
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
- Cancer cells usurp environment and turn on for survival
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
- 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
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