The Peter Attia Drive

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Andrew Huberman, Professor of Neurobiology at Stanford University and host of the Huberman Lab podcast joins us in a special journal club episode. Peter and Andrew each present a recent paper that sparked their interests, delving into the findings, dissecting their significance, discussing potential confounders and limitations, and exploring remaining questions. Importantly, they share their methodologies for comprehending research studies, providing valuable insights for listeners to navigate this process independently. Peter presents an epidemiological study reevaluating a noteworthy metformin result that intrigued the anti-aging community, leading to discussions on metformin's geroprotective potential (or lack thereof) and the current lack of aging biomarkers. Andrew introduces a paper examining how our beliefs about the medications we take influence their biological effects, distinguishing the "belief effect" from a placebo effect and highlighting its exciting implications for the future.

We discuss:

• The motivation behind this journal club conversation [2:45];
• Why Peter chose a paper on metformin, how metformin works, and why it generated excitement as a longevity-enhancing agent [9:00];
• Defining insulin resistance and its underlying causes [16:15];
• Metformin as a first-line treatment for type 2 diabetes, and Peter's evolving interest in metformin as a geroprotective drug [22:00];
• Defining the term "geroprotection" [24:45];
• The 2014 study that got the anti-aging community interested in metformin [26:00];
• Peter presents the 2022 paper that repeats the analytical approach from the 2014 Bannister study [33:15];
• Greater mortality in the metformin group: how results differed between the 2022 paper and the 2014 paper [40:00];
• Understanding statistical significance, statistical power, sample size, and why epidemiology uses enormous cohorts [51:45];
• Interpreting the hazard ratios from the 2022 metformin study, and the notable takeaways from the study [56:45];
• Drugs that may extend lifespan, why Peter stopped taking metformin, and a discussion of caloric restriction [1:08:45];
• Current thoughts on the use of metformin for longevity [1:21:00];
• Could there be any longevity benefit to short periods of caloric restriction? [1:22:45];
• Peter and Andrew's process for reading scientific papers [1:26:45];
• The biological effects of belief, and how "belief effects" differ from placebo effects [1:32:30];
• The neurobiology of nicotine: a precursor conversation before delving into the paper Andrew chose [1:39:45];
• Andrew presents a paper that demonstrates the impact of belief [1:45:30];
• Analyzing the fascinating results of the Perl paper [1:54:30];
• Exciting implications of the findings about "belief" reported by Perl and colleagues [2:03:15]; and
• More.

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This special episode is a rebroadcast of AMA #30, now made available to everyone, in which Peter and Bob Kaplan dive deep into all things related to studying studies to help one sift through the noise to find the signal. They define various types of studies, how a study progresses from idea to execution, and how to identify study strengths and limitations. They explain how clinical trials work, as well as biases and common pitfalls to watch out for. They dig into key factors that contribute to the rigor (or lack thereof) of an experiment, and they discuss how to measure effect size, differentiate relative risk from absolute risk, and what it really means when a study is statistically significant. Finally, Peter lays out his personal process when reading through scientific papers.

We discuss:

• The ever-changing landscape of scientific literature [2:30];
• The process for a study to progress from idea to design to execution [5:00];
• Various types of studies and how they differ [8:00];
• The different phases of clinical trials [19:45];
• Observational studies and the potential for bias [27:00];
• Experimental studies: randomization, blinding, and other factors that make or break a study [44:30];
• Power, p-values, and statistical significance [56:45];
• Measuring effect size: relative risk vs. absolute risk, hazard ratios, and "number needed to treat" [1:08:15];
• How to interpret confidence intervals [1:18:00];
• Why a study might be stopped before its completion [1:24:00];
• Why only a fraction of studies are ever published and how to combat publication bias [1:32:00];
• Frequency of training for Olympic weightlifting [1:22:15];
• How post-activation potentiation (and the opposite) can improve power training and speed training [1:24:30];
• The Strongman competition: more breadth of movement, strength, and stamina [1:32:00];
• Why certain journals are more respected than others [1:41:00];
• Peter's process when reading a scientific paper [1:44:15]; and
• More.

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Wendy Chung is a board-certified clinical and molecular geneticist with more than 25 years of experience in human genetic disease research. In this episode, Wendy delves deep into the world of genetics by first exploring the historical landscape of genetics prior to decoding the human genome, contrasting it with what we know today thanks to whole genome and exome sequencing. She provides an overview of genetic testing by differentiating between various genetic tests such as direct-to-consumer, clinical, whole genome sequencing, and more. Additionally, Wendy unravels the genetic underpinnings of conditions such as PKU, breast cancer, obesity, autism, and cardiovascular disease. Finally, Wendy goes in depth on the current state and exciting potential of gene therapy while also contemplating the economic implications and ethical nature of gene editing.

We discuss:

• Wendy's interest in genetics and work as a physician-scientist [2:45];
• The genetics of phenylketonuria (PKU), a rare inherited disorder [5:15];
• The evolution of genetic research: from DNA structure to whole genome sequencing [18:30];
• Insights and surprises that came out of the Human Genome Project [28:30];
• Overview of various types of genetic tests: direct-to-consumer, clinical, whole genome sequencing, and more [34:00];
• Whole genome sequencing [39:30];
• Germline mutations and the implications for older parents [45:15];
• Whole exome sequencing and the importance of read depth [50:30];
• Genetic testing for breast cancer [54:00];
• What information does direct-to-consumer testing provide (from companies like 23andMe and Ancestry.com)? [1:01:30];
• The GUARDIAN study and newborn genetic screening [1:06:30];
• Treating genetic disease with gene therapy [1:18:00];
• How gene therapy works, and the tragic story of Jesse Gelsinger [1:22:00];
• Use cases for gene therapy, gene addition vs. gene editing, CRISPR, and more [1:28:00];
• Two distinct gene editing strategies for addressing Tay-Sachs and fragile X syndrome [1:37:00];
• Exploring obesity as a polygenic disease: heritability, epigenetics, and more [1:41:15];
• The genetics of autism [1:48:45];
• The genetics of cardiovascular disease [2:01:45];
• The financial costs and economic considerations of gene therapy [2:06:15];
• The ethics of gene editing [2:12:00];
• The future of clinical genetics [2:21:00]; and
• More.

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Keith Flaherty is the director of clinical research at the Massachusetts General Hospital Cancer Center and a previous guest on The Drive. In this episode, Keith first delves into the statistics on cancer's prevalence as we age, underscoring the significance of finding effective treatments and early detection methodologies. He touches on the history of cancer therapeutics and illuminates the notable enhancements in cancer therapy within the last decade that are setting the stage for a promising future. He goes into detail on the potential of immunotherapy and therapies that can combat cancer's evasive tactics while explaining some of the existing challenges around specificity, cost, and scalability. Additionally, Keith highlights the significant leap in early detection methodologies, namely liquid biopsies, which have the potential not only to determine if a cancer is present in an early stage, but also identify the possible tissue of origin.

We discuss:

• Keith's interest and expertise in cancer [3:15];
• Cancer deaths by decade of life, and how cancer compares to other top causes of death [7:00];
• The relationship between hormones and cancer [12:00];
• The link between obesity and cancer [18:45];
• Current state of treatments for metastatic cancer and reasons for the lack of progress over the decades [22:30];
• The interplay between the immune system and cancer cells [32:00];
• Different ways cancer can suppress the immune response, and how immunotherapy can combat cancer's evasive tactics [39:30];
• Elimination of a substantial portion of cancers through immune cell engineering faces challenges of specificity, cost, and scalability [52:15];
• Why TIL therapy isn't always effective, and the necessity for multimodal therapy to address various aspects of the cancer microenvironment [1:01:00];
• Potential developments in cancer therapy over the next five years: T-cell activation, metabolic interventions, targeting tumor microenvironments, and more [1:06:30];
• The challenge of treating metastatic cancer underscores the importance of early detection to improve survivability [1:19:15];
• Liquid biopsies for early detection of cancer and determining the possible tissue of origin [1:24:45];
• Commercially available cancer screening tests [1:33:45];
• How to address the disparity in cancer care, and the exciting pace of progress for cancer detection and treatment [1:40:15]; and
• More.

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In this "Ask Me Anything" (AMA) episode, Peter delves into the realm of genetics, unraveling its connection to disease and emphasizing the value of understanding one's genetic risks. He elucidates essential background knowledge on genetics before delving into the myriad reasons why individuals might consider genetic testing. Peter differentiates scenarios where genetic testing provides genuine insights from those where it may not be as useful. From there, Peter explores a comprehensive comparison of commercial direct-to-consumer genetic tests, providing insights on interpreting results and identifying the standout options for gaining insights into personal health.

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

We discuss:

• Defining the term "genetics" and why it's important [2:15];
• What is DNA, and how does it impact our biology and traits? [5:45];
• How are genetics passed down from parent to child? [8:45];
• How much do genes vary across individuals? [13:00];
• Which traits are determined by genetics versus experience or environmental factors? [17:00];
• Reasons for genetic testing [22:30];
• What exactly is being measured by a genetic test? [29:15];
• Testing for monogenic disorders [35:15];
• Understanding polygenic risk [39:30];
• Is genetic testing more important for someone who doesn't know their family history? [40:45];
• What does it mean to be positive for a particular variant? [43:00];
• What does it mean to be negative for a particular variant? [45:45];
• How does someone get genetic testing through their healthcare provider, and how are these tests performed? [48:15];
• The financial cost of various genetic tests [54:30];
• Could having a risk allele for a disease result in an increase in one's insurance premium? [57:15];
• Other risks associated with genetic testing [59:00];
• How do commercial, direct-to-consumer genetic tests compare to the information one might receive from clinical genetic testing? [1:01:45];
• Are certain direct-to-consumer tests better than others? [1:03:45];
• How long until whole genome sequencing becomes genuinely useful? [1:16:00];
• How useful are personalized dietary recommendations based on genetics? [1:18:15];
• Final thoughts and advice regarding genetic testing [1:20:00]; and
• More.

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Oliver Burkeman is the author of The New York Times best-seller Four Thousand Weeks: Time Management for Mortals. In this episode, Oliver delves into the pervasive idea that time can be mastered, exploring whether maximizing productivity is an attainable goal or a perpetual trap. He discusses the allure of attempting to control time—and, therefore, the future—and shares his personal journey of experimenting with diverse time management techniques that failed to deliver the emotional satisfaction he sought. Ultimately, they explore the mismatch between being a finite human and existing in a world of infinite possibilities and how all of these concepts intertwine with finding a sense of purpose and meaning. Additionally, Oliver shares insights from his book on productivity, using our time wisely, and embracing our finitude to live a more fulfilling life.

We discuss:

• Oliver's experience that led him to write the book Four Thousand Weeks [3:15];
• Human's relationship with time and the struggle with the finite nature of time [7:15];
• How productivity can be a trap [11:00];
• The fallacy that being more efficient will open up more time and bring a feeling of control [16:45];
• The paradoxical nature of trying too hard to be present in the current moment [22:45];
• The value of relationships in meaningful experiences and fulfillment, and how time gets its value from being shared [26:45];
• The importance of time synchronicity [36:00];
• Identifying your biggest priorities and the paradox of wanting to do more than you have time for [41:00];
• Oliver's moment of clarity in 2014 [47:15];
• The role of a sense of purpose in fulfillment [50:15];
• Reconciling the finite nature of time and letting go of trying to master your time [59:00];
• Why we tend to have a future-focused attitude and how to combat that with atelic activities [1:05:45];
• The power of shifting your perspective about time and your experiences [1:12:45];
• How to operationalize the three principles for the dilemma of finite time [1:20:15];
• Harnessing the power of patience in the face of a problem or experience [1:28:00];
• The value of incrementalism for being productive [1:34:15];
• Embracing your finitude with curiosity [1:38:00];
• Acting on an idea in the moment rather than letting the idea be the obstacle [1:41:15]; and
• More.

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Adam Cohen is an orthopedic surgeon with expertise in sports medicine. In this episode, Adam breaks down the anatomy of the lower extremities: the hip, knee, ankle, and foot. He explains in detail the common injuries, sources of pain, and what leads to the development of arthritis. He lays out the non-surgical and surgical treatment options as well as the factors that determine whether surgery is appropriate. The discussion includes various procedures like hip replacement, knee replacement, ACL reconstruction, repair of meniscus tears, and more. Additionally, Adam sheds light on the utility of biological therapies like stem cells and platelet-rich plasma (PRP) and how they compare to more traditional approaches.

We discuss:

• Anatomy of the hip, hip dysplasia in infants, and the development of arthritis [3:00];
• Diagnosing hip pain in people under 50, stress fractures in the femoral neck, and more [11:15];
• Common hip injuries, gender differences, and problems that occur when the hip isn't formed normally [19:30];
• Advancements in hip replacement surgery [25:15];
• Common hip problems in people over age 60 [27:30];
• The importance of muscular strength around the hips for injury prevention [30:30];
• Hip fractures due to osteopenia and osteoporosis [36:00];
• The utility of biological therapies like stem cells and platelet-rich plasma (PRP) [40:30];
• Cortisone as a treatment to delay the need for surgical intervention [53:30];
• Anatomy of the knee [56:30];
• Are activities like running that amplify forces bad for the knee? [59:45];
• Risk of future knee issues and arthritis following an ACL tear or other substantial knee injury [1:04:30];
• How the ACL injury happens and how it is repaired [1:08:30];
• Arthritis of the knee [1:19:00];
• Meniscus tears: how they happen and when surgery is appropriate [1:21:30];
• Total knee replacement: when it's appropriate and how the recovery process compares to hip replacement [1:30:30];
• Learning from elite athletes, heart rate recovery, V02 max, and other metrics [1:58:45];
• Surgical vs. non-surgical approaches to various knee injuries [1:40:45];
• Achilles tendon: tendinitis, rupture of the Achilles tendon, and prevention strategies [1:44:15];
• Anatomy of the ankle and foot [1:49:00];
• Common injuries to the ankle and foot [1:51:15];
• Tips for finding a good orthopedic surgeon [2:01:45]; and
• More.

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Michael "Micky" Collins is an internationally renowned expert in sports-related concussions and a consultant for multiple professional sports organizations. In this episode, Mickey first explains the definition and diagnosis of a concussion, as well as the diverse signs and symptoms associated with different types of concussions. He discusses the risk factors that contribute to increased susceptibility and/or severity of concussions in certain individuals, emphasizes the significance of prompt treatment, and uses case studies to illustrate the latest in treatment protocols and recovery process. Additionally, Mickey provides insight into the evolving field of concussion treatments, including the exploration of hyperbaric oxygen and synthetic ketones. He gives advice to parents of kids who play sports and discusses the promising prospects in the realm of concussion management.

We discuss:

• Micky's interest in concussion and how he started the first concussion clinic [3:15];
• Concussion: definition, pathophysiology, and risk factors making someone more susceptible [9:45];
• Symptoms of concussion, predictors of severity, and the importance of early and effective treatment [20:00];
• The six types of concussion, the effectiveness of treatment, and factors that impact recovery [25:45];
• The importance of seeing a specialist and the prognosis for recovery [30:00];
• Case study of a racecar driver who suffered a vestibular concussion [32:15];
• Why vestibular concussions are particularly problematic [42:45];
• A treatment plan for the racecar driver, possible use of medications, and how to address the root cause [45:45];
• Exploring alternative treatments: hyperbaric oxygen, synthetic ketones, and more [52:00];
• The natural history of a concussion if untreated and the effect, if any, of concussion on subsequent risk of brain disease [57:15];
• Chronic traumatic encephalopathy (CTE) [1:01:45];
• Advice for parents of kids who play sports: when and where to seek treatment for a possible concussion [1:04:45];
• Is there any evidence that the APOE4 genotype increases susceptibility to concussion or TBI? [1:10:15];
• The increased risk of concussions in older adults and a case study of a 90-year-old patient who suffered a head injury in a fall [1:11:15];
• Funding for concussion research and fellowship programs to train concussion specialists [1:15:30]; and
• More.

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In this "Ask Me Anything" (AMA) episode, Peter goes into depth on the topic of brain health, starting with how Alzheimer's disease is diagnosed, the significance of blood-based biomarkers in diagnosis, and what the various APOE gene variants mean in terms of a person's risk of developing Alzheimer's disease. Next, Peter discusses the various strategies for preventing Alzheimer's disease and neurodegeneration. He touches briefly on exercise as a potent tool, but focuses more on lesser-known factors that could impact brain health, such as nutrition supplementation, lipid management, brain games, sauna, oral health, hearing loss, and 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 #49 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• Topics: exercise, kidneys, and brain health [1:30];
• Rucking: advice for beginners, proper load, packs, and shoes [4:30];
• Rucking for women, bone health, using a treadmill, zone 2, and more [11:45];
• Building vs. maintaining: when and how to transition from the goal of building muscle and strength to focusing on maintenance [16:00];
• Should you lift weights before or after a cardio session? [24:00];
• Heart rate recovery: defining heart rate recovery and how it relates to cardiovascular fitness [28:45];
• How to measure heart rate recovery, and what is considered a "good" heart rate recovery [33:15];
• How kidney health and function typically measured [42:30];
• Differentiating between creatine and creatinine [48:15];
• The cystatin C blood test as a practical way to assess kidney health [52:45];
• How kidney function impacts lifespan and the five stages of kidney disease [59:15];
• Slowing the decline of kidney function [1:08:15];
• The main drivers of kidney disease [1:11:15];
• The importance of managing homocysteine levels for brain health [1:14:00];
• The relationship between alcohol consumption and brain health [1:21:30]; and
• More.

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In this special episode filmed live in front of readers of Outlive, Peter answers questions revolving around his concept of the centenarian decathlon. He starts by defining the "marginal decade" and how that shapes his training for the events and activities that make up his personal centenarian decathlon. Peter explains how he coaches patients through the challenges of customizing their own list and building out a training plan, including how to set fitness goals early in life in preparation for the marginal decade. From there, he dives into training within the four pillars (zone 2, VO2 max, stability, and strength), including the minimum effective dose, how to split your time, his personal protocols, and other considerations. Additionally, he touches on bone mineral density, female-specific considerations, working through injuries, and the profound impact training can have on the overall quality of life.

We discuss:

• The best interventions for longevity [2:15];
• The marginal decade and the centenarian decathlon [4:45];
• Peter's personal list of events for his "centenarian decathlon" and how he helps patients create their own list [8:00];
• Determining your fitness goals early in life in preparation for the marginal decade, metrics to track, and more [15:00];
• How does playing sports like tennis, basketball, or golf fit into training for the centenarian decathlon? [24:15];
• Training within the four pillars: minimum effect dose, how to split your time, and other considerations [27:45];
• Advice for the older person and why it's never too late to start [33:45];
• Bone mineral density and other female-specific concerns and considerations [36:15];
• Training advice for those with minimal access to a gym or equipment [39:30];
• Injuries: prevention and working through existing conditions [41:00];
• Cardiorespiratory training: how to split time between zone 2 and VO2 max training, and different modalities for a true zone 2 workout [44:15];
• VO2 max training: modalities, Peter's protocol, and how to monitor progress [54:45];
• The profound impact training can have on the overall quality of life [58:15]; and
• More.

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