Podcasts about mtorc2

Drs. David Pearce and John Demko discuss the results of their study, "Coordinated Regulation of Renal Glucose Reabsorption and Gluconeogenesis by mTORC2 and Potassium," with JASN Deputy Editor David H. Ellison.

There are a lot of terms bantered about in the biohacker and longevity space. With that, you've likely heard of mTOR – mechanistic (mammalian) target of rapamycin. But what exactly is it? mTOR is a key regulator in your body's metabolic and growth processes. It integrates various signals, including nutrients and growth factors, to control processes like protein synthesis, autophagy, and lipid metabolism. Because it regulates growth, dysregulation of mTOR has been implicated in various diseases, including cancer. In today's episode, we simplify the science behind mTOR – mechanistic target of rapamycin. This crucial enzyme may be the key to unlocking groundbreaking advancements in wellness, anti-aging, disease prevention, and health optimization. Today on The Lab Report: 3:00 mTOR – Why are we even covering this topic? 4:40 What is it? Muscle growth vs. autophagy 6:25 Why is it called mTOR? 9:00 Highly conserved and in every cell, every organ 10:30 mTORC1 and mTORC2 11:25 Influences and sensors – it's more than leucine 14:25 Dysregulation of mTOR – does protein cause cancer? 17:30 Should people take rapamycin for longevity? 20:20 Question of the Day Where does mTOR work in muscle protein synthesis? Additional Resources: Genova Connect **PROMO CODE TheLabReport20 for 20% off your purchase** Subscribe, Rate, & Review The Lab Report Thanks for tuning in to this week's episode of The Lab Report, presented by Genova Diagnostics, with your hosts Michael Chapman and Patti Devers. If you enjoyed this episode, please hit the subscribe button and give us a rating or leave a review. Don't forget to visit our website, like us on Facebook, follow us on Twitter, Instagram, and LinkedIn. Email Patti and Michael with your most interesting and pressing questions on functional medicine: podcast@gdx.net. And, be sure to share your favorite Lab Report episodes with your friends and colleagues on social media to help others learn more about Genova and all things related to functional medicine and specialty lab testing. To find a qualified healthcare provider to connect you with Genova testing, or to access select products directly yourself, visit Genova Connect. Disclaimer: The content and information shared in The Lab Report is for educational purposes only and should not be taken as medical advice. The views and opinions expressed in The Lab Report represent the opinions and views of Michael Chapman and Patti Devers and their guests.See omnystudio.com/listener for privacy information.

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

I'm a senior this year, double majoring in Molecular and Cellular Biology and Neuroscience and Cognitive Science. I've been working in the Charest Lab for almost 2 years, studying the role of the Ras-mTOR pathway, specifically the protein mTORC2. Our research focuses on chemotaxis, and how these gradients are involved in the metastasis of breast cancer cells. Aside from school and lab, I'm very involved in the Tucson community. I started my own political organization with some of my friends called Stand Up, Fight Back Tucson, organizing protests and rallies to fight for civil rights. Our org. works with other local mutual aide and civil rights organizations as well! I also love music, and I'm a jazz singer, singing around Tucson with different jazz bands.

The mammalian target of rapamycin (mTOR) operates within two distinct protein complexes—mTOR complex 1 (mTORC1) and complex 2 (mTORC2). These protein complexes are not yet fully understood, as they were only recently identified in humans in 1994. What researchers do know is that mTORC1 is involved in the regulation of many cellular processes and is a key mediator of cell growth and proliferation. mTORC1 is activated by growth factor receptor signals through the PI3K–AKT and RAS–ERK mitogen-activated protein kinase (MAPK) pathways. The PI3K/AKT/mTOR pathway may be an efficacious target in the treatment of patients with non-small cell lung cancer (NSCLC). This theory is based on the identification of particular gene mutations in NSCLC that are associated with the PI3K/AKT/mTOR pathway. However, previous studies have not yet succeeded in defining an effective monotherapy or combination of therapies that targets this pathway while improving NSCLC patient outcome. Researchers from Institut Curie, PSL University, Xentech, BioPôle Alfort, Hôpital Foch, and Centre Léon Bérard designed a study using a new methodology to test treatment combinations based on specific targets identified as biomarkers of resistance to PI3K-targeting treatments, and not based on the NSCLC mutations themselves. Their trending research paper was published by Oncotarget in 2021 and entitled, “High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC.” Full blog - https://www.oncotarget.org/2021/09/30/trending-with-impact-unconventional-method-effectively-targets-nsclc/ Press release - https://www.oncotarget.com/news/pr/mtorc1-and-plk1-inhibition-in-adenocarcinoma-nsclc/ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.27930 DOI - https://doi.org/10.18632/oncotarget.27930 Full text - https://www.oncotarget.com/article/27930/text/ Correspondence to - Didier Decaudin - Didier.decaudin@curie.fr Keywords - NSCLC, Pi3K signalling pathway, mTORC1, RAD001 (everolimus), PLK1 About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget YouTube - https://www.youtube.com/c/OncotargetYouTube/ LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

In this video Dr. Sabatini discusses rapamycin, how it acts on mTORC1 and mTORC2 and the rapalogs, drugs which are similar to rapamycin but may be more clinically effective. Dr. David Sabatini is an American scientist and Professor of Biology at the Massachusetts Institute of Technology as well as a member of the Whitehead Institute for Biomedical Research. He is known for his important contributions in the areas of cell signaling and cancer metabolism, most notably the discovery of mTOR, more than 20 years ago. Since then Dr. Sabatini has continued to work on better understanding this complex regulator of our metabolism Some key references. Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction https://www.biorxiv.org/content/10.1101/2020.10.22.351361v1.full.pdf Twenty-five years of mTOR: Uncovering the link from nutrients to growth https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5692607/ mTOR introduction YouTube Series with Dr. Sabatini https://www.youtube.com/watch?v=EnIerDljc7g https://www.youtube.com/watch?v=defOfBEuw_M https://www.youtube.com/watch?v=tGA9RALG66s

In this video Dr. Sabatini discusses the role of mTOR as the master regulator of the cell and distinguishes between mTORC1 and mTORC2. Dr. David Sabatini is an American scientist and Professor of Biology at the Massachusetts Institute of Technology as well as a member of the Whitehead Institute for Biomedical Research. He is known for his important contributions in the areas of cell signaling and cancer metabolism, most notably the discovery of mTOR, more than 20 years ago. Since then Dr. Sabatini has continued to work on better understanding this complex regulator of our metabolism

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.18.160416v1?rss=1 Authors: Ramirez-Jarquin, U. N., Shahani, N., Pryor, W., Usiello, A., Subramaniam, S. Abstract: The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side-effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side-effects of haloperidol in psychiatric illness. Copy rights belong to original authors. Visit the link for more info

Today Hannah Courtauld (Psychologist) and spoke to Guillermo Velasco Diez, (PhD). Guillermo is a biochemist heavily involved in the research of the therapeutic potential of cannabinoids in the treatment of Cancer. In this episode, Hannah and Guillermo Discuss: -Guillermo’s academic background and route into the world of cannabinoid research -The mechanisms of action of cannabinoids in terms of attenuating the physiological impact of carcinoma -Crowdsourced funding strategies including the medical cannabis bike tour -The current state of play with regards to clinical studies in this field -Glioblastoma and how cannabinoids are being used to treat this condition -His work with the Spanish Observatory of Medical Cannabis -Charitable and educational organisations like the canna foundation Guillermo Velasco Díez, PhD - BIO Guillermo Velasco was born in Madrid, studied Biology and obtained his PhD degree (1997) at the School of Biology of the Complutense University, Madrid, Spain. After defending his PhD, he got an EMBO long-term fellowship to work in Philip Cohen’s laboratory at the MRC Protein Phosphorylation Unit (Dundee, Scotland) on a project aimed at studying the regulation and of the Rho-activated protein kinase (ROCK). In 1999 he was awarded a position as an Assistant Teacher at the School of Chemistry of the Complutense University and in 2003 was awarded an associate professorship. In 2001 Guillermo started a line of research aimed at investigating the mechanisms underlying cannabinoid anti-tumour action as well as at optimising the potential clinical utilisation of these agents in cancer therapies. Many different avenues are currently been explored by in his group - they are currently investigating the role of endoplasmic reticulum stress, autophagy, apoptosis, intracellular trafficking of ceramide and regulation of mTORC1 and mTORC2 in cannabinoid anti-tumour action, as well as the participation of growth factor receptor-activated pathways in the resistance to the anti-neoplasic actions of cannabinoids. Guillermo Velasco was born in Madrid, studied Biology and obtained his PhD degree (1997) at the School of Biology of the Complutense University, Madrid, Spain. After defending his PhD, he got an EMBO long-term fellowship to work in Philip Cohen’s laboratory at the MRC Protein Phosphorylation Unit (Dundee, Scotland) on a project aimed at studying the regulation and of the Rho-activated protein kinase (ROCK). In 1999 he was awarded a position as an Assistant Teacher at the School of Chemistry of the Complutense University and in 2003 was awarded an associate professorship. In 2001 Guillermo started a line of research aimed at investigating the mechanisms underlying cannabinoid anti-tumour action as well as at optimising the potential clinical utilisation of these agents in cancer therapies. Many different avenues are currently been explored by in his group - they are currently investigating the role of endoplasmic reticulum stress, autophagy, apoptosis, intracellular trafficking of ceramide and regulation of mTORC1 and mTORC2 in cannabinoid anti-tumour action, as well as the participation of growth factor receptor-activated pathways in the resistance to the anti-neoplastic actions of cannabinoids.

Peter Attia, who was our very first guest on STEM-Talk, describes David Sabatini’s discovery of mTOR as one of his two favorite science stories. Today, Dr. David Sabatini joins us and gives us a first-hand account of how his research into rapamycin in 1994 as a graduate student led him to the discovery of mTOR, which we now know is a critical regulator of cellular growth. Our interview with David delves into his continuing research into mTOR, which has led to promising opportunities for the development of new treatments for debilitating diseases such as cancer, diabetes and neurological disorders. He also discusses mTOR’s role in healthspan and lifespan. David is a molecular cell biologist who, according to Reuters News Service, is on the short list for a Nobel Prize. David is on the faculty at MIT and heads up the Sabatini Lab at the Whitehead Institute. In today’s episode, we discuss: • Rapamycin, a macrolide antibiotic discovered in the soil of Easter Island • David’s discovery of mTOR while a grad student at Johns Hopkins • mTOR’s role as one of the major growth pathways in the body • mTOR’s role as a nutrient sensor • How mTOR inhibiton has become one of the hottest topics in longevity research • mTOR’s role in diseases, especially its connection to cancer • The role of RAG GTPases as key mTOR mediators • Protein intake and downstream mTOR activation • Research into ketogenic diets effect on longevity and healthspan • Whether David would take rapamycin as a means to enhance his longevity • And much, much more Show notes: [00:03:32] David talks about growing up in New York and having parents who immigrated to the United States from Argentina. [00:04:00] Dawn asks what David was like as a kid. [00:04:59] Dawn asks David about his decision to attend Brown University. [00:05:56] David talks about his decision to become a scientist and the time he spent in the lab of Al Dahlberg [00:06:53] Ken mentions that after his time at Brown, David headed off for Johns Hopkins to work in Sol Snyder’s lab, a professor known particularly for the work he and his colleagues did on the opioid receptor. Ken asks what drew David to Sol’s lab. [00:08:25] David talks about how as graduate student at Johns Hopkins in the M.D./Ph.D. program, he began trying to understand the molecular mechanism of rapamycin, a macrolide antibiotic discovered in the soil of Easter Island. Rapamycin was known as a potent antifungal, immunosuppressive with anti-tumorigenic properties. That research led David to the major discovery in 1994 of the protein to which rapamycin binds, now referred to as the mechanistic target of rapamycin, or mTOR. [00:11:46] Dawn asks David to give a high-level definition and overview of what mTOR does. [00:13:44] Dawn asks why the “m” in mTOR went from standing for “mammalian” to “mechanistic.” [00:14:11] Ken mentions that we now know mTOR is one of the major growth pathways in the body that is responsible for growth in both a positive sense and a pathologic sense. He goes on to mention that mTOR acts as a major switch between catabolism and anabolism, and asks David to explain why both of these processes are essential for survival. [00:16:10] Dawn asks how the two different mTOR protein complexes, mTORC1 and mTORC2, differ with regards to their activation and downstream function. [00:17:40] Dawn asks David about his decision to join the faculty atMIT and embark on a research-focused career there, starting his own lab at the Whitehead Institute rather than following the clinical path arising from his M.D. [00:20:50] Ken asks about how nutrients and other inputs are sensed and integrated by the mTOR complexes, given how one of the most fascinating aspects about mTORC1 is its role as a nutrient sensor. [00:23:46] Ken asks why both nutrients and growth factors are required to activate mTORC1. [00:25:54] Dawn mentions her interest in the connection of mTOR to aging,

In episode 15 Gabor and I review two studies looking at liver health by linking the process of de novo lipogenesis, with the activity of mTORC2, ChREBP-β and SREBP1c.

Saumya Das explains how the protein DDiT4L protects the heart from pathological hypertrophy.

Localizing mTORC2 activity The mTORC2 complex regulates cell growth and proliferation by phosphorylating the protein kinase Akt, but where in the cell mTORC2 is active, and how growth factors direct its activity towards Akt, remains unclear. Ebner et al. use a novel reporter to show that endogenous mTORC2 activity localizes to plasma membrane, mitochondrial, and endosomal pools with distinct sensitivities to PI3 kinase and growth factor signaling, and that growth factors induce Akt phosphorylation by promoting Akt's recruitment to the plasma membrane. This biosights episode presents the paper by Ebner et al. from the February 6th, 2017, issue of The Journal of Cell Biology and includes an interview with two of the paper's authors, Michael Ebner and Ivan Yudushkin (Max F. Perutz Laboratories and Medical University of Vienna, Vienna, Austria). Produced by Caitlin Sedwick and Ben Short. See the associated paper in JCB for details on the funding provided to support this original research. Subscribe to biosights via iTunes or RSS View biosights archive The Rockefeller University Press biosights@rockefeller.edu

Rapamycin’s effects on longevity and insulin sensitivity are mediated by different molecular targets.

Science Signaling's Chief Scientific Editor gives an overview of mTOR signaling.