( continued from page 17) mitochondrion. A symbiotic bacterium we humans appropriated for our own benefit? A tiny, kidney-shaped key to obesity, longevity, and malignancy? Dr. Thomas Seyfried, researcher at the University of Illinois and author of Cancer as a Metabolic Disease, devotes a lot of time to studying mitochondria. He describes the“ retrograde response,” a mitochondrial distress signal sent to the cell nucleus when there is trouble. This signal acts on Myc, Tor, Ras, NfkB, CHOP- genes involved in energy creation and cell proliferation. Dr.

Seyfried proposes that the mitochondria get sick first, then the DNA gets damaged. Epigenetic stimuli lead to alterations in nuclear DNA.

Cancer starts in the cytoplasm, not the nucleus.

calorie restriction( in a meta-analysis of 21 animal models, CR’ s association to tumor incidence has an odds ratio of 0.20, p < 0.01). Seyfried began to explore a diet that induced metabolic changes similar to calorie restriction. The Ketogenic Diet( KD), originally used in treatment of refractory epilepsy in children, now shows up all over the internet with diverse proposed benefits: weight loss, tolerance of deep sea diving and high altitude, Parkinson’ s, Alzheimer’ s, ALS, and many others.

One more deep breath, I promise it will be worth it. Ketone bodies are synthesized in times of controlled fasting or starvation; but also if consuming a high fat, low carbohydrate( HFLC) diet( and if supplemented exogenously).

Ketones must be metabolized

Dr. Warren Schaeffer and

Dr. Jerry Shay investigated this cytoplasm / nucleus interplay. Schaeffer placed cancerous nuclei into normal enucleated cells and placed these“ recon cells” into mice. One out of 68 of the mice developed tumors.

He then placed normal nuclei into enucleated cancer cells and implanted them. 97 percent of those mice developed tumors.

Shay repeated the first recon test and had 0 / 10 mice with cancer, then performed a control: Nuclei of cancer cells into enucleated cancer cells. Result: 7 / 8 mice riddled with tumors.

Evidently, many cancers of genetic basis have mitochondrial links: retinoblastoma, xeroderma pigmentosum, paraganglioma, renal cell carcinoma. The guardian of the genome, p53,

in the mitochondria and do so at the cost of less oxygen. Cells produce ATP more efficiently with ketones than with glucose.

Ketones also prepare cells very well to resist damage by free radicals( aka reactive oxygen species( ROS)) by activating glutathione, our major cellular antioxidant.

Without getting into the nuances of ketone-fueled metabolism alternating with glucose-fueled, I believe the switch happened regularly in humans for thousands of years. We starved for a few days, then we ran after a large animal( depleting some glycogen), then we ate. Now we are“ starving” when we miss the snack between dinner and 4 th meal, and we are the large animals driving to Taco Bell( or ordering food to be delivered to limit our movement even more).

is involved in transcription of a key component of the electron transport chain in mitochondria. BRCA repairs DNA but is also

“ intimately involved in biogenesis of mitochondria.” Apparently even GLEEVEC, the designer drug to treat CML, has a link to mitochondria. GLEEVEC’ s target, the manic bcr-abl tyrosine kinase, activates the PI3K / AKT pathway to increase glucoses utilization and uptake. This same PI3K / AKT pathway is activated by damaged mitochondria.

Also intriguing to Dr. Seyfried were the anti-cancer effects of

Referring back to the Warburg Effect, " cancer cells have poor mitochondrial activity and therefore do not metabolize ketones very well. They use glucose to activate glutathione, not as efficient as using ketones. Chemotherapy and radiation work by creating large amounts of free radicals, and this works because cancer cells have a hard time anti-oxidizing."

Now let’ s synthesize these concepts: place a ketone-burning normal cell next to a glucose-burning cancer cell in a low glucose, high ketone milieu. The cancer cell is already choking, it cannot

18

LOUISVILLE MEDICINE