Summary
Tim Ferriss and Dr. Dominic D'Agostino go deep on ketones, brain health, and metabolic strategies in this wide-ranging episode. D'Agostino explains how ketones function not just as fuel but as signaling molecules with anti- inflammatory and neuroprotective properties. He shares the origin story of sardine fasting — developed while working with Fred Hatfield ("Dr. Squat"), who had metastatic prostate cancer and went into remission using a protocol of one can of sardines per day for a week each month. D'Agostino describes using sardine fasting situationally: when feeling inflamed, during travel, or when he has a work deadline and his wife is away. He recommends it for cancer patients specifically to avoid the muscle wasting (cachexia) that comes with water-only fasting, since omega-3s from sardines are potent mitigators of cancer cachexia. The episode also covers exogenous ketones, glucose ketone index (GKI) targets of 1-2 for maximal autophagy, potential liver toxicity from certain ketone esters, melatonin, and hyperbaric oxygen therapy.
Key Points
- Dr. D'Agostino coined "sardine fasting" while working with cancer patient Fred Hatfield, who ate one can of sardines per day for a week each month
- Fred Hatfield was given 3 months to live with metastatic prostate cancer but went into remission and lived 8+ more years
- Sardine fasting targets a glucose ketone index (GKI) of 1-2 for 3-5 days to maximize autophagy
- Omega-3 fatty acids from sardines are potent mitigators of cancer cachexia (muscle wasting)
- D'Agostino uses sardine fasting situationally: when feeling inflamed, during deadlines, or when traveling solo
- Ketones (BHB) are HDAC class 1 and 2 inhibitors — activating genes that enhance antioxidant defenses
- Exogenous BHB plus MCT oil increases ketone levels higher than either taken alone
- Some 1,3-butanediol-based ketone esters may cause liver toxicity with chronic use above 100mL/day
- The Goldilocks ketone level of 1.2-2 mmol is anxiolytic, but too high causes rebound anxiety
- D'Agostino has been taking substantial melatonin doses nightly for years without endocrine disruption
Key Moments
Origin story of sardine fasting — Dr. Squat's cancer remission
Dom D'Agostino tells the origin story of sardine fasting. He developed the protocol while working with Fred Hatfield (Dr. Squat), who had metastatic prostate cancer and was given 3 months to live. Hatfield ate one can of sardines per day for a week each month, went into rapid remission, and lived another 8 years.
"I like to do what I call, I mean, I kind of coined it, it's like sardine fasting. And I had a cancer patient a long time, one of the first that I sort of engaged with, his name was Dr. Fred Hatfield. So he was like kind of a famous Dr. Squat."
Sardine fasting for cancer patients — preventing cachexia with omega-3s
D'Agostino explains why he recommends sardine fasting for cancer patients instead of water-only fasting. Omega-3 fatty acids are potent mitigators of cancer cachexia (muscle wasting). He targets a glucose ketone index of 1-2 for 3-5 days to maximize autophagy, measuring it through autophagasome markers like P62.
"The sardine fasting is, and I advise it for cancer patients. I want them to avoid a water-only fast in the context to prevent cancer cachexia. Omega-3 fatty acids are very potent mitigators of cancer cachexia."
GKI of 1-2 for autophagy — the best proxy measurement available
D'Agostino explains that achieving a glucose ketone index (GKI) of 1-2 for 3-5 days is the best proxy for measuring autophagy. His lab actually measures autophagasomes, but for regular people the GKI via a Keto Mojo device is the most practical tool. They discuss glucometer accuracy and the importance of proper measurement.
"If you do that in a protracted way and you can achieve a glucose ketone index of one to two for about three to five days, the constellation of things that would sort of correlate with inducing and maximizing autophagy."
D'Agostino uses sardine fasting situationally — inflammation, travel, deadlines
D'Agostino describes when he personally uses sardine fasting: when his wife is traveling, when he has a grant deadline, when he feels an inflammatory flare-up or brain fog. His hs-CRP is now non-detectable on keto, compared to 1-2 on a higher carb diet.
"If I get for any reason an inflammatory flare-up, I'll feel a little bit off, like brain fog or my joints. Occasionally I'll use it situationally just if I feel like something is coming on, like I'm getting a flu."
