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Peter Attia MD#114 – Eileen White, Ph.D.: Autophagy, fasting, and promising new cancer therapies
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CHAPTERS
- 0:11 – 7:50
Eileen White's Path from Science-Minded Childhood to Building a Cancer Center
Peter Attia introduces Eileen White and the episode's themes, then asks about her background. She describes her family's interest in science, her training under Arnie Levine and Bruce Stillman, and helping build the Rutgers Cancer Institute.
- •Episode preview: autophagy in cancer, neurodegeneration, and the dosing of fasting
- •White grew up in a family that discussed scientific discoveries
- •Trained with Arnie Levine and Bruce Stillman at Cold Spring Harbor
- •Joined Rutgers in 1990 and helped grow a cancer center from nothing
- 7:50 – 10:08
Discovering a Viral BCL2 Homolog That Blocks Apoptosis
White explains how a postdoc project on an adenovirus oncogene led to the finding that it was a BCL2 homolog that blocks programmed cell death. This helped establish evasion of cell death as a feature of cancer and led to drugs that inhibit BCL2.
- •The assigned adenovirus gene turned out to be a viral homolog of BCL2
- •Evading cell death is a key function of cancer
- •Pharmaceutical companies developed BCL2 inhibitors to promote apoptosis
- •Her lab still works on optimizing these drugs in solid tumors
- 10:08 – 17:34
How Apoptosis Works: BCL2 Family, p53, and Clean Cell Death
White and Attia walk through the BCL2 family, Bax and Bak, and the role of p53 in triggering apoptosis. They discuss p53 mutations in cancer and compare apoptosis to necrosis in terms of inflammation.
- •BCL2-like proteins inhibit apoptosis, BH3-only proteins antagonize them, and Bax/Bak poke holes in mitochondria
- •p53 turns on Puma and Noxa to promote apoptosis in response to damage
- •Mutant p53 acts as a dominant negative and may gain cancer-promoting functions
- •Apoptosis packages cell debris, whereas necrosis releases contents and is pro-inflammatory
- 17:34 – 22:55
Eureka Moment: Apoptosis-Deficient Cancer Cells Turn On Autophagy
White describes how cells that couldn't undergo apoptosis survived in buffer with no nutrients. Electron microscopy revealed autophagosomes, and the team realized cancer cells had co-opted autophagy for survival.
- •Apoptosis-deficient tumor cells survived starvation unexpectedly
- •Electron micrographs showed double membrane vesicles, which were autophagosomes
- •Yeast literature showed autophagy as a starvation survival mechanism
- •Inhibiting autophagy reduced cancer cell survival in many cell lines
- 22:55 – 29:23
Autophagy in Cancer Metabolism, Nucleotides, and Ribophagy
The discussion covers how cancer cells have elevated autophagy even when fed, and links this to the idea that tumors optimize for building blocks. White explains that nucleotides appear rate limiting and that ribosome recycling is an important survival mechanism.
- •Normal fed cells have low autophagy, while cancer cells have it elevated even when fed
- •Attia raises the alternative explanation of the Warburg effect favoring building blocks over ATP
- •Nucleotide synthesis seems to be rate limiting in cancer cells
- •Ribophagy recycles ribosomes as a store of protein and nucleic acids
- •Autophagy is highly conserved from yeast to mammals
- 29:23 – 37:35
Stressors That Induce Autophagy and the Autophagy-Deficient Mouse
Attia and White cover triggers of autophagy such as nutrient sensing pathways, organelle damage, exercise, and hypoxia. White then describes knockout mice: neonatal lethality of Atg5 and Atg7 knockouts, and her adult-inducible knockout.
- •Triggers include mTOR, AMPK, and acetyl-CoA signaling plus organelle damage and misfolding
- •Exercise and hypoxia potently induce autophagy
- •Autophagy-deficient tumors become hollow in their hypoxic centers
- •Autophagy-deficient newborn mice die during the neonatal starvation period
- •Adult knockout mice live two to three months, then die of neurodegeneration, and die within 16 hours if fasted
- 37:35 – 42:57
Autophagy Dependence of Brain and Liver and Fasting's Role in Longevity
White explains that tissues vary in their autophagy dependence: the brain is highly sensitive, the liver develops steatosis, and the lung appears relatively normal. Attia lays out his view that delaying chronic disease is the key to longevity and previews questions about fasting and drugs that mimic it.
- •Neurons are post-mitotic and cannot tolerate accumulated garbage
- •Liver-specific knockout causes fatty liver and p62 protein aggregates but not death
- •Increased neuronal apoptosis is seen in the autophagy-deficient brain
- •Attia argues longevity depends on delaying onset of chronic disease
- •Attia notes rapamycin and metformin as potential autophagy inducers
- 42:57 – 46:53
Proof of Principle: Shutting Off Autophagy in Mice with Tumors
White describes the experiment of inducing autophagy loss in adult mice that already had cancer, where the tumor died before the mouse. She also discusses newer toggle models showing normal tissues can recover and notes the limits of genetic versus drug approaches.
- •The adult knockout mouse was made to test whether autophagy could be targeted for therapy
- •In mice with lung cancer, the tumor died before the mouse
- •A newer toggle model shows normal tissues can restore themselves when autophagy returns
- •Genetic deletion is proof of principle, not identical to drug inhibition
- 46:53 – 52:44
Which Cancers Depend Most on Autophagy
Attia asks about tumor type and driver mutations. White says KRAS-driven lung and pancreatic cancers are highly dependent, along with BRAF-driven, homologous-recombination-deficient breast, APC-deficient colon and prostate cancers, with LKB1-deficient RAS lung cancer the most sensitive.
- •KRAS-driven lung and pancreatic cancers are extraordinarily autophagy-dependent
- •RAS has been very hard to drug, and downstream inhibitors face workarounds
- •BRAF-driven cancers are even more sensitive than RAS-driven lung cancers
- •LKB1 loss removes AMPK-driven autophagy activation and makes tumors most sensitive
- 52:44 – 59:15
The Autophagy Paradox: Protecting Against Cancer Yet Helping Established Tumors
Attia poses the apparent contradiction between autophagy preventing cancer and aiding existing tumors. White explains that autophagy limits chronic damage and inflammation in normal tissue but is co-opted by tumors, so its role is context dependent, and the fasting-with-chemotherapy question remains unresolved.
- •Mice lacking autophagy in non-brain tissues develop benign liver tumors
- •Loss of autophagy in liver and pancreas drives chronic damage, repair, and inflammation
- •Stimulating autophagy may preserve health, while inhibiting it harms established tumors
- •White says caloric restriction and autophagy loss are not equivalent
- •Fasting's benefits in cancer therapy may arise from reduced tumor nutrients
- 59:15 – 1:16:40
Dosing Fasting and the Search for a Molecular Autophagy Signature
Attia explains he cannot tell patients how long to fast and describes his own fasting protocols and the blood changes he sees. White explains the limits of measuring autophagic flux in humans and suggests metabolite signatures, tested first in wild-type versus autophagy-deficient mice.
- •White asks why fasting isn't cultivated instead of autophagy-stimulating pills
- •Attia describes seven-day fasts and changes in glucose, uric acid, and thyroid hormones
- •LC3 conversion in PBMCs gives only a clue to flux
- •White suggests metabolite surrogates and mouse studies to find the autophagy-dependent changes
- •Attia argues the dose-response question is fundable through philanthropy
- 1:16:40 – 1:36:48
Isotope Tracing, Fasting Phases, and Prevention Versus Treatment Funding
White describes using isotope tracers with Josh Rabinowitz to study metabolism in living mice. The conversation turns to fasting phases, the rapamycin and metformin questions, and Attia's argument that research funding focuses on treatment rather than prevention.
- •Isotope-labeled tracers reveal nutrient use and sharing between tissues
- •Fasting involves glycogen, fat, and eventually muscle protein mobilization
- •Metformin, rapamycin, and senescence relationships to autophagy are not well understood
- •Drug development favors disease treatment over safe prevention
- •Attia and White discuss diet quality and unlucky genetic risk alongside metabolic health
- 1:36:48 – 1:38:45
The 2016 Nobel Prize and Ohsumi's Yeast Genetics
Attia asks about the Nobel Prize for autophagy research. White explains Ohsumi's work in identifying essential autophagy genes in yeast and reflects on how basic discoveries can be hard to fund.
- •Ohsumi asked which genes yeast needs for nitrogen survival
- •This identified the essential autophagy genes
- •White wonders whether such work would be funded in the United States
- •Mammalian homologs of the genes were readily found
- 1:38:45 – 1:49:27
Autophagy Inhibition and Immune Checkpoint Blockade
White says she wants to develop small molecule autophagy inhibitors, now through a company, and links autophagy loss to inflammation that could make tumors respond to immune checkpoint blockade. They discuss mutation burden models, mitochondrial mutations, and autophagy in immune cells.
- •White co-founded a company to develop autophagy inhibitors for cancer therapy
- •Immune checkpoint blockade has produced striking responses, such as a patient whose tumors disappeared
- •Attia shares a friend's response to Keytruda
- •An NIH grant supports mouse models with varying mutation burden
- •Autophagy inhibition may turn cold tumors hot, and T cells seem to function well acutely
- 1:49:27 – 1:58:54
Alzheimer's Prevention, Metabolic Tracing, and Closing Thoughts
Attia raises Alzheimer's disease as a case demanding prevention, and White argues recent drug failures reflect treating symptoms rather than root causes. She describes future metabolic flux work and expresses interest in studying fasting, before the episode closes.
- •Attia cites failures of anti-amyloid drug trials and argues fasting needs testing
- •White says Alzheimer's approaches treat symptoms and not the root cause
- •Isotope tracer methods can examine metabolism in vivo, including in humans with cancer
- •White is interested in studying fasting and diet together to preserve health
