What are the challenges and benefits of ketogenic diets, especially regarding genetic variations?

Ketogenic diets can improve healthspan and cognitive function, especially when time-restricted. However, some individuals with specific genetic variations in PPAR alpha and gamma genes may experience adverse effects like increased LDL particle numbers and inflammation, particularly with high saturated fat intake. Protein intake must also be carefully managed to maintain ketosis.

Can exogenous ketones improve endurance and cognitive function?

Yes, exogenous ketones, particularly BHB esters, have been shown to enhance endurance performance and improve focus while lowering anxiety levels. They can also significantly reduce blood glucose, even after a high-carbohydrate meal.

How does fasting influence the immune system and stem cell function for rejuvenation?

Prolonged fasting can cause a massive shrinking of organs, leading to the activation of stem cells during the refeeding phase. This process, which requires IGF-1, allows for the proliferation and differentiation of new, healthy cells, potentially clearing dysfunctional cells and rejuvenating tissues.

Why is exercise considered crucial for brain health and longevity?

Exercise is now strongly believed to be the most important factor for preserving brain health, influencing neurogenesis, reducing atrophy, improving executive function, and lowering anxiety. It also elevates core body temperature and leads to similar anti-inflammatory and antioxidant adaptations observed with heat stress.

What is the role of inflammation in aging and mortality?

Low inflammation is a strong predictor of longevity, even more so than other biomarkers like telomere length or blood glucose. Chronic low-level inflammation can significantly shorten lifespan, and interventions targeting inflammation, such as IL-1 antagonists or potentially methotrexate, show promise in reducing cardiovascular mortality.

What are the cardiovascular and mood benefits of sauna use?

Regular sauna use, particularly dry saunas at 175-179°F for 20 minutes, is strongly linked to reduced cardiovascular mortality, improved arterial compliance, and lower blood pressure. Heat stress also profoundly affects the immune system, causing an IL-6 release that correlates with an antidepressant effect and improved mood.

How does cold exposure contribute to health and performance?

Cold exposure, through ice baths or cold showers, can significantly increase norepinephrine levels, enhancing focus and reducing anxiety. It also boosts mitochondrial biogenesis indicators in muscle and adipose tissue, but should be timed carefully after strength training to avoid blunting hypertrophy.

How do NAD+ precursors relate to aging and DNA repair?

NAD+ levels decline with age due to increased consumption by DNA repair enzymes (PARP) and immune responses. Supplements like nicotinamide riboside (NR) can increase NAD+ levels, which is hypothesized to support mitochondrial function and potentially improve healthspan, particularly in the brain and muscle.

What are the latest insights on Rapamycin for longevity?

Rapamycin is the only drug proven to extend lifespan across a wide range of organisms, from yeast to mammals. Research shows it can increase median lifespan even when started late in life and has positive effects on heart function in dogs, potentially by selectively targeting senescent cells.

Key Moments

#02 – Rhonda Patrick, Ph.D.: paradox of IGF-1, ketogenic diets and genetics, benefits of sauna, NAD+

Peter Attia MD

People & Blogs3 min read110 min video

Dec 17, 2019|96,245 views|1,294|118

longevity IGF IGF-1 ketogenic diet keto sauna NAD NAD+PPAR

Save to Pod

Key Moments

TL;DR

Rhonda Patrick and Peter Attia discuss IGF-1, keto diets, sauna benefits, NAD+, exercise, and fasting for health and longevity.

Key Insights

The role of IGF-1 in healthspan may be more nuanced than previously thought, with periods of growth potentially being as important as suppression.

Ketogenic diets can enhance healthspan in animals, but genetic factors and fat composition may influence human responses, potentially leading to adverse effects for some.

Sauna use is linked to reduced cardiovascular mortality, dementia, and all-cause mortality, with mechanisms potentially involving heat shock proteins and immune system modulation.

NAD+ levels decline with age, and while supplementation shows promise in animal studies, its effectiveness and optimal use in humans require more research.

Exercise is a crucial factor for brain health, influencing vascular, metabolic, and growth factor pathways, and may be more impactful than previously assumed.

Prolonged fasting shows potential for autoimmune disease and cancer treatment by inducing organ shrinkage and stem cell regeneration, with ref eding phases being critical.

RETHINKING IGF-1 AND DIETARY STRATEGIES

Dr. Patrick shares a significant shift in her understanding of IGF-1, moving away from the belief that chronically low levels are always optimal for healthspan. While caloric restriction, which lowers IGF-1, has shown benefits in some models, emerging research suggests that periods of growth, facilitated by adequate IGF-1 during refeeding phases after fasting, are crucial for development, repair, and maintaining essential functions like muscle mass and neurogenesis. This challenges the long-held view of IGF-1 as purely detrimental and highlights the potential importance of cycling levels.

THE COMPLEXITIES OF KETOGENIC DIETS AND GENETICS

The discussion explores the evolving perspective on ketogenic diets. While animal studies indicate improved healthspan and cognitive function, human responses are more varied. Genetic polymorphisms, particularly in PPAR alpha and gamma, may influence an individual's ability to generate ketones and metabolize fats. Furthermore, the composition of fat intake is critical; a high saturated fat intake can lead to adverse lipid profiles and inflammation in susceptible individuals, emphasizing the need for personalized approaches that consider genetic predispositions and the quality of fats consumed.

THE SURPRISING BENEFITS OF SAUNAS

Sauna use, particularly frequent sessions, is strongly correlated with reduced risks of cardiovascular mortality, dementia, and all-cause mortality. The mechanisms are thought to involve increased plasma volume, improved vascular compliance, enhanced heat shock protein production, and modulation of the immune system, leading to anti-inflammatory and antioxidant effects. These adaptations share similarities with those seen from exercise, suggesting that heat therapy can offer significant cardiovascular and neurological protective benefits, independent of exercise.

NAD+ AND THE CHALLENGES OF SUPPLEMENTATION

As levels of NAD+ decline with age, the role of NAD+ precursors like NR and NMN in promoting longevity is under investigation. NAD+ is vital for mitochondrial function, DNA repair, and the activity of sirtuins. While animal studies show promise, particularly in models of muscle and brain health, the bioavailability and efficacy of oral supplements in humans remain areas of active research. The potential impact of drugs like Metformin, which inhibits complex I and influences the NAD+/NADH ratio, on DNA repair pathways also warrants further investigation.

EXERCISE AS A PILLAR OF BRAIN AND BODY HEALTH

Exercise is highlighted as a fundamental driver of overall health, particularly for brain health, impacting vascular, metabolic, and growth factor pathways. The data suggests that consistent physical activity is among the most compelling interventions for preserving cognitive function and preventing neurodegeneration. Furthermore, exercise plays a critical role in maintaining muscle mass and aerobic capacity, which are essential for healthy aging and longevity, reinforcing the idea that a combination of aerobic and strength training offers comprehensive benefits.

PROLONGED FASTING AND STEM CELL REGENERATION

Prolonged fasting, including water-only fasts and fasting-mimicking diets, is gaining traction for its potential therapeutic applications. Research suggests that these periods of deprivation, followed by refeeding, can induce organ shrinkage, stimulate stem cell activation and regeneration, and selectively clear damaged cells. This process holds promise for treating autoimmune diseases, improving cancer treatment outcomes by sensitizing cancer cells to therapy, and potentially contributing to a cycle of cellular rejuvenation and improved healthspan.

Mentioned in This Episode

●Supplements

●Software & Apps

●Companies

●Organizations

●Books

●Drugs & Medications

●Concepts

●People Referenced

Common Questions

Initially, chronic calorie restriction and low IGF-1 were thought to be the main drivers of healthspan extension. However, newer research suggests that periods of growth and higher IGF-1 are crucial for tissue repair and stem cell activation, making periodic fasting or calorie cycling potentially more beneficial than chronic restriction.

Topics

Fasting Exercise Physiology Brain-Health Calorie Restriction Health & Longevity Neuroscience & the Brain Mindset & Self-Improvement Sauna Benefits Cold Therapy Ketogenic Diets IGF-1 Signaling

Mentioned in this video

People

Peter Attia

Host of the podcast, who shares his experiences and evolving perspectives on ketogenic diets, IGF-1, exercise, and other longevity topics.

Dom D'Agostino

A prominent researcher in ketogenic diets and exogenous ketones, mentioned as a contact for discussing research papers and for practicing a modified ketogenic diet.

Sachin Panda

A researcher whose insights clarifying that ketogenic diet studies in mice involved time-restricted feeding, thus influencing the interpretation of their results.

Rhonda Patrick

Host of FoundMyFitness podcast, known for her expertise in healthspan, dietary restriction, ketogenic diets, and the role of IGF-1. She discusses how her beliefs have evolved regarding these topics.

Valter Longo

A researcher whose work on fasting and dietary restriction has influenced Rhonda Patrick's views on the importance of periodic growth and low IGF-1 periods for healthspan.

Joseph Opperman

A researcher at St. Jude Children's Research Hospital, with whom Rhonda Patrick studied cancer cell metabolism and apoptosis.

Richard Isaacs

Co-author of a paper with Peter Attia that concluded exercise is the single most compelling thing for preserving brain health.

Matt Kaeberlein

A researcher at the University of Washington known for administering Rapamycin to pet dogs to study its effects on lifespan and age-related diseases like cardiomyopathy and cancer.

Eric Verdin

A researcher whose long-term animal studies on ketogenic diets in mice influenced Rhonda Patrick's evolving views on their effectiveness, particularly when calorie-restricted or cycled.

Tim Ferriss

An entrepreneur and author known for his 'minimum effective dose' approach, referenced in the discussion on optimizing exercise for health benefits.

David Sabatini

A scientist specializing in fundamental aspects of metabolism and cellular growth, mentioned for his work and his recent visit to San Diego.

Judith Campisi

A researcher known for her expertise in cellular senescence, whose podcast interview deepened understanding of Rapamycin's effects on senescent cells.

Charles Raison

A researcher who measured the antidepressant effects of heat stress and its correlation with IL-6 release, suggesting mechanisms for mood improvement through sauna.

Cynthia Kenyon

A researcher known for her work on the daf-16 mutants in C. elegans, which demonstrated significant lifespan extension by attenuating IGF-1 signaling.

Yoel Laukkanen

A Finnish researcher known for extensive observational studies in Finland on sauna use and its profound effects on lowering cardiovascular-related mortality, dementia, and Alzheimer's disease.

Jay Mitchell

A researcher at Harvard whose experiment on mice showed that acute caloric restriction before surgery could provide similar benefits to lifelong caloric restriction in preventing reperfusion injury.

Navdeep Chandel

An expert in cancer metabolism and mitochondrial function, mentioned as a go-to resource for questions about Metformin's effect on NAD+ and mitochondrial complex one.

Concepts

Peroxisome Proliferator-Activated Receptors (PPAR) gamma

A nuclear receptor predominantly found in adipose tissue, playing a role in fatty acid uptake into fat and muscle tissue and its impact on insulin sensitivity.

Acromegaly

A hormonal disorder resulting from excessive growth hormone and IGF-1, linked to increased cancer susceptibility, used to compare with Laron Syndrome.

Y-chromosome

Incorrect transcription: 'Yowies' was transcribed as 'Y-chromosome' but context clearly indicates the name of a person. It refers to 'Yoel Laukkanen', a Finnish researcher.

C. Elegans

A transparent nematode (worm) used as a model organism in longevity research, particularly in studies on IGF-1 and daf-16 mutants.

Peroxisome Proliferator-Activated Receptors (PPAR) alpha

A nuclear receptor involved in fatty acid catabolism and ketone body production, primarily found in the liver, discussed in relation to individual responses to ketogenic diets.

Ketogenic Diet

A diet high in fat, adequate in protein, and low in carbohydrates, discussed for its effects on healthspan, cognition, and individual variability in ketone production.

IGF-1

A hormone central to discussions on growth, aging, and longevity. The speakers discuss the paradox of maintaining optimal levels, considering its roles in both growth/repair and potential cancer risk.

Cryotherapy

A cold therapy technique, including whole-body cryotherapy and cold showers, discussed for its benefits in reducing delayed onset muscle soreness (DOMS), improving focus, and lowering anxiety.

Organizations

Finland

A country where sauna use is ubiquitous and has been the subject of observational studies showing significant health benefits, particularly in cardiovascular mortality.

YMCA

A community organization with facilities where Rhonda Patrick first started using a sauna during her graduate school years, noticing its positive effects on her mood.

Nature

A scientific journal where a study on lemurs and caloric restriction was published, showing an increase in lifespan but also brain atrophy.

Harvard

The institution where Jay Mitchell conducted a notable experiment on caloric restriction and surgical outcomes in mice.

University of California, Davis

An institution where research on ketogenic diets in rodents was conducted, showing benefits when combined with time-restricted feeding.

Salk Institute

A renowned scientific research institute where Rhonda Patrick conducted early experiments on C. elegans and IGF-1 signaling.

Mayo Clinic

A medical center where a study demonstrated that drugs selectively targeting senescent cells could lead to a 20% increase in median lifespan in an accelerated aging model.

University of Washington

An institution where Matt Kaeberlain is conducting research on Rapamycin in pet dogs, studying its effects on cardiomyopathy and cancer.

Software & Apps

FoundMyFitness

Rhonda Patrick's podcast and website, known for its in-depth, scientifically rigorous content on health and longevity, often with detailed video explanations.

FOXO3

A transcription factor in humans, homologous to daf-16 in C. elegans, that regulates genes involved in DNA repair, autophagy, stem cell function, and antioxidant pathways.

Rhonda Patrick's Genetic Tool

A tool developed by Rhonda Patrick with a former NIH geneticist to help individuals understand their genetic predispositions related to fatty acid metabolism and other health aspects.

Locations

San Diego

The city where both Peter Attia and Rhonda Patrick reside, a point of commonality mentioned at the beginning of their conversation.

Colorado River

A river where Peter Attia experienced swimming in extremely cold 42-degree water, leading to a sensation of burning due to profound vasoconstriction.

Supplements

NAD

A coenzyme important for mitochondrial function, DNA repair, and sirtuin activity, whose levels decline with age. Precursors are discussed as potential longevity enhancers.

Acarbose

A medication capable of flatlining glucose levels after high-carbohydrate intake, considered by Peter Attia to be more potent than Metformin for glucose reduction.

beta hydroxybutyrate

A ketone body that can be produced endogenously or consumed exogenously, discussed for its role in metabolism, endurance, and cognitive function.

MCT oil

An oil that can be used to produce ketones, mentioned as an ingredient for exogenous ketone consumption and its potential to transiently improve cognition in early dementia.

Exogenous ketones

Ketone supplements, specifically BHB esters, utilized for enhancing endurance, focus, and reducing anxiety, as well as their significant effect on lowering blood glucose.

Nicotinamide Riboside

A precursor to NAD+, discussed as a supplement that can increase NAD+ levels in plasma and improve mitochondrial function in animal models.

Companies

23andMe

A personal genomics and biotechnology company that provides DNA testing and analysis, mentioned as a source of raw genetic data for use with Rhonda Patrick's genetic tool.

Drugs & Medications

Rapamycin

A drug known for its lifespan-extending effects across various organisms and its impact on senescent cells, discussed in the context of optimizing dosage and frequency for longevity.

Metformin

A common diabetes medication, discussed for its effects on glucose reduction and its potential inhibition of mitochondrial complex one, leading to questions about its NAD+ effects.

condition

Laron Syndrome

A genetic disorder characterized by low growth hormone and IGF-1 levels, associated with a reduced risk of cancer, discussed in the context of IGF-1 and longevity.