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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?

    enJanuary 28, 2019

    Podcast Summary

    • Funding Podcasts Through Listener SupportPeter 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.

      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 like PET and functional MRI can detect early signs of disease and provide insights into brain activity, helping physicians educate patients about their health.

      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 OrganThe 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 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 development of specific brain networks differs among species, enabling different levels of information processing and behavior.

      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 DiseaseUnderstanding how the cerebral cortex controls movement and reassessing our understanding of Alzheimer's disease are crucial for progress in research and treatment.

      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 DiseaseAlzheimer'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.

      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 DiseaseAmyloid 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 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 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.

      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 DeficitsUnderstanding 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.

      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 ImpactsMemory 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.

      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 DiseaseDecreased 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.

      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 SystemsControlling 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.

      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 HypoperfusionLowering total cholesterol may not significantly impact chronic hypoperfusion in the brain, but detecting and addressing vascular problems can improve cardiovascular and brain health.

      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 MitochondriaInterrupting the activity of the electron transport chain can have serious consequences as it is essential for generating ATP, which is crucial for cellular energy.

      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 supplyMaintaining a proper oxygen supply is vital for optimal mitochondrial function, which is essential for energy production in all organisms.

      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 SystemThe mitochondrial system, specifically complex 4, can adjust and recover based on demand, offering potential insights for health conditions such as Alzheimer's disease.

      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 ImpairmentCyanide, at lower doses, can cause functional hypoperfusion leading to Alzheimer's-like conditions and cognitive impairment, challenging the traditional understanding of Alzheimer's disease.

      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.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.

      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.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.

      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 FunctionMethylene 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, 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 ApplicationsMethylene 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 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 breakthroughMethylene 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, 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 BlueMethylene blue has potential benefits for dementia treatment, but its reputation has been tarnished by misunderstandings, impurities, and misrepresentations by certain companies and researchers.

      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 ResearchCritical evaluation of data and established hypotheses is crucial for progress in Alzheimer's research and finding effective treatment options for patients.

      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 DiseasesMemantine 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.

      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 ConditionsPrevention 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 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.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.

      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 approachBy targeting the prefrontal cortex, making dietary changes, and utilizing fasting and ketogenesis, individuals can effectively address cognitive decline and improve metabolic health.

      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 issuesLack of interest and funding for promising brain injury treatments like methylene blue raises doubts about future clinical trials and the realization of potential solutions.

      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 BusinessSuccess 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.

      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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    • How to incorporate high intensity training (Zone 5) to increase VO2 max and optimize fitness [1:50:30];
    • Compounding benefits of Zone 2 exercise and how we can improve metabolic health into old age [2:01:00];
    • The effects of metformin, NAD, and supplements on mitochondrial function [2:04:30];
    • The role of lactate and exercise in cancer [2:12:45];
    • How assessing metabolic parameters in long COVID patients provides insights into this disease [2:18:30];
    • The advantages of using cellular surrogates of metabolism instead of VO2 max for prescribing exercise [2:25:00];
    • Metabolomics reveals how cellular metabolism is altered in sedentary individuals [2:33:00];
    • Cellular changes in the metabolism of people with diabetes and metabolic syndrome [2:38:30]; and
    • More.

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    The Peter Attia Drive
    enJuly 08, 2024

    #308 - AMA #61: Sun exposure, sunscreen, and skin health: relationship between sun exposure and skin cancer, vitamin D production, and photoaging, how to choose a sunscreen, and more

    #308 - AMA #61: Sun exposure, sunscreen, and skin health: relationship between sun exposure and skin cancer, vitamin D production, and photoaging, how to choose a sunscreen, and more

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    In this “Ask Me Anything” (AMA) episode, Peter delves into two topics that have generated a lot of questions over the years: skin cancer and sunscreen. He begins by exploring the basics of UV radiation, discussing its effects on vitamin D conversion, photoaging, and its role in skin cancer. He examines various skin types, discussing their implications for sun exposure and vitamin D levels, as well as how to determine where you fall on the skin type scale. He then delves into the various types of skin cancer, with a particular emphasis on melanoma, exploring its complex relationship with UV exposure and other contributing risk factors. Additionally, he covers tanning beds, the importance of early skin cancer detection through regular skin checks, and the often confusing topic of sunscreen. He explains how sunscreen affects UV radiation and skin cancer risk, what SPF levels to choose, the differences between organic and mineral sunscreens, and what to consider when selecting the best sunscreen for your needs.

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

    We discuss:

    • The impact of UV radiation on the skin [2:00];
    • Understanding solar UV: from the electromagnetic spectrum to skin health [3:45];
    • The role of sunlight in vitamin D production [8:30];
    • Factors contributing to vitamin D deficiency: insufficient UV exposure, magnesium levels, and more [9:45];
    • Sun exposure needs for different skin types, and the limitations of current studies in defining vitamin D deficiency [12:45];
    • The acute and long-term effects of excessive UV exposure: sunburn, photoaging, and the increased risk of skin cancer [15:30];
    • Types of skin cancer and associations with UV exposure [17:45];
    • The complex relationship between melanoma and UV exposure [22:15];
    • Why UV exposure alone doesn’t necessarily explain the risk for melanoma [25:15];
    • Other risk factors for melanoma [29:15];
    • Tanning beds and skin cancer risk [34:45];
    • Balancing sun exposure: benefits and risks [38:15];
    • Tattoos and sun exposure [40:30];
    • The importance of regular skin checks, dermatologists, and emerging technologies showing promise for early detection of cancer [41:45];
    • Self-skin checks: what to look for [46:30];
    • Prevalence of skin cancer and the importance of early detection [49:30];
    • Summary of the major risk factors for melanoma [54:15];
    • The role of sunscreen in reducing skin cancer risk [55:45];
    • How sunscreen works, the differences between chemical and mineral sunscreens, an explanation of SPF, and more [58:30];
    • How to determine the appropriate sunscreen SPF to use based on the UV index [1:04:45];
    • Choosing the right sunscreen for your individual needs [1:07:00];
    • The impact of water and perspiration on sunscreen effectiveness [1:12:00];
    • Chemical vs. mineral sunscreens: safety concerns and recommendations [1:14:00];
    • Concerns about hormone effects from chemical sunscreens [1:19:15];
    • Sunscreen summary: skin types, key considerations, recommended brands, and more [1:23:15]; and
    • More.

    Connect With Peter on TwitterInstagramFacebook and YouTube

    The Peter Attia Drive
    enJuly 01, 2024

    #307 ‒ Exercise for aging people: where to begin, and how to minimize risk while maximizing potential | Peter Attia, M.D.

    #307 ‒ Exercise for aging people: where to begin, and how to minimize risk while maximizing potential | Peter Attia, M.D.

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    In this special episode, Peter addresses the common questions about starting or returning to an exercise routine over the age of 50. Individuals in this age group have frequently reached out with questions about whether it's too late to start exercising and often express concern over a lack of prior training, a fear of injury, or uncertainty about where to begin. Peter delves into the importance of fitness for older adults, examining all four pillars of exercise, and provides practical advice on how to start exercising safely, minimize injury risk, and maximize potential benefits. Although this conversation focuses on people in the “older” age category, it also applies to anyone of any age who is deconditioned and looking to ease into regular exercise.

    We discuss:

    • Key points about starting exercise as an older adult [2:45];
    • Why it’s never too late to begin exercising and incorporating the four pillars of exercise [5:45];
    • The gradual, then sharp, decline in muscle mass and activity level that occur with age [10:00];
    • The decline of VO2 max that occurs with age [15:30];
    • Starting a training program: exercise variability, movement quality, realistic goals, and more [18:30];
    • Improving aerobic capacity: the malleability of the system, the importance of consistency, and setting long-term fitness goals [25:15];
    • Starting cardio training: base building, starting with low volume, and zone 2 training [30:45];
    • The critical role of VO2 max in longevity [36:45];
    • How to introduce VO2 max training to older or deconditioned individuals [46:15];
    • Options for performing zone 2 and VO2 max training [53:45];
    • The ability to make gains in strength and muscle mass as we age [57:00];
    • How to implement strength training for older individuals [1:01:00];
    • Advice for avoiding injury when strength training [1:07:30];
    • Risk of falls: the devastating consequences and the factors that increase fall risk [1:12:15];
    • Mitigating fall risk: the importance of foot and lower leg strength, ankle mobility, and balance [1:19:45];
    • Improving bone mineral density through resistance training [1:24:30];
    • The importance of protein in stimulating muscle protein synthesis, especially in older adults [1:31:00];
    • Parting advice from Peter [1:34:00]; and
    • More.

    Connect With Peter on TwitterInstagramFacebook and YouTube

    The Peter Attia Drive
    enJune 24, 2024

    #306 - AMA #60: preventing cognitive decline, nutrition myths, lowering blood glucose, apoB, and blood pressure, and more

    #306 - AMA #60: preventing cognitive decline, nutrition myths, lowering blood glucose, apoB, and blood pressure, and more

    View the Show Notes Page for This Episode

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    In this “Ask Me Anything” (AMA) episode, Peter provides insights on a broad range of important topics. He delves into the prevention of cognitive decline, the link between cardiovascular disease and Alzheimer's disease, and methods to lower blood glucose, insulin, and apoB. He also addresses nutrition-related queries, exploring the impact of dietary habits on weight loss and longevity, how a person can identify the best diet for themselves, and common nutrition myths. Additional discussions include optimal blood pressure, daily step goals, the benefits of standing versus sitting desks, and much more.

    If you’re not a subscriber and are listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or our website at the AMA #60 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

    We discuss:

    • Overview of topics and episode format [1:40];
    • Preventing cognitive decline [5:00];
    • How to lower blood glucose and insulin [13:30];
    • The relationship between lipids, CVD, and Alzheimer’s disease, and whether statins can increase the risk of neurodegenerative disorders and AD [23:15];
    • Reducing apoB levels through exercise and diet [31:45];
    • Pharmacological options for lowering apoB [38:00];
    • How nutrition impacts longevity via metabolic health, muscle mass, BMD and more [40:15];
    • How can someone determine the best diet for themselves? [43:45];
    • Nutrition myth: All weight loss is good [46:45];
    • Nutrition myth: Metabolic rates are dramatically different among individuals based on genetics [49:00];
    • Nutrition myth: Losing weight after a brief period of overeating is impossible [53:45];
    • Nutrition myth: GLP-1 agonists are a replacement for a healthy lifestyle [57:45];
    • Nutrition myth: There is a single best diet for weight loss [1:03:00];
    • Nutrition oversimplification: All calories are created equal [1:05:45];
    • Daily step goals [1:06:45];
    • The benefits of standing versus sitting throughout the day [1:10:45];
    • How to identify the most impactful and easiest-to-implement ways to improve your health [1:12:30];
    • The critical importance of emotional health [1:14:30];
    • Why supplements should be considered as supportive aids rather than primary solutions in one’s strategy to improve longevity [1:18:00];
    • Strategies for reducing high blood pressure [1:20:45];
    • Peter’s biggest frustrations with "mainstream health advice" [1:28:00];
    • Peter’s chaotic, yet cherished, morning routine [1:31:00]; and
    • More.

    Connect With Peter on TwitterInstagramFacebook and YouTube

    The Peter Attia Drive
    enJune 17, 2024

    #305 ‒ Heart rate variability: how to measure, interpret, and utilize HRV for training and health optimization | Joel Jamieson

    #305 ‒ Heart rate variability: how to measure, interpret, and utilize HRV for training and health optimization | Joel Jamieson

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    Joel Jamieson is a conditioning expert who developed Morpheus to give people a smarter way to build their conditioning regimen and improve their recovery. In this episode, Joel dives deep into the world of heart rate variability (HRV), explaining its scientific foundation, how it measures the balance between the sympathetic and parasympathetic nervous systems, the various methods of measurement, and how it can guide healthier lifestyle choices and improved training performance. He explores the nuances of HRV calculation, the impact of aging on HRV, and the roles of genetics, exercise, and other lifestyle factors in this process. He also covers Morpheus, the innovative training tool that won Peter over after his initial skepticism, highlighting its practicality and effectiveness in guiding training and optimizing fitness outcomes.

    We discuss:

    • Heart rate variability (HRV): evolution, science, and practical applications of HRV in athletic training [4:00];
    • Methods of measuring HRV: EKG, wrist-based sensors, and more [11:30];
    • How HRV is calculated from the data [22:30];
    • The role of the autonomic nervous system (ANS) in regulating HRV [25:45];
    • The decline in HRV with age, and the mitigating effects of fitness and other lifestyle factors [33:30];
    • The role of genetics in HRV, the modifiability of HRV, and a comparison of VO2 max and HRV as predictors of mortality [37:00];
    • How aging affects HRV and sympathetic drive, and the importance of spontaneous movement and exercise in maintaining the body's adaptability [43:30];
    • How Morpheus measures HRV using RMSSD and normalizes it to a 100-point scale for easier interpretation [49:45];
    • The Morpheus system: development, integration with various metrics, and personalized daily training recommendations to optimize fitness and recovery [51:30];
    • The benefits of morning HRV readings for assessing daily readiness compared to overnight HRV measurements [1:03:00];
    • Why Morpheus recommends using a chest strap rather than an arm band [1:10:00];
    • The impact of consistent exercise, stress, alcohol, and other lifestyle factors on HRV [1:11:15];
    • Optimizing zone 2 training with Morpheus [1:18:15];
    • Using heart rate recovery (HRR) as an indicator of athletic conditioning and the balance between aerobic and anaerobic systems [1:22:45];
    • The importance of tracking HRV trends over time rather than focusing on data from a given day [1:29:00];
    • Effect of GLP-1 agonists on heart rate and HRV [1:34:45];
    • Where HRV belongs in the hierarchy of health metrics [1:42:00];
    • Parting thoughts [1:46:30]; and
    • More.

    Connect With Peter on TwitterInstagramFacebook and YouTube

    The Peter Attia Drive
    enJune 10, 2024

    #304 – NEW: Introducing quarterly podcast summaries - Peter shares his biggest takeaways on muscle protein synthesis, VO2 max, toe strength, gut health, and more

    #304 – NEW: Introducing quarterly podcast summaries - Peter shares his biggest takeaways on muscle protein synthesis, VO2 max, toe strength, gut health, and more

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    In this quarterly podcast summary (QPS) episode, Peter introduces a new format aimed at summarizing his biggest takeaways from the last three months of guest interviews on the podcast. Peter shares key insights from each episode, covering diverse topics such as protein and muscle building with Luc van Loon, toe strength with Courtney Conley, VO2 max with Olav Aleksander Bu, liquid biopsies for cancer with Alex Aravanis, gut health and probiotics with Colleen Cutcliffe, and road safety with Mark Rosekind. Additionally, Peter shares any personal behavioral adjustments or modifications to his patient care practices that have arisen from these engaging discussions.

    If you’re not a subscriber and are listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or our website at the episode #304 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

    We discuss:

    • How Peter keeps track of his takeaways from each podcast episode [5:15];
    • Luc van Loon episode: fat utilization, muscle protein synthesis, dietary protein, aging and inactivity, and more [8:45];
    • Behavioral changes that have come about from the conversation with Luc van Loon [23:45];
    • Courtney Conley episode: importance of toe strength and the impact of dedicated foot training [26:45];
    • Olav Aleksander Bu episode: the importance of VO2 max for lifespan, and the practicalities of measuring and improving VO2 max [36:45];
    • Behavioral changes that have come about from the conversation with Olav [56:00];
    • Alex Aravanis episode: liquid biopsies for cancer detection [1:01:30];
    • Colleen Cutcliffe episode: the importance of gut bacteria balance, and the potential therapeutic uses of probiotics, particularly Akkermansia [1:16:45];
    • Mark Rosekind: the significant issue of road fatalities and injuries, their causes, and practical safety measures to reduce risks [1:27:00]; and
    • More.

    Connect With Peter on TwitterInstagramFacebook and YouTube

    The Peter Attia Drive
    enJune 03, 2024

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

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

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    Dena Dubal is a physician-scientist and professor of neurology at UCSF whose work focuses on mechanisms of longevity and brain resilience. In this episode, Dena delves into the intricacies of the longevity factor klotho: its formation and distribution in the body, the factors such as stress and exercise that impact its levels, and its profound impact on cognitive function and overall brain health. Dena shares insights from exciting research in animal models showing the potential of klotho in treating neurodegenerative diseases as well as its broader implications for organ health and disease prevention. She concludes with an optimistic outlook for future research in humans and the potential of klotho for the prevention and treatment of Alzheimer’s disease.

    Disclosure: Peter is an investor in Jocasta Neuroscience, a company working to develop klotho as a therapy for people with Alzheimer’s disease.

    We discuss:

    • Dena’s fascination with aging and how she came to study klotho [3:30];
    • Biological properties of klotho: production, regulation, decline with age, and factors influencing its levels [11:45];
    • Potential benefits of klotho on brain health [22:00];
    • The relationship between soluble klotho protein, platelet factors, and cognitive enhancement [33:45];
    • The role of platelet factor 4 (PF4) and it’s interaction with GluN2B in mediating cognitive enhancement [46:45];
    • Benefits of klotho observed in a mouse model of Parkinson’s disease [55:45];
    • Benefits of klotho observed in a mouse model of Alzheimer’s disease [1:03:00];
    • Promising results of klotho in primate models, and the importance of finding an appropriate therapeutic dose before moving to human trials [1:08:00];
    • Speculating why a single klotho injection has such long-lasting effects [1:25:30];
    • Potential cognitive benefits of klotho in humans, the impact of the KL-VS genetic variant on klotho levels, and the need for human trials to confirm these effects [1:27:45];
    • The interaction between the KL-VS genetic variant and APOE4 and how it impacts risk of Alzheimer’s disease [1:34:45];
    • The significance of klotho levels: studies linking lower levels to increased mortality and the broader implications for organ health and disease prevention [1:47:15];
    • Measuring klotho levels and determining an individual’s KL-VS status [1:52:15];
    • The promising potential of klotho for Alzheimer’s disease treatment, and the importance of philanthropy for funding research [1:58:00]; and
    • More.

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    The Peter Attia Drive
    enMay 27, 2024

    #302 - Confronting a metabolic epidemic: understanding liver health and how to prevent, diagnose, and manage liver disease | Julia Wattacheril, M.D., M.P.H.

    #302 - Confronting a metabolic epidemic: understanding liver health and how to prevent, diagnose, and manage liver disease | Julia Wattacheril, M.D., M.P.H.

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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.

    Connect With Peter on TwitterInstagramFacebook and YouTube

    The Peter Attia Drive
    enMay 20, 2024

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