Peter Attia MD#02 – Rhonda Patrick, Ph.D.: paradox of IGF-1, ketogenic diets and genetics, benefits of sauna, NAD+
CHAPTERS
- 0:04 – 5:48
Episode Preview and Guest Introduction
Peter Attia introduces Rhonda Patrick, explains the unscripted nature of the conversation, and previews topics including IGF-1, PPAR genes, ketogenic diet genetics, and how beliefs evolve. He also stresses how often scientific facts get revised.
- •Attia introduces Rhonda Patrick of FoundMyFitness and praises her video production
- •Preview of topics: IGF-1 paradox, PPAR alpha/gamma, genetics of ketogenic diet response
- •The conversation was unscripted and went beyond planned topics
- •Attia opens by asking what each believes now that they didn't before
- 5:48 – 10:27
How Patrick's Views on Caloric Restriction and Ketogenic Diets Changed
Attia asks what Patrick believes now that she didn't four or five years ago. Patrick explains she has moved away from caloric restriction as the main healthspan strategy, citing the role of IGF-1 growth periods and the lemur study. She has also become less skeptical of ketogenic diets after rodent studies from Verdin and UC Davis.
- •Patrick no longer sees chronic caloric restriction as the key healthspan modality
- •Periods of IGF-1 growth matter, and periodic prolonged fasts may be a better approach
- •The lemur study showed longer lifespan but gray matter atrophy
- •Rodent ketogenic studies increased healthspan, though with cycling or calorie caps
- •Attia describes his mirror-image journey with ketogenic diets
- 10:27 – 17:59
Why Ketogenic Mice Get Obese and Exogenous Ketones
Attia and Patrick discuss why mice overate on constant ketogenic feeding, including a malonyl CoA hypothesis from Patrick and the role of PPAR alpha. They then talk about exogenous ketones, Patrick's personal experience with them, and the study showing ester effects on performance.
- •Patrick proposes constant malonyl CoA could inhibit fat transport into mitochondria
- •Attia suggests experiments with high-fat, higher-carb diets plus exogenous ketones
- •PPAR alpha induction differed between the ketogenic and high-fat diets
- •Patrick likes exogenous ketones for focus, lower anxiety, and endurance
- •Patrick prefers getting ketosis from fasting and values plant variety
- 17:59 – 23:02
Attia's Ketogenic Diet Practice and Protein Limits
Attia describes how he ate ketogenically for three years, including the huge volume of olive oil, salads, and dairy needed. He argues protein, not fat, is what usually knocks people out of ketosis. He also notes his lowest IGF-1 levels occurred during that time, which Patrick says fits with protein and insulin regulating IGF-1.
- •Attia needed about 4,500 calories, about 90% from fat, with protein held near 100-110 grams
- •Salads with olive oil dressing, macadamia nuts, avocado and dairy were staples
- •Attia says protein is the bigger problem in the roughly 50-60 patients he's seen
- •His IGF-1 was around the 25th percentile on keto versus the 75th now
- •Patrick notes protein and insulin are major dietary regulators of IGF-1
- 23:02 – 33:05
Genetics of PPAR, FTO and Ketogenic Diet Responders
Attia asks about PPAR alpha versus gamma and describes the roughly 10-20% of patients whose LDL particle number and inflammation soar on keto, then normalize when saturated fat is swapped for monounsaturated. Patrick explains the relevant SNPs and her genetic tool, and they discuss matching phenotype to genotype.
- •PPAR alpha is mainly in the liver (ketogenesis); gamma in adipose tissue
- •Some patients' LDL-P rose above 3,500 on keto and fell to 1,300 after swapping saturated for monounsaturated fat
- •Patrick says PPAR and FTO SNPs affect response to saturated fat, likely under 20% of people
- •Patrick is building a genetic tool with free and $10 comprehensive reports
- •A rarer group can't reach even 0.5 mM BHB despite strict adherence
- 33:05 – 42:17
Getting Non-Ketotic Patients into Ketosis and Patrick's Own Ketone Levels
Attia describes patients who can't make ketones and how fasting combined with hard exercise has helped. Patrick discusses glycogen depletion and her own morning ketone readings, then recounts her large response to a BHB ester, including its glucose-lowering effect.
- •Attia says fasting plus hard exercise helped two patients using a monthly five-day ketogenic fasting-mimicking approach
- •Patrick suggests glycogen depletion may be the bottleneck
- •Patrick reaches about 0.7-0.9 mM after a 15-hour fast when very active
- •A BHB ester took her from 0.1 to 6 mM in an hour and dropped her glucose 30 points
- •Attia mentions acarbose as a tool for flattening glucose
- 42:17 – 50:24
The IGF-1 Paradox: Worms, Humans and Mortality Curves
Attia explains why he doubts the IGF-1-is-bad paradigm, citing the limits of C. elegans data and a U-shaped mortality curve. Patrick describes her worm work on DAF-2 and DAF-16/FOXO and notes the cancer link, then both agree IGF-1 matters for muscle and brain.
- •Attia questions applying worm longevity findings to humans because worm cancer differs
- •Patrick says lifespan extension depends on FOXO, while cancer reduction did not
- •Human epidemiology shows IGF-1 mortality is U-shaped; only very high levels look harmful, driven by cancer
- •Patrick notes IGF-1 is needed for muscle and neurogenesis, and exercise moves it into muscle and brain
- •Cycling high and low IGF-1 may be preferable to keeping it low
- 50:24 – 59:31
Prolonged Fasting, Cancer Treatment and Cycling
Patrick describes Valter Longo's work on prolonged fasting, stem cell activation, and refeeding, including effects in autoimmune models and during chemotherapy. Attia adds his concerns about oncology nutrition and the Jay Mitchell reperfusion study, and both conclude that cycling fasting and feeding fits evolution.
- •Prolonged fasts shrink organs and induce apoptosis, then refeeding regrows them with IGF-1 required
- •Longo's studies suggest less toxicity and more cancer cell death with fasting during chemo
- •Attia criticizes oncology's emphasis on preserving weight, such as Ensure
- •Mitchell's mouse study showed brief pre-surgery fasting protected like lifelong restriction
- •Both view cycling as consistent with how humans evolved
- 59:31 – 1:07:15
Exercise as the Top Lever for Brain Health and Healthspan
Both discuss changing beliefs about exercise. Attia explains that his review with Richard Isaacs found exercise the most compelling intervention for brain health. Patrick explains she exercises for her brain and cites a HIIT study that raised VO2 max by 12%, and they discuss median lifespan goals.
- •Attia once thought exercise mattered little for longevity; the brain-health literature review changed his mind
- •Patrick exercises mainly for executive function, anxiety, and decision-making
- •Different exercise types offer different benefits, and the minimum effective dose is unclear
- •24 HIIT sessions raised VO2 max by 12%, offsetting roughly a decade of decline
- •Both aim to extend healthspan and median lifespan rather than maximum lifespan
- 1:07:15 – 1:12:35
Inflammation, Centenarians and Immune-Targeting Trials
Patrick describes a Japanese study of centenarians where low inflammation best predicted survival, and a rodent NF-kappa B study. Attia follows with the IL-1 antagonist cardiovascular trial and the halted methotrexate trial, and imagines a personalized toolkit of cycled interventions.
- •In the Japanese study, low inflammation outpredicted other biomarkers across oldest age groups
- •Removing NF-kappa B's anti-inflammatory component cut rodent lifespan by about 30%
- •An IL-1 antagonist improved cardiovascular outcomes without changing lipids
- •A low-dose methotrexate trial was halted early, possibly for efficacy
- •Attia hopes for a personalized toolkit of cycled drugs, hormones and nutrients
- 1:12:35 – 1:22:23
Sauna: Cardiovascular, Mood and Immune Effects
Patrick raises sauna research from Jari Laukkanen showing dose-dependent reductions in cardiovascular and all-cause mortality. Attia admits his earlier skepticism over healthy-user bias. They cover mechanisms such as blood pressure, IL-6, hedgehog proteins and Charles Raison's antidepressant work, plus dry versus infrared saunas.
- •Finnish observational data show larger mortality reductions with four to seven sessions weekly than with two or three
- •Attia first dismissed it as healthy-user bias but was persuaded by mechanisms
- •Sauna mimics some exercise effects, including heart rate and IL-6 release
- •Raison's work links IL-6 response to antidepressant effect
- •Patrick prefers a traditional dry sauna over infrared, saying infrared involves marketing
- 1:22:23 – 1:24:43
Alzheimer's Heterogeneity, Ketones in the Brain, and Heat Discomfort
Attia discusses Alzheimer's as likely several diseases and Richard Veech's work on BHB bypassing PDH. He and Patrick note that sauna is a more pleasant intervention than fasting, and Patrick explains the role of dynorphin and discomfort. They speculate about pain tolerance variation among athletes.
- •Attia says Alzheimer's is likely several diseases with a common final pathway
- •BHB can bypass pyruvate dehydrogenase resistance in neurons
- •Sauna is an enjoyable longevity practice compared with fasting
- •Patrick says heat discomfort involves dynorphin and the kappa-opioid pathway
- •Variants in kappa-opioid pathways may explain differing pain tolerance
- 1:24:43 – 1:32:48
Cold Exposure, Stacking with Sauna, and Recovery Trade-offs
They discuss cold therapy for recovery, mood and focus, with norepinephrine as a likely mediator. Patrick describes stacking sauna and cold for sleep and mood, notes cold's effect on mitochondrial biogenesis, and warns that cold or anti-inflammatories after strength training may blunt hypertrophy.
- •Attia used ice baths and cryo for delayed onset muscle soreness
- •Patrick uses cold showers before talks for focus and anxiety, thought to involve norepinephrine
- •Sauna followed by cold gives Patrick excellent sleep
- •Cold exposure boosts markers of mitochondrial biogenesis
- •Cold after strength training may blunt hypertrophy, as would anti-inflammatories like ibuprofen
- 1:32:48 – 1:39:16
NAD+ Precursors, PARP and Metformin
Attia asks whether raising NAD matters, and Patrick explains NAD's roles in mitochondria, sirtuins and PARP DNA repair, and why levels fall with age. They discuss animal and pilot human evidence for precursors, bioavailability doubts, and Attia's question about metformin and complex I.
- •NAD is a cofactor for mitochondrial function, sirtuins and PARP
- •PARP and inflammation act as NAD sinks, which may explain age-related decline
- •Animal evidence shows benefits in mitochondrial myopathy models and brain
- •Nicotinamide riboside raises plasma NAD in pilot studies, but cell and mitochondrial delivery is unclear
- •Attia wonders whether metformin's complex I inhibition could affect NAD and DNA repair and plans to ask Nav Chandel
- 1:39:16 – 1:49:49
Open Questions: Fasting Frequency, Rapamycin, Senescence and Wrap-up
Patrick says she most wants to know whether occasional prolonged fasts could rejuvenate tissues via stem cells, and Attia compares this to the open dose and frequency question for rapamycin. They touch on senescent cells, dog trials, and targeting specific tissues, then Patrick shares where to find her work.
- •Patrick asks how often and how long people would need to fast to get stem cell rejuvenation
- •Attia is wary of inferring from rodents because they lose 20% of body weight in a 48-hour fast
- •Rapamycin dose and frequency are similarly unknown, and Patrick is interested in its effect on senescent cells
- •Kaeberlein's dog trials showed improved ejection fraction in short studies, per Attia
- •Patrick directs listeners to FoundMyFitness and her social handles
