Key Moments
#114 – Eileen White, Ph.D.: Autophagy, fasting, and promising new cancer therapies
Peter Attia MDKey Moments
Autophagy is crucial for health and cancer prevention, but cancer cells can hijack it for survival. New therapies may target this connection.
Key Insights
Autophagy is a cellular recycling process vital for maintaining health, preventing neurodegeneration, and combating cancer.
While autophagy protects against cancer development, established cancer cells can exploit it to survive and proliferate.
Disabling autophagy in cancer cells can be an effective therapeutic strategy, particularly in certain cancer types (e.g., KRAS-driven cancers).
Fasting is a potent natural inducer of autophagy, but its optimal dosage and frequency for health and disease treatment remain unclear.
Research into autophagy is critical for understanding its complex roles in both preventing chronic diseases and as a target for cancer therapy.
Developing ways to measure autophagy activity in humans is essential for optimizing therapeutic interventions and preventative strategies.
FROM APOPTOSIS TO AUTOPHAGY: A CAREER EVOLUTION
Dr. Eileen White's research journey transitioned from studying apoptosis, or programmed cell death, to exploring autophagy, a cellular self-eating process. Initially focused on how cancer cells evade apoptosis using molecules like BCL-2, her lab serendipitously discovered that cells unable to undergo apoptosis were utilizing autophagy for survival under nutrient-deprived conditions. This pivotal finding shifted her focus to understanding how cancer cells might hijack this fundamental survival mechanism for their own benefit, opening new avenues for cancer therapy.
UNDERSTANDING AUTOPHAGY: MECHANISMS AND TRIGGERS
Autophagy involves the formation of double-membraned vesicles called autophagosomes that engulf cellular debris and organelles, delivering them to lysosomes for degradation and recycling. This process is crucial for cellular and organismal health, particularly under stress. Key triggers include nutrient deprivation, energy depletion (AMPK pathway), amino acid scarcity (mTOR pathway), and substrate availability (acetyl-CoA). Other significant inducers encompass organelle damage, protein misfolding, hypoxia, and even exercise.
AUTOPHAGY'S PROTECTIVE ROLE IN DISEASE PREVENTION
In healthy cells and organisms, autophagy plays a critical role in preventing disease. Studies in mice demonstrate that a complete lack of autophagy is uniformly fatal in newborns, leading to death from starvation. In adult mice, disabling autophagy primarily results in neurodegeneration and fatty liver disease, highlighting its essential function in maintaining neuronal health and liver homeostasis. This suggests that enhancing autophagy, perhaps through fasting, could be a powerful strategy for preventing chronic conditions like Alzheimer's and metabolic disorders.
THE PARADOXICAL ROLE OF AUTOPHAGY IN CANCER GROWTH
A striking paradox emerges when considering autophagy in the context of existing cancer. While autophagy protects against the initial development of cancer by clearing damaged cells, established cancer cells can exploit this survival pathway to endure harsh tumor microenvironments, such as hypoxia, and to fuel their rapid proliferation. This hijacking of autophagy by cancer cells makes them particularly dependent on it for survival, presenting a therapeutic vulnerability. Inhibiting autophagy has shown significant promise in reducing tumor growth, especially in certain genetic subtypes of cancer.
TARGETING AUTOPHAGY FOR CANCER THERAPY: EMERGING STRATEGIES
The discovery that cancer cells rely on autophagy has led to the development of strategies aimed at inhibiting this pathway for therapeutic benefit. Research indicates that certain cancers, particularly those driven by mutations in KRAS or BRAF, are highly dependent on autophagy. Genetically engineered mouse models have shown that inhibiting autophagy can lead to tumor regression. This supports the concept of developing small molecule inhibitors to target autophagy in specific cancers, potentially augmenting existing treatments and improving response rates, particularly in conjunction with immunotherapies.
THE CHALLENGE OF DOSING and MEASURING AUTOPHAGY
Despite the clear benefits and therapeutic potential of autophagy, a significant challenge lies in determining the optimal dosage and frequency for interventions like fasting. While fasting is a potent inducer of autophagy, its precise effects and how they vary with different fasting durations (e.g., 3 days per month vs. 7 days per quarter) are not well understood. Developing reliable methods to measure autophagy flux in humans, beyond invasive tissue biopsies, is crucial for translating this knowledge into practical clinical applications and personalized health strategies.
AUTOPHAGY'S INTERPLAY WITH IMMUNOTHERAPY AND METABOLISM
Emerging research suggests a complex interplay between autophagy and the immune system, particularly in cancer therapy. Inhibiting autophagy may promote inflammation, potentially 'heating up' cold tumors and making them more susceptible to immune checkpoint blockade therapies. Furthermore, understanding the metabolic demands of cancer cells and how autophagy influences them is an active area of investigation. Advanced technologies using isotope tracers are beginning to unravel the intricate metabolic pathways in vivo, paving the way for identifying new therapeutic targets and understanding the nuances of autophagy's role.
Mentioned in This Episode
●Supplements
●Organizations
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●People Referenced
Common Questions
Apoptosis is programmed cell death where dysfunctional cells 'commit suicide,' a process regulated by proteins like bcl-2, Bax, and Bak. It's a clean process that typically reduces inflammation. Autophagy, in contrast, is a cellular recycling process where cells degrade and reuse their own components, primarily for survival during stress or nutrient deprivation.
Topics
Mentioned in this video
David Sabatini introduced Peter Attia and Eileen White a few years prior to the podcast, and his work on ribosomal RNA and ribophagy is mentioned.
Eileen White mentions Jafra Bennewith as a collaborator in developing technology to use isotope tracers for thorough understanding of metabolism in living mammals.
Researcher at UT Southwestern who infuses isotope tracers into humans with cancer to measure the metabolism of human tumors.
His lab developed the original autophagy deficient mouse models.
Known for his famous fasting study that examined the metabolic phases of a 40-day fast in healthy human subjects.
Eileen White completed her postdoc with Bruce Stillman at Cold Spring Harbor Laboratory.
Eileen White's graduate school department was led by Dr. Arnold Levine, who discovered p53.
Co-founder with Eileen White of a company aimed at developing small molecule inhibitors to target autophagy for cancer therapy.
A researcher known for his work on fasting-mimicking diets, suggesting benefits without full fasting.
A metabolic pathway sensing energy and ATP levels, whose upregulation signals energy deficiency and triggers autophagy.
The acetyl-CoA protein deacetylation pathway, also related to sensing fatty acid and glucose substrates, is mentioned alongside mTOR and AMPK as a third pathway signaling nutrient scarcity to trigger autophagy.
One of the essential autophagy genes, mice deficient in ATG7 fail to survive the neonatal starvation period.
A human oncogene that functions by blocking apoptosis (programmed cell death), keeping tumor cells alive. Inhibitors of bcl-2 were developed to promote apoptosis in cancer treatment.
A class of proteins involved in cellular metabolism and aging, their role in autophagy is not directly known by Eileen White.
One of the essential autophagy genes, mice deficient in ATG5 fail to survive the neonatal starvation period.
A protein residing in the mitochondrial membrane that oligomerizes and pokes holes in the outer mitochondrial membrane when triggered by apoptosis.
An organic molecule that accumulated when Eileen White's team inhibited autophagy, suggesting its potential as a metabolic marker.
A tumor suppressor protein and transcription factor, p53 promotes apoptosis by activating proteins like Puma and Nox, which antagonize bcl-2. Loss of p53 function accounts for about half of all cancers.
A metabolic pathway primarily sensing amino acids, whose downregulation signals nutrient scarcity and triggers autophagy.
Autophagy plays a crucial role in preventing neurodegeneration, with evidence suggesting that defects in autophagy can lead to Alzheimer's-like pathology.
A protein residing in the mitochondrial membrane that oligomerizes and pokes holes in the outer mitochondrial membrane when triggered by apoptosis.
An anti-PD-1 immune checkpoint inhibitor used in an anecdotal case for a patient with unresectable pancreatic adenocarcinoma, leading to disease remission.
A potent inhibitor of mTOR, which signals autophagy, and has demonstrated longevity benefits across all four models of eukaryotic cells. Its neuroprotective effects are being explored.
A chemical used to block the degradation of LC3-II in the lysosome to measure autophagic flux.
A drug that mimics fasting by activating AMPK, potentially inducing autophagy. It has not been tested in autophagy-deficient mice.
Mentioned as a pharmacologic agent that is a potent stimulator of autophagy, explored for healthy individuals as a 'Fountain of Youth' type pill.
A drug used to block the degradation of LC3-II in the lysosome to measure autophagic flux. It is also an active component of some cancer clinical trials.
Eileen White is the Deputy Director and Chief Scientific Officer, as well as the Associate Director for Basic Research and co-leader of the Cancer Metabolism and Growth Research Program at this institution.
Eileen White completed her postdoc and later joined the faculty at Cold Spring Harbor Laboratory, describing it as an incredible scientific environment.
Eileen White observes a growing interest in cancer prevention at the NCI.
Ralph DeBerardinis, a researcher mentioned for his work on infusing isotope tracers into humans to measure tumor metabolism, is based here.
Eileen White's lab received an NIH grant to study mouse models of cancer with varying mutation burdens and their response to immune checkpoint blockade.
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