All Things Ketones, How to Boost Cognition, Sardine Fasting, Diet Rules, & More — Dr. Dom D’Agostino

The Role of Alcohol in Health

Dr. D'Agostino opens with a reflection on alcohol, particularly wine, challenging the prevailing consensus that views alcohol negatively. Unlike generalized studies on alcohol, research specific to wine suggests potential benefits, including a decreased cancer risk and reduced platelet aggregation, which decreases blood viscosity and can lower the risk of clot-related conditions like stroke. Drawing from both personal observation and literature, he points out that moderate consumption, especially in the context of social and physical activity, as seen in blue zones like Sardinia and Greece, aligns with longevity and health.

Ketogenic Diet and Neurodegenerative Disease

A recurring theme is the ketogenic diet's therapeutic potential, especially regarding neurodegenerative disorders such as Alzheimer's disease. Dr. D'Agostino recounts his early encounters with Alzheimer's patients, including a case involving Steve Newport, highlighting dramatic symptomatic improvements when ketone levels were elevated via coconut oil, MCT oil, and later ketone esters. The conversation elaborates on how Alzheimer's and similar diseases involve glucose hypometabolism in the brain, vascular dysfunction, neuroinflammation, and impaired glucose transporters, establishing a metabolic basis for the disease.

This metabolic dysfunction may be compounded or initiated by chronic infections—herpes simplex virus, Epstein-Barr virus, and others—adding an immune dimension to the pathogenesis of Alzheimer's. Ketogenic metabolic therapy offers an alternative fuel source in the form of ketones, bypassing impaired glucose metabolism and aiming to reduce neuroinflammation, a concept aligned with the idea of Alzheimer's as "type 3 diabetes." The importance of maintaining metabolic flexibility via ketogenic diets or supplements is emphasized as a strategic approach for both prevention and symptom management.

Sardine Fasting

One of the unique approaches discussed is "sardine fasting," a variant of the fasting mimicking diet where minimal caloric intake is provided primarily through nutrient-rich sardines while maintaining a low-calorie state. Inspired by a cancer patient's experience, Dr. D'Agostino explains that such a protocol can achieve many benefits of fasting, including autophagy activation and decreasing insulin and mTOR signaling, but with less muscle loss and decreased risk of cachexia. He advises that sardine fasting—consisting essentially of omega-3 rich sardines and minimal calories—can be performed monthly or every couple of months, providing a sustainable alternative to water-only fasting and supporting cancer patients as well as healthy individuals.

To address common fasting-related challenges such as insomnia and sympathetic nervous system activation, supplementation with electrolytes, GABA, low-dose diphenhydramine, melatonin, and magnesium can ease adaptation. Importantly, water fasts are still used situationally, such as to abort shingles outbreaks or inflammatory flares, hinting at the nuanced, personalized application of these dietary interventions.

Measuring Ketones and Glucose

The dialogue touches on ketone and glucose measurement technologies, comparing devices such as Abbott Precision Xtra and Keto Mojo. Dr. D'Agostino notes that Keto Mojo generally aligns better with biological assays and has the added convenience of calculating the glucose-ketone index (GKI), an important marker reflecting metabolic state. While glucose readings from these devices can trend higher than laboratory measurements—sometimes by 10-20%—this variance is typical and not necessarily a cause for alarm if contextualized with broader metabolic markers including insulin and HbA1c. Wearing continuous glucose monitors (CGMs) is highlighted as valuable, especially for early identification of impaired glucose tolerance missed by fasting glucose alone.

Practical Protocols

Dr. D'Agostino describes his personal diet primarily as a low-carb Mediterranean style eating pattern with an emphasis on high-quality protein and fat sources, such as eggs (with careful moderation of yolks), mackerel, sardines, beef, chicken, fish, and vegetables like broccoli. Fiber intake is intentionally high to mitigate glycemic impact, aiming for about 25% of carbohydrates as fiber predominantly from vegetables and low-sugar fruits such as wild berries and limited apples. He stresses the importance of early dinner times and regular physical activity, often supplemented with moderate wine consumption combined with exercise to improve sleep and minimize metabolic downsides.

The conversation also revisits common ketogenic adaptation challenges and how beginners can overcome them. Tips include hydration, electrolyte replenishment, low-intensity fasted cardio like walking, and the use of MCT oil and ketone electrolytes to accelerate ketosis without overwhelming the system. Dr. D'Agostino recommends cautious dosing of ketone esters to avoid inhibition of endogenous ketone production and potential acidosis.

Supplements and Medications

Among supplements, creatine monohydrate features prominently for cognitive and overall health benefits, with doses potentially ramped up in advanced neurodegenerative cases. Vitamin D is another cornerstone supplement, but only after confirming levels to avoid overdosing. Melatonin holds value as a neuroprotective agent beyond its sleep-inducing effects, and Dr. D'Agostino has personally found no evidence of endocrine disruption from moderate dosing in humans.

He expresses cautious interest in metformin and berberine, drugs that modestly improve glucose metabolism and may provide longevity and cancer-risk reduction benefits, particularly in metabolically compromised individuals. However, for those already metabolically healthy and active, benefits are less clear. GLP-1 receptor agonists like semaglutide are recognized as transformative metabolic drugs with potential neuroprotective properties, acting mainly via appetite suppression and caloric restriction. SGLT2 inhibitors are highlighted as another emerging tool for glucose control.

Regarding mitochondrial support, Dr. D'Agostino mentions ongoing research with various NAD+ precursors and analogs. While commercially available compounds such as nicotinamide riboside have some limitations in bioavailability, newer stabilized forms are under investigation. The balance of NAD+/NADH is critical to redox homeostasis and sirtuin activity, impacting metabolism and DNA repair. He briefly discusses CoQ10 analogs, particularly ibenone, recognized for cardiovascular benefits, though he personally does not use them regularly.

Metabolic Psychiatry

Ketogenic therapies show promise beyond neurodegenerative diseases, extending into metabolic psychiatry for conditions such as bipolar disorder, depression, anxiety, schizophrenia, and ADHD. Dr. D'Agostino refers to work by leaders like Dr. Chris Palmer and emerging digital platforms supporting ketogenic lifestyle coaching. Animal studies confirm significant anxiolytic effects of ketone supplementation, altering neurotransmitter balances to promote GABAergic (calming) over glutamatergic (excitatory) activity, akin to mild benzodiazepine effects without their drawbacks.

He cautions that ketone levels have an optimal therapeutic window—typically 1 to 2 millimolar—beyond which acidosis and adverse effects can arise. The pleiotropic nature of ketones modulating energy metabolism, neurotransmission, inflammation, and immune function underpins their broad potential efficacy.

Innovations in Hyperbaric Oxygen Therapy

Exciting ongoing research includes a large, rigorously controlled hyperbaric oxygen therapy trial at the University of South Florida, targeting traumatic brain injury and cognitive improvement. The trial uses innovative sham controls to ensure blinding, an advancement over prior "muddy" investigations. Hyperbaric oxygen, by augmenting immune function and reducing inflammation, is considered a promising complementary therapy for neurological conditions and cancer support, especially when combined with ketogenic metabolic therapies to mitigate risks such as oxygen toxicity seizures.

The Future of Ketogenic Metabolic Therapies

Throughout the discussion, Dr. D'Agostino stresses individual variability in genetics, metabolism, and clinical status. He highlights his own experience with an LDL receptor mutation causing cholesterol hyperabsorption, managed with medications alongside diet adjustments. This exemplifies the emerging field of precision metabolic medicine, supported by continuous biomarker monitoring (glucose, ketones, insulin, lipids) and genetic insights.

His work includes extensive collaborations, educational efforts through platforms like KetoNutrition.org and Metabolic Health Initiative, and contribution to the development of commercial ketone products designed for research and therapeutic use.