View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter 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. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter 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. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter 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. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter 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. Connect With Peter on Twitter, Instagram, Facebook and YouTube

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter 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. Connect With Peter on Twitter, Instagram, Facebook and YouTube