The Peter Attia Drive

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Arthur Brooks is a social scientist, professor at Harvard University, columnist for The Atlantic, and bestselling author. In this episode, Arthur returns to the podcast to discuss his new book, Build the Life You Want. He delves into the nuanced concept of happiness, differentiating between momentary feelings and overall wellbeing. He explains the importance of understanding one’s personality pattern with respect to positive and negative emotions in order to better self-manage emotions. He delves into the three key elements of happiness, offering practical strategies for enhancing those specific domains through methods such as metacognition, transcendent experiences, discipline, minimizing self-focus while directing attention outward, and more. Through personal examples, Arthur demonstrates that one can actively track well-being levels and take intentional steps to cultivate happiness and enhance overall well-being.

We discuss:

• Happiness vs. happy feelings, and how happiness and unhappiness can coexist [4:30];
• The six fundamental emotions [8:00];
• The evolution and heritability of happiness, and the four personality patterns with respect to positive and negative emotions [17:30];
• Navigating relationships: the power of complementarity over compatibility [23:30];
• The importance of self-managing your mental habits [25:30];
• Enjoyment: one of the three macronutrients of happiness [32:00];
• Satisfaction: one of the three macronutrients of happiness [43:45];
• The reverse bucket list, metacognition, and other techniques to protect yourself from your limbic system [51:00];
• Meaning: one of the three macronutrients of happiness [57:30];
• The four quarters of your life and how that relates to the meaning of your life [1:05:00];
• Putting metacognition into practice [1:09:00];
• What might explain the societal downdrift in happiness over the last few decades? [1:17:00];
• Taking charge of your happiness: discipline, transcendent experiences, and other deliberate actions for happiness [1:30:30];
• Tracking happiness: biomarkers and micronutrients behind the macronutrients of happiness [1:42:00];
• The value in minimizing the self and looking outward [1:49:45];
• How Arthur surprised himself with his ability to improve his happiness [1:54:00]; and
• More.

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To support Tom’s mission and work, please visit: https://africanmissionhealthcare.org/donation/catena/.

In this episode, Tom Catena, a missionary physician who runs Mother of Mercy Hospital in the Nuba Mountains in Sudan, describes some of his extraordinary work as the only doctor in a remote, war-torn region of Africa. In terms of individual lives saved, you could argue that there is no other person on the front lines doing more than Tom. Additionally, we explore the manner in which the Nuba people die, which is in striking contrast to the ubiquity of chronic disease and self-harm in the West, despite the extreme poverty and unimaginable suffering experienced by the Nuba people. Lastly, we discuss the lessons to be gleaned from the Nuba people, who, despite their suffering, live so harmoniously, happily, and resiliently.

We discuss:

• Background, medical training, and early days of missionary work in Africa [5:15];
• Tom arrives at Mother of Mercy Hospital in the Nuba Mountains of Sudan, civil war breaks out, and his staff evacuates [12:30];
• Learning surgery on the job and earning the trust of the community [37:00];
• The amazing people of Nuba, and why Nuba feels like home to Tom [47:45];
• NY Times article about Tom’s work, and Tom’s new venture on the board of the Aurora Prize Foundation, raising awareness and funds for other missionaries [59:45];
• Tom’s mind-blowing ability to deal with chaos while seeing hundreds of patients per day [1:12:00];
• The most afraid Tom has ever been, and how he copes with the emotional trauma of his daily experiences [1:19:45];
• The basic tools, technologies, and medicines that Tom is lacking that could save many lives [1:30:00];
• The logistical challenge of helping Tom’s hospital, and what Tom really needs [1:35:15];
• Diseases in the adult population [1:38:30];
• Living without possessions, finding meaning, and being a missionary [1:55:45];
• Happiness, sense of purpose, and suicide: contrasting the US with Nuba [2:07:15];
• Other than donations, is there a way people can help Tom and other similar causes? [2:15:15];
• The food in Nuba [2:18:30];
• Tom’s annual bout of malaria [2:23:45];
• Patients Tom will never forget [2:26:00];
• Resources for people wanting to get involved in helping Tom’s work [2:31:00];
• Peter tells a story that defines Tom [2:32:00]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter explores various pharmacologic tools commonly utilized to improve metabolic health and treat diabetes, including SGLT-2 inhibitors, metformin, and GLP-1 agonists. He examines the available data on these drugs, assessing their comparative effectiveness and their potential in the context of lifestyle interventions. Additionally, he offers insights into whether SGLT2 inhibitors hold promise as geroprotective agents beyond their effects on glycemic control. Next, Peter analyzes the relationship between statin usage and the risk of developing insulin resistance and type 2 diabetes, investigating possible causal pathways and providing insights into strategies for risk reduction. He offers insights on monitoring adverse statin effects and evaluating the need for adjustments, ultimately weighing the trade-off between the risk to overall metabolic health against the benefits of reducing apoB levels through statin use.

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

We discuss:

• Pharmacologic tools for improving metabolic health, and the relationship between statins and insulin resistance [2:00];
• SGLT-2 inhibitors: how they work and help to manage type 2 diabetes [4:15];
• The history of SGLT2 inhibitors – from discovery to the current state [10:15];
• Comparing the various FDA-approved SGLT2 inhibitors [15:00];
• Other beneficial effects of SGLT2 inhibitors outside of glycemic control [20:15];
• Exploring SGLT2 inhibitors as potential geroprotective molecules [22:45];
• The side effects and risks associated with SGLT2 inhibitors [31:45];
• Medications, lifestyle interventions, and other considerations for treating diabetes and improving metabolic health [37:45];
• Metformin as a tool for pre-diabetics, and how metformin compares to lifestyle interventions [44:00];
• How GLP-1 agonists compare to metformin and SGLT2 inhibitors in terms of glycemic control and weight loss [49:15];
• Exploring the relationship between statin use and the risk of developing insulin resistance and type 2 diabetes [52:30];
• Possible mechanisms of statin-induced insulin resistance and diabetes, and potential mitigation strategies [1:04:30];
• How to monitor for adverse effects of statin use and assess the need for adjustments [1:11:45];
• Weighing the benefits and risks of statin use: does the diabetes risk outweigh the benefits of lowering apoB with a statin? [1:15:30];
• Parting thoughts [1:20:45]; and
• More.

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Harold (Hal) Burstein is an internationally renowned breast cancer expert. In this episode, Hal discusses a broad range of topics related to breast cancer, starting with the intricacies of breast anatomy and the endocrinological factors at play. He covers the spectrum of breast cancer, from precancerous lesions to invasive breast cancer, classifying these conditions into a helpful framework. He delves into various screening methods, including self-exams, mammograms, ultrasounds, and MRIs, and addresses the ongoing debate surrounding early screening and detection. Hal provides insights into the latest advancements in cancer treatment, offering valuable guidance for individuals to understand their unique circumstances within the three primary categories of breast cancer. Finally, Hal delves into the role of genetics in breast cancer and brings attention to the less commonly addressed issue of male breast cancer.

We discuss:

• The prevalence and mortality rate of breast cancer in women [4:15];
• The anatomy of the breast and the complex factors behind breast cancer development [6:30];
• The three main categories of breast cancer [16:45];
• Breast cancer risk: the impact of menopause, estrogen, breast density, obesity, and more [21:15];
• Finding and evaluating lumps in the breast [25:30];
• Identifying and treating precancerous lesions like ductal carcinoma in situ (DCIS) [31:00];
• Post-lumpectomy for DCIS: standard of care, future risk of cancer, and pros and cons of radiation and other preventative options [41:15];
• Lobular carcinoma in situ (LCIS): how it differs from DCIS in terms of treatment and future risk of invasive cancer [55:00];
• Breast cancer screening: mammography, ultrasound, MRI, and more [1:03:45];
• Invasive breast cancer: pathology report, surgery, and survival [1:11:00];
• The argument for aggressive screening for breast cancer [1:22:15];
• Advances in the treatment of breast cancer, adjuvant therapy, and neoadjuvant therapy [1:27:00];
• The use of hormone replacement therapy in women who are in remission from breast cancer [1:41:15];
• The role of genetics in breast cancer [1:44:45];
• The importance of multidisciplinary care delivered by cancer centers [1:53:15];
• Breast cancer in men [2:03:30];
• Parting thoughts and takeaways [2:05:45]; and
• More.

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Kari Nadeau is a physician scientist with expertise in treating food allergies. In this episode, Kari first explains the fascinating workings of the immune system, exploring how it adeptly defends against bacteria and viruses but how the same system can lead to food allergies. She proceeds to explore the complexities of food allergies, detailing their typical developmental patterns, underscoring the significance of preventative approaches like early exposure, and highlighting the potentially life-threatening nature of severe food allergies. Kari illuminates the latest advancements in immunotherapies that not only mitigate allergy severity but also hold the potential to completely cure the patient. Additionally, Kari shares her concerns about the increasing levels of air pollution, elucidating its adverse effects on health while providing valuable suggestions for reducing exposure.

We discuss:

• Kari’s motivation to study food allergies [4:00];
• Overview of the immune system and the family of immunoglobulins [9:00];
• How our immune system fights viruses, bacteria, or fungi, and some exceptions to the rule [13:00];
• Why our immune system is generally better at fighting viruses than bacterial infections [18:45];
• Differentiating a food sensitivity from a food allergy, and a discussion about celiac disease [25:30];
• How food allergies develop, why they can be lethal, and factors contributing to the uptrend in food allergies [35:45];
• The role of environmental factors in the onset of food allergies and strategies for prevention [50:15];
• How immunotherapy helps to overcome, and even cure, food allergies [1:04:15];
• Can immunotherapy work for environmental allergens like pollen? [1:24:00];
• Air pollution: impact on health and tips for reducing your risk [1:25:30];
• Resources for those wanting to learn more or find clinical trials related to food allergies [1:40:45]; and
• More.

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In this special episode of The Drive, Peter discusses a variety of topics, breaking away from the typical deep-dive format to explore a wide range of common questions submitted by listeners. Peter tackles subjects like the viability of living to 120 and beyond, addressing some of the optimistic theories regarding achievement of this remarkable feat. Peter then shares his drug and supplement regimen while emphasizing how individualized these protocols need to be. The conversation also touches on lowering apoB, the long-term use of statins, the myth of good vs. bad cholesterol, the complexities of nutrition research, the quest for the ideal diet, and Peter's strategies for hitting daily protein goals. Peter finishes with a discussion about his favorite health-tracking wearables, the role of CGM in non-diabetics, and more.

We discuss:

• Overview of topics and previous episodes of a similar format [2:45];
• The viability of living to 120 and beyond: some optimistic theories [4:45];
• The potential of mTOR inhibition as a mid-life intervention, and longevity potential for the next generation [13:30];
• A framework for thinking about geroprotective drugs and supplements in the context of a lack of aging biomarkers [17:00];
• Supplements Peter takes and how his regimen has changed in the last year [26:15];
• Pharmacologic strategies to lower ASCVD risk, the limitations of statins, nutritional interventions, and more [36:15];
• Misnomers about cholesterol [48:00];
• Why nutritional research is so challenging, some general principles of nutrition, and why Peter stopped doing prolonged fasts [50:45];
• Optimizing protein intake [59:45];
• Wearables for sleep and exercise, continuous glucose monitors (CGM), and a continuous blood pressure monitor on the horizon [1:04:45]; and
• More.

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In this "Ask Me Anything" (AMA) episode, the discussion zeroed in on the practical application of hormone replacement therapy in women. Peter walks through the signs, symptoms, and hormonal changes in women approaching – and going through – menopause. He provides an overview of the FDA-approved HRT formulations and explains how women might go about choosing the right option for themselves. Peter also describes the significant changes in testosterone levels in women over time and the options, as well as the considerations and challenges of testosterone replacement therapy (TRT) for women. Lastly, Peter highlights the necessary role of compounding pharmacies in HRT, underscores concerns regarding the quality and sterility of compounded drugs, and offers guidance on locating a trustworthy pharmacy.

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

We discuss:

• Why hormone replacement therapy is such an important topic [2:00];
• The onset of menopause: symptoms, blood tests, and when to consider HRT [6:00];
• Tests that may provide indications of perimenopause and their implications for fertility [9:15];
• Vasomotor symptoms: hormonal changes that cause hot flashes/night sweats, and HRT therapies that can help [13:45];
• The role of estrogen in menopausal HRT [17:30];
• The limited role of progesterone in HRT protocols [25:15];
• What is a “bioidentical” hormone? [28:30];
• Overview of the FDA-approved HRT formulations [31:45];
• Determining HRT dosing and considerations for perimenopausal women [37:45];
• Choosing the right HRT formulation: pros and cons [43:30];
• Examining the link between certain forms of estrogen and breast cancer [46:45];
• Changes in testosterone levels in women over time and why it matters [50:00];
• Recognizing low testosterone in women: common symptoms and diagnosis [53:45];
• Testosterone replacement therapy for women: options, considerations, and challenges [57:30];
• The long-term use of testosterone in women: examining the limited data [1:00:15];
• What is a compounding pharmacy? [1:09:30];
• Reasons to opt for a compounding pharmacy over a pharmacy that adheres to stricter regulations [1:16:00];
• The tragic incidents that heightened concerns about compounding pharmacies [1:20:45];
• Tips for finding a reputable compounding pharmacy [1:27:45]; and
• More.

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We discuss:

• Derek’s interest in weightlifting and experimentation with anabolic steroids at a young age [3:15];
• Derek’s experience acquiring steroids from underground labs and the potential long-term fertility concerns early in his bodybuilding career [12:00];
• The backstory on More Plates, More Dates and Derek’s unique ability to blend scientific knowledge with personal observation [17:00];
• Growth hormone – from extreme use-cases to the more typical – and the misconception that it’s the “elixir of life” [21:30];
• Growth hormone 101: definition, where it comes from, and the challenges of measuring it [28:45];
• Does exogenous growth hormone compromise one’s ability to make endogenous growth hormone? [40:00];
• The use of growth hormone in restoration of tissue during periods of healing [42:00];
• Growth hormone-releasing peptides to increase endogenous GH: various peptides, risks, benefits, and comparison to exogenous growth hormone [48:45];
• The role of growth hormone in building muscle and burning fat, as well as its effects on sleep and daytime lethargy [1:02:30];
• The evolution of drug use in the sport of bodybuilding [1:10:30];
• What explains the protruding abdomens on some bodybuilders and athletes? [1:20:30];
• Death of bodybuilders [1:26:00];
• The complex interplay of hormones, and the conversion of testosterone into metabolites like DHT and estrogen [1:33:45];
• Post-finasteride syndrome and how Derek successfully treated his hair loss [1:43:15];
• Testosterone replacement therapy: compelling use-cases, side effects, and optimal dosing schedules [1:57:15];
• Aromatase inhibitors to suppress estrogen, and the misconceptions around estrogen in men [2:16:00];
• Other hormones beyond testosterone for male sex hormone replacement [2:21:00];
• The history of anabolic compounds, and the differing effects of various anabolic testosterone derivatives and related drugs [2:24:30];
• Use of SARMs by bodybuilders [2:29:45];
• Anabolic steroid and testosterone regimens of professional bodybuilders and the downstream consequences [2:36:15];
• The challenge of accurate hormone testing in the presence of anabolic steroids and supplements [2:44:45];
• The use of Clomid, hCG, and enclomiphene [2:47:15];
• Concerns about fertility: comparing the use of testosterone and hCG [3:00:30];
• The use of BPC-157 peptide for healing injuries [3:12:00]; and
• More.

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Ted Schaeffer is an internationally recognized urologist who specializes in prostate cancer. In this episode, Ted delves deep into the realm of prostate health, starting with strategies for vigilance and effective management of the issues that can arise with aging, including urinary symptoms, prostatitis, pelvic pain, and prostate inflammation. Ted sheds light on the popular drug finasteride, renowned for its dual purpose in prostate shrinkage and hair loss prevention, as well as the contentious topic of post-finasteride syndrome. Ted then shifts to the topic of cancer, explaining how androgens, genetics, and non-genetic factors contribute to the pathogenesis of prostate cancer. He provides valuable insights into cancer screening, examining blood-based screening tools like PSA and the use of MRI in facilitating biopsies and their interpretation. Finally, he explores the various treatment options for prostate cancer, including surgical interventions, androgen deprivation therapy, and more.

We discuss:

• Changes to the prostate with age and problems that can develop [3:45];
• Behavioral modifications to help manage nocturnal urinary frequency and other lower urinary tract symptoms [8:30];
• Pharmacologic tools for treating nocturnal urinary frequency and lower urinary tract symptoms [16:30];
• Surgical tools for treating symptoms of the lower urinary tract [26:15];
• HoLEP surgery for reducing prostate size [32:30];
• Prostate size: correlation with cancer and considerations for small prostates with persistent symptoms [40:30];
• Prostatitis due to infection: symptoms, pathogenesis, and treatment [46:45];
• Prostatitis caused by factors besides infection [58:45];
• How to minimize risk of urosepsis in patients with Alzheimer’s disease [1:05:00];
• Prostate cancer: 5-alpha reductase inhibitors, how androgens factor into pathogenesis, and more [1:10:00];
• Post-finasteride syndrome [1:18:15];
• The relationship between testosterone and DHT and the development of prostate cancer over a man's lifetime [1:26:30];
• How genetic analysis of a tumor can indicate the aggressiveness of cancer [1:35:15];
• Pathogenesis and genetic risk factors of prostate cancer and the use of PSA to screen for cancer [1:37:45];
• Non-genetic risk factors for prostate cancer [1:45:45];
• Deep dive into PSA as a screening tool: what is PSA, definition of terms, and how to interpret results [1:56:30];
• MRI as a secondary screening tool and the prostate biopsy options [2:13:15];
• Ted’s ongoing randomized trial comparing different methods of prostate biopsy [2:24:00];
• Determining when a biopsy is necessary, interpreting results, explaining Gleason score, and more [2:27:00];
• Implications of a Gleason score of 7 or higher [2:46:45];
• Metastasis of prostate cancer to different body locations, treatment options, staging, and considerations for patients' quality of life and survival [2:53:30];
• How prostate cancer surgery has improved [3:09:30];;
• Questions to ask your neurologist if you are considering prostatectomy for cancer [3:21:45]; and
• More.

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In this episode of The Drive, Peter welcomes guests David Sabatini and Matt Kaeberlein, two world-leading experts on rapamycin and mTOR. David and Matt begin by telling the fascinating story of the discovery of rapamycin and its brief history as a pharmacological agent in humans. They then unravel the function of mTOR, a central regulator of numerous biological processes, and they discuss the pathways through which rapamycin exerts its potential benefits on lifespan. They touch upon initial studies that suggested rapamycin may have geroprotective effects and the ongoing research that continues to shed light on this unique molecule. Furthermore, they discuss the elusive details surrounding the frequency and dosing of rapamycin use in humans, and Peter emphasizes his reservations about indiscriminately prescribing rapamycin as a longevity drug for patients.

We discuss:

• David and Matt’s expertise in mTOR and rapamycin [3:00];
• The discovery of rapamycin and its first use in humans as an immunosuppressant [13:15];
• The emergence of rapamycin as a molecule with the potential to prolong lifespan [19:30];
• The groundbreaking rapamycin study on mouse lifespan extension and the open questions about the timing and frequency of dosing [26:00];
• Explaining mTOR and the biology behind rapamycin’s effects [35:30];
• Differences in how rapamycin inhibits mTOR complex 1 (MTORC1) versus mTOR complex 2 (MTORC2) [45:15];
• Reconciling the biochemical mechanism of rapamycin with its longevity benefit [49:15];
• Important discoveries about the interplay of amino acids (leucine in particular) and mTOR [54:15];
• Reconciling rapamycin-mediated mTOR inhibition with mTOR's significance in building and maintaining muscle [1:01:30];
• Unanswered questions around the tissue specificity of rapamycin [1:08:30];
• What we know about rapamycin’s ability to cross the blood-brain barrier and its potential impacts on brain health and neurodegeneration [1:13:45];
• Rapamycin may act as an immune modulator in addition to immunosuppressive effects [1:21:30];
• Might rapamycin induce changes in T cell methylation patterns, potentially reversing biological aging? [1:34:15];
• Rapamycin side effects and impacts on mental health: fascinating results of Matt’s survey on off-label rapamycin use [1:42:00];
• The impact of taking rapamycin in people who contracted COVID-19: more insights from Matt’s survey [1:51:15];
• What David would like to study with mTOR inhibitors [1:54:45];
• Joan Mannick’s studies of RTB101 and other ATP-competitive inhibitors of mTOR [2:00:30];
• The impact of mTOR inhibition on autophagy and inflammation and a discussion of biomarkers [2:10:00];
• The Dog Aging Project: what we’ve learned and what’s to come from testing rapamycin in companion dogs [2:17:30];
• Preliminary results of primate studies with rapamycin [2:24:45];
• Dosing of rapamycin [2:27:45];
• The effect of rapamycin on fertility [2:36:45];
• The outlook for future research of rapamycin and the development of rapalogs [2:39:00]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter dives deep into the critical topic of metabolic disease. He first sheds light on how poor metabolic health drives up the risk of developing other chronic diseases such as cardiovascular disease, cancer, neurodegenerative disease, and overall mortality. He explores the array of metrics and tests used to assess metabolic health, underscoring his preferred methodologies utilized with patients. Finally, Peter provides an overview of the factors one can manipulate in order to improve metabolic 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 #51 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• Importance of metabolic health and a primer on metabolic disease [1:30];
• How poor metabolic health increases one’s risk for other chronic diseases [6:00];
• How useful is body weight and BMI for estimating metabolic health? [9:45];
• Overview of various tests and metrics used to understand metabolic health [12:15];
• Traditional biomarkers and how Peter’s point of view may differ from the guidelines [15:00];
• Lactate: insights into metabolic health through fasting and resting lactate levels [17:00];
• Zone 2 output: an important functional test of metabolic health [20:00];
• Cardiopulmonary exercise testing (CPET) [25:45];
• Visceral adipose tissue (VAT): what is VAT and how does it impact health? [27:00];
• Oral glucose tolerance test (OGTT): how it works and why it is such an important metric for assessing metabolic health [32:15];
• The utility of a continuous glucose monitor (CGM) [40:45];
• Liver function and NAFLD [42:15];
• Sleep as an intervention [46:00];
• Exercise as an intervention [53:15];
• Diet and nutrition [59:00];
• How reducing stress can improve metabolic health [1:05:15]; and
• More.

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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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