant supplements beneficial for health and longevity?

Clinical trials for widespread dietary antioxidant supplements like vitamin E and C have shown negligible to no benefit for human health and disease. In some cases, like lung cancer trials with vitamin E, they even showed worse outcomes. This is because reactive oxygen species can serve beneficial signaling roles, and excessive antioxidant intake might interfere with these normal biological processes.

How does cortisol impact metabolic function and overall health?

Cortisol can significantly stress the system and potentially become toxic to mitochondria at high doses, leading to the shedding of mitochondrial DNA and inflammatory responses. While difficult to measure, chronic hypercortisolism may contribute to issues like high blood pressure, inhibited melatonin secretion (affecting sleep and neuro-regeneration), and broader metabolic dysfunction. Managing stress response is considered a critical, yet challenging, aspect of health.

What are the key considerations when evaluating different dietary approaches?

When evaluating diets, it's important to be specific about their composition, rather than broad terms. Studies often face limitations like performance bias or randomization issues. Short-term effects, like transient insulin resistance on ketogenic diets, should be distinguished from long-term impacts. Increasingly, approaches like caloric deprivation through fasting are gaining interest over fixating on precise macronutrient ratios, but no clear 'best' diet universally exists.

Why is mitochondrial DNA unique and what are its implications?

Mitochondria contain their own small circular DNA, distinct from nuclear DNA, encoding 37 genes, 13 of which are critical for the respiratory chain. This DNA is maternally inherited and is highly vulnerable to damage due to its proximity to reactive oxygen species and lack of robust repair mechanisms found in the nucleus. However, the mitochondrial matrix has high antioxidant activity to protect this 'naked' DNA.

How do Metformin and NAD+ supplements interact or compare in their metabolic effects?

Both Metformin and NAD+ precursors influence metabolism, particularly in the liver and potentially immune cells. Metformin targets mitochondrial complex one, affecting the NAD+/NADH ratio, while NAD+ precursors aim to increase absolute NAD+ levels, mainly for sirtuin activity. Liver uptake of NAD+ precursors is significant, and they are both hypothesized to act as mild anti-inflammatory agents. The overall benefit and risk profile of NAD+ supplements needs further rigorous clinical trials, similar to what is ongoing for Metformin beyond diabetes.

What is the new theory of 'metabolites toxicity' in neurodegeneration?

Beyond classic 'proteotoxicity' (misfolded proteins), Navdeep Chandel proposes 'metabolites toxicity.' This theory suggests that certain metabolites, usually found at low, functional levels, can become pathological if their concentrations rise significantly. For example, L-2-hydroxyglutarate (L2HG) accumulates when mitochondria are dysfunctional (low NAD+, high NADH) and has been linked to severe neuro-pathology in genetic mutations. This offers a new framework for understanding diseases like Parkinson's and Alzheimer's.

How does the traditional view of mitochondria as 'powerhouses' contrast with their role as 'signaling organelles'?

Historically, mitochondria were exclusively seen as the 'powerhouses' of the cell, primarily responsible for ATP production. While ATP generation is fundamental, research, particularly since 1996 with the discovery of cytochrome C's role in apoptosis, has expanded this view. Mitochondria are now recognized as 'signaling organelles' that release molecules like hydrogen peroxide, certain metabolites (e.g., citrate), and even mitochondrial DNA fragments to dictate cellular functions like immune responses, growth, and programmed cell death.

Key Moments

#31 – Navdeep Chandel, Ph.D.: metabolism, mitochondria, and metformin in health and disease

Peter Attia MD

People & Blogs4 min read143 min video

Jan 7, 2020|16,963 views|314|26

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Key Moments

TL;DR

Mitochondria are signaling organelles, ROS can be beneficial, and Metformin's complex effects. Focus on metabolism, cancer, and aging.

Key Insights

Mitochondria are not just powerhouses but also crucial signaling organelles, influencing cellular functions beyond ATP production.

Reactive oxygen species (ROS), often considered harmful, can play beneficial signaling roles in physiological processes like immune response and exercise.

Antioxidant supplements may not be beneficial and could even be harmful, particularly in specific contexts like cancer or sepsis, suggesting a need for balance.

Mitochondrial DNA, though small, is critical and its unique inheritance and location raise questions about its vulnerability and role in disease.

Metformin, a common anti-diabetic drug, exhibits multifaceted effects including anti-inflammatory, anti-cancer, and potential anti-aging properties, primarily by inhibiting mitochondrial complex I.

Cancer cells are heavily reliant on mitochondrial function for genesis and growth, challenging the historical dogma that cancer cells solely rely on glycolysis.

THE EVOLVING ROLE OF MITOCHONDRIA

Mitochondria were historically viewed solely as the 'powerhouses' of the cell, producing ATP through oxidative phosphorylation. However, recent research, including work by Navdeep Chandel, highlights their critical role as signaling organelles. This shift in understanding suggests that mitochondria actively participate in cellular communication and influence a wide range of biological processes, including cell death, immune responses, and adaptation to stress. Their function extends far beyond simple energy generation.

REACTIVE OXYGEN SPECIES: A DOUBLE-EDGED SWORD

While reactive oxygen species (ROS) like hydrogen peroxide are often associated with cellular damage and aging, Chandel's work suggests they play vital signaling roles. Under physiological conditions, mitochondria-generated ROS can signal for beneficial cellular functions, such as activating the immune system or mediating the benefits of exercise. This challenges the conventional view that all ROS are detrimental and emphasizes the importance of context and balance in their effects.

THE COMPLEXITY OF ANTIOXIDANTS AND AGING

The prevailing notion that antioxidants are universally beneficial is questioned. Clinical trials on antioxidant supplements have largely failed to show benefits and, in some cases, have shown harm. Chandel posits that by scavenging ROS, antioxidants might interfere with beneficial signaling pathways essential for health and longevity, particularly in response to stress like exercise or during immune activation. Furthermore, the decline in mitochondrial function observed with aging may be an adaptive response rather than solely a pathological state.

MITOCHONDRIAL DNA: A UNIQUE AND VULNERABLE COMPONENT

The presence of distinct mitochondrial DNA (mtDNA) within mitochondria, of bacterial origin and maternally inherited, presents unique biological questions. This mtDNA is largely unprotected compared to nuclear DNA, making it vulnerable to damage from ROS. While high levels of antioxidants exist within mitochondria to protect mtDNA, its fragility and the potential for damage from factors like hypercortisolism raise concerns about its role in age-related diseases and neurological conditions.

METFORMIN'S MULTIFACETED EFFECTS AND MECHANISMS

Metformin, a widely used anti-diabetic drug, exerts its effects through complex mechanisms, primarily by weakly inhibiting mitochondrial complex I. This inhibition leads to a cascade of downstream effects, including activation of AMPK, reduced glucose production by the liver, and potential anti-inflammatory and anti-cancer benefits. While its primary anti-diabetic role is well-established, ongoing research explores its broader applications in longevity and disease prevention.

MITOCHONDRIA AND CANCER: RE-EVALUATING THE WARBURG EFFECT

Contrary to the long-held Warburg effect theory, which suggested cancer cells rely solely on glycolysis and suppress mitochondria, Chandel's research indicates that mitochondrial function is essential for tumor genesis and growth. Genetic experiments show that inhibiting mitochondrial respiration significantly reduces tumor formation. This suggests that both glycolysis and mitochondrial respiration are necessary, though not sufficient, for cancer cell proliferation, opening new avenues for cancer therapy targeting mitochondrial pathways.

HORMONAL INFLUENCES: CORTISOL AND ENDOCRINE BALANCE

The discussion highlights the crucial role of hormones like cortisol in health and disease. Chronic stress and hypercortisolism can negatively impact mitochondrial function and overall endocrine balance. The difficulty in easily measuring free cortisol and the challenge of managing stress responses underscore the need for greater attention to these often-overlooked physiological factors, which can influence metabolism and cellular health.

NAD+ SUPPLEMENTATION AND THE REDOX RATIO

The declining levels of NAD+ with age have fueled interest in NAD+ precursor supplements like NR and NMN. While these precursors are thought to boost NAD+ levels, their precise mechanisms, tissue specificity, and effectiveness, particularly regarding the NAD+/NADH ratio, remain areas of active research. Potential crosstalk with inflammatory cells and the liver is being explored, suggesting broader roles beyond direct NAD+ replenishment for processes like sirtuin activity.

THE DIETARY DEBATE: FROM MEDITERRANEAN TO FASTING

Navigating dietary recommendations is complex. While the Mediterranean diet is often lauded, its broad definition and potential methodological issues in some studies warrant careful consideration. The conversation touches upon the limitations of mouse studies for human nutrition and distinguishes between short-term and long-term effects of diets like the ketogenic diet. Emphasis is increasingly shifting towards caloric restriction and fasting as potent metabolic modulators.

Mentioned in This Episode

●Supplements

●Companies

●Organizations

●Books

●Drugs & Medications

●Studies Cited

●Concepts

●People Referenced

Common Questions

Reactive oxygen species like superoxide and hydrogen peroxide are traditionally seen as toxic. However, they can also act as beneficial signaling molecules under physiological conditions, influencing immune function and adaptive responses to stress like exercise. The balance between pro-oxidative and antioxidative stress is critical, as too much antioxidant activity can sometimes be harmful, especially when enhanced immune function is needed.

Topics

Health & Longevity Neuroscience & the Brain Mindset & Self-Improvement Stress Management Mitochondrial Function Cancer Therapy Medicine & Clinical Aging Theory Metformin Benefits Antioxidant Controversy

Mentioned in this video

People

Peter Mitchell

Scientist who published a paper in 1960 on how ATP is made, a significant discovery in the mitochondria field.

Iris Romero

Collaborated with Jason Locasale on Metformin studies in ovarian cancer.

Matt Vander Heiden

Co-authored a paper with Craig Thompson and Luke Cantley proposing that glycolysis in cancer cells is for biomass production, not just energetics.

Luke Cantley

Co-authored a paper with Matt Vander Heiden and Craig Thompson on cancer metabolism and glycolysis for biomass.

Ernst Lingle

University of Chicago ovarian cancer expert, collaborated with Jason Locasale on Metformin studies.

Navdeep Chandel

Professor of medicine and cell and molecular biology at Northwestern University, author of 'Navigating Metabolism', and expert on mitochondria.

Hans Krebs

Won a Nobel Prize for discovering the TCA cycle, a central part of cellular respiration.

Peter Attia

Host of The Drive podcast, interested in optimizing performance, health, and longevity.

David Sabatini

A mutual friend and colleague mentioned as having traveled to Easter Island with Peter Attia and Navdeep Chandel, and also discussed in relation to mTOR.

Tim Ferriss

Podcast host who recorded an episode at Easter Island with Peter Attia, Navdeep Chandel, and David Sabatini.

Brent Stockwell

Discovered the new form of cell death called ferroptosis in 2011.

Scott Dixon

Co-discoverer of ferroptosis at Columbia University.

Jason Locasale

A scientist at Duke University who worked with human ovarian cancer biopsies to show that Metformin alters TCA cycle metabolites.

Steve Fesik

Involved in developing a drug targeting anti-apoptotic proteins in cancer, now at Vanderbilt.

Josh Rabinowitz

A classmate of Peter Attia from medical school and colleague at Princeton, who published a paper on NAD+ precursors and their uptake by the liver.

Adrienne L. Traxler

Co-author (presumably) of the textbook 'Stryer's Biochemistry', which is a well-regarded resource for biochemistry.

Otto Warburg

Nobel Prize winner who observed that cancer cells produce a lot of lactate and consume less oxygen, leading to the Warburg effect theory.

Craig Thompson

Co-authored a paper with Matt Vander Heiden on cancer metabolism and glycolysis for biomass.

Ralph DeBerardinis

Co-authored a review with Navdeep Chandel called 'Fundamentals of Cancer Metabolism', demonstrating that both glycolysis and mitochondria are necessary for tumor genesis.

Andy Dillin

Scientist who has done work showing that decreasing mitochondrial complex one or three in worms can extend lifespan.

Stephen Simpson

Last author on a study (presumably in mice) that looked at different diets, favoring one with moderate protein, carbs, and good fats.

Locations

Easter Island

Location where Peter Attia, Navdeep Chandel, David Sabatini, and Tim Ferriss previously met.

Concepts

Cytochrome c oxidase

An enzyme that uses cytochrome C as a substrate and is critical for respiration, part of the electron transport chain.

Ketogenic Diet

A diet that may have benefits for the brain but can cause short-term insulin resistance in muscles.

Cytochrome C

A protein involved in the energy-generating system of mitochondria which, if released into the cytoplasm, can rapidly kill a cell through apoptosis.

L-2-hydroxyglutarate

A metabolite that accumulates when mitochondria are dysfunctional and NAD+ is low/NADH is high; its increase can cause neurodegeneration.

Hydrogen peroxide

A reactive oxygen species released by mitochondria, which can act as a signaling molecule under physiological conditions, with beneficial effects like immune function.

Warburg effect

The observation that cancer cells rely more on glycolysis (glucose to lactate) than oxidative phosphorylation for energy, even in the presence of oxygen.

autophagy

A cellular process promoted by AMPK activation, important for cellular cleanup.

TCA cycle

Tricarboxylic acid cycle, also known as the citric acid cycle, a series of enzymatic steps in the mitochondria that generates reducing equivalents for ATP production.

Apoptosis

Programmed cell death, a cascade initiated by the release of cytochrome C from mitochondria into the cytoplasm.

Ferroptosis

A new form of cell death involving hydrogen peroxide, free iron, and lipid hydroperoxides, which can be toxic if not regulated by enzymes like GPX4.

GPX4

An enzyme in the body that constantly eliminates lipid hydroperoxides, preventing cell death by ferroptosis.

Mitochondrial Pyruvate Carrier

A transporter protein that imports pyruvate into the mitochondria, potentially a therapeutic target.

CD38

An enzyme that breaks down NAD+, most abundant on immune cells, suggesting an immune connection to NAD+ metabolism.

Mediterranean diet

A dietary pattern that includes nuts and avocados, which Peter Attia found to be a good diet despite recent critiques of the PREDIMED study.

Supplements

Antioxidants

Molecules that can neutralize reactive oxygen species. Discussion includes whether they are always beneficial or can be harmful when ROS are needed for signaling.

Cyanide

A potent toxin that disrupts ATP production in the mitochondria, leading to fatal consequences.

MytoQ

A form of Coenzyme Q10 (CoQ10) with a cation attached, designed to increase its affinity for mitochondria. It can reduce ROS production, which can have negative biological consequences.

NAD

Nicotinamide adenine dinucleotide, its precursors (NR, NMN), and its role in an anti-aging context and as a cofactor.

reactive oxygen species

Molecules like superoxide and hydrogen peroxide which can be toxic but also beneficial as signaling molecules in mitochondria.

Ubiquinol

The reduced form of coenzyme Q (CoQ10), which is an antioxidant. It is super hydrophobic and often has poor bioavailability.

Organizations

MD Anderson Cancer Center

Developed a complex one inhibitor that is being tested in clinical trials for AML.

Northwestern University

Academic institution where Navdeep Chandel is a professor.

Companies

Raffella Pharmaceuticals

A pharmaceutical company developing a drug that targets alpha-ketoglutarate, an enzyme in the TCA cycle, for pancreatic cancer therapy.

Drugs & Medications

Metformin

A commonly used anti-diabetic drug, discussed for its role in longevity, cancer, and inflammation, believed to be a weak mitochondrial complex one inhibitor.

Books

Navigating Metabolism

Navdeep Chandel's book published in 2015, recommended for general audience understanding of metabolism.

Studies & Research

PREDIMED study

A large primary prevention nutrition study that compared a Mediterranean diet with extra-virgin olive oil, a Mediterranean diet with nuts, and a low-fat diet. The study showed benefits from the Mediterranean arms but faced criticism regarding performance bias and randomization irregularities.