#303 - A breakthrough in Alzheimer’s disease: the promising potential of klotho for brain health, cognitive decline, and as a therapeutic tool for Alzheimer's disease | Dena Dubal, M.D., Ph.D.

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter In this special episode, Peter addresses the common questions about starting or returning to an exercise routine over the age of 50. Individuals in this age group have frequently reached out with questions about whether it's too late to start exercising and often express concern over a lack of prior training, a fear of injury, or uncertainty about where to begin. Peter delves into the importance of fitness for older adults, examining all four pillars of exercise, and provides practical advice on how to start exercising safely, minimize injury risk, and maximize potential benefits. Although this conversation focuses on people in the “older” age category, it also applies to anyone of any age who is deconditioned and looking to ease into regular exercise. We discuss: Key points about starting exercise as an older adult [2:45]; Why it’s never too late to begin exercising and incorporating the four pillars of exercise [5:45]; The gradual, then sharp, decline in muscle mass and activity level that occur with age [10:00]; The decline of VO2 max that occurs with age [15:30]; Starting a training program: exercise variability, movement quality, realistic goals, and more [18:30]; Improving aerobic capacity: the malleability of the system, the importance of consistency, and setting long-term fitness goals [25:15]; Starting cardio training: base building, starting with low volume, and zone 2 training [30:45]; The critical role of VO2 max in longevity [36:45]; How to introduce VO2 max training to older or deconditioned individuals [46:15]; Options for performing zone 2 and VO2 max training [53:45]; The ability to make gains in strength and muscle mass as we age [57:00]; How to implement strength training for older individuals [1:01:00]; Advice for avoiding injury when strength training [1:07:30]; Risk of falls: the devastating consequences and the factors that increase fall risk [1:12:15]; Mitigating fall risk: the importance of foot and lower leg strength, ankle mobility, and balance [1:19:45]; Improving bone mineral density through resistance training [1:24:30]; The importance of protein in stimulating muscle protein synthesis, especially in older adults [1:31:00]; Parting advice from Peter [1:34:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter In this “Ask Me Anything” (AMA) episode, Peter provides insights on a broad range of important topics. He delves into the prevention of cognitive decline, the link between cardiovascular disease and Alzheimer's disease, and methods to lower blood glucose, insulin, and apoB. He also addresses nutrition-related queries, exploring the impact of dietary habits on weight loss and longevity, how a person can identify the best diet for themselves, and common nutrition myths. Additional discussions include optimal blood pressure, daily step goals, the benefits of standing versus sitting desks, and much more. If you’re not a subscriber and are listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or our website at the AMA #60 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. We discuss: Overview of topics and episode format [1:40]; Preventing cognitive decline [5:00]; How to lower blood glucose and insulin [13:30]; The relationship between lipids, CVD, and Alzheimer’s disease, and whether statins can increase the risk of neurodegenerative disorders and AD [23:15]; Reducing apoB levels through exercise and diet [31:45]; Pharmacological options for lowering apoB [38:00]; How nutrition impacts longevity via metabolic health, muscle mass, BMD and more [40:15]; How can someone determine the best diet for themselves? [43:45]; Nutrition myth: All weight loss is good [46:45]; Nutrition myth: Metabolic rates are dramatically different among individuals based on genetics [49:00]; Nutrition myth: Losing weight after a brief period of overeating is impossible [53:45]; Nutrition myth: GLP-1 agonists are a replacement for a healthy lifestyle [57:45]; Nutrition myth: There is a single best diet for weight loss [1:03:00]; Nutrition oversimplification: All calories are created equal [1:05:45]; Daily step goals [1:06:45]; The benefits of standing versus sitting throughout the day [1:10:45]; How to identify the most impactful and easiest-to-implement ways to improve your health [1:12:30]; The critical importance of emotional health [1:14:30]; Why supplements should be considered as supportive aids rather than primary solutions in one’s strategy to improve longevity [1:18:00]; Strategies for reducing high blood pressure [1:20:45]; Peter’s biggest frustrations with "mainstream health advice" [1:28:00]; Peter’s chaotic, yet cherished, morning routine [1:31:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Joel Jamieson is a conditioning expert who developed Morpheus to give people a smarter way to build their conditioning regimen and improve their recovery. In this episode, Joel dives deep into the world of heart rate variability (HRV), explaining its scientific foundation, how it measures the balance between the sympathetic and parasympathetic nervous systems, the various methods of measurement, and how it can guide healthier lifestyle choices and improved training performance. He explores the nuances of HRV calculation, the impact of aging on HRV, and the roles of genetics, exercise, and other lifestyle factors in this process. He also covers Morpheus, the innovative training tool that won Peter over after his initial skepticism, highlighting its practicality and effectiveness in guiding training and optimizing fitness outcomes. We discuss: Heart rate variability (HRV): evolution, science, and practical applications of HRV in athletic training [4:00]; Methods of measuring HRV: EKG, wrist-based sensors, and more [11:30]; How HRV is calculated from the data [22:30]; The role of the autonomic nervous system (ANS) in regulating HRV [25:45]; The decline in HRV with age, and the mitigating effects of fitness and other lifestyle factors [33:30]; The role of genetics in HRV, the modifiability of HRV, and a comparison of VO2 max and HRV as predictors of mortality [37:00]; How aging affects HRV and sympathetic drive, and the importance of spontaneous movement and exercise in maintaining the body's adaptability [43:30]; How Morpheus measures HRV using RMSSD and normalizes it to a 100-point scale for easier interpretation [49:45]; The Morpheus system: development, integration with various metrics, and personalized daily training recommendations to optimize fitness and recovery [51:30]; The benefits of morning HRV readings for assessing daily readiness compared to overnight HRV measurements [1:03:00]; Why Morpheus recommends using a chest strap rather than an arm band [1:10:00]; The impact of consistent exercise, stress, alcohol, and other lifestyle factors on HRV [1:11:15]; Optimizing zone 2 training with Morpheus [1:18:15]; Using heart rate recovery (HRR) as an indicator of athletic conditioning and the balance between aerobic and anaerobic systems [1:22:45]; The importance of tracking HRV trends over time rather than focusing on data from a given day [1:29:00]; Effect of GLP-1 agonists on heart rate and HRV [1:34:45]; Where HRV belongs in the hierarchy of health metrics [1:42:00]; Parting thoughts [1:46:30]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter In this quarterly podcast summary (QPS) episode, Peter introduces a new format aimed at summarizing his biggest takeaways from the last three months of guest interviews on the podcast. Peter shares key insights from each episode, covering diverse topics such as protein and muscle building with Luc van Loon, toe strength with Courtney Conley, VO2 max with Olav Aleksander Bu, liquid biopsies for cancer with Alex Aravanis, gut health and probiotics with Colleen Cutcliffe, and road safety with Mark Rosekind. Additionally, Peter shares any personal behavioral adjustments or modifications to his patient care practices that have arisen from these engaging discussions. If you’re not a subscriber and are listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or our website at the episode #304 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. We discuss: How Peter keeps track of his takeaways from each podcast episode [5:15]; Luc van Loon episode: fat utilization, muscle protein synthesis, dietary protein, aging and inactivity, and more [8:45]; Behavioral changes that have come about from the conversation with Luc van Loon [23:45]; Courtney Conley episode: importance of toe strength and the impact of dedicated foot training [26:45]; Olav Aleksander Bu episode: the importance of VO2 max for lifespan, and the practicalities of measuring and improving VO2 max [36:45]; Behavioral changes that have come about from the conversation with Olav [56:00]; Alex Aravanis episode: liquid biopsies for cancer detection [1:01:30]; Colleen Cutcliffe episode: the importance of gut bacteria balance, and the potential therapeutic uses of probiotics, particularly Akkermansia [1:16:45]; Mark Rosekind: the significant issue of road fatalities and injuries, their causes, and practical safety measures to reduce risks [1:27:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter 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. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter 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. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter 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. If you’re not a subscriber and are listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or our website at the AMA #59 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. 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. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter In this special edition celebrating 300 episodes of The Drive, Peter discusses a variety of popular topics and health interventions and classifies them based on their level of evidence and relevance using the following categories: proven, promising, fuzzy, noise, and nonsense. Peter first delves into the topic of geroprotective molecules, covering rapamycin, metformin, NAD and its precursors, and resveratrol. Next, he explores the significance of metrics like VO2 max and muscle mass, as well as emerging concepts like blood flow restriction and stem cells. The conversation extends to nutrition, addressing questions surrounding long-term fasting, sugar consumption, sugar substitutes, and the contentious role of red meat in cancer. Peter not only provides his current stance on each topic—most of which have been covered in great detail in the previous 300 episodes—but also reflects on how his opinion may have evolved over the years. We discuss: Defining the categories of “proven, promising, fuzzy, noise, and nonsense” [3:15]; Rapamycin [9:30]; Metformin [17:00]; NAD and its precursors [24:30]; Resveratrol [32:45]; The importance of VO2 max, muscle mass, and muscular strength for lifespan [38:15]; Blood flow restriction (BFR) training [44:00]; Using stem cells to treat osteoarthritis or injury [51:30]; Fasting as a tool for longevity (and why Peter stopped his fasting protocol) [55:45]; The energy balance theory [1:06:30]; The idea that sugar is poison [1:12:00]; The idea that sugar substitutes are dangerous [1:22:15]; The debate on red meat and cancer [1:28:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter This is a special episode of The Drive with Peter’s friend and fellow car enthusiast Dax Shepard. In this podcast, which commemorates the 30th anniversary of the death of Brazilian Formula One legend Ayrton Senna, Dax sits down with Peter to better understand what made Senna so special and why Peter remains an enormous fan. This conversation focuses on Senna’s life, the circumstances of his death, and his lasting impact and legacy on the sport of F1. We discuss: Peter’s interest in motorsports began as a child [2:30]; The drama and dangers of F1 [6:00]; What made Senna special [13:00]; What Senna meant to Brazilians [24:00]; The cause of the fatal crash [28:15]; Why Peter is obsessed with Senna [40:30]; Being the best versus having the best record [43:30]; Senna’s unique driving style and incredible intuition about automotive engineering [46:30]; Back to the day of the dreadful race [53:00]; What Peter believes caused the crash [1:02:45]; Views on dying young, in the prime of life [1:13:00]; Senna lives on in his foundation and in safety changes adopted by F1 [1:21:00]; Statistics aren’t enough for fandom, and why people like who they do [1:24:15]; The biggest difference between F1 today and F1 in the 80s [1:28:30]; Senna’s driving superpower [1:30:30]; The fastest drivers currently in F1 [1:38:30]; Current F1 obsessions [1:45:00]; How hard it is to do what the top F1 drivers do [1:50:15]; Dax’s love of motorcycles and his AMG E63 station wagon [1:52:15]; Awesome Senna mementos from Etsy [2:01:15]; What makes specialists interesting, and Max’s devotion to F1 [2:10:15]; What Senna might have done if he had not died that day [2:14:00]; Michael Schumacher and Max Verstappen are also top F1 drivers [2:17:30]; Interlagos in Sao Paulo Brazil is always an incredible experience [2:18:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Luc van Loon is an internationally renowned expert in skeletal muscle metabolism. In this episode, Luc starts with an exploration of the roles of insulin and triglycerides in endurance exercise, highlighting their impact on skeletal muscle metabolism, and he offers profound insights into the significance of protein in this context. He elucidates how different protein types and forms influence muscle protein synthesis rates, exploring the nuances of protein absorption, digestibility, amino acid quality, and their implications for performance and recovery. Delving deeper, he differentiates between animal and plant protein sources, unraveling the distinctive properties of various protein types, from the differences between whey and casein to the emerging trends in collagen protein supplementation. Moreover, Luc dissects the intricate connections among physical activity, lean muscle mass, muscle protein synthesis induced by resistance training, and dietary protein. We discuss: Luc’s background and insights about fuel selection during exercise [3:30]; Fuel utilization during endurance exercise [9:30]; Fat metabolism, intramuscular lipids, and the nutritional dynamics of endurance sports [17:15]; The optimal window for replenishing intramuscular fat stores and glycogen post-exercise [25:15]; Luc’s interest in protein metabolism and exploration of amino acids' dual role as building blocks and signaling molecules in driving muscle protein synthesis [32:15]; How protein metabolism differs between sedentary individuals and those engaged in predominantly strength training or endurance training [38:45]; The basics of how proteins are digested and absorbed, and how muscle protein synthesis is measured [50:30]; How factors like food texture, cooking methods, and protein composition impact muscle protein synthesis, and the importance of protein distribution throughout the day [59:45]; Differences in whey and casein proteins, and the ability of ingested protein to stimulate muscle protein synthesis [1:03:30]; Dietary protein distribution and quantity for the maximization of muscle protein synthesis [1:09:00]; Muscle loss with age and inactivity and the importance of resistance exercise to maintain type II muscle fibers [1:17:15]; Differences between whey and casein proteins, and the importance of both quantity and quality of protein sources [1:28:30]; Optimizing muscle protein synthesis: exercise, timing of protein intake, protein quality, and more [1:37:00]; How to preserve muscle while trying to lose weight [1:46:00]; Anabolic resistance and overcoming it with physical activity [1:55:45]; Importance of protein intake and physical activity in hospitalized patients [2:06:30]; Reviewing the efficacy of collagen supplements [2:13:30]; Plant-based diets: how to ensure a balance of amino acids, and other considerations [2:20:30]; Future research: understanding protein metabolism in the brain [2:23:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube