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Dena Dubal is a physician-scientist and professor of neurology at UCSF whose work focuses on mechanisms of longevity and brain resilience. In this episode, Dena delves into the intricacies of the longevity factor klotho: its formation and distribution in the body, the factors such as stress and exercise that impact its levels, and its profound impact on cognitive function and overall brain health. Dena shares insights from exciting research in animal models showing the potential of klotho in treating neurodegenerative diseases as well as its broader implications for organ health and disease prevention. She concludes with an optimistic outlook for future research in humans and the potential of klotho for the prevention and treatment of Alzheimer’s disease.

Disclosure: Peter is an investor in Jocasta Neuroscience, a company working to develop klotho as a therapy for people with Alzheimer’s disease.

We discuss:

• Dena’s fascination with aging and how she came to study klotho [3:30];
• Biological properties of klotho: production, regulation, decline with age, and factors influencing its levels [11:45];
• Potential benefits of klotho on brain health [22:00];
• The relationship between soluble klotho protein, platelet factors, and cognitive enhancement [33:45];
• The role of platelet factor 4 (PF4) and it’s interaction with GluN2B in mediating cognitive enhancement [46:45];
• Benefits of klotho observed in a mouse model of Parkinson’s disease [55:45];
• Benefits of klotho observed in a mouse model of Alzheimer’s disease [1:03:00];
• Promising results of klotho in primate models, and the importance of finding an appropriate therapeutic dose before moving to human trials [1:08:00];
• Speculating why a single klotho injection has such long-lasting effects [1:25:30];
• Potential cognitive benefits of klotho in humans, the impact of the KL-VS genetic variant on klotho levels, and the need for human trials to confirm these effects [1:27:45];
• The interaction between the KL-VS genetic variant and APOE4 and how it impacts risk of Alzheimer’s disease [1:34:45];
• The significance of klotho levels: studies linking lower levels to increased mortality and the broader implications for organ health and disease prevention [1:47:15];
• Measuring klotho levels and determining an individual’s KL-VS status [1:52:15];
• The promising potential of klotho for Alzheimer’s disease treatment, and the importance of philanthropy for funding research [1:58:00]; and
• More.

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Julia Wattacheril is a physician scientist and director of the Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) program at Columbia University Irving Medical Center. In this episode, Julia delves deep into the complex world of liver health, beginning with a foundational overview of liver physiology. She provides an in-depth look at how alcohol impacts liver function, breaking down the metabolism of ethanol and its detrimental effects. Julia then shifts the focus to understanding liver function tests and optimal enzyme levels, providing a detailed explanation of AST and ALT and elucidating why fluctuations in these levels may or may not be concerning. She provides a primer on the four major stages of liver disease, discussing risk and emphasizing the importance of early diagnosis. Julia highlights the role of liver disease in increasing the risk of cancer and cardiovascular disease and covers in detail the various strategies for diagnosing, treating, and preventing the progression of liver disease.

We discuss:

• Julia’s training, the importance of liver health, and the challenges and innovations of hepatology [3:15];
• The complex and crucial functionality of the liver, its four most essential functions, and more [8:45];
• Liver injuries: historical and evolving understanding of causal factors, and the progression to liver diseases and cancer [13:15];
• How the liver metabolizes nutrients and what happens in the presence of excess calories or alcohol [24:45];
• Methods of diagnosing liver disease and how insights guide treatment and management strategies [33:30];
• The poisonous nature of ethanol to the liver [40:30];
• Varied responses to alcohol, damaging effects of alcohol beyond the liver, and the process of advising patients on their alcohol consumption [47:15];
• Understanding liver enzymes AST and ALT—interpreting levels, lifestyle factors that affect them, and diagnostic approaches [58:30];
• Interpreting liver function tests for fatty liver disease, and the challenges of diagnosing liver pathologies, particularly in children versus adults [1:13:15];
• Comprehensive liver health assessments via imaging and various diagnostic tools to prevent overlooking potential liver pathologies [1:18:45];
• Potential impact of recreational drugs, statins, and other medications on liver function test results [1:26:45];
• Shifting nomenclature from NAFLD to MASLD to reflect accuracy in the underlying pathophysiology and understanding of liver diseases [1:30:30];
• Pathophysiology of MASLD, the need for proactive screening, and the significance of liver fat percentage as an indicator of metabolic health [1:36:30];
• The importance of screening for rare conditions alongside common metabolic diseases associated with fatty liver accumulation [1:42:45];
• Practical strategies for managing MAFLD [1:45:30];
• The impact of fructose consumption on liver health and the challenges of disentangling its effects from other factors like obesity and insulin resistance [1:52:45];
• The potential of GLP-1 agonists for the treatment of MASLD [1:57:45];
• How the four stages of liver disease have evolved [2:00:30];
• Increased cancer and heart disease risk associated with early-stage MAFLD [2:05:15];
• Emerging drugs and therapies for addressing fat accumulation and fibrosis related to MAFLD [2:12:15];
• Peter’s major takeaways [2:18:45]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter delves into the often misunderstood concept of inflammation. He first defines inflammation and differentiates between acute inflammation and chronic inflammation, the latter of which is linked to aging and a plethora of age-related diseases. Peter breaks down the intricate relationship between chronic inflammation, obesity, and metabolic health, and highlights the signs that might suggest someone may be suffering from chronic inflammation. From there, the conversation centers on actionable advice and practical steps one can take to manage and minimize chronic inflammation. He explores how diet plays a crucial role, including the potential benefits of elimination diets, and he examines the impact of lifestyle factors such as exercise, sleep, and stress management. Additionally, he discusses the relevance of food inflammatory tests and concludes by examining the potential benefits and drawbacks of drugs and supplements in managing inflammation.

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We discuss:

• Defining inflammation (and the cultural impact of Napoleon Dynamite) [1:45];
• Acute vs chronic inflammation [8:00];
• The connection between chronic inflammation, aging, and age-related diseases [11:00];
• The impact of inflammation on metabolic health [18:30];
• Understanding and diagnosing chronic inflammation: blood tests and other approaches, and challenges with measurement [20:00];
• Factors that contribute to low-level chronic inflammation [28:00];
• Minimizing inflammation through diet [29:45];
• The important role of fiber for gut health and inflammation [33:45];
• A closer look at the impact of trans fats and saturated fats on overall health [34:45];
• Why Peter prefers dietary fiber from food sources over supplements [38:30];
• Debunking “superfoods”: emphasizing proven methods over marketing claims for reducing inflammation [39:00];
• Is there any value in over-the-counter food inflammatory tests? [42:30];
• Food elimination diets: how they work, symptoms and markers to watch, challenges and limitations [45:15];
• Identifying dietary triggers for gut-related symptoms through low-FODMAP diets like the “carnivore diet” [51:15];
• Dairy: the complex role of dairy on inflammation and individual responses [55:00];
• Wheat: the complexities and conflicting evidence around wheat's inflammatory effects [57:45];
• How exercise influences inflammation [1:02:00];
• How sleep quality and duration impacts inflammation [1:07:00];
• The potential impact of chronic psychological stressors on inflammation [1:13:00];
• The impact of oral health on inflammation and overall well-being [1:15:00];
• The role of medications in managing chronic inflammation [1:18:15];
• Supplements: evaluating the efficacy of various anti-inflammatory supplements [1:22:15];
• Parting thoughts and takeaways [1:27:00]; and
• More.

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