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Stephan Guyenet is a neuroscientist focused on the neuroscience of obesity and energy homeostasis.  He is the author of the book, The Hungry Brain and founder/director of Red Pen Reviews. In this episode, Stephan explains how obesity has changed phenotypically over the course of human history as well as what might explain the dramatic increase in prevalence of obesity in the last few decades. He talks in depth about the role of genetics, the brain, and hormones like leptin play in the regulation of fat mass. He dives deep into two common theories of obesity—the carbohydrate-insulin model and the energy balance model and provides his take on which theory has stronger evidence. Additionally, he provides insights on how we’re hard-wired to think about food and the consequences of modern foods designed for maximal pleasure. Finally, he goes through the factors that affect body weight, set points, and provides takeaways for people wanting to take advantage of what we know about the brain’s role in regulating our body weight.

We discuss:

• Stephan’s neuroscience background and his focus on the nuances of obesity [2:15];
• How obesity has changed for humans throughout history [8:00];
• The association between obesity and adverse health outcomes, the “obesity paradox,” and confounders when relating BMI to longevity [14:00];
• The sharp increase in obesity across demographics [23:30];
• The hypothalamus and its role in obesity [30:00]; 
• The role of the hormone leptin in obesity [40:00];
• The genetic component of obesity [46:30];
• Understanding the tendency of humans to store fat through an evolutionary lens [57:00];  
• The hedonic aspect of food, and how the brain reacts to modern, highly-rewarding foods [1:03:30];
• How we are hard-wired to think about food [1:14:30];
• A review of the “Carnivore diet” [1:21:45];
• The energy balance model, carbohydrate-insulin model, and unifying the theories around adiposity [1:34:15];
• Body weight set points: a hypothetical comparison of two individuals [1:41:45];
• Takeaways for people who want to lose weight and keep it off [1:48:30];
• Evidence that favors the energy balance model of weight gain [1:56:00];
• The synergistic effect of fat and carbohydrates and observations that a low-fat diet or a low-carb diet can cause weight loss [2:04:30];
• Red Pen Reviews [2:11:00];
• More.

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In this “Ask Me Anything” (AMA) episode, Peter discusses the nutritional profiles of various fruits and vegetables as a means of assessing their relative value. He explains the difference between eating them vs. drinking them, how processing fruits and vegetables can change their properties, and how one’s current state of health affects nutrition strategy when it comes to fruits and vegetable consumption. Additionally, Peter explains the potential benefits and negative effects of certain phytochemicals found in produce and concludes with a discussion of supplementing with green powders, multivitamins, and more.

If you’re not a subscriber and 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 on our website at the AMA #36 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• The limitations of nutritional data and challenges of making broad recommendations [2:00];
• How one’s current state of health impacts their “optimal” diet [11:30];
• Defining “metabolic health” [14:45];
• The wide-ranging nutrition profiles of various fruits and vegetables [16:30];
• The benefits of fiber [20:45];
• Eating whole fruits vs. drinking fruit juice or smoothies [22:30];
• Drinking alcohol: metabolic effects, calories in alcohol, and more [28:30];
• Can excess fruit consumption lead to insulin resistance? [30:30];
• Glycemic impact of different fruits, using CGM data to assist decision making, and how fruit is fundamentally different from what we evolved to eat [31:30];
• Dietary approaches for people with a carbohydrate tolerance disorder (TD2, NAFLD, etc.), and when it makes sense to restrict fruit consumption [34:30];
• Nutrition profile of select vegetables: sugar content, micronutrients, and more [40:00];
• Phytochemicals in produce: potential positive health impacts on inflammation, cardiovascular (CV) risk, and cancer [44:30];
• Phytochemicals with potential negative health impacts [50:45];
• Nightshades and inflammation [53:15];
• How important is it to eat organic foods? [56:00];
• How necessary is it to wash fruits and vegetables? [1:00:45];
• How does food preparation change the nutritional composition? [1:03:45];
• Considerations when eating canned and frozen food, and paying attention to processed food additives [1:04:45];
• Supplementing vitamins and nutrients as an alternative to eating whole fruits and vegetables [1:06:15];
• Green powder supplements [1:11:15];
• Important takeaways [1:16:00]; and
• More.

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Benoît Arsenault is a research scientist focused on understanding how lifestyle and genetic factors contribute to cardiovascular disease risk. In this episode, the discussion casts a spotlight on Lp(a)—the single most important genetically-inherited trait when it comes to atherosclerotic cardiovascular disease (ASCVD) risk. Benoît explains the biology of Lp(a), how it’s inherited, the importance of measuring Lp(a) levels, and the diseases most associated with high Lp(a). He dives into data on the possible treatments for lowering Lp(a) such niacin, statins, and PCSK9 inhibitors, as well as the most exciting new potential therapeutic—antisense oligonucleotides.

We discuss:

• How Benoît came to study Lp(a)—a new marker for cardiovascular risk [3:15];
• The relationship between Lp(a) and CVD risk [6:45];
• What genome-wide association studies (GWAS) revealed about Lp(a) [16:00];
• Clinical tests to measure Lp(a) [22:00];
• The biology of Lp(a) [25:45];
• How statins lower LDL-cholesterol and why this doesn't work for an Lp(a) [29:15];
• The structure of LDL-p and Lp(a) and what makes Lp(a) more atherogenic than an equivalent LDL particle [34:00];
• The role of Lp(a) in aortic valve disease [42:45];
• How greater numbers of Lp(a) particles are associated with increased risk of disease [48:00];
• The genetics and inheritance of Lp(a) and how and when to measure Lp(a) levels [52:00];
• Niacin and other proposed therapies to lower Lp(a), apoB, and CVD risk [1:00:45];
• Why awareness of Lp(a) among physicians remains low despite the importance of managing risk factors for ASCVD [1:14:00];
• The variability of disease in patients with high Lp(a) [1:19:00];
• Diseases most associated with high Lp(a) [1:26:30];
• The biology of PCSK9 protein, familial hypercholesterolemia, and the case for inhibiting PCSK9 [1:35:00];
• The variability in PCSK9 inhibitors’ ability to lower Lp(a) and why we need more research on individuals with high levels of Lp(a) [1:50:30];
• Peter’s approach to managing patients with high Lp(a), and Benoît’s personal approach to managing his risk [1:54:45];
• Antisense oligonucleotides—a potential new therapeutic for Lp(a) [1:57:15]; and
• More.

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Marty Makary is a surgeon, public policy researcher, and author of the New York times best-sellers Unaccountable and The Price We Pay. In this episode, Marty dives deep into the topic of patient safety. He describes the risk of medical errors that patients face when they walk into the hospital and how those errors take place, and he highlights what amounts to an epidemic of medical mistakes. He explains how the culture of patient safety has advanced in recent decades, the specific improvements driven by a patient safety movement, and what’s holding back further progress. The second half of this episode discusses the high-profile case of RaDonda Vaught, a nurse at Vanderbilt Hospital convicted of negligent homicide after she mistakenly gave a patient the wrong medication in 2017. He discusses the fallout from this case and how it has in some ways unraveled decades of progress in patient safety. Furthermore, Marty provides insights in how to advocate for a loved one in the hospital, details the changes needed to meaningfully reduce the death rate from medical errors, and provides a hopeful vision for future improvements to patient safety.

We discuss:

• Brief history of patient safety, preventable medical mistakes, and catalysts for major changes to patient safety protocols [0:12];
• Advancements in patient safety and the dramatic reduction in central line infections [14:55];
• A surgical safety checklist—a major milestone in patient safety [23:03];
• A tragic case stimulates a culture of speaking up about concerns among surgical teams [25:19];
• Studies showing the ubiquitous nature of medical mistakes leading to patient death [29:42];
• The medical mistake of over-prescribing of opioids [33:48];
• Other types of errors—electronic medical records, nosocomial infections, and more [35:43];
• Importance of honesty from physicians and what really drives malpractice claims [40:26];
• A high-profile medical mistake case involving nurse RaDonda Vaught [47:31];
• Investigations leading to the arrest of RaDonda Vaught [59:48];
• Vaught’s trial—a charge of “negligent homicide” [1:05:16];
• A guilty charge and an outpouring of support for Vaught [1:12:09];
• Concerns from the nursing profession over the RaDonda Vaught conviction [1:18:09];
• How to advocate for a friend or family member in the hospital [1:20:22];
• Changes needed for meaningful reduction in the death rate from medical errors [1:26:42];
• Blind spots in our current national funding mechanism and the need for more research into patient safety [1:31:42];
• Parting thoughts—where do we go from here? [1:35:48];
• More.

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Kelsey Chittick is the author of Second Half: Surviving Loss and Finding Magic in the Missing. In this episode, Kelsey describes her long healing process following the sudden death of her husband, former NFL player Nate Hobgood-Chittick. She describes her life with Nate before and after football, including her premonitions that something was off about Nate and the subsequent finding that he suffered from chronic traumatic encephalopathy (CTE). She speaks openly about how she handled his death with her children, the trauma and grief they faced in the aftermath, and how she’s found ways to be happy in her new life. She shares deep insights into her healing process, including her experience with psychedelics and how the concept of “radical acceptance” has helped her to find joy once again.

We discuss:

• Kelsey’s childhood in Florida as an athlete [2:15];
• Meeting Nate and early relationship with him [7:45];
• Nate’s unbelievable work ethic and desire to play in the NFL [12:30];
• Life with a professional football player, playing through pain, and head injuries related to football [17:00];
• Nate’s final days of football and early retirement struggles [23:30];
• The tough transition from the NFL to a “regular life” and how Nate found a way to serve others [28:45];
• Nate’s struggle with his weight and overall health after retirement [34:45];
• Kelsey’s anxiety and premonitions of Nate’s impending death, and Nate’s changing demeanor [37:30];
• The traumatic experience of learning of Nate’s death during her own spiritual journey to Jamaica [45:30];
• Breaking the news to her children of their father’s death [51:00];
• The darkest days following Nate’s passing and how her children were handling grief [55:30];
• A new relationship with death, finding happiness, and the duality of feelings [1:02:45];
• Nate’s autopsy results showing evidence of CTE [1:07:00];
• The grieving process [1:15:00];
• Dealing with grief with kids and how children grieve differently [1:19:15];
• Healing through her first psychedelic experience [1:23:00];
• The therapeutic potential of psychedelics, meditation, and more [1:33:45];
• The concept of “radical acceptance” and the peace that comes with it [1:42:30];
• The up and down experience of writing her book [1:47:45];
• More.

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In this “Ask Me Anything” (AMA) episode, Peter is joined by special guest, Dr. Matt Kaeberlein. Together they answer many questions around the field of aging with an emphasis on three specific molecules—NAD, metformin, and rapamycin—and their purported geroprotective qualities. They first discuss aging biomarkers and epigenetic clocks before breaking down the advantages and limitations of the most common experimental models being used today to study aging and pharmacological possibilities for extending lifespan. Next they dive deep into NAD and the much-hyped NAD precursors, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). They compare data from NAD precursors to studies on metformin and rapamycin, assessing how they stack up against each other and using the comparison as an opportunity to illustrate how to make sense of new experimental data and make smart decisions about how to approach future research.

If you’re not a subscriber and 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 on our website at the AMA #35 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• Logic behind comparing NAD precursors to rapamycin and metformin [3:40];
• Aging biomarkers: current state, usefulness, and future promise [7:00];
• Epigenetic clocks: definition, use case, and limitations [14:45];  
• Advantages and limitations of studying aging in non-humans and the strengths and weaknesses of different model systems [26:30];
• Aging studies: importance of control lifespans and the problems with reproducibility [34:15];
• Intro to NAD, potential role in aging, relationship to sirtuins, and more [48:15];
• NAD precursors (NR and NMN): current data [1:10:00];
• Human studies with NAD precursors [1:25:45];
• Comparing NAD lifespan data to data from metformin and rapamycin [1:28:30];
• Defining a “clean drug” and a “dirty drug” [1:38:00];
• Reason for the lack of rapamycin studies in humans compared to NAD and metformin [1:41:00];
• Ranking the geroprotective molecules in terms of risk and reward [1:48:00]; and
• More.

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In this special episode of The Drive, we have pulled together a variety of clips from previous podcasts about exercise to help listeners understand this topic more deeply, as well as to identify previous episodes which may be of interest. In this episode, Peter discusses his framework for exercise, what he’s really optimizing for, and how to train today to be prepared for a good life at age 100. He describes the importance of strength and stability, and why deadlifting is an important tool to consider for longevity. Additionally, he details why training in zone 2 and zone 5 is important, gives a primer on VO2 max, and describes the most effective ways to engage in those types of exercise. Finally, Peter reveals his current exercise routine.

We discuss:

• What is Peter optimizing for with his exercise? [3:00];
• Preparing for a good life at age 100: Training for the “Centenarian Olympics” [6:00];
• The importance of preserving strength and muscle mass as we age [21:45];
• The value of deadlifts for stability and longevity when done properly [27:30];
• The importance of zone 2 aerobic training [35:45];
• The most effective ways to engage in zone 2 exercise [40:00];
• Zone 5 training and VO2 max [44:15];
• A primer on VO2 max [52:00];
• Stability—the cornerstone upon which all exercise and movement relies [1:03:00];
• Peter’s current exercise routine [1:07:45];
• More.

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Layne Norton holds a Ph.D. in nutritional sciences and is a physique coach, natural bodybuilder, and previous guest on The Drive. In the first half of this episode, Layne dives deep into the topic of energy balance, including the role that macronutrients and calories play in weight loss. He describes how many people struggle with tracking food and calories on their own across a variety of diets and how all of this can impact nutritional habits and behaviors. In the second half of the episode, Layne discusses the importance of protein and weightlifting for improving one’s body composition and increasing muscle mass. He explains how he would prescribe different training and nutrition programs for two hypothetical clients—a 50-year-old female who is entering menopause and wants to improve her health, and a 40-to-50-year-old male who wants to maximize muscle mass. Additionally, Layne discusses a number of supplements that could potentially benefit a training program including whey protein, branch chain amino acids, creatine, nitric oxide boosters, and more.

We discuss:

• Defining energy balance and the role of calories [2:30];
• Defining a calorie, whether they are all created equal, and how much energy you can extract from the food you eat [8:00];
• Factors influencing total daily energy expenditure [12:15]:
• The challenge of tracking energy expenditure accurately, and the thermic effect of different macronutrients [23:30];
• Challenges of sustained weight loss: metabolic adaptation, set points, and more [34:45];
• Weight loss strategies: tracking calories, cheat meals, snacks, fasting, exercise, and more [40:45];
• Sitting in discomfort, focusing on habits, and other lessons Layne learned as a natural bodybuilder [52:15];
• Commonalities in people who maintain long-term weight-loss [1:01:15];
• Does a ketogenic diet result in greater energy expenditure? [1:03:15];
• The metabolic benefits of exercise, muscle mass, and protein intake [1:15:00];
• The impact of lean muscle and strength on lifespan and healthspan [1:20:00];
• Hypothetical case study #1: Training program for 50-year-old female [1:27:45];
• Muscle protein synthesis in a trained athlete vs. untrained individual following a resistance training program [1:31:30];
• Protein and amino acids needed to build and maintain muscle mass [1:37:15];
• Nutrition plan for the hypothetical 50-year-old woman starting to build lean muscle [1:42:45];
• Dispelling myths that excess protein intake increases cancer risk through elevations in mTOR and IGF [1:55:30];
• Hypothetical case study #2: Training program for a 50-year-old, trained male wanting to increase muscle mass [2:04:00];
• Maximizing hypertrophy while minimizing fatigue—is it necessary to train to muscular failure? [2:11:30];
• Ideal sets and reps for the hypothetical 50-year-old male interested in hypertrophy [2:16:15];  
• Maximizing hypertrophy by working a muscle at a long muscle length [2:22:15];
• Recommended lower body exercise routines and tips about training frequency [2:24:00];
• Nutrition plan for the hypothetical 50-year old male wanting to add muscle [2:29:00];
• Cycling weight gain and weight loss when building lean muscle mass, and expectations for progress over time [2:33:30];
• Supplements to aid in hypertrophy training [2:38:30];
• More.

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Nir Barzilai, Director of the Institute for Aging Research at the Albert Einstein College of Medicine, is back for his third appearance on The Drive. In this episode, Nir divulges insights into lifespan and healthspan through the lens of his extensive research on centenarians as well as the latest from the TAME trial (Targeting/Taming Aging with Metformin), a multi-center study investigating the concept that the multi-morbidities of aging can be delayed in humans. He discusses common gene variants found in centenarians, important pathways for longevity, and ultimately what we can learn from centenarians about extending lifespan while also trying to improve healthspan. Additionally, Nir goes into depth on metformin as a longevity tool for humans, including studies with positive and negative results. He discusses the impact metformin can have on exercise for both strength training and cardiovascular training, as well as future research facilitated by data from the TAME Trial. He also touches on epigenetic clocks and concludes with his take on the usefulness of NAD precursors as a potential gero-protective agent.

We discuss:

• Insights from genetic studies of centenarians and twins [3:00];
• Genes with protective variants that aid longevity [13:00];
• The relationship between growth hormone and IGF-1 [22:45];
• Use of growth hormone as a longevity tool [34:00];
• Longevity genotypes: the role of APOE e2, Lp(a), Klotho, and CETP [41:45];
• The correlation between high TSH and longevity [46:30];
• Important pathways for longevity [52:00];
• Insights from centenarian studies, nature vs. nurture, and more [59:00];
• The contraction of morbidity that comes with improved healthspan [1:08:00];
• Defining healthspan [1:13:13];
• Unique perspectives and positive attitudes of centenarians [1:17:30];
• Lessons to take away from centenarians [1:24:00];
• Metformin overview: history, studies, and potential for gero-protection [1:28:45];
• The TAME trial (Targeting Aging with Metformin) [1:39:00];
• The challenge of studying metformin in animals models [1:46:45];
• How data from the TAME trial could provide insights into biomarkers of aging and facilitate a future study on proteomics [1:53:30];
• The search for biomarkers to identify who can benefit from treatment [2:00:30];
• The impact of metformin on exercise, and finding the right indication for the use of metformin [2:10:30];
• Are NAD precursors geroprotective? [2:21:30]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter dives deep into the topic of atherosclerotic cardiovascular disease (ASCVD)—the number one killer in the developed world. Peter argues for the importance of paying attention to and understanding ASCVD given its ubiquity and inevitability. He goes into great detail about the development of atherosclerosis and how it can take hold at a very early age, the role of cholesterol, and the causal factors of ASCVD that determine prevention strategies. Additionally, he discusses the important metrics and biomarkers found in blood work, as well as diagnostic tests such as coronary artery calcium scores (CAC) and CT angiograms which help to determine the level of arterial damage present. Finally, Peter lays out the keys to understanding and interpreting calcium scores before wrapping up the conversation with his key takeaways regarding prevention.

If you’re not a subscriber and 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 on our website at the AMA #34 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• The importance of understanding atherosclerosis early in life [2:15];
• Defining atherosclerotic cardiovascular disease (ASCVD), its causes, and the role of cholesterol [9:00];
• The process of developing ASCVD, part 1 [15:00]; 
• The process of developing ASCVD, part 2 [24:00];
• The process of developing ASCVD, part 3 [32:45];
• How early in life ASCVD can start to develop [40:30];
• Case studies of atherosclerosis and figures showing real pathology [43:00];
• Coronary artery lesions present in autopsies of different age groups [49:15];
• The causal factors of ASCVD that determine prevention strategies [52:15];
• Labs to identify biomarkers of ASCVD ]59:00];
• Diagnostic tests to determine the level of arterial damage present—CAC, CTA, CIMT, and more [1:00:30]
• Keys to understanding and interpreting a CAC score and/or CTA results [1:05:15];
• Is there a risk from cholesterol levels being too low? [1:13:00];
• Key takeaways regarding prevention [1:15:45];
• More.

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