View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter John Kastelein is a renowned expert in lipoprotein metabolism and atherosclerotic cardiovascular disease (ASCVD) research. In this discussion, John delves deep into familial hypercholesterolemia (FH), a genetic disorder characterized by high levels of LDL cholesterol in the blood that increases the risk of developing heart disease. He covers its definition, genetic underpinnings, and clinical identification. He then explores the therapeutic options available for the prevention and treatment of cardiovascular disease, including the captivating history of CETP inhibitors. He explains the past shortcomings of previous CETP inhibitors before underscoring the compelling potential of the latest iterations, not only for cardiovascular disease but also for conditions like Alzheimer's disease and type 2 diabetes. Moreover, he unveils the intricate role of APOE, shedding light on why the APOE4 isoform codes for a protein that significantly increases the risk of Alzheimer's disease and cardiovascular disease. Concluding the discussion, John shares a profound sense of optimism, envisioning the possibility of targeted therapeutic interventions for high-risk patients in the near future. We discuss: Familial hypercholesterolemia (FH): a genetic condition [4:30]; Differentiating between phenotype and genotype when it comes to FH [9:45]; The pathophysiology related to mutations of FH [15:30]; Clinical presentations, physical manifestations, and diagnosis of FH [22:00]; Why a small fraction of people with FH do not develop premature ASCVD [34:15]; Treatment and prevention for those with FH [39:45]; Addressing the assertion by some that elevated LDL is not casual in cardiovascular disease [52:45]; The history of CETP inhibitors, and the role of the CETP protein [55:45]; The thrifty gene hypothesis and why genes underlying FH may have been preserved [1:09:00]; The compelling potential of the latest CETP inhibitor (obicetrapib) [1:13:00]; Promising results from phase 3 trials exploring obicetrapib [1:27:45]; Why the APOE4 allele increases the risk of Alzheimer’s disease, and the connection to blood lipids [1:41:30]; The role of APOE in cardiovascular disease [1:51:45]; Takeaways and looking ahead [1:57:00]; 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 delves deep into the data surrounding different forms of cold therapy, including cold water immersion, cryotherapy, and cold showers, aiming to unveil the potential benefits and drawbacks associated with cold therapy. He dissects the studies examining the effects of cold therapy on delayed onset muscle soreness (DOMS), activation of brown adipose tissue, and its potential impact on mood and as a therapeutic approach for depression. Furthermore, Peter discusses the potential negative impact cold therapy may have on muscular hypertrophy and offers his perspective on the extent to which the data support the notion of cold therapy providing longevity benefits. Finally, he also discusses the existing consensus, or lack thereof, regarding the optimal structure of an effective cold therapy protocol. 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 #47 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. We discuss: Overview of discussion on cold therapy (and a Formula 1 tangent) [1:45]; The most common cold exposure therapies [5:45]; Potential benefits of cold water immersion: a look at the data [9:30]; Comparing the effects of cold water immersion with whole-body cryotherapy [18:30]; The potential impact of cold exposure on mood and as a treatment for depression [20:45]; How do cold showers compare to cold water immersion? [28:15]; Cold exposure and the activation of brown adipose tissue (BAT) [34:15]; Things that clearly impact brain health: smoking, alcohol, sleep, head injuries, blood pressure, and more [34:15]; Exercising in cold temperatures: impact on exercise performance [38:30]; Potential downsides of cold therapy and its impact on hypertrophy, strength, and recovery [44:45]; Are the blunting effects of cold on hypertrophy due to the effects on inflammation? [50:45]; Does cold exposure offer any potential geroprotective benefits? [53:15]; Cold therapy protocols for delayed onset muscle soreness (DOMS) [56:30]; Summarizing the data and takeaways from Peter [1:01:00]; 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 JoAnn Manson is a world-renowned endocrinologist, epidemiologist, and Principal Investigator for the Women’s Health Initiative (WHI). In this episode, she dives deep into the WHI to explain the study design, primary outcome, confounding factors, and nuanced benefits and risks of hormone replacement therapy (HRT). JoAnn reflects on how a misinterpretation of the results, combined with sensationalized headlines regarding an elevated risk of breast cancer, led to a significant shift in the perception and utilization of HRT. From there, they take a closer look at the breast cancer data to separate fact from fiction. Additionally, JoAnn gives her take on how one should weigh the risks and benefits of HRT and concludes with a discussion on how physicians can move towards better HRT practices. We discuss: The Women’s Health Initiative: the original goal of the study, hormone formulations used, and potential confounders [4:15]; Study design of the Women’s Health Initiative, primary outcome, and more [16:00]; JoAnn’s personal hypothesis about the ability of hormone replacement therapy to reduce heart disease risk prior to the WHI [26:45]; The relationship between estrogen and breast cancer [30:45]; Why the WHI study was stopped early, and the dramatic change in the perception and use of HRT due to the alleged increase in breast cancer risk [37:30]; What Peter finds most troubling about the mainstream view of HRT and a more nuanced look at the benefits and risks of HRT [45:15]; HRT and bone health [56:00]; The importance of timing when it comes to HRT, the best use cases, and advice on finding a clinician [59:30]; A discussion on the potential impact of HRT on mortality and a thought experiment on a long-duration use of HRT [1:03:15]; Moving toward better HRT practices, and the need for more studies [1:10:00]; 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 Rhonda Patrick, Ph.D., is a scientist with expertise in the areas of aging, cancer, and nutrition who translates complex scientific topics into actionable insights on her podcast, Found My Fitness. In this episode, Rhonda provides her latest thinking as it relates to Alzheimer's disease including the possibility of a vascular hypothesis as well as the factors that can impact disease risk such as type 2 diabetes, blood pressure, omega supplementation, exercise, sauna, and more. She also touches on cancer risk including the relationship between cancer and exercise as well as the link between alcohol consumption and cancer. Additionally, Rhonda explains her new focus on exercise and protein consumption as well as how her perspective has shifted as it pertains to fasting and time-restricted feeding. We discuss: Alzheimer’s disease: Rhonda’s evolved thinking on neurodegenerative diseases [2:30]; The breakdown of the blood-brain barrier in neurodegenerative disease [8:45]; An explanation for the observation that type 2 diabetes increases risk of Alzheimer’s disease [15:45]; The role of omega-3 fatty acids (EPA and DHA) in brain health and prevention of neurodegeneration [19:45]; Comparing the preventable nature of type 2 diabetes, atherosclerosis, cancer, and dementia [32:15]; Blood pressure: an important modifiable lifestyle factor that can affect Alzheimer's disease risk [35:15]; Rhonda’s outlook on “precision medicine” as it pertains to one’s genetic predispositions [38:45]; Possible mechanisms by which exercise reduces the risk of Alzheimer’s disease [45:45]; Building your aerobic pyramid: neurobiological effects of exercise, benefits of lactate peaks, and more [53:45]; Maximizing mitochondrial biogenesis: alternative training approaches and strategies [58:45]; Possible brain benefits of sauna, and Rhonda’s personal protocol [1:09:30]; The relationship between cardiorespiratory fitness and dementia risk [1:15:30]; How exercise may reduce the risk of cancer [1:20:30]; The overarching impact of exercise on health, and the importance of focusing the factors that matter most [1:33:15]; Impact of alcohol consumption on breast cancer risk and overall health [1:37:15]; Exercise as an intervention for poor sleep habits [1:42:30]; The longevity benefits of consuming adequate protein and strength training to preserve muscle mass and strength [1:46:30]; How to get enough of the right kind of protein in your diet [2:05:15]; Fasting: weighing the risk vs. reward [2:12:15]; How Rhonda’s views have shifted on diet and exercise [2:15:30]; How to follow Rhonda’s work and more about the benefits of lactate for the brain [2:21:00]; 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 episode, Robert Sapolsky, Ph.D., discusses the widespread impact of stress on our physical and emotional health as well as the mechanisms by which it can precipitate chronic illness, dementia, depression, and more. He also provides insight into the factors that contribute to the stress response (and our ability to handle it) such as social rank, personality, environment, and genetics. Lastly, we discuss how our behavior is altered in the face of stress and how that not only has a pervasive effect on a personal level, but also on society as a whole in how we interact with each other. We discuss: Background, interest in stress, and Robert’s time in Kenya studying baboons [2:45]; Physiology of a stress response, and why it’s ingrained in our DNA [9:45]; Individual variation in the response to stress, and how everyone has a different optimal level [19:45]; How social rank and personality differences affect our stress response [26:30]; What’s happening in the brain when faced with stressful situations? [35:00]; What makes the human brain different than all other species? [44:15]; Imprinting stress to your kids epigenetically [48:00]; The role of stress on memory and the consequences of hypercortisolemia [53:00]; The impact of subjective socioeconomic status and social media on stress levels and health [57:45]; Tips for managing stress in the modern world [1:13:15]; What Robert learned about himself studying the social behavior of baboons [1:25:30]; The multilayered factors behind every human behavior, the context of “good and bad”, and exploring the human capacity of the wild extremes of violence and altruism from moment to moment [1:30:15]; PMS: How two women with identical hormone levels can have completely different emotional experiences [1:34:45]; How much of a role do genes play in depression and other emotional states? [1:38:00]; Why is cortisol elevated under sleep deprivation? [1:46:00]; The impact of stress on cancer [1:50:30]; The impact of stress on atherosclerosis, dementia, addiction, and depression [1:57:00]; Impulsiveness, impaired judgment, and lack of empathy in times of stress [2:01:45]; What advice would Robert give his 25-year-old self? [2:08:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube