June 11, 2020

Autophagy, fasting, and promising new cancer therapies | Eileen White, Ph.D. on The Drive with Peter Attia #114

Key Takeaways

• We barely understand how autophagy impacts metabolism
• Context of autophagy is very important – autophagy protects a person from getting cancer but once someone has cancer it appears autophagy benefits cancer cells instead of healthy cells
• Fasting is one of the most potent stimulators of autophagy
• We have a critical need to study and identify the proper dose of fasting to improve human health
•  “The key to living longer is delaying the onset of chronic disease…not living longer with the chronic disease” – Dr. Peter Attia
• “Fasting is probably protective against all chronic diseases.” – Dr. Peter Attia

Introduction

Dr. Eileen White, Ph.D. is the Chief Scientific Officer and Deputy Director for Basic Science at the Rutgers Cancer Institute of New Jersey. She is also a Distinguished Professor of Molecular Biology and Biochemistry at Rutgers University.

Dr. White currently serves on the Board of Scientific Advisors for the National Cancer Institute.

 Host: Peter Attia (@PeterAttiaMD)

Apoptosis and Its Role in Cancer Prevention

• Apoptosis is programmed cell death
• BCL-2 family of proteins inhibit apoptosis and keep tumor cells alive
• BH3 only proteins are activated to inhibit BCL-2 to trigger apoptosis

Cancer, p53 protein, and Apoptosis

• p53 is a protein found in the nucleus of the cell that controls cell division and cell death
• p53 promotes apoptosis and helps keep abnormal cells (such as cancer cells) from growing
• Loss of function in parts of p53 accounts for half of all cancers
• When we disable apoptosis in a cancer cell, it can’t commit suicide and grows

Cancer Cells Use Autophagy to Thrive

• Cancer cells have an incredible propensity to survive, even in the absence of nutrients
• Cells turn on autophagy and recycle as a means of survival  
• With cancer, even in fed state, autophagy is elevated and increases further if stressed
• Need to inhibit autophagy for cancer therapy
  • When autophagy was inhibited in cancer cells, survival was reduced
  • In short-term, immune cells were functional and T-cells were more anti-tumorigenic

Studies Support Autophagy Inhibition in Cancer

• Studied normal mice and genetically knocked out ability for autophagy
  • Observed that 16 hours of fasting can be fatal
  • The well-fed mice only survived a few months and ultimately succumbed to neurodegeneration
  • This suggests that the role of autophagy in neurodegeneration is essential for survival
    • Brain tissues are more autophagy-dependent than others
    • Autophagy plays a role in preventing fat accumulation in the liver
    • Lungs were relatively normal and didn’t seem to rely on autophagy mechanisms for survival        
• Studied cancerous mice and shutoff autophagy
  • Cancerous mice were also intolerant to fasting
  • Tumor died before mice succumbed to any other cause of death

What Stressors Induce Autophagy in Non-Cancerous Cells?

• Stresses that result in organelle damage (e.g., mitochondrial damage)
• Nutrient deprivation is one of the biggest triggers for autophagy
• Three main metabolic signaling pathways:
  • mTor pathway sensing amino acids
  • AMPK pathway sensing energy and ATP
  • Acetyl-coA protein acetylation pathway sensing substrate of fatty acid and glucose
• Non-metabolic factors that induce autophagy
  • Temperature extremes
  • Exercise induces autophagy
    • Exercise damages muscle and autophagy mitigates damage
  • Hypoxia is a potent inducer of autophagy
    • Tumors are well-known to have hypoxia in center – autophagy is most active

Autophagy’s Impact on Disease Prevention vs Disease Treatment

• Stimulating autophagy can preserve health but once there’s cancer, it’s a different ball game and at that point is a different context
  • In the presence of cancer, inhibiting autophagy is preferentially damaging to tumor compared to normal tissue
• Autophagy has two roles depending on presence of disease
  • Cancer cells usurp environment and turn on for survival
    • Autophagy helps certain cancers that are KRAS drive, such as pancreatic and liver
  • In normal cells, autophagy is protective and preserves cellular function and prevents chronic damage and inflammation

Fasting and chemotherapy literature  

• Fasting has been shown in previous studies to augment the impact of chemotherapy against cancer
  • However, it might reduce inflammation that accompanies fasting instead of autophagy itself

Biotech Industry and Desire to Induce Autophagy with Pharmaceuticals

• Biotech companies are rapidly exploring ways to trick the body into thinking nutrients are scarce and induce autophagy pharmacologically and chemically
• Fasting is the most potent stimulator of autophagy but it’s hard to recommend since we don’t know the dose  
• However, we lack tools to measure signals of autophagy

Phases of fasting

• What’s happening day to day in fasting is very different
  • When monitoring his blood levels, Peter sees benefits start after 3 days but not after 2 days
  • After 7 days of water fast, there appears to be a steady state of benefits reached
    • Decreases: glucose, insulin, T3, gonadotropins
    • Increases: uric acid, reverse T3

Where do you begin to look for signature of autophagy in blood?

• LC3 is protein attached to autophagosome membrane and links to autophagosome
  • LC3 used to assess autophagy in a living mouse by using tissue but we don’t have the tools to measure autophagic flux in humans
    • Autophagy turned on in fasting but not uniform in every tissue
  • We’d have to infer based on LC1 and disappearance of LC2 into the lysosome
  • We can look at metabolites as markers to track autophagy
    • Expect decreases in leucine, methionine, glucose
    • Expect increases in uric acid
    • Muscle biopsy can track muscle degradation
    • We could use a mouse model to provide information for humans
      • Take metabolic characterization of normal fasting mouse vs autophagy-deficient fasting mouse and identify metabolic changes that are autophagy-dependent

Dr. White’s Future Research

• Ultimately, he wants to translate findings on autophagy’s role in cancer to treatments
  • Find small molecule inhibitors to inhibit autophagy in cancer therapy
  • Define functional requirements for autophagy at the molecular level in individual cancers
  • Understand the metabolic role of autophagy – why one cancer needs autophagy more than another
  • Optimize checkpoint blockade treatments by using mouse models with low, medium, and high mutation burden and manipulating autophagy

Drive with Dr. Peter Attia : autophagy, cancer, fasting, longevity
Notes By Maryann