#114 - Eileen White, Ph.D.: Autophagy, fasting, and promising new cancer therapies
This episode with Dr. Eileen White, Chief Scientific Officer at Rutgers Cancer Institute, explores autophagy's role in health, neurodegeneration, and cancer. It details how autophagy protects against disease but paradoxically aids existing cancer, and discusses the critical need to understand the optimal "dose" and frequency of fasting for human health.
Deep Dive Analysis
17 Topic Outline
Eileen White's Scientific Journey and Background
Transition from Apoptosis to Autophagy Research
Defining Apoptosis and its Role in Cancer Evasion
Serendipitous Discovery of Autophagy in Cancer Survival
Autophagy's Role in Cancer Cell Metabolism and Proliferation
Stressors Inducing Autophagy in Normal Cells
Impact of Autophagy Deficiency in Mouse Models
Tissue-Specific Autophagy Dependence and Disease Phenotypes
Targeting Autophagy for Cancer Therapy in Adult Mice
Autophagy Dependence Across Different Cancer Types
Reconciling Autophagy's Dual Role in Cancer (Paradox)
The Challenge of Dosing Fasting for Autophagy in Humans
Developing a Molecular Signature for Autophagy Induction
Pharmacological Inducers of Autophagy: Metformin and Rapamycin
The Nobel Prize for Autophagy Research
Future Research: Autophagy, Metabolism, and Immunotherapy
Autophagy's Potential in Alzheimer's Disease Prevention
6 Key Concepts
Apoptosis (Programmed Cell Death)
A highly regulated process where cells self-destruct, crucial for preventing cancer by eliminating damaged cells. It involves BCL2 family proteins, BAX/BAK, and mitochondrial membrane permeabilization, often triggered by tumor suppressor P53.
Autophagy (Self-Eating)
A fundamental cellular recycling process where cells degrade and recycle their own components (proteins, organelles) to generate energy and building blocks, particularly important for survival during nutrient deprivation.
Autophagosomes
Double-membrane vesicles that form around cellular components targeted for degradation during autophagy, eventually fusing with lysosomes for breakdown and recycling.
Autophagic Flux
The dynamic process of autophagy, involving the formation of autophagosomes, their fusion with lysosomes, and the subsequent degradation of cargo. It's measured by tracking proteins like LC3-I to LC3-II conversion and degradation.
Autophagy Paradox in Cancer
The observation that while autophagy is crucial for preventing cancer by maintaining cellular health and reducing inflammation, cancer cells can also hijack and upregulate autophagy to survive and proliferate, especially under stress.
KRAS-driven Cancers
Cancers characterized by mutations in the KRAS gene, which lead to perpetual activation of cell proliferation pathways (like MAP kinase), making these cancers often highly dependent on autophagy for survival.
11 Questions Answered
Apoptosis is a programmed cell death pathway involving the BCL2 protein family, BAX/BAK proteins that permeabilize mitochondrial membranes, and proteases that degrade the cell, often initiated by tumor suppressors like P53.
P53, a tumor suppressor, promotes apoptosis by activating proteins like PUMA and NOXA, which antagonize BCL2 and trigger cell suicide, thus preventing the progression of emerging cancer cells.
Cancer cells can elevate autophagic flux even in a fed state and further increase it under stress, using it to recycle cellular components for building blocks and energy, thereby supporting their survival and proliferation.
Nutrient deprivation (sensed by mTOR, AMPK, sirtuins), organelle damage (e.g., mitochondrial dysfunction), protein misfolding, exercise, and hypoxia are potent inducers of autophagy.
Adult mice with systemic autophagy knockout survive for 2-3 months before succumbing to neurodegeneration, and they die within 16 hours if fasted, highlighting autophagy's essential role in long-term health and stress response.
The brain is highly autophagy-dependent due to its post-mitotic neurons needing quality control, and the liver is also very sensitive, with autophagy loss leading to steatosis and protein aggregate accumulation.
Autophagy is context-dependent; it preserves health by preventing chronic damage and inflammation that can lead to cancer, but once cancer is established, inhibiting autophagy can preferentially damage tumor cells.
There is currently no reliable way to quantify the degree of autophagy induced by different fasting durations or frequencies in humans, making it impossible to determine the optimal "dose" for health benefits.
Yoshinori Ohsumi received the Nobel Prize in 2016 for his profound and creative work in identifying the essential autophagy genes in yeast, which provided the foundation for understanding autophagy in mammals.
Inhibiting autophagy can stimulate inflammation within tumors, potentially "heating up" immunologically "cold" tumors and making them more responsive to immune checkpoint blockade therapies.
Autophagy is critical for clearing accumulated toxic proteins and damaged organelles in post-mitotic neurons, suggesting a vital role in preventing neurodegenerative diseases like Alzheimer's.
12 Actionable Insights
1. Prioritize Disease Prevention for Longevity
Understand that true longevity is achieved by delaying the onset of chronic diseases, making disease prevention the single most important tool in your health toolkit.
2. Autophagy’s Context-Dependent Role in Cancer
Stimulating autophagy can prevent cancer by delaying chronic damage and inflammation in normal tissues; however, once cancer is established, inhibiting autophagy may be beneficial as tumors often usurp it for survival.
3. Fasting to Reduce Chronic Disease Risk
Improve your metabolic health through fasting to significantly reduce the risk of major chronic diseases, including cardiovascular disease, cancer, Alzheimer’s disease, and diabetes complications.
4. Cultivate Fasting as a Health Tool
Prioritize the use of fasting as a potent and accessible method for health preservation, rather than solely seeking pharmacological agents to stimulate autophagy.
5. Exercise Potently Induces Autophagy
Engage in regular exercise, as it potently induces autophagy, which is crucial for mitigating muscle damage and supporting cellular repair processes.
6. Stimulate Autophagy for Brain Health
Focus on stimulating autophagy as a potential strategy to delay neurodegenerative diseases, given its essential role in neuronal protein and organelle quality control.
7. Autophagy Prevents Fatty Liver Disease
Autophagy is important in preventing fat accumulation and protein aggregate formation in the liver, highlighting its role in maintaining liver health and preventing conditions like steatosis.
8. Prolonged Fasting for Maximal Autophagy
To achieve a fully ‘cranked’ state of autophagy, consider a water-only fast of approximately seven days, as shorter fasts (e.g., 12 hours) are likely insufficient.
9. Three-Day Fasting for Metabolic Shifts
A three-day fast appears to be a minimum duration required to induce significant metabolic changes, such as a spike in uric acid and a bottoming out of glucose, indicating a meaningful metabolic shift.
10. Integrate Diet Quality with Fasting Practices
When implementing fasting for health, also consider the quality of your diet, as ‘what you eat’ is as crucial as ‘how many calories you eat’ or ‘how often you eat them.’
11. Rapamycin for Potential Neuroprotection
Explore rapamycin as a potential neuroprotective agent, noting pilot data suggests its benefits, likely mediated through mTOR inhibition and subsequent autophagy induction.
12. Access Deeper Longevity Content
To further enhance your understanding of longevity, consider subscribing to the podcast’s membership program for exclusive, in-depth content.
11 Key Quotes
Well, you were excited about the science. And so nerds like me like to talk about science.
Eileen White
one novel function of cancer is to evade cell death.
Eileen White
just because a cell can't commit suicide doesn't explain how it can be a cancer cell can just sit in buffer and be fine.
Eileen White
when you inhibited autophagy, the survival of the cancer cells was reduced.
Eileen White
If you knock it out, it is uniformly fatal. Do not pass go, do not collect $200, you're gone.
Peter Attia
the key to living longer is delaying the onset of chronic disease.
Peter Attia
I think it's a matter of thinking of the role of autophagy in cancer as being context dependent.
Eileen White
I think that our biomedical community is mostly focused on putting out fires rather than disease prevention, although I've seen a change.
Eileen White
Longevity is about delaying the time it takes until disease comes.
Peter Attia
The problem is we didn't know how to dose it. How long would we tolerate that ignorance?
Peter Attia
sometimes scientific discoveries are so basic that you can't ever anticipate what it would ultimately lead to.
Eileen White
1 Protocols
Proof-of-Principle Protocol for Autophagy Inhibition in Cancer Therapy
Eileen White- Engineer an adult mouse model where an essential autophagy gene can be deleted throughout the entire animal.
- Induce cancer in this adult mouse.
- Once the mouse has cancer (e.g., lung cancer), delete the essential autophagy gene in the entire mouse (tumor and all normal tissues).
- Observe whether the tumor or the mouse dies first to determine the therapeutic window and efficacy.