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    #33 - Rudy Leibel, M.D.: Finding the obesity gene and discovering leptin

    enDecember 17, 2018

    Podcast Summary

    • The Discovery of Leptin: Unraveling the Genetics of Obesity and DiabetesCollaboration and shared passion in science can lead to significant breakthroughs, as seen in the discovery of leptin and its impact on our understanding of obesity and diabetes.

      The discovery of leptin, with Rudy playing a critical role, was a significant scientific achievement in the field of type 2 diabetes and obesity. While the discussion delves into technical and complex scientific concepts, it provides valuable insights into the genetics of obesity, energy expenditure measurements, and the role of insulin resistance. Rudy and Peter's long-standing friendship and shared passion for science create an engaging and informative dialogue. It is clear that Rudy's expertise and contributions have had a substantial impact on our understanding of obesity and diabetes. The conversation also highlights the importance of collaboration and the joy of sharing intellectual discoveries over good food and drinks.

    • Investigating the biology of body weight regulation and its connection to obesity and diabetes.Rudy Leibel's research on obesity has provided insights into the role of genetics, adipose tissue, and stem cells in body weight regulation, contributing to a better understanding of the relationship between obesity and diabetes.

      Rudy Leibel is a renowned researcher and physician who has dedicated his career to studying the biology of body weight regulation in animals and humans. He has focused on the clinical problem of obesity for over 30 years and has explored various approaches, including studying human adipose tissue, investigating the genetics of obesity, and conducting studies in mice. Recently, he has also delved into the use of stem cells to understand brain cells and pancreatic cells related to body weight regulation and insulin production. Leibel's interest in the hypothalamus, a small organ situated above the pituitary gland, stems from his early exposure to its importance in physiology during his time at the Walter Reed Army Institute of Research. Overall, his studies have led to a deeper understanding of the interconnectedness of obesity and diabetes.

    • The critical role of the hypothalamus in regulating bodily functions and behaviors.Understanding the role of the hypothalamus in regulating appetite and metabolism is crucial for maintaining a healthy balance and addressing obesity and related disorders. Further research in this area is needed.

      The hypothalamus, a critical part of the brain, plays a vital role in regulating various bodily functions and behaviors, including appetite and metabolism. Both Rudy Leibel and Peter Attia emphasize the importance of this brain region. Leibel explains that the hypothalamus and the part of the brain regulating respiration are crucial for survival. This highlights the significance of maintaining a healthy balance in these brain areas. Additionally, the conversation sheds light on the challenges in understanding the complexity of obesity, as evidenced by Leibel's encounter with an obese child and his realization of the limited knowledge and treatments available at that time. Ultimately, the conversation emphasizes the need for further research and understanding of the brain's role in obesity and related disorders.

    • The Broad Perspective of Medical EducationMedical education offers physicians the ability to examine problems from various levels and make significant contributions to improving human health through research and mentorship.

      A medical education provides a unique opportunity for physicians to have a broad perspective on the human condition. It allows them to examine problems from psychological to biological and even social levels. The ability to pause, reflect, and seek answers to clinical situations is a common trait among great physician scientists. In the case of Rudy Leibel, a chance encounter altered the entire course of his career, leading to remarkable research and discoveries. Additionally, mentorship plays a crucial role in the success of scientists. Overall, medicine presents a privilege that can be leveraged to make significant contributions to the understanding and improvement of human health.

    • The Evolution of Understanding Adipose TissueQuestioning existing beliefs and exploring new avenues of scientific inquiry led to the discovery of important hormonal functions in fat cells, highlighting the importance of continuous exploration in scientific research.

      The understanding of adipose tissue, or fat, has evolved over time. During the 1970s, adipose tissue was primarily seen as a passive storage depot for fat. However, scientists like Rudy Leibel began to question this view and explore the possibility that fat cells could have important hormonal functions. This shift in thinking was prompted by observations of how fat mass affected insulin levels in the body. It was not until later, through the work of researchers like Douglas Coleman and the study of mice mutations, that the hormone leptin was discovered as a significant factor secreted by fat cells. This conversation highlights the importance of questioning existing beliefs and continuously exploring new avenues of scientific inquiry.

    • The role of hormones in controlling body weightHormones play a vital role in regulating body weight, as demonstrated through experiments on mice with obesity and diabetes mutations.

      The OB mouse, which is prone to obesity due to excessive food intake, was found to be missing a specific circulating hormone that regulates body weight. This hormone, referred to as the ligand, is produced by the wild type mouse. Additionally, another mutation called the diabetes mouse, which also displayed overeating but had a tendency to develop diabetes, was found to be missing the ability to respond to the ligand. Through parabiosis experiments, it was discovered that when the OB mouse was connected to a wild type mouse, it corrected its excessive appetite and began to lose weight. On the other hand, when the wild type mouse was connected to the diabetes mouse, it stopped eating and eventually died of starvation. These findings highlight the importance of hormonal regulation in controlling body weight.

    • Signals from adipose tissue control the expansion of fat cells in obese individualsSignals released by fat cells recruit more fat cells, leading to hyperplastic adipose tissue in obese individuals. This knowledge could lead to new approaches in managing obesity.

      The expansion of fat cells and the generation of new fat cells in obese individuals is regulated by signals from adipose tissue. This discovery was made in the late 1970s by researchers like Jules Hirsch and Rudy Leibel. They found that as fat cells reach a maximum size, they release signals that recruit more fat cells, leading to hyperplastic adipose tissue in very obese individuals. The adipose tissue, which contains organelles like any other cell, plays a crucial role in this process. Additionally, experiments conducted on rats, both lean and obese, showed that the regeneration of fat cells occurred even in lean animals. This knowledge contributes to our understanding of obesity and could potentially lead to new approaches in managing it.

    • Models of Obesity and the Role of Lipoprotein LipaseUnderstanding the mechanisms behind obesity is challenging due to conflicting models such as the pool model and the push model. The role of lipoprotein lipase (LPL) in obesity is also complex, with evidence suggesting it may not be necessary for normal adipose tissue.

      There are different models for understanding the mechanisms behind obesity. One model suggests that the adipose tissue acts like a vacuum cleaner, sucking up circulating fat and storing it, leading to obesity. This is known as the pool model. Another model, known as the push model, suggests that the brain itself is pushing the substrate into the fat cells, causing them to be filled up from the outside. Both models have evidence to support them, making it a challenge to determine the primary mechanisms for controlling body weight. Additionally, the conversation highlights the significance of lipoprotein lipase (LPL) in obesity. However, individuals who are completely deficient in LPL can have normal adipose tissue, suggesting that LPL may not be absolutely necessary.

    • Early techniques for mapping obesity genes were time-consuming and complex.Early experiments using genetic techniques laid the foundation for understanding obesity genetics, despite being limited in their ability to provide quantitative assessments.

      Early experiments in mapping and identifying obesity genes required complex techniques and took a significant amount of time compared to modern methods. Scientists like Rudy Leibel used techniques such as genetic crossing and Southern blotting to identify genetic markers and track obesity-related genes in rats. By correlating the presence of these markers with the obesity levels of the animals, they could narrow down the region of the genome where the obesity gene resided. This process provided a qualitative assessment of obesity rather than a quantitative one. While the resolution was limited to identifying the gene's location on a specific region of the chromosome, these experiments laid the foundation for further research and understanding of obesity genetics.

    • Exploring the OB Gene and Its Role in Body Weight RegulationThe OB gene, discovered through extensive research on rats and humans, is a significant player in controlling body weight, offering valuable insights into the genetics of obesity.

      Rudy Leibel and his team conducted extensive research on both rats and humans to understand the regulation of body weight and energy metabolism. Through their studies, they discovered the existence of a single gene, known as the OB gene, which played a significant role in controlling body weight. This finding was supported by the breeding patterns observed in both rats and mice. By mapping the location of the OB gene in different species, they were able to rule out other potential genes, such as the lipoprotein lipase gene, that could have been responsible for obesity-related traits. This research provided valuable insights into the genetics behind obesity and laid the foundation for further discoveries in the field.

    • Cloning genes in the mid-1980s: Challenges, perseverance, and trial and errorThe process of cloning genes in the mid-1980s required patience, perseverance, and precise manipulation of chromosomes, despite the lack of advanced tools.

      The process of cloning genes in the mid-1980s was challenging and required a lot of perseverance and trial and error. The researchers, Rudy Leibel and Jeff Friedman, were not experts in molecular genetics but trained themselves to do the work. They faced similar difficulties as other scientists who were trying to clone genes for diseases like Huntington's disease and cystic fibrosis. The process involved using techniques like southern blotting and using markers to locate specific genes on chromosomes. The researchers had to carefully examine obese mice to determine their genotype and use their DNA to create a map of the gene's location. Patience and precise manipulation of chromosomes were crucial for the success of this project at that time when advanced tools were not available.

    • Gene location and relationship not necessary for ligand receptor functionThrough careful analysis of gene transcripts and comparing mutated animals to normal ones, researchers discovered the OB gene's role in weight regulation, despite its location on different chromosomes in mice and humans.

      The function of ligand receptor genes does not require them to be on the same chromosome or in close proximity to each other. The researchers knew that the ligand receptor genes were not on the same chromosome, and it was confirmed that there is no relationship between them. The critical breakthrough in cloning the gene involved creating a fine map of the region and analyzing the transcripts being read off of the DNA. By comparing transcripts from mutated animals to normal ones, they discovered the gene responsible for the phenotype. This gene, known as the OB gene, was found to be predominantly expressed in adipose tissue, aligning with previous experiments that implicated adipose tissue in weight regulation. The OB gene is located on chromosome 6 in mice and chromosome 7 in humans.

    • The Role of Leptin in Obesity Research.Leptin plays a crucial role in regulating body weight, signaling the brain about available energy and potentially preventing pregnancy in certain circumstances.

      The discovery of the OB gene, also known as leptin, and its role in regulating body weight was a significant breakthrough in obesity research. It was found that the fat cell secretes leptin, and the lack of leptin in the OB mouse can be cured by introducing it. However, the DB mouse, which produces excessive amounts of leptin, cannot be fixed in the same way. This demonstrates the importance of understanding both ligand and receptor deficiencies in genetic disorders. The identification of the DB gene and its mapping to chromosome 4 in the mouse further validated the role of leptin in obesity. Additionally, it was realized that leptin primarily serves as a signal to the brain, indicating the availability of energy for survival and reproductive processes. Nature evolved leptin to regulate food intake and potentially prevent pregnancy under certain circumstances.

    • Challenges in Regulation and Treatment of Obesity Associated with LeptinLeptin therapy is effective for individuals with OB gene mutations but not for those with leptin receptor mutations, highlighting the complexity of regulating appetite and developing interventions for obesity.

      There are individuals with mutations in the OB gene and leptin receptor mutations who experience obesity due to disruptions in the regulation of leptin, a hormone that signals satiety. While leptin supplementation has proven to be an effective treatment for those with OB gene mutations, individuals with leptin receptor mutations do not respond to leptin therapy. Currently, there is no effective intervention for this group, although drugs targeting the melanocortin 4 receptor are being developed as a potential solution. Additionally, Amgen's attempt to develop leptin as an obesity drug was not successful, as only individuals with leptin deficiency showed significant improvement with increased leptin levels. Overall, leptin regulation is complex and not easily manipulated to control appetite in every individual.

    • Prader Willy: A Genetic Disorder with Distinct PhenotypePrader Willy is a genetic disorder characterized by poor growth, feeding difficulties, and extreme hunger. Close monitoring of food access and parental attention are crucial in managing the condition.

      Prader Willy is a genetic disorder characterized by a large deletion in a region of chromosome 15. In this region, the paternal genes are deleted, while the maternal genes are silenced. Individuals with Prader Willy have a distinct phenotype, including poor growth, feeding difficulties, and hyperphagia (extreme hunger). They often require close monitoring of their food access, and in some cases, food needs to be locked away to prevent overeating. However, with careful management, the severity of the disease can be reduced. Treatments such as growth hormone therapy can help alleviate some of the endocrine disturbances associated with the disorder. While clinical trials are necessary to investigate potential interventions, managing the condition with parental attention is crucial.

    • Exploring the Potential Benefits of a Ketogenic Diet for Prader-Willi Syndrome and Its Link to HyperinsulinemiaA ketogenic diet shows promise in improving cognitive development and managing Prader-Willi syndrome, while hyperinsulinemia and the activity of proconvertase 1 may play a role in the condition. Understanding Prader-Willi syndrome can also inform obesity treatment.

      A ketogenic diet may have positive effects on children with Prader-Willi syndrome, correcting their phenotype and improving cognitive development. This anecdotal evidence from a support group of parents highlights the potential benefits of this dietary approach for managing the condition, although controlled data is still needed. Additionally, the conversation discusses the hyperinsulinemia observed in Prader-Willi patients and its potential link to the deficiency or under activity of an enzyme called proconvertase 1. This enzyme plays a crucial role in processing hormones, including insulin. If this theory proves to be true, increasing the activity of proconvertase 1 could potentially alleviate some of the phenotypes associated with Prader-Willi syndrome. Furthermore, the conversation raises questions about how insights gained from studying Prader-Willi syndrome can contribute to our understanding and treatment of obesity, a widespread issue affecting a significant portion of the population. Research suggests that weight reduction often leads to a disproportional decrease in energy expenditure, primarily driven by a reduction in the energy cost of low levels of physical activity. This reduction may be influenced by low levels of leptin, a hormone associated with body fat.

    • Restoring Energy Expenditure with Leptin InjectionInjecting leptin into weight-reduced individuals can increase their energy expenditure, primarily in skeletal muscle, without the need to regain previous body weight.

      Injecting leptin into weight-reduced individuals can restore their energy expenditure to pre-weight loss levels, even without returning to their previous body weight. This intervention, conducted with low doses of leptin, resulted in an increase of 2 to 300 Kcal per day in energy expenditure. Furthermore, it was found that this effect primarily occurs in skeletal muscle, which becomes less efficient after leptin administration. The conversation also touched upon two methods of measuring energy expenditure - indirect calorimetry and doubly labeled water. Indirect calorimetry involves measuring the rate of oxygen consumption and carbon dioxide production, while metabolic chambers allow for long-term measurements over several days.

    • The Challenges and Engineering of Metabolic Chambers and the Use of Doubly Labeled Water in Energy Expenditure Measurement.Metabolic chambers are costly and require careful attention to leaks and airflow, while the doubly labeled water technique provides a longer data collection period for assessing energy expenditure.

      The construction and maintenance of Metabolic Chambers require a substantial amount of money, attention, and expertise. These chambers, although fun and appealing for the whole family, are expensive and need careful consideration of factors like leaks and airflow. The engineering involved is remarkable, but any mishaps can be challenging to identify and rectify. Additionally, the conversation highlights the use of doubly labeled water as a technique for measuring energy expenditure. This method involves analyzing the concentration of isotopes in urine and exhaled air to calculate carbon dioxide production. While both methods have their limitations, the doubly labeled water technique provides a more extended period for data collection, allowing researchers to assess energy expenditure over days or even weeks.

    • Understanding the Complexity of Appetite RegulationAppetite regulation involves various central and peripheral mechanisms, including hormones and neural signals, emphasizing the need for comprehensive understanding of its multifaceted nature for overall well-being.

      Appetite regulation is a complex and multi-faceted process involving both central and peripheral mechanisms in the body. While the central nervous system, particularly the hypothalamus, plays a significant role in receiving signals related to food intake and energy expenditure, it is not the sole determinant of appetite. Other organs and tissues, such as adipose tissue, the gastrointestinal tract, and neural signals, also contribute to appetite regulation. It is now evident that there are numerous hormones and neural inputs originating from these peripheral sources that interact with the brain to influence both conscious and unconscious responses related to food consumption and body weight regulation. This intricate system highlights the importance of understanding the multifaceted nature of appetite regulation for overall survival and well-being.

    • The complexities of body weight regulation and the impact of environmental factors and genetics.Environmental factors, genetics, and the availability of high-calorie foods contribute to the challenges in regulating body weight. Epigenetic implications and critical periods of development play a role in maintaining higher body weights.

      Body weight regulation is a complex process influenced by various factors, including our environment and genetic predispositions. The frontal cortex plays a role in decision-making related to body weight, while bacteria in the colon also produce molecules that can impact regulation. However, our current environment, with its abundance of easily accessible high-calorie foods, poses challenges to this system that was not designed for such conditions. While obesity rates have shown some signs of slowing down or leveling off, they are still on the rise, albeit at a slower pace. There may be epigenetic implications as well, with early exposure to an obesogenic environment potentially affecting future generations. Understanding critical periods of development and the consequences of manipulation can provide insights into the maintenance of higher body weights.

    • Maternal factors and offspring weight: Understanding the long-term effectsEarly manipulation of a pregnant individual's diet or endocrine system can impact the weight and health of their offspring, emphasizing the need to recognize the influence of maternal factors on future child health.

      Early manipulations in a pregnant animal or human's diet or endocrine system can potentially lead to higher body weight in the offspring. Research suggests that manipulating the metabolism of a pregnant individual can have consequences on the developing brain and physiology of the fetus. There is evidence that obesity in pregnant women increases the risk of obesity in their children. Additionally, the timing of nutrient or insulin exposure during pregnancy, specifically during critical windows of islet cell formation, may have a more profound effect on the offspring's weight. These effects appear to be long-lasting and may not be reversible even if the environment changes. Overall, this highlights the importance of understanding the impact of maternal factors on the future health of offspring.

    • The impact of diet composition on body weight and the effectiveness of low carb diets for weight loss.The composition of a person's diet plays a significant role in their body weight, and low carbohydrate diets can be effective for weight loss due to reduced hunger and potential activation of the body's internal calorie reserves. However, managing hunger can be difficult in sustainable weight loss.

      The composition of a person's diet can have a significant impact on their body weight. Diet composition affects the hedonic aspects of food, influencing the individual's desire to eat and their drive to ingest specific types of food. Different individuals have varying sensitivities to different diet compositions, with some responding well to high carb diets and others to low carb diets. The effectiveness of low carbohydrate diets for weight loss may be attributed to a combination of factors, including reduced hunger, decreased diversity or palatability of the food, and the potential activation of the body's internal calorie reserves. While the theory of less palatable food leading to reduced intake is not entirely convincing, it is clear that hunger can be a challenging and unsustainable aspect of weight loss.

    • The complexity of obesity and the varying effectiveness of low carbohydrate diets in weight loss.Not all diets work for everyone in treating obesity, and it's crucial to maintain a negative energy balance to lose weight, but sustainable strategies are necessary for long-term success.

      The challenge of obesity is complex and not everyone responds to the same treatment. While low carbohydrate diets have shown success for some, they may not work for everybody. The composition of the diet can influence aspects of ingestive behavior and may have metabolic consequences on the drive to eat. It is important for individuals to be in negative energy balance, consuming fewer calories than they expend, in order to lose weight. However, asking someone to be constantly hungry is not sustainable. Low carbohydrate diets seem to be more satiating, but whether this is due to their composition or increased self-control is still unclear. The field of body weight regulation and energy expenditure has expanded beyond the hypothalamus, revealing new aspects of the central nervous system's impact on regulation.

    • Unraveling the Genetic Factors of Obesity and OvereatingThe FTO gene plays a significant role in obesity, but its exact impact on food intake is still unclear. Identifying the mechanisms involved can help prevent and manage obesity through effective interventions.

      There is still a lot to learn about the genetic factors influencing obesity and overeating. While the FTO gene has been identified as having the strongest genetic signal for obesity, the mechanism by which it affects food intake is still unknown. Some researchers believe it may be related to the browning of adipose tissue, while others suggest it affects central nervous system circuits. What is clear is that individuals with the risk variants of this gene tend to eat slightly more and have a preference for higher-fat foods. Understanding the specific mechanisms in the central nervous system would provide valuable insights into preventing and managing obesity. Further research is needed to uncover these mechanisms and develop effective interventions.

    • Genetic Factors and Environmental Triggers Leading to ObesityGenetic variations increase susceptibility to obesity, but they do not directly cause it. By studying the impact of these genes on the nervous system, researchers can gain insights into obesity and potentially develop interventions.

      Obesity is influenced by a combination of genetic factors and environmental triggers. The presence of certain genes, such as those found in the first intron, can increase an individual's susceptibility to obesity. While these genetic variations do not directly cause obesity, they widen the vulnerability to environmental factors that contribute to weight gain. Understanding the structural and functional impacts of these genes on the nervous system can provide valuable insights into the genetic susceptibility to obesity. By studying animals and manipulating these genes, researchers can investigate the effects on food intake and the development of the brain. This knowledge may eventually lead to interventions, such as pharmacological treatments, to combat obesity, although further research is needed in this area.

    • The Impact of Noncoding DNA Sequences on the Central Nervous System and the Potential for Introns to Influence Traits and Conditions.Noncoding DNA sequences called introns can impact the central nervous system, affecting an individual's susceptibility to certain traits or conditions. Removing these introns through CRISPR technology may fix associated phenotypes, indicating their influence occurs at the fertilization level.

      The presence of noncoding DNA sequences, known as introns, can have a structural and consequential impact on the central nervous system. This predisposition can influence the nature and development of the central nervous system, making individuals more or less susceptible to certain traits or conditions. Through experiments using CRISPR technology, it has been observed that editing and removing these introns can fix the phenotypes associated with them. This indicates that the influence of introns transcends development and occurs at the fertilization level. Additionally, the discussion highlights the complexity of insulin resistance and its primary defect in the muscle, where glucose transporters fail to respond to insulin signals. The liver also plays a role in glucose uptake, but the partitioning of glucose between the muscle and liver is determined by other factors aside from capacity.

    • Understanding the Complex Relationships in Insulin ResistanceInsulin resistance in the liver affects lipid synthesis and glycogen release differently based on insulin sensitivity. Obesity and elevated fatty acids may impact muscle glucose homeostasis, emphasizing the importance of comprehending these relationships.

      Insulin resistance in the liver can have different effects on lipid synthesis and glycogen release, depending on the individual's insulin sensitivity. In individuals with issues related to insulin homeostasis, the liver may become resistant to the suppression of gluconeogenesis while maintaining sensitivity to insulin's effects on lipogenesis. The worst outcome occurs when the muscles also become resistant to insulin, leading to a lack of glucose uptake. The debate lies in whether obesity affects adipose tissue, which then affects muscle insulin sensitivity, or if increased lipid content in adipose tissue directly affects muscle glucose homeostasis. It is suggested that high levels of ambient fatty acids may suppress insulin signaling in the muscles. Cahill's 40-day fasted subjects exhibited high free fatty acid levels and low insulin and glucose levels, but their response to glucose may vary depending on the duration of refeeding. Overall, understanding the complex relationships between insulin resistance, lipogenesis, and glycogen release in different tissues is crucial for addressing issues related to insulin homeostasis.

    • Approaching Health and Genetics from Different PerspectivesCollaboration and open-mindedness in scientific research are crucial for unraveling the mechanisms behind complex problems and making valuable discoveries.

      There are different perspectives in approaching complex problems like health and genetics. Rudy Leibel and Peter Attia discuss their differing viewpoints on understanding the impact of environmental triggers on genetic predispositions. While Rudy focuses on identifying the factors that lead to specific outcomes, Peter takes a broader approach, looking for solutions that can benefit a wider range of individuals. They both recognize the importance of unraveling the mechanisms behind these phenomena, whether it be for preventing lung cancer or manipulating biological circuits for overall well-being. This conversation highlights the significance of collaboration and open-mindedness in scientific research, as different approaches can lead to valuable discoveries.

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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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    The Peter Attia Drive
    enMay 20, 2024

    #301 - AMA #59: Inflammation: its impact on aging and disease risk, and how to identify, prevent, and reduce it

    #301 - AMA #59: Inflammation: its impact on aging and disease risk, and how to identify, prevent, and reduce it

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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.

    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.

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    The Peter Attia Drive
    enMay 13, 2024

    #300 - Special episode: Peter on exercise, fasting, nutrition, stem cells, geroprotective drugs, and more — promising interventions or just noise?

    #300 - Special episode: Peter on exercise, fasting, nutrition, stem cells, geroprotective drugs, and more — promising interventions or just noise?

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    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.

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    Special episode with Dax Shepard: F1 and the 30th anniversary of Ayrton Senna’s death

    Special episode with Dax Shepard: F1 and the 30th anniversary of Ayrton Senna’s death

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    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.

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    #299 ‒ Optimizing muscle protein synthesis: the crucial impact of protein quality and quantity, and the key role of resistance training | Luc van Loon, Ph.D.

    #299 ‒ Optimizing muscle protein synthesis: the crucial impact of protein quality and quantity, and the key role of resistance training | Luc van Loon, Ph.D.

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    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.

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    #298 ‒ The impact of emotional health on longevity, self-audit strategies, improving well-being, and more | Paul Conti, M.D.

    #298 ‒ The impact of emotional health on longevity, self-audit strategies, improving well-being, and more | Paul Conti, M.D.

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    Paul Conti is an author and practicing psychiatrist who specializes in helping people heal from trauma. In this episode, Paul returns to The Drive to delve into the intricate relationship between emotional health, healthspan, and lifespan. He first challenges common assumptions about the inevitable decline of emotional health with age, providing strategies for conducting a comprehensive audit of internal emotional health. He establishes a framework for the foundation of good emotional health: a balance between the generative drive, the assertive drive, and the pleasure drive. Paul also explores the nuanced dynamics of motivation, happiness, and satisfaction as it relates to material possessions, draws connections between physical and emotional well-being, confronts the impact of negative self-talk, and describes how making peace with our mortality can foster a sense of hope, purpose and well-being. Additionally, Paul offers many practical insights into initiating emotional health improvements and navigating the search for a suitable therapist.

    We discuss:

    • The importance of prioritizing emotional health as we age [2:45];
    • The impact of emotional health on healthspan and how to foster a proactive approach to emotional well-being [7:00];
    • The discrepancy between outward success and inner fulfillment, and the importance of a healthy “generative drive” for genuine well-being [13:00];
    • A deeper dive into generative drive: impact on human behavior, resilience, purpose, and more [23:15];
    • Evaluating one’s inner self: introspection, self-awareness, challenging societal norms, and returning to the basics of physical and emotional well-being [29:00];
    • Self-auditing tools: introspection, curiosity, and exploring underlying reasons for unwanted behaviors [41:45];
    • Breaking free from destructive cycles by understanding the continuum of self-care and addictive behaviors and remaining curious [50:15];
    • Critical self talk: the malleability of one’s inner dialogue and the potential for transformative change with perseverance and self-compassion [1:00:15];
    • Slowing the anger response and gaining insights into the underlying triggers to achieve lasting change and self-understanding [1:13:45];
    • Foster gratitude and humility by achieving balance between the three drives—assertion, pleasure, and generative [1:20:45];
    • The conflict between intellectual understanding and emotional feelings, problematic comparison frameworks, and the importance of living in the present with intentionality [1:24:15];
    • How making peace with our mortality can foster a sense of hope, purpose and well-being [1:34:45];
    • Advice for finding a compatible therapist [1:43:45];
    • The key components of therapeutic progress [1:57:00];
    • The caricatures of four common patient phenotypes, and how to get through to them [2:05:30];
    • How Paul manages his own well-being and the emotional challenges that come with his line of work [2:15:15]; and
    • More.

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    #297 - AMA #58: Iron: its role in health, testing methods, and strategies for preventing and managing iron deficiency

    #297 - AMA #58: Iron: its role in health, testing methods, and strategies for preventing and managing iron deficiency

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    In this “Ask Me Anything” (AMA) episode, Peter delves into the crucial yet often overlooked topic of iron and iron deficiency. He explores why iron is indispensable for the body, explains the repercussions of iron deficiency, and sheds light on the prevalence of this issue and who is most susceptible. Peter outlines strategies for increasing iron levels, covering dietary iron, supplementation, and infusion options, while also discussing the suitability of each approach for different individuals. Shifting gears, Peter tackles rapid-fire questions on creatine and sodium, as well as inquiries related to his book.

    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 #58 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

    We discuss:

    • Overview of today’s topics and the importance of understanding iron levels in the body [1:45];
    • The importance and ubiquity of iron in the body, and the role of the protein called ferritin [4:30];
    • The processes of iron absorption, utilization, and transportation [9:30];
    • Options for testing iron levels and how to interpret the results [13:45];
    • What does it mean to be iron deficient, and how is it different from anemia? [17:15];
    • Symptoms of iron deficiency and/or anemia [22:15];
    • How prevalent is iron deficiency, and who is most susceptible? [24:30];
    • The importance of consuming an adequate amount of iron daily to prevent deficiency [30:30];
    • The best way to improve iron levels for someone who is deficient [34:45];
    • Iron supplementation: various formulations and potential side effects [37:45];
    • Intravenous iron infusion as an alternative to oral supplements -- plus restless legs syndrome and other topics [42:00];
    • Iron supplementation: who should and should not consider it [44:00];
    • Peter’s approach to creatine and his pre- and post-workout supplements [50:15];
    • Navigating sodium intake: effect on blood pressure, who should use precaution, and other considerations [54:45];
    • Peter’s thoughts about the potential of writing another book [57:15]; and
    • More.

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    Related Episodes

    Episode 96- Combining Genetics, Lab Testing and Personalized Nutrition to Finally Heal with Dr. Mike Mallin

    Episode 96- Combining Genetics, Lab Testing and Personalized Nutrition to Finally Heal with Dr. Mike Mallin

    Today we welcome guest Dr. Mike Mallin. Dr. Mallin started the company Wild Health in hopes to transform the ways of modern day medicine. Here, the team at Wild Health combine genomics and blood testing to find the root causes of many stubborn health issues. They personally work with individuals to heal the body through food and supplement specific recommendations. 

    This week we discuss:

    [3:22]- We are two weeks away from the launch of my online reversing insulin resistance course, Finding Nutritional PEACE. It launches on OCT 3, and registration is now open HERE! 

    [4:50]- I am hosting three FREE master classes for you to learn more about Finding Nutritional PEACE! Register for 3 Little Known Secrets to Effortlessly Manage Your Weight and Bloodsugar HERE. 

    [8:32]- Personalized protocols have been one of my most highly requested services lately, and I have received wonderful feedback about them! More information on this service HERE. 

    [10:43]- How Dr. Mallin left the conventional medical system and transformed his teachings

    [17:32]- The services Dr. Mallin offers and what it is like to work with him

    [24:28]- What it means to be metabolically flexible

    [27:51]- Dr. Mallin’s views on time restricted eating and fasting

    [34:30]- The correlation between insulin resistance and blood pressure and how healing insulin resistance positively changes blood pressure

    [41:28]- What is the one thing Dr. Mallin would like people to know more about nutrition?

    [48:00]- Tips for parents to help prevent insulin resistance amongst their children and type 2 diabetes 

    [54:08]- Find Wild Health HERE and the different programs they offer! 

    FOR MORE INFORMATION FROM DR. MALLIN:

    Dr. Mallin's Podcast: Wild Health Podcast

    Wild Health Website: Wild Health 

    FOLLOW ME ON:

    Instagram: @shana.hussin.rdn

    Facebook: Fast To Heal With Shana Hussin

    Website: https://www.fasttoheal.info/

    ADDITIONAL LINKS:

    ENROLL in my FREE Masterclass, 3 Little Known Secrets to Effortlessly Manage Your Weight and Blood Sugar.

    ENROLL IN FAST TRACK, my new monthly membership program for onging learning, support, and accountability.

    GRAB YOUR COPY of the Fast To Heal Recipe book with 85 low-carb, whole food recipes that are simple to prepare!

    GET YOUR FREE STARTING GUIDES that will set you well on your way toward a low-carb lifestyle of timed eating!

    SCHEDULE A PERSONALIZED SESSION if you are stuck in a rut, or suffer from a stubborn case of obesity, Type 2 diabetes, or metabolic illness.

    JUMPSTART your fasting and low-carb protocol by enrolling in my 10-Day Hormone Healing Jumpstart!

    ENROLL in Metabolic Makeover, my STARTER COURSE to find your fasting method, implement therapeutic carb restriction, and learn how to bust through weight and health stalls.

    Is Ozempic a Weight Loss Miracle?

    Is Ozempic a Weight Loss Miracle?

    Unless you’ve been living off-grid for the last few months, chances are you’ve heard of Ozempic (or semaglutide)– the newest FDA approved miracle injection for weight loss. Social media has ignited feeds across the world with weight loss transformation posts from semaglutide injections- and 812 million views on TikTok to be exact.

    Tailored to diabetes, this drug works by stimulating insulin secretion and therefore lowering fasting and postprandial glucose levels in four mechanisms. During the Ozempic drug trials, it was noted that weight loss was such a consistent and dramatic side effect that the FDA approved semaglutide for weight loss under the brand name Wegovy in 2021.

    In this episode, I discuss:

    • The four mechanisms of Ozempic
      •  Changes in insulin sensitivity
      • Increased energy expenditure by encouraging stored fat to turn into energy.
      • Slows gastric emptying
      • The impact on appetite.
    • And what current research is finding. (Hint: It might not be a long-term weight loss miracle!)

    To sum it up, weight loss medications like Ozempic cannot have substantial results without compromise (i.e. losing lean muscle mass). Most importantly, NONE of the weight loss medications are fixing the root cause of the problem. The purpose of this podcast is to help you make an informed decision about your options for weight loss. If you are considering semaglutide injections for weight loss, talk to your doctor about the pros and cons!

    Love it? Hate it? We’d love to hear your feedback!

     

    References used for this episode:  

    1.    https://pubmed.ncbi.nlm.nih.gov/30122305/

    O'Neil PM, Birkenfeld AL, McGowan B, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018;392(10148):637-649. doi:10.1016/S0140-6736(18)31773-2

    2.   https://pubmed.ncbi.nlm.nih.gov/33755728/ 

    Rubino D, Abrahamsson N, Davies M, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021;325(14):1414-1425. doi:10.1001/jama.2021.322

    3.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769337/ 

    Sargeant JA, Henson J, King JA, Yates T, Khunti K, Davies MJ. A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans. Endocrinol Metab (Seoul). 2019 Sep;34(3):247-262. doi: 10.3803/EnM.2019.34.3.247. PMID: 31565876; PMCID: PMC6769337.

    4.  https://pubmed.ncbi.nlm.nih.gov/35441470/ 

    Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022;24(8):1553-1564. doi:10.1111/dom.14725

     

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    EP 3: Let's Go!

    EP 3: Let's Go!
    Alright, so you've got everything together, you've listened to the other episodes and you're ready to start, pen is in hand...

    Let's do this! :)

    In this episode, I'll go over in details my best practices for starting out as a total beginner to all things fasting, lots of tips and advice to what is most important when you start to integrate this tool into your lifestyle and how it can make the difference between success or frustration. 

    >>For supportive coaching help from me, please visit: TheFastingFocusedLifestyle.com

    The Genetics of Obesity

    The Genetics of Obesity
    Genetics and the brain play a key role in predisposing some people to obesity. In this Cambridge podcast Catherine Carr looks at how biochemists and neuroscientists are working together to discover the triggers to weight gain. Professor Stephen O'Rahilly of the Institute of Metabolic Science at Cambridge University describes how key genes can contribute to severe cases of obesity, while Dr Sadaf Farooqi a Senior Clinical Fellow at the University, recalls the eureka moment of singling out the first gene to be directly linked with obesity. Psychiatrist Paul Fletcher meanwhile, considers how genetics can directly affect our feelings and behaviours around food. Image credit: FightObesity from Flickr

    The Secret to the Happy Healthy Guys

    The Secret to the Happy Healthy Guys

    It’s not every day you get to meet real super heroes. Dr. Rob Vasquez and Dr. Randall Johns sat down with me for a candid interview to share a little bit of their health challenges and how it changed the direction of their lives. Both of them were poster boys for success, health and fitness and at different times had both experienced life changing health challenges. Check out how these two gentlemen turned their personal tragedies into their biggest vision to serve and have a positive impact on others. Join me with The Secret of the Happy Healthy Guys.

    HappyHealthyCentral.com
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