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    #38 - Francisco Gonzalez-Lima, Ph.D.: Advancing Alzheimer’s disease treatment and prevention – is AD actually a vascular and metabolic disease?

    Decreased blood supply to the brain, caused by vascular changes, could be a contributing factor to the increasing prevalence of Alzheimer's disease, suggesting the need for further research in this area.

    enJanuary 28, 2019

    About this Episode

    In this episode, Francisco Gonzalez-Lima, a Professor of Neuroscience and Pharmacology & Toxicology, explains the vascular hypothesis of Alzheimer’s disease which says the central problem is a progressive neuronal energy crisis of impaired blood flow to the brain and impaired mitochondrial respiration. He walks us through the ways we can intervene in this process and also shares details of the exciting future of Alzheimer’s treatment and prevention.

    We discuss:

    • Background and interest in the brain [5:15];
    • The unique nature of the human brain [9:15];
    • Why we’ve made so little progress in Alzheimer’s research [23:00];
    • The amyloid beta hypothesis [28:30];
    • Hypometabolism in the brain leading to cognitive decline [39:30];
    • Early signs of AD, and deciphering between age-related decline versus something pathologic [47:45];
    • The vascular hypothesis of Alzheimer’s disease [54:00];
    • The relationship between mitochondria, cytochrome c oxidase, and Alzheimer’s disease [1:08:00];
    • Chronic inhibition of cytochrome c oxidase leads to chronic neurodegenerative disease [1:22:45];
    • Major risk factors for AD, head trauma, and other forms of dementia [1:33:45];
    • Methylene blue for treating and preventing neurodegeneration [1:38:15];
    • Current standard of care for AD, and the reasons for a lack of advancement [2:01:45];
    • Near infrared light as a targeted treatment for cognitive decline [2:05:30];
    • The ketogenic diet as a treatment and preventative measure [2:13:15];
    • Exciting future research coming from Francisco [2:23:00];
    • Methylene blue for traumatic brain injuries [2:25:15]; and
    • More.

    Learn more at www.PeterAttiaMD.com

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    🔑 Key Takeaways

    • Peter Attia relies on listener support for his podcast to maintain trust and advocate for products he genuinely endorses, offering exclusive benefits to ensure his supporters receive more value than they give.
    • Functional imaging techniques like PET and functional MRI can detect early signs of disease and provide insights into brain activity, helping physicians educate patients about their health.
    • The brain's complex circuitry and redundant operations enable it to adapt, solve problems, and make decisions, selecting only the most successful solutions similar to NASA's approach for space missions.
    • The development of specific brain networks differs among species, enabling different levels of information processing and behavior.
    • Understanding how the cerebral cortex controls movement and reassessing our understanding of Alzheimer's disease are crucial for progress in research and treatment.
    • Alzheimer's disease is primarily an aging-related disease, with misconceptions about it primarily affecting younger individuals. Understanding the disease's true nature can aid in prevention and treatment.
    • Amyloid beta may not be the sole cause or indicator of Alzheimer's disease, leading to the need for a broader understanding of the complexities involved in its development and progression.
    • The presence of amyloid beta does not always mean that a person has dementia, and other factors such as functional disconnection may contribute to cognitive decline in Alzheimer's disease.
    • Understanding the impact of functional changes in the brain is crucial for comprehending memory deficits in diseases like Alzheimer's, as structural damage alone may not fully explain the underlying phenomena.
    • Memory functions are categorized into stages, with immediate memory being the most affected in conditions like Alzheimer's and dementia. Retrograde memory problems can occur when the transition to more permanent memory is disrupted. Awareness of cognitive changes is essential for intervention.
    • Decreased blood supply to the brain, caused by vascular changes, could be a contributing factor to the increasing prevalence of Alzheimer's disease, suggesting the need for further research in this area.
    • Controlling high blood pressure is crucial to minimize the risk of vascular damage and related complications. Maintain a systolic blood pressure below 120 mmHg and a diastolic pressure below 80 mmHg for optimal outcomes.
    • Lowering total cholesterol may not significantly impact chronic hypoperfusion in the brain, but detecting and addressing vascular problems can improve cardiovascular and brain health.
    • Interrupting the activity of the electron transport chain can have serious consequences as it is essential for generating ATP, which is crucial for cellular energy.
    • Maintaining a proper oxygen supply is vital for optimal mitochondrial function, which is essential for energy production in all organisms.
    • The mitochondrial system, specifically complex 4, can adjust and recover based on demand, offering potential insights for health conditions such as Alzheimer's disease.
    • Cyanide, at lower doses, can cause functional hypoperfusion leading to Alzheimer's-like conditions and cognitive impairment, challenging the traditional understanding of Alzheimer's disease.
    • Impaired mitochondrial function and energy supply in the brain lead to cognitive problems, memory deficits, and ultimately cell death, highlighting the importance of addressing these issues in the treatment of neurodegenerative disorders.
    • Mitochondrial respiration plays a crucial role in various forms of dementia, and targeting it with interventions like mitophagy and electron donors may help mitigate damage caused by dysfunctional mitochondria.
    • Methylene blue has the ability to bypass blockages in the electron transport chain, making it a potential alternative route for electron transport. It also has potential applications in mitochondrial staining, but caution is needed at higher doses.
    • Methylene blue can be used to prevent or rescue from methemoglobinemia at low doses, treat urinary bladder infections by increasing its concentration in the bladder, and potentially treat malaria.
    • Methylene blue, originally a textile dye, became the first antipsychotic medication and has been used for over a century for various purposes, despite facing challenges in gaining FDA approval. It holds potential for diverse medical applications.
    • Methylene blue has potential benefits for dementia treatment, but its reputation has been tarnished by misunderstandings, impurities, and misrepresentations by certain companies and researchers.
    • Critical evaluation of data and established hypotheses is crucial for progress in Alzheimer's research and finding effective treatment options for patients.
    • Memantine shows promise in preventing cell damage, but rescuing dysfunctional cells may not be beneficial. Further research is needed on using infrared light to improve cellular function, with safety considerations for longer wavelengths.
    • Prevention is key to maintaining overall well-being, as it is essential to focus on prevention rather than treatment for individuals at risk of dementia.
    • The brain's ability to receive energy declines with age, but the ketogenic diet and exogenous ketones can help provide alternative sources of energy and support brain health.
    • By targeting the prefrontal cortex, making dietary changes, and utilizing fasting and ketogenesis, individuals can effectively address cognitive decline and improve metabolic health.
    • Lack of interest and funding for promising brain injury treatments like methylene blue raises doubts about future clinical trials and the realization of potential solutions.
    • Success in business is possible for everyone, but it's crucial to be mindful of different perspectives and consider the cosmetic aspect of products or ideas. Medical advice should always come from healthcare professionals.

    📝 Podcast Summary

    Funding Podcasts Through Listener Support

    Peter Attia has chosen to rely entirely on listener support for his podcast, rather than running ads. This decision is driven by two main reasons. Firstly, he values trust and believes that his audience may have a hard time trusting him if he is being paid by the companies he promotes. Secondly, he wants to advocate for products and services he truly believes in, and selling ads would require him to promote things he may not genuinely endorse. Instead, he has created a subscriber support model, where members receive exclusive benefits such as access to show notes, transcripts, and AMA episodes. Peter's goal is to ensure that his supporters receive more value than they give. He also plans to work with companies he already loves to offer his supporters the best deals possible.

    Functional imaging techniques: Identifying early stages of diseases and understanding the brain's complexity for better healthcare.

    Functional imaging techniques, such as PET and functional MRI, are crucial for identifying early stages of diseases that may not have visible structural changes in the brain. While traditional imaging methods provide anatomic resolution, functional studies offer insights into brain activity and can detect functional changes before any other signs of the disease manifest. This distinction is often misunderstood by patients, and it is important for physicians to educate them about the difference between these two types of studies. Additionally, the brain's complexity and brilliance are often underappreciated, as it holds a unique and significant role in regulating behavior and overall health.

    The Brain: A Complex and Unique Organ

    The brain is a highly complex and unique organ compared to other organs in the body. Its functioning is more similar to that of an electrical engineer and a computer scientist rather than a traditional organ. The brain consists of numerous circuits that not only facilitate communication but also compute outcomes and guide the functioning of other tissues in the body. Unlike other organs, the brain operates in a redundant and parallel manner, maximizing communication and information processing. This redundancy allows the brain to adapt and develop new networks and circuitry, enabling it to solve problems and make decisions. The brain's convergence of multiple parallel systems ensures that only the most successful solutions are utilized, similar to how NASA selects the most repeated computations for space missions.

    Variations in Nervous System Across Species.

    The structure and functioning of the nervous system varies across different species. While mammals and primates, including humans, share a similar basic plan, the differences lie in the development of specific brain networks. As we move down the evolutionary chain, simpler organisms like reptiles and amphibians have a larger midbrain, while the cerebral cortex becomes dominant in mammals. Information processing in the nervous system occurs through parallel stages, with each stage adding new pieces of information. Reflexes, such as the knee-jerk response, occur at the lowest level of response outside the brain. However, higher-level processing and decision-making occur in the midbrain and thalamus, allowing for complex behaviors and inhibiting immediate responses.

    The Role of the Cerebral Cortex and Misconceptions about Alzheimer's Disease

    The cerebral cortex plays a crucial role in inhibiting responses and allowing for selective activation. The brain controls movements by inhibiting all possible vectors of movement and then releasing some of them through inhibitory signals. This level of control helps individuals have more precise and intentional movements rather than simply emulating vectors. In terms of disease, most pathologies in the brain occur in the cerebral cortex, including dementia and degenerative disorders like Alzheimer's disease. The conventional thinking on Alzheimer's disease has not led to significant progress in prevention or treatment, possibly due to a misinterpretation of an initial observation made by Louis Alzheimer in 1907. It is important to reassess and reevaluate our understanding of the disease to make meaningful advancements in research and treatment.

    Debunking Misconceptions about Alzheimer's Disease

    Alzheimer's disease is often misunderstood and misinterpreted. There was a historical competition between two groups studying dementia, with one group led by Oscar Fisher, who described the abnormalities seen in younger individuals with senile dementia. However, rivalries and biases led to the misconception that Alzheimer's primarily affects younger people and is unrelated to aging. In reality, Alzheimer's is primarily an aging-related disease, with only a small percentage of cases being early-onset or familial. The dominant amyloid beta hypothesis, which focuses on abnormal proteins, is false and does not reflect what is seen in older individuals with dementia. Understanding the true nature of Alzheimer's disease can help identify risk factors and interventions for prevention and treatment.

    Reconsidering the Role of Amyloid Beta in Alzheimer's Disease

    The prevailing belief regarding the role of amyloid beta in Alzheimer's disease may be flawed. While there is evidence to support the causal role of amyloid beta in early onset Alzheimer's disease, this correlation does not hold true for late-onset cases. The presence of amyloid beta deposition does not necessarily indicate the development of cognitive impairment or the progression of the disease. Furthermore, examining the brains of individuals who were cognitively normal but showed amyloid and neurofibrillary tangles challenges the assumption that these markers are definitive indicators of Alzheimer's. This highlights the need to consider other factors and complexities involved in the development and progression of Alzheimer's disease, calling into question the singular focus on molecular biology in research.

    Amyloid beta alone cannot accurately determine the presence of dementia in Alzheimer's patients.

    The majority of patients diagnosed with Alzheimer's disease have the same level of amyloid beta deposition, regardless of whether they exhibit dementia symptoms or not. The presence of amyloid beta alone cannot accurately determine the presence of dementia. Pathology is an approximation and relies on a limited number of brain sections, making it difficult to distinguish between demented and non-demented individuals based on histopathologic features alone. Additionally, research has shown that patients in the early stages of cognitive decline or mild neurocognitive disorder exhibit hypometabolism in the posterior cingulate cortex, a region that provides input to the entorhinal cortex and hippocampal formation. This functional disconnection may contribute to the cognitive decline observed in Alzheimer's disease.

    The Role of Functional Changes in Memory Deficits

    Functional changes in the brain, rather than just structural damage, play a crucial role in memory deficits associated with diseases like Alzheimer's. When a region in the brain is functionally denervated or deactivated, it can lead to atrophy and memory problems. The brain operates as a network of pathways and influences, and studying the end result of pathology may not reveal the true underlying phenomena. It is important to understand that memory formation is a result of a complex system involving multiple brain regions, such as the hippocampus, entorhinal cortex, mammillary bodies, and thalamus. Damage to any part of this circuit system can result in memory diseases. In the early stages of dementia, the inability to form new short-term memories (antegrade amnesia) may be a bigger issue before retrograde amnesia sets in.

    Understanding the Different Stages of Memory and Their Impacts

    Memory functions can be categorized into different stages, with immediate memory being the first and most affected in conditions like Alzheimer's and dementia. Immediate memory is limited and can only hold a small amount of information for a short period of time. However, memories can be transferred to a more recent memory mode through the prefrontal cortex, allowing them to become more permanent. This transition is aided by repetition and exposure to the same information. Retrograde memory problems arise when this circuit is disrupted, causing difficulties in remembering previously learned information. Family members tend to notice these memory deficits later, while patients become concerned earlier on. Differentiating between normal age-related decline and pathological memory impairment can be challenging, but individuals and their immediate partners are often more aware of changes in cognitive performance. Intervening and targeting the prefrontal cortex can be crucial in addressing these memory decline issues.

    The Role of Compromised Circulation in Alzheimer's Disease

    Alzheimer's disease, particularly late-onset dementia, is becoming more common. Despite the increase in human longevity, the rate of growth of Alzheimer's is disproportionate, indicating a real increase in the disease. Francisco Gonzalez suggests that compromised circulation to the brain, specifically chronic hypoperfusion, could be a contributing factor to this increase. It is known that between the ages of 22 to 60, there is a decrease of about 20% in blood supply to the brain. Vascular changes at both macroscopic and microscopic levels, including intimal thickening of the carotid artery, play a role in cognitive decline. Although one would expect a nonlinear relationship between intimal thickening and perfusion, it remains linear. Further research into the vascular hypothesis of Alzheimer's disease is needed to better understand its underlying mechanisms.

    The Impact of High Blood Pressure on Vascular Systems

    High blood pressure can lead to significant damage in both macro and microvascular systems. When blood pressure increases, the body tries to compensate by increasing perfusion. However, this can cause the walls of arteries to thicken and become irregular, resulting in turbulence and the formation of plaques. This turbulence causes white blood cells, like macrophages, to aggregate and stick to the endothelial walls, compromising microcirculation. Moreover, high blood pressure puts additional mechanical pressure on the endothelial walls, leading to extravasation and further damage. Recent clinical trials suggest that maintaining a systolic blood pressure below 120 mmHg and a diastolic pressure below 80 mmHg yields the best outcomes. Therefore, it is important to control high blood pressure to minimize the risk of vascular pathology and related complications.

    The Role of Total Cholesterol in Vascular Hypoperfusion

    There is a misconception in medicine that lowering total cholesterol can significantly impact the progression of vascular hypo perfusion. While total cholesterol is important in heart disease, it does not play as significant a role in the chronic hypoperfusion seen in the brain. This chronic hypoperfusion can occur due to both cardiovascular causes, such as heart failure, and cerebral vascular disease, leading to stroke. Detecting and addressing these vascular problems can improve cardiovascular and brain health. The epidemiology shows that age is strongly associated with both Alzheimer's disease and cardiovascular disease. However, further research is needed to determine the specific role of hypertension and cardiometabolic disease in these conditions. Ultimately, the main purpose of circulation is to bring oxygen to the tissues for optimal tissue oxygenation.

    The Importance of Electron Transport Chain and Oxidative Phosphorylation in Mitochondria

    The electron transport chain and oxidative phosphorylation are crucial processes for generating chemical energy in mitochondria. These processes rely on the reduction of oxygen to water and the donation of electrons from NADH and FADH. The electron transport chain consists of four complexes, with complex 1 being the largest and spanning both the inner and outer membrane. Interrupting the activity of these complexes even for a short period can be detrimental to life. The purpose of the chemistry involved in food digestion is to generate electron donors that can contribute to the electron transport chain. This ultimately leads to the creation of an electron gradient and the production of ATP, which is essential for cellular energy.

    The importance of mitochondria in energy production and oxygen supply

    The mitochondria play a crucial role in converting chemical energy into electrical energy and vice versa. This conversion is essential for all organisms that use oxygen to obtain energy. Even red blood cells, which do not have mitochondria, still rely on cytochrome oxidase to generate ATP. When the circulation is compromised and oxygen supply decreases, electron transfer and energy production become impaired. This leads to feelings of energy deprivation, increased food consumption (especially of simple carbohydrates), and a lack of energy production in the brain. The chronic and insidious changes caused by hypoxia ultimately impact the mitochondria's ability to facilitate electron transfer, highlighting the importance of maintaining proper oxygen supply for optimal mitochondrial function.

    Flexibility and Recovery of the Mitochondrial System

    The mitochondrial system, specifically complex 4, is an inducible system that can be regulated based on demand. This means that it is not irreversible and can be adjusted in response to various factors. Complex 4 has more flexibility compared to the other complexes, making it the preferred modulator of the system. Additionally, this conversation explains that even in cases of ischemia, the mitochondrial system can recover and become functional again through induction. The significance of this finding is particularly evident in the study of Alzheimer's disease, where the inhibition of cytochrome oxidase has been identified as a major problem. Understanding the regulation and inducibility of the mitochondrial system can potentially lead to insights and interventions for various health conditions.

    Cyanide's Varying Effects: From Lethal to Cognitive Impairment

    Cyanide, while potent enough to kill even in trace amounts, can also have varying degrees of reduction in its ability to kill depending on the dose. In fact, at a low enough dose, cyanide can induce a functional hypoperfusion without killing the organism, leading to conditions like Alzheimer's at a chronic illness level. By partially restricting blood vessels to the brain, cytokormoxides can be downregulated, affecting mitochondria respiration and ATP production, resulting in cognitive impairment. Behaviorally, the animals may appear normal, but when tested with memory challenges, they struggle. This model, although overshadowed by the amyloid and tangles hypothesis, offers insights into studying Alzheimer's disease in animals and suggests that amyloid beta may not be a reliable indicator of these processes.

    Mitochondrial dysfunction and energy shortage contribute to neurodegenerative disorders like dementia and Alzheimer's disease.

    Compromised mitochondrial function and energy supply play a significant role in neurodegenerative disorders like dementia and Alzheimer's disease. The brain, being the most energy-demanding organ, is highly vulnerable to a reduction in available energy. The reliance on oxidative phosphorylation without an anaerobic escape route further adds to the brain's susceptibility. The impaired supply of oxygen and toxic insults to the mitochondria can lead to the down regulation of cytochrome oxidase and the inability to use oxygen for energy generation. This ultimately results in cognitive problems and memory deficits. Additionally, the interaction between different brain regions and the distributed nature of memory functions make neurodegenerative disorders initially appear as memory problems. Ultimately, the loss of mitochondrial machinery leads to cell death. The extent of defective mitophagy and autophagy in later stages of Alzheimer's is not fully understood but may contribute to the accumulation of damaged mitochondria and the release of mitochondrial DNA.

    Potential interventions and considerations for slowing down mitochondrial dysfunction and addressing risk factors in dementia.

    There are potential interventions that can curb the progression of damage caused by mitochondrial dysfunction. Increasing mitophagy or autophagy could help slow down the feed forward loop that accelerates this damage. However, it may be too late to intervene once the machinery for obtaining energy is compromised. Risk factors related to cardiovascular compromise, such as atherosclerosis and generalized trauma to the brain, are important considerations for intervention. There may also be overlap between chronic traumatic encephalopathy and dementia, which can be caused by blows to the head and affect the midbrain and upper brain stem. Mitochondrial respiration appears to be a common denominator in different forms of dementia, making it a potential target for intervention. One approach is using compounds like metal and blue that act as electron donors in mitochondrial respiration.

    The Versatile Role of Methylene Blue in Electron Transport and Mitochondrial Function

    Methylene blue, a synthetic dye, has the ability to bypass a bottleneck in the electron transport chain and still allow the transport of electrons. This finding is significant because it suggests that even if a crucial component of the electron transport chain is blocked, methylene blue can serve as an alternate route for electron transport. This discovery has been demonstrated in animal models, specifically in the retina and brain. The history of methylene blue is also fascinating, as it originated as a synthetic dye used in clothing during the industrial revolution. Additionally, at low concentrations, methylene blue has an affinity for redox reactions that occur in mitochondria, making it a potential tool for mitochondrial staining. However, caution must be taken at higher doses, as it can compete with oxygen and become toxic.

    The Bimodal Functional Response of Methylene Blue and its Diverse Applications

    Methylene blue has a bimodal functional response, meaning it has opposite effects at low and high concentrations. At low doses, methylene blue can be used to prevent or rescue from methemoglobinemia, a condition where the oxygen-binding capacity of hemoglobin is reduced. However, at higher concentrations, it can induce methemoglobinemia. Additionally, methylene blue can be used to treat urinary bladder infections by increasing its concentration in the bladder and becoming oxidative, eliminating bacteria and viruses. It also has potential as a treatment for malaria, as it can affect the enzyme of the parasite that causes the disease. Overall, methylene blue has diverse applications and can be used in both therapeutic and preventative measures.

    Methylene blue: From textile dye to medical breakthrough

    Methylene blue, the first synthetic chemical used for medicinal purposes, had a major breakthrough in medical research. It was initially used as a textile dye, but its synthetic derivatives were found to have medicinal properties. One derivative, called chlorpromazine, became the first antipsychotic medication and revolutionized psychiatric treatment. However, methylene blue's potential uses extend beyond mental health. It has been used for over 120 years for various purposes, including treating malaria and protecting the brain during chemotherapy. Despite its proven effectiveness, methylene blue faces challenges in gaining FDA approval due to its lack of patentability, which discourages pharmaceutical companies from investing in its research and development. Nonetheless, its availability in some countries and through the internet allows for potential utilization.

    Misunderstandings and Impurities: The Complexities of Methylene Blue

    Methylene blue, a chemical compound, has potential benefits but has been misunderstood and misrepresented in certain studies. It is more stringent in the US compared to the European Midland Blue variant, and there are concerns about impurities in some versions of the compound. The compound LMTM, which is a derivative of methylene blue, was the subject of a controversial trial for dementia treatment. The trial failed to show a difference in neuroimaging outcomes but did show potential cognitive function benefits in a subset of patients receiving LMTM monotherapy. However, the results may have been influenced by the combination of LMTM with other drugs. The misunderstandings and misrepresentation of methylene blue by certain companies and researchers have undermined its potential benefits and hindered further exploration.

    Flawed Studies and Ineffective Drugs in Alzheimer's Research

    The initial studies on the effectiveness of methylene blue for tau aggregation in Alzheimer's disease were flawed and misleading. The researchers manipulated and misrepresented their data to support their hypothesis, even though it contradicted their actual findings. This is similar to what has been happening with the amyloid hypothesis in Alzheimer's research. Furthermore, the commonly prescribed drugs for Alzheimer's, such as cholinesterase inhibitors and memantine, have been proven to be ineffective and even harmful. Countries like the UK have banned these drugs due to evidence of their ineffectiveness and counterproductive nature. It is essential to critically examine the data and question established hypotheses to ensure progress in Alzheimer's research and provide better treatment options for patients.

    Exploring Treatments and Interventions for Neurodegenerative Diseases

    There is ongoing research into finding effective treatments for neurodegenerative diseases, such as Alzheimer's. The use of memantine has shown promise in preventing some cytotoxicity in hippocampal cells. However, rescuing functionally incompetent cells may not be productive in the long run and could potentially cause more damage. The challenge lies in triangulating between neurobiology, anatomy, functional signaling, and clinical outcomes. Additionally, there is excitement around using infrared light to intervene with mitochondrial respiration, which could potentially improve oxygen consumption and cellular function. The safety of using longer wavelengths, such as 1064 nanometers, needs to be further studied, but they have shown the ability to penetrate tissues to some degree.

    Different Approaches to Treating Brain Conditions

    The use of transcranial stimulation with near-infrared light and the administration of methylene blue are separate approaches in treating brain-related conditions. The near-infrared light stimulates the electron transport in the gray matter layer of the cortex, aiding in the redox changes and increasing the enzyme's affinity to bind oxygen. On the other hand, methylene blue can be injected into specific regions and activated with light to kill cells, making it useful for certain conditions like cancer or viral infections. When it comes to administering methylene blue, oral administration is safer and allows for slower release, making it suitable for various applications, including malaria treatment. Prevention is crucial, as the discussion highlights that focusing on prevention rather than treating clinically evident dementia is essential for the overall well-being of individuals at risk.

    Taking preventative measures for cardiovascular health and understanding the brain's unique needs are key to overall well-being.

    Preventative measures should be taken by everyone, regardless of their risk level for cardiovascular disease. Lowering smoking, blood pressure, and managing lipoproteins are important for heart health. However, the brain has unique needs, especially when it comes to glucose transport. As the brain ages, the transport of glucose is affected, making it harder for the brain to receive the energy it needs. The ketogenic diet can help by facilitating mitochondrial respiration and providing an alternative source of energy in the form of ketone bodies. Supplementing with exogenous ketones may also be beneficial. Understanding the metabolic needs of the brain and finding ways to support it, such as through diet and potentially pharmacological interventions, is crucial for overall health.

    Addressing cognitive decline and metabolic syndrome through a multi-faceted approach

    Addressing cognitive decline and metabolic syndrome in older individuals requires a multi-faceted approach. Francisco Gonzalez explains that one way to target cognitive difficulties is by focusing on the prefrontal cortex, which can be accessed through the forehead. Additionally, dietary changes can help with insulin resistance and glucose regulation, as high glucose levels can lead to insulin release and metabolic syndrome. Peter Attia adds that starvation, at a cellular level, can lead to functional starvation even in the presence of obesity. They discuss the importance of fasting and ketogenesis in utilizing body fat for energy, particularly for the brain. By combining approaches like fasting, transcranial laser stimulation, and dietary changes, individuals may be able to mitigate cognitive decline and improve metabolic health.

    Neglected Potential: Brain Injury Treatments underfunded due to patent issues

    There are promising potential treatments for brain injuries and cognitive impairments that are not receiving enough attention and funding due to issues with patentability and profitability. Francisco Gonzalez and Peter Attia discuss the benefits of using methylene blue as a rest agent during traumatic brain injury, as it has shown the ability to salvage and rescue some of the damage caused by the insult. However, there is a lack of interest from pharmaceutical companies and the National Institute of Aging due to the inability to patent the medication and make profits. Clinical trials are needed to further study the efficacy of methylene blue, but without sufficient investment, it is uncertain if these trials will occur, leaving potential solutions untapped.

    Embracing Differences and Success in Business

    While companies may imitate each other, there is enough room for everyone to succeed. However, it is important to consider the cosmetic aspect and understand that not everyone may accept certain aspects of a product or idea. The discussion between Francisco Gonzalez and Peter Attia has been enlightening and educational, providing valuable insights for the listeners as well. Show notes with references to papers, a link to Jack's book, and other related materials will be provided, giving further resources for those interested. Peter also offers additional information through his website and social media platforms, allowing people to stay updated on his work and interesting topics such as longevity, science, performance, and sleep. It is important to note that the podcast and its content should not be taken as medical advice, and users should always consult healthcare professionals for any medical conditions. Transparency regarding conflicts of interest is also emphasized by Peter.

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    • 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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    #296 ‒ Foot health: preventing and treating common injuries, enhancing strength and mobility, picking footwear, and more | Courtney Conley, D.C.

    #296 ‒ Foot health: preventing and treating common injuries, enhancing strength and mobility, picking footwear, and more | Courtney Conley, D.C.

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    Courtney Conley is an internationally renowned foot and gait specialist. In this episode, Courtney delves into the intricate world of foot anatomy and functionality. She explores the complexities of the foot, discussing its anatomy, common injuries, and the importance of understanding its structure in preventing issues. She covers a range of foot ailments, factors contributing to them, treatment options, and prevention strategies. She delves into the significance of loading, balance, range of motion, and posture, emphasizing the crucial role of strength in preventing both injuries and falls. Additionally, she sheds light on the interconnectedness of the kinetic chain, from the leg muscles down to the foot, and how issues within this chain can cascade downstream, leading to various injuries and pathologies. Additionally, she provides a comprehensive overview of footwear, discussing suitable options for both adults and children to promote foot health and mitigate potential problems.

    In addition to this interview, Courtney also recorded a series of videos to better explain a number of the concepts discussed such as diagnostic tests that are used to determine mobility and strength and the exercises one should perform to improve the outcomes based on the diagnostics. The interview will be available to everyone while the videos from the gym will only be available to paid subscribers (found at the end of the show notes page).

    We discuss:

    • Why Courtney chose to specialize in the foot [3:30];
    • The vital role of foot strength, function, and health in human movement and well-being [6:15];
    • Anatomy of the rear foot and midfoot [10:15];
    • The development of flat feet, the impact of footwear, and the benefits of going barefoot [19:45];
    • Anatomy of the forefoot, common injuries, and why most injuries occur in the forefoot [23:15];
    • Foot musculature and its role in maintaining foot stability and preventing deformities like bunions and hammer toes [30:15];
    • The intrinsic musculature of the foot, plantar fasciitis, footwear, and more [39:00];
    • Plantar fasciitis: diagnosis, causes, and treatment [51:30];
    • Posterior leg muscles: strength assessment methods, role in ACL injuries, and more [59:15];
    • Lateral and medial muscles: ankle stability, arch support, big toe stabilization, and exercises to strengthen and prevent injuries [1:04:15];
    • Importance of strength of lower leg muscles for gait and preventing shin splints, stress injuries, and more [1:08:15];
    • Tendinopathies and other common pathologies related to the anterior and lateral compartments of the foot [1:13:00];
    • The importance of midfoot integrity, ankle dorsiflexion, and a discussion of gait alterations [1:19:45];
    • Proximal stability and its implications for posture and movement patterns [1:27:00];
    • The age-related decline in foot sensation and strength [1:32:45];
    • Common toe injuries, treatment, and how to prevent further progression of the injury [1:36:30];
    • Preventing falls and managing arthritis with proactive foot care and exercises [1:46:45];
    • Footwear: advice for picking shoes that promote foot health [1:54:45];
    • Footwear for runners [2:05:30];
    • The importance of prioritizing footwear that promotes natural foot movement and strength while considering individual comfort and foot health needs [2:09:30]; and
    • More.

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    #295 ‒ Roadway death and injury: why everyone should care and what you can do to reduce risk | Mark Rosekind, Ph.D.

    #295 ‒ Roadway death and injury: why everyone should care and what you can do to reduce risk | Mark Rosekind, Ph.D.

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    Mark Rosekind is an expert on road safety and a policy leader with more than 30 years of experience enacting strategic, practical, and effective data-based solutions that enhance driver and pedestrian safety and health in complex environments. In this episode, Mark delves into the persistent issue of accidental deaths resulting from roadway accidents, a concern for those focused on longevity given its consistent risk throughout life. From exploring statistics on car crashes to identifying the demographics most at risk and the key locations of incidents, he uncovers various risk factors including distractions like smartphone usage, the influence of alcohol and cannabis, the dangers of sleep deprivation, and speeding. Mark also provides practical advice for both drivers and pedestrians to enhance safety, while delving into the potential and challenges of emerging technologies such as autonomous vehicles. Additionally, Mark provides valuable resources for listeners, particularly parents navigating the road safety landscape with teenage drivers.

    We discuss:

    • Mark’s background and education, and the profound impact of transportation accidents on human lives [4:15];
    • From sleep science to safety leadership: Mark’s journey in transportation innovation [14:15];
    • Stats on transportation accidents and fatalities [18:00];
    • Historical trends in road fatalities and the key contributors—impairment, distraction, and more [28:00];
    • The demographics of drivers involved in crashes, and the life-saving potential of better driver education programs [34:30];
    • The most critical areas where drivers need to be hyper-aware to protect themselves [41:00];
    • The role of the National Transportation Safety Board (NTSB) in accident investigations, and the importance of data sources like event data recorders (EDRs) in accident reconstruction and investigations [47:00];
    • The dangers of phone use while driving [53:45];
    • How drunk driving was addressed through advocacy and legal changes [1:01:30];
    • The need to address distracted driving and the psychological impact of distracted driving accidents on both victims and perpetrators[1:07:15];
    • Navigating the roads and lowering your risk of accidents: weather, human error, and defensive driving [1:15:45];
    • The impact of impaired driving: alcohol, cannabis, prescription drugs, and more [1:26:15];
    • Mitigating the effects of vehicle speed [1:38:15];
    • The promise and challenges of autonomous vehicles for road safety [1:44:15];
    • Automatic emergency braking (AEB): the effectiveness and challenges of implementing AEB as a standard feature in new vehicles [1:53:00];
    • Sleep deprivation: the impact of poor sleep, drowsiness, and disrupted circadian rhythm on driving [1:58:15];
    • Protecting pedestrians: strategies for reducing the risk of fatal accidents with pedestrians on foot or bicycle [2:02:30];
    • Empowering safe driving: essential resources and tips for parents and teenage drivers [2:14:00];
    • Promoting a culture of proactive safety: parting thoughts from Mark [2:19:15]; and
    • More.

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    #294 ‒ Peak athletic performance: How to measure it and how to train for it from the coach of the most elite athletes on earth | Olav Aleksander Bu

    #294 ‒ Peak athletic performance: How to measure it and how to train for it from the coach of the most elite athletes on earth | Olav Aleksander Bu

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    Olav Aleksander Bu is an internationally renowned sports scientist acclaimed for his coaching prowess with elite athletes spanning a diverse range of sports disciplines. In this episode, Olav delves deep into the intricacies of VO2 max and its profound impact on performance. They explore the relationship between VO2 max and ATP production, energy efficiency, and power, as well as the impact of low-intensity training on VO2 max. The conversation extends to Olav’s experiences pushing the boundaries with high-performance athletes and the data driven interventions he uses to improve performance. They also dissect the role of lactate threshold, discuss other important metrics to track, and explore the exciting possibility of utilizing a portable VO2 testing device as a practical alternative to traditional lab-based assessments.

    We discuss:

    • Olav’s background, expertise in exercise physiology, coaching experience, and interest in the extremes of human capability [4:15];
    • The processes of energy conversion within the human body and its implications for performance [9:30];
    • Improving movement efficiency, and the importance of mindfulness in training to optimize performance [20:00];
    • The relationship between VO2 max, power output, and endurance performance in different sporting contexts [34:45];
    • How VO2 max is measured in the lab, and why it’s a crucial predictor of both lifespan and quality of life [44:45];
    • Absolute vs relative VO2 max, the significance of functional threshold power in cycling, and the importance of longer duration tests for accurate assessments [54:00];
    • Portable VO2 testing devices as a practical alternative to lab-based tests [1:05:15];
    • The complexities of measuring ventilation and its impact on performance metrics like VO2 max and heart rate [1:15:45];
    • Training interventions to increase VO2 max, and factors that impact performance outcomes [1:23:30];
    • The respiratory exchange ratio (RER) and endurance sports, and how factors such as diet composition and exercise intensity influence RER values and performance [1:32:45];
    • Science-guided training for versatile athletes: maximizing VO2 max, power, torque, and cadence in cycling, and the importance of incorporating diverse stimuli to enhance performance [1:41:00];
    • Physiological limitations on VO2 max [2:02:15];
    • The different energy systems used during work, and other things to monitor like VCO2 and heart rate [2:06:00];
    • Lactate threshold and other metrics to guide your training [2:10:30];
    • Analysis of a lactate power curve: exploring lactate dynamics in endurance training and performance [2:23:15]; and
    • More.

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