#825: Dr. Dominic D’Agostino — All Things Ketones, How to Protect the Brain and Boost Cognition, Sardine Fasting, Diet Rules, Revisiting Metformin and Melatonin, and More

When molecules behave like messages: the expanding life of ketones

The conversation between a curious investigator and a laboratory-minded clinician reveals a quiet revolution in how we think about metabolic fuel. Beta-hydroxybutyrate, long framed as an alternate energy source for times of fasting or dietary restriction, is emerging as a multifaceted signaling molecule with potential applications across neurology, oncology, and everyday performance. The appeal is not merely caloric; the story lies in how ketone bodies reroute cellular programs, nudge immune responses, and sometimes behave more like hormones than fuel.

Ketones beyond calories: epigenetics, inflammation, and resilience

At doses that are physiologically achievable through diet, fasting, or supplementation, beta-hydroxybutyrate (BHB) inhibits select histone deacetylases and modulates gene expression tied to antioxidant defenses and cellular maintenance. That biochemical tilt helps explain why ketone therapies are being investigated for conditions characterized by energy failure in the brain, including cognitive decline. Separate studies show BHB dampens the NLRP3 inflammasome, an intracellular complex implicated in chronic inflammation and age-related disease, giving ketones an anti-inflammatory axis that is independent of their role as substrates for ATP production.

Combining strategies: diet, exogenous ketones, and MCT synergy

Practical translation matters. Exogenous ketone salts and esters raise circulating BHB, but their pharmacology differs. Pairing supplemental BHB with medium-chain triglycerides (MCT oil) creates synergy: the MCTs sustain and extend BHB elevation by slowing absorption and stimulating endogenous ketogenesis. This practical pairing—ketone plus MCT—offers a predictable route to reach the so-called Goldilocks range of circulating ketones, the levels where anxiolytic and neuroprotective effects have been observed without the side effects of excessive acid load.

Fasting reimagined: sardines, autophagy, and targeted caloric restriction

Fasting need not look like dry deprivation. The practice described as "sardine fasting"—a week-long, low-calorie, omega-3–rich regimen—illustrates how a modest, nutrient-dense protocol can preserve muscle mass while producing the metabolic signals that drive autophagy and immune modulation. For people with cancer or frailty concerns, the addition of omega-3 fatty acids during short-term caloric restriction helps prevent cachexia while still permitting the metabolic stressors that favor cellular cleanup. Timing and cadence matter: monthly or bi-monthly short cycles can be both practical and therapeutic.

Tools and markers: GKI, meters, and continuous monitoring

Quantifying the metabolic state is a recurring theme. The glucose ketone index (GKI) provides a simple ratio that links blood glucose and BHB into a single actionable metric; targets around 1.2–2 are often discussed for anxiolytic and neuroprotective aims. Devices vary: finger-prick meters differ from lab assays and from continuous glucose monitors, so an awareness of each tool’s bias matters when you interpret day-to-day numbers or make clinical adjustments.

Risks, personalization, and the limits of one-size-fits-all medicine

No metabolic therapy is risk-free. Some commercially available ketone esters that contain 1,3‑butanediol have been associated with liver stress in prolonged, high-dose use, highlighting the need for cycling, moderation, and medical oversight. Likewise, supplements such as NAD precursors, GLP-1 agonists, or metformin can be powerful levers but require context: genetics, lipid profiles, and baseline metabolic health determine whether benefits outweigh risks. A person who hyperabsorbs cholesterol, for example, may need targeted lipid interventions if a ketogenic approach elevates LDL beyond safe thresholds.

Where the science is headed: immune augmentation and cancer

One of the most electrifying directions is the combination of metabolic therapy with modern immuno-oncology. Preclinical work suggests that ketone metabolic therapy can prime adaptive immunity and potentially make checkpoint inhibitors and CAR‑T approaches more effective. If ketones enhance T‑cell function, they could become an adjunct to treatments that rely on a robust, targeted immune response against tumors.

Behavioral health and metabolic psychiatry

Metabolic approaches are also making inroads into psychiatry. In animal models, ketone elevation modulates neurotransmitter balance—shifting glutamate toward GABA—and reduces anxiety-like behaviors. Pilot human data and clinical case series suggest ketogenic strategies may benefit depression, bipolar disorder, and other conditions traditionally treated with psychotropic medications, opening a parallel path that targets cellular metabolism as a therapeutic axis.

• Practical takeaways: target modest, sustained ketone levels (roughly 1–2 mmol/L), pair BHB with MCTs for longevity of effect, and use GKI rather than ketone concentration alone when pursuing therapeutic goals.
• Safety note: avoid chronic high-dose exposure to 1,3‑butanediol–based ketone esters without monitoring liver function, and consult clinicians before combining metabolic drugs.

The conversation between an inquisitive host and an interdisciplinary scientist reveals how a molecule once relegated to famine physiology may reshape approaches to resilience, repair, and recovery. Across neurology, oncology, and mental health the through-line is the same: small shifts in energy metabolism ripple out to change immune patterns, gene expression, and behavior. That insight reframes fasting, ketogenic diets, and exogenous ketones not as niche tactics but as tools for modulating biological priorities—if wielded thoughtfully, personalized, and with an eye on unintended consequences. The challenge ahead will be turning provocative mechanisms into clear, safe protocols that honor individual variation—and measuring what truly matters as those protocols scale into clinical practice.