STEM-Talk

Nearly 60,000 Americans are diagnosed with Parkinson’s disease every year in the U.S. The disease is an incredibly complex disorder that affects more than 10 million people worldwide. Our guest today is Dr. Michael Okun, who is considered the world’s foremost authority on the treatment of Parkinson’s.He is the Adelaide Lackner Professor and Chair of Neurology at the University of Florida Health College of Medicine as well as the co-director of the university’s Fixel Center for Neurological Diseases. The center is known for its interdisciplinary faculty that provides a one-stop, patient-centered clinical research experience that attracts patients from around the world. Since 2006, Michael has been the National Medical Director for the Parkinson’s Foundation and works very closely with a wide range of organizations such as the Michael J. Fox Foundation. The American Society for Experimental Nuerotherapeutics recently awarded Michael the 2018 Presidential Award.  In 2015, he was recognized during a White House ceremony by the Obama administration as a “Champion for Parkinson’s Disease.” Michael also is an accomplished writer with more than 400 peer-reviewed articles and even a book of poetry. In today’s episode, we discuss: [00:17:56]What Parkinson’s disease is and the wide range of symptoms that can arise as a result of the disease. [00:29:19] How Parkinson’s disease is diagnosed since there is no specific test that can diagnose the disease. [00:32:11] The common risk factors associated with neurodegenerative disease. [00:38:20] The actor Alan Alda’s recent announcement that he has been living with Parkinson’s for more than a year. [00:41:04] A UCSF study that looked at the prevalence of Parkinson’s among veterans who had experienced traumatic brain injury. [00:46:32] Treatments that are available for Parkinson’s. [00:55:57] The cognitive, behavioral and mood effects of deep-brain stimulation. [01:17:11] The potential use of brain prosthetics or orthotics in patients with neurological disease. [01:29:26] Whether Parkinson’s therapy is moving toward local, systemic or a combination of the therapies. [01:31:48] The relationship between metabolism and nutrition and the progression of Parkinson’s disease. And much more.  Show notes: [00:02:53] Michael begins the interview taking about growing up in West Palm Beach, Florida, and his love of baseball and collecting baseball cards. [00:03:39] After high school, Michael decided to attend Florida State University and focus on a liberal arts education. Dawn asks Michael if it’s safe to assume he wasn’t thinking about medical school when he started college. [00:04:53] Dawn asks Michael how a history major ultimately decides to become an MD. [00:06:18] Ken asks Michael to elaborate on a funny story about how he ended up going to the University of Florida for medical school. [00:10:10] Michael talks about how went to med school thinking he wanted to be a black-back family practitioner, but became so interested in neurology that he changed his mind. [00:13:06] Ken mentions that during Michael’s time at Florida, he became fascinated by what was going on in the brain of people who had tremors. Ken asks Michael if that is what led him to focus on Parkinson’s disease during his postdoc at Emory? [00:17:56] Even though most people are familiar with images of people like Michael J. Fox and Mohammed Ali who have tremors, most people aren’t aware that Parkinson’s has a wide range of symptoms, which makes it an incredibly complex disease. Michael gives an overview of Parkinson’s and the various symptoms that can arise as result of the disease. [00:22:29] Since Parkinson’s is such a remarkably complex and multi-system disease, Ken asks Michael how he integrates the different clinical disciplines that are required to treat someone with Parkinson’s. [00:29:19] Ken mentions that there is no specific test to diagnose Parkinson’s, and asks Michael if the disease is primarily diagnosed by symptoms. [00:32:11] Dawn mentions that when people are diagnosed with Parkinson’s, it means they don’t have Alzheimer’s or ALS. However, neurodegenerative diseases often have common risk factors such as type 2 diabetes or environmental exposures or trauma, as well as a neuroinflammatory or oxidative stress component. Ken asks what makes these diseases different beyond the specific areas of brain anatomy that they affect, and why might somebody with a given set of risk factors get one rather than the other? [00:38:20] Dawn mentions that more than a million people in the U.S. have Parkinson’s, including actor Alan Alda, who announced in July that he has been living with the disease for more than a year. In announcing he had the disease, Alda stressed that he has been living a full and happy life. As the national medical director for the Parkinson’s Foundation, Michael often stresses that people with Parkinson’s can lead happy and healthy lives, and Dawn asks Michael to talk about that. [00:41:04] Ken mentions a UCSF study in the online issue of Neurologythat looked at the prevalence of Parkinson’s among veterans who had experienced a traumatic brain injury. The study found that these veterans faced a 56 percent increased risk for Parkinson’s. Ken asks Michael to talk about the study and its implications behind a military population. [00:44:35] With a growing understanding of repeat TBI and CTE, Dawn talks about how we are learning that there is a link between brain injury and neurodegenerative pathology. She asks Michael if we have any idea as to why there is a link between TBI and neurodegeneration? [00:46:32] Michael gives an overview of the treatments that are available to treat Parkinson’s. [00:52:39] Dawn asks Michael to talk about the current state of biomarkers for tracking the progression of Parkinson’s and tracking the response to a disease-modifying intervention. [00:55:57] Dawn points out that Michael has had a prolific career as a researcher exploring non-motor basil ganglia brain functions. He also has helped pioneer studies exploring the cognitive, behavioral and mood effects of deep brain stimulation. She asks Michael to give listeners an overview of deep brain stimulation, also known as DBS. [01:00:35] Ken asks Michael to talk about the primary mechanism of action of DBS. [01:05:09] Michael discusses DBS’s dark past and how the intervention’s reputation has recently rebounded. [01:10:53] Dawns asks what kind of patient is a good candidate for DBS. [01:12:42] Michael talks about autonomic nervous system symptoms in Parkinson’s disease. [01:14:40] Dawn wonders about other forms of non-invasive nervous system stimulation and asks if approaches such as transcutaneous vagal nerve stimulation have shown an impact on Parkinson’s disease or Parkinson’s symptoms. [01:17:11] Ken points out that researchers at IHMC often work toward development of AI software systems intended as cognitive orthotics aimed at amplifying and extending human cognition. He asks Michael about the potential use of brain prosthetics or orthotics in patients with neurological diseases and what opportunities Michael sees to better understand the brain and brain networks. Ken also asks about the ethical challenges involved in such technology and who should be operated on. [1:20:32] Dawn mentions that one arm of research for Parkinson’s treatment is developing vaccines or other approaches to aid in the removal of alpha-synuclein protein aggregation. Similar approaches have so far failed with the analogous approach to beta-amyloid in Alzheimer’s disease, where the amyloid burden also doesn’t directly correlate with disease progression or severity. Dawn asks if there is evidence that this might be a more successful approach in Parkinson’s. [01:25:07] Ken brings up that stem cells are often mentioned in the context of Parkinson’s and asks Michael about the prospects. [01:28:08] Dawns asks about editing certain genes in situ with a CRISPR-Cas9. [01:29:26] Ken points out that PINK1 is involved with the ubiquitin pathway, and that LRRK2 is involved with the immune response. Ken asks if a systemic approach to treatment is more promising than a local treatment. He also asks if Parkinson’s disease therapy is moving toward local or systemic treatment or a combination of the therapies. [01:31:48] Dawn asks if there are known relationships between metabolism and nutrition and the progression of Parkinson’s disease or its symptoms. [01:33:21] Dawn talks about how the Obama administration recognized Michael during a White House ceremony in 2015 and how earlier this year the American Society for Experimental Neurotherapeutics honored Michael with its Presidential Award. Dawn asks Michael to share what that was like. [01:34:40] Dawn ends the interview by asking Michael about his passion for writing. She points out that Michael received a scholarship for creative writing in school and that today he has more than 400 peer-reviewed articles and has also written a book of poetry. Dawn asks Michael to talk about the role that writing has played in his life. Links Michael’s UF Department of Neurology faculty page Michael’s papers on PubMed IHMC talk on “Parkinson’s Disease: The Latest Advances in Treatment and Research.” IHMC talk on “Parkinson’s Treatment: 10 Secrets to a Happier Life” UF’s Movement Disorders and Neurorestoration Program “Parkinson’s Treatment: 10 Secrets to a Happier Life” “10 Breakthrough Therapies for Parkinson’s Disease” “Ask the Doctor About Parkinson’s Disease” “Lessons From the Bedside” Learn more about IHMC STEM-Talk homepage

Today’s episode features a timely interview with Google’s Director of Research, Peter Norvig.  He is also the co-author of “Artificial Intelligence: A Modern Approach,” which is in its third edition and is a leading AI textbook. In today’s interview, we talk to Peter about fake news, trolls, self-driving cars, killer robots, the future of artificial intelligence, and a lot more. We also talk to Peter about digital privacy. Tech companies such as Google, Facebook, Twitter and others have been facing heavy criticism recently over the way they handle people’s digital data. In May, Europe began enforcing a new law that restricts how people’s online data is obtained and used. In June, California passed a privacy law that requires tech and information companies to share how they’re collecting people’s data and how they’re sharing that information.  At the moment, Congress is considering a federal privacy law that also covers how personal digital data is handled. Ken and Peter have a history that goes back to their days at the NASA Ames Research Center in Silicon Valley. Ken was the center’s associate director at the time and recruited Peter to become the center’s chief of the Computational Sciences Division. In today’s episode, we discuss: How artificial intelligence has changed since the days when Peter first became a practicing AI professional. [00:19:20] How AI research is now increasingly driven by commercial interests rather than government grants. [00:23:39] What deep learning is and what the word “deep” means in this context. [00:27:48] The philosophical questions that surround AI, such as: “What does it mean to be intelligent?” and “Can a machine be conscious?” [00:36:58] Search function and privacy. [00:44:32] Google’s responsibility for the content posted on their platforms. [00:50:06] The problems that arise when tech companies police content. [00:51:17] Peter’s thoughts about a meeting Elon Musk had with U.S. governors where he urged them to adopt AI legislation before “robots start going down the street killing people.” [00:56:18] The meaning of “singularity” and whether Peter believes in it. [01:03:19] Peter’s advice for listeners who are interested in going to work for Google someday. [01:12:10] Show notes: [00:02:15] Dawn begins the interview asking Peter about an interview he did with FORBES magazine where he said, “I don’t care so much whether what we are building is real intelligence. We know how to build real intelligence. My wife and I did it twice, although she did a lot more of the work. We don’t need to duplicate humans, that’s why I focus on creating tools to help us rather than duplicating what we already know how to do. We want humans and machines to partner and do what humans and machines couldn’t do on their own.” Dawn asks Peter to expand on this belief and how it influenced his career. [00:03:23] Dawn asks Peter about growing up in Boston and his habit of writing the local newspaper to complain about innumeracy and the sloppy language in its science stories. [00:04:36] Ken mentions Peter’s father was a math professor and his mother an English literature professor. While in high school, even though teachers suggested a career in journalism, Peter decided to learn programming instead. Peter talks about how he also took a class in linguistics, which led him to start thinking about using computers to process natural language. [00:05:54] Dawn asks Peter about classes he took at Brown University that led him to start thinking about artificial intelligence. [00:07:00] Dawn mentions that Peter went to the University of California Berkeley for his Ph.D. and asks him what motivated him to enroll in the computer science department and research AI. [00:08:03] Dawn asks Peter about the research he did after receiving his Ph.D. and becoming an assistant professor at University of Southern California as a research faculty member. [00:08:36] Peter talks about the work he did in various labs during the early years of his career. [00:09:45] Peter talks about how Ken, while on leave from IHMC, recruited Peter in 1998 to become the division chief of the Computational Sciences Division at NASA Ames. [00:11:32] Ken and Peter recall a tag-team address they made at the 1999 conference of the Association for the Advancement of Artificial Intelligence. The talk was titled, “AI and Space Exploration: Where No Machine Has Gone Before”. [00:14:07] Dawn mentions that in 1996 a couple of Stanford students developed a search algorithm that was originally known as “Back Rub,” which eventually led to the formation of Google in 1998. Peter joined Google in 2001 and Dawns asks how that came about. [00:16:11] Dawn asks Peter to talk about the differences in the work cultures of Google and NASA. [00:17:41] Ken mentions that the textbook Peter co-wrote with Stuart Russell is now in its third edition since its original publication in 1995, and that it is considered one of the leading textbooks on artificial intelligence. Ken asks if Peter is considering a new version of the textbook in the face of the fast evolution of the field. [00:19:20] Dawn comments on how AI programming itself has changed over time with the iteration of new languages, tools, and communities. She asks how things are now different for the practicing AI professional, compared to when Peter was getting started. [00:21:28] Ken asks if Peter has any thoughts on the relationship between reality and some of the inflated expectations that arise from the current overhyping of AI that has stoked fears as well as utopian dreams. [00:23:39] Because AI is now increasingly being driven by commercial interests rather than government research grants, Dawn asks how the field will change. [00:25:10] Dawn asks why the look and feel of Google web searches hasn’t changed that much over the past 10 years. [00:26:09] Dawn mentions that Google’s search engine has flourished for 20 years because of its speed, relevance, coverage, and other such measures of performance. Given that Google is still the gold standard in search, she asks how Google tests for performance. [00:27:48] Ken mentions that about a decade ago Google was slightly disparaging about the utility of AI, but then Google started to suddenly change its tune, at least that’s how it looked from the outside. Ken comments that this seems to be because of the sudden explosion of applications of deep learning which, when applied to very large data, yield numerous state-of-the-art results in domains such as speech recognition, image recognition and language translation. Ken asks Peter to explain what deep learning is, what it does well, and what the word “deep” means in this context. [00:36:58] Ken comments on how, back in the day, good old-fashioned AI raised many big philosophical questions. Questions ranged from “What does it mean to be intelligent?” to “Can a machine be conscious?” Many of these questions were explored in famous films such as “Blade Runner,” and “Ex Machina.” Ken and Peter talk about whether there are new big questions being raised in the context of newer forms of AI. [00:39:41] Ken brings up how he and Pat Hayes developed an award in the ‘90s that they called the Simon Newcomb Award that recognized the most wrong-headed arguments against the possibility of intelligent machines. [00:41:25] Ken observes that the papers at the National AI Conference, while often technically excellent, are typically statistical in nature and narrowly cast. Ken goes on to propose that this could be a sign of the field maturing, or perhaps ducking the hard and interesting questions, or a bit of both. He asks Peter for his thoughts on this. [00:44:32] Ken brings the conversation back to Google and asks about search function and privacy. He mentions that Google provides some of the web’s most used and appreciated software, including Gmail, Docs, Drive, Calendar, and more. But given Google’s access to vast amounts of data that has led to personalized searches and advertisements, Ken asks Peter for his thoughts about the concerns regarding loss of privacy and the use of personal information. [00:47:45] Dawn asks Peter how Google recommends news articles based on people’s recent searches. Dawn says that some people argue that sending people news articles based on their history is not such a good thing. [00:50:06] Dawn asks Peter if Google feels as if it has any kind of responsibility to weed out fake news and international trolling. She also asks if the controversies about fake news and trolls are beginning to muddle the definition of information itself. [00:51:17] Ken mentions that problems are arising for platform providers not so much because of legal reasons but because of ideological reasons. Providers are now deciding to police content that comes onto their site and ban one group of ideological crazy people while not addressing another equally unhinged group.  Ken asks Peter how society will construe the role of Google, Facebook and others as they work to police the content that appears on their sites. [00:55:31] Dawn asks Peter for his take on companies such as Powerset as well as others who see natural language search, which allows people to use sentences rather than keywords, as the future of search. [00:56:18] Dawn mentions how last year she turned the tables on Ken and interviewed him for STEM-Talk on episodes 49 and 50. In one interview she asked Ken about a New York Times story that referenced the meeting Elon Musk had with governors where Musk said that they should adopt AI legislation before “robots start going down the street killing people.” She asks Peter if he ascribes to this killer AI theory. [00:59:03] Ken comments on how interesting he finds the sudden change in the arguments, which has evolved from pundits saying AI was provably impossible to now saying that superhuman AI represents the greatest danger ever faced by the human race. [00:59:49] Dawn mentions that the biggest question people asked Peter during a trip to Australia last year was the impact of self-driving cars on professions like truck drivers. She asks Peter to talk about the fear that algorithms and machine learning are replacing jobs. [01:03:19] Ken mentions that earlier in this decade Peter spoke at the Singularity Summit where he remarked that he was not a believer in what some refer to as “the singularity.” He asks Peter to explain what is generally meant by that term, and also to talk about his views on it. [01:07:44] Dawn comments on the coming “post app era” where a new type of human, computer, and smart-phone technology will replace the need for apps. She asks if this is something that Google is working on. [01:10:25] Dawn mentions that Peter is widely quoted as saying that he has the best job in the world, and asks what it is that he does. [01:12:10] Dawn asks Peter to share some advice for listeners who are still in school and are thinking about going to work for Google someday. [01:12:55] Ken mentions that Peter and his wife enjoy cycling and ends the interview by asking Peter if he has picked up any other new hobbies over the years. Peter’s Google AI page Peter’s Wikipedia page Peter’s web page Peter’s CV Peter’s Google Scholar page Peter’s Amazon page Peter’s Ted Talk Lecture by Peter: “The Science and Engineering of Online Learning” Lecture by Ken: “On Computational Wings: The Prospects & Putative Perils of AI” Learn more about IHMC STEM-Talk homepage  

Episode 71: Elizabeth Nance talks about using nanotechnology to understand and treat brain diseases SEO: Elizabeth Nance, Nance Lab, University of Washington, nanotechnology, autism, traumatic brain injury, epilepsy, nanoparticles, blood-brain barrier,diffusion,dendrimer-NAC conjugates,Einstein’s brain, chemical engineering,Ken Ford,Dawn Kernagis,IHMC Our guest today has been described by Forbes magazine as one of the “most disruptive, game-changing and innovating young personalities in science.” Dr. Elizabeth Nance is known for her passionate search to find ways to more efficiently connect resources and information across multiple scientific and engineering disciplines. Her research focuses on using nanotechnology to understand the movement of molecules in the brain. She is particularly focused on better ways to treat brain diseases like autism, stroke, traumatic brain injury and epilepsy. Elizabeth is the Clare Boothe Luce Assistant Professor of Chemical Engineering at the University of Washington. She also has an adjunct appointment in the school’s radiology department. Elizabeth and her lab, the Nance Lab, recently was awarded a $1.8-million-dollar grant from the National Institutes of Health to develop quantitative, high resolution imaging and analysis platforms to understand nanoparticle behavior, with a specific focus on the brain. In today’s episode, we discuss: The pushback Elizabeth received in college when she tried to apply chemical engineering to neurological diseases. [00:11:33] How Elizabeth developed the first nanoparticles that could penetrate deep within the brain. [00:13:52] The many potential applications of nanoparticle technology in the treatment of neurological disorders, diseases and injuries. [00:17:10] The structure, and unique functions of the blood-brain barrier. [00:28:11] The dendrimer-NAC conjugates, and how they increase intracellular glutathione to reduce injury in the inflamed brain. [00:35:01] How “disease directing engineering” has the potential to allow for the leveraging of common hallmarks of neurological disease to better deliver therapies. [00:40:19] How change in brain metabolism affects targeted therapeutic deliveries to a specific region of the brain. [00:52:14] Show notes: [00:03:31] Elizabeth talks about growing up in North Carolina and how her family goes back nine generations to the original homesteaders of Charlotte. [00:04:06] Dawn mentions that Elizabeth liked to spend a lot of time outdoors as a child and asks her if it is true that she was especially good at climbing trees. [00:05:12] Dawn asks Elizabeth about her hectic schedule in high school, which, in addition to her studies, included soccer, track and volleyball. [00:06:03] Ken asks Elizabeth when she became interested in science. [00:08:22] Dawn mentions how in North Carolina a person has to decide early on if they are a Chapel Hill fan or a North Carolina State fan. Dawn asks if this culture contributed to Elizabeth going to NC State. [00:09:28] Dawn asks Elizabeth about her decision to major in chemical engineering. [00:11:33] Dawn asks Elizabeth to discuss the pushback she received in college when she tried to apply chemical engineering to neurological diseases. [00:13:52] Ken mentions that Elizabeth developed the first nanoparticles that could penetrate deep within the brain. This was a major reason why Forbes named her one of its “30 Under 30 Disruptive Influencers in Science” back in 2015. He asks if she could talk about the work she did in developing that platform and how it changed the way we might think about delivering drugs in the brain. [00:17:10]Ken mentions that there are many potential applications of nanoparticle technology in the treatment of neurological disorders, diseases and injuries. He asks Elizabeth to describe the structure of a nanoparticle in general, and how it can accomplish targeted delivery of a therapeutic. [00:21:47] Ken comments on how after publishing her nanoparticle paper in “Science Translational Medicine” in 2012, one publication commented that they were worried about potential nefarious applications of such technology. [00:25:23] Dawn asks why research and development for drugs used to treat people with injured or diseased brains take about 35% longer to develop than drugs for any other type of disease. [00:28:11] Dawn asks Elizabeth to give some background on the structure, and unique functions of the blood-brain barrier. [00:29:57] Ken discusses how a lot of Elizabeth’s work involves the use of nanotechnology and its potential applications in both understanding and treating the injured brain. He asks about the use of nanoparticles as probes, and how that helps us better understand the human brain microenvironment. [00:32:11] Dawn comments on how much of Elizabeth’s post-doctoral work focused on the use of dendrimer-based nanoparticles in multiple different settings as a model for how to approach neurological disease treatment. Dawn asks Elizabeth how that has informed her current research. [00:35:01] Dawn brings up how Elizabeth has published multiple papers on the dendrimer-NAC conjugates, and how it increases intracellular glutathione to reduce injury in the inflamed brain. Dawn goes on to say that some people have begun to take NAC to increase glutathione in the brain after a concussion or TBI. She asks Elizabeth to talk about the potential problems with giving NAC in the setting of excitotoxic brain injury, and why the use of a nanoparticle might be a potential solution to this problem. [00:37:30] Ken comments on how Elizabeth is known to be fascinated by diffusion, to the point where she has said that it has kept her up at night. He asks why understanding diffusion is so critical to overcoming the barriers to investigating and treating the injured brain. [00:40:19] Dawn mentions that a number of things that happen after brain injury can dramatically alter our ability to deliver a therapy. She points out that Elizabeth has coined the term “disease directing engineering” to describe an approach that has the potential to allow for leveraging of common hallmarks of neurological disease to better deliver therapies. She asks how that thought process informs the research in Elizabeth’s lab. [00:43:37] Ken brings up one of Elizabeth’s review papers, where she summarized how nanoparticle properties affect movement within the brain, and from that she developed a formula with the highest likelihood of success. He asks what that formula is. [00:46:16] Dawn comments on Elizabeth being very vocal about the drug delivery field’s movement toward increasingly complex delivery vehicles despite the limited translation of these approaches in the clinic. She goes on to ask why there is this gap. [00:48:34] Dawn mentions that Elizabeth and her lab were recently awarded a $1.8 million grant from the NIH, and how she will be using the grant to develop quantitative high-resolution imaging and analysis platforms to understand nanoparticle behavior and compartmentalization on brain tissues. [00:49:45] Dawn asks if Elizabeth could explain the idea behind her current work, which focuses on integrating biological data from the molecular level all the way up to animal behavior. [00:52:14] Ken comments on how we know that in certain types of brain injury or disease, that metabolism and inflammation are significant components of the underlying pathophysiology. He asks if a change in brain metabolism affects targeted therapeutic delivery to a specific region of the brain. [00:54:47] Ken asks if the leakiness of the blood brain barrier that occurs in certain forms of neurological injury and disease can be utilized in a targeted way to deliver a drug in the brain. [00:56:54] Ken asks what Elizabeth sees as the most exciting up and coming areas of nanoparticle therapeutics research and development. [00:58:20] Dawn asks Elizabeth about her decision to join the University of Washington. [00:59:40] Dawn asks if Elizabeth’s adjunct position in the department of radiology helps her interact with clinicians or medical researchers who might wonder why a ChemE is working on the brain. [01:00:49] Dawn asks if Elizabeth can expand on her idea that while interdisciplinary research is frequently talked about, that people are usually just giving it lip service. [01:02:37] Dawn mentions that Elizabeth’s father was a minister, and her mother a nurse, and that one thing they instilled in her early on was that every person and conversation has value; and that a person has to be constantly willing to go outside their comfort zone in order to grow. She asks how these lessons shaped the philosophy behind Elizabeth’s lab. [01:03:56] Dawn brings up a TED Talk that Elizabeth did where she stressed that we have made significant advancements in treating disease because of better prevention, better surgical intervention, and better diagnosis. But despite all this, we are still struggling to understand the majority of complex diseases, and that it is possible that we already have the tools we need to solve those problems but our approach to using them might be the issue, and that we might have the solutions already but we are just asking the wrong questions. [01:05:06] Dawn mentions Elizabeth’s shift from ChemE to neuroscience and pediatrics after her Ph.D. led people to ask her on a regular basis, “What are you? What is your specialty?” Dawn asks if that is why Elizabeth often refers to herself as a glorified match maker? [01:06:41] Dawn refers back to something Elizabeth said in her TED Talk about the idea of “specializing in not specializing”, and asks her to expand on that concept. [01:08:28] Dawn asks Elizabeth about recently being named the European Union’s NanoMed Innovative Training Network’s Inspiring Young Investigator of 2018. [01:10:08] Ken mentions that Elizabeth was recently on a podcast where she shared a remarkable story about how pathologist Thomas Harvey kept parts of Einstein’s brain after performing the autopsy on him in 1955. Some of the sections of the brain were recovered and analyzed decades later, showing that the structure and composition of his brain might have been slightly different from what we might normally expect to see. Ken asks if Elizabeth could discuss what those differences were and how this highlights the importance of probing. [01:12:40] Dawn mentions that episodes 47 and 48 of STEM-Talk featured a two-part interview with Tommy Wood, a UK trained physician and Ph.D. who now also works at the University of Washington. When Dawn and Ken asked Tommy what brought him over to the U.S., he said “a girl.” Dawn asks Elizabeth if she knows something about that. [01:13:31] Even though Forbes named Elizabeth one of its “30 under 30 in Science” in 2015, Dawn mentions that she understands Elizabeth was terrible at chemistry in high school. Dawn wraps up the interview by asking Elizabeth if that’s true. Links: Elizabeth’s University of Washington faculty page Nance Lab website Elizabeth’s TEDx Talk Facebook page Instagram Elizabeth’s podcast interview where she talks about Einstein’s brain A Dense Poly(Ethylene Glycol) Coating Improves Penetration of Large Polymeric Nanoparticles Within Brain Tissue Systems-level thinking for nanoparticle-mediated therapeutic delivery to neurological diseases Tommy Wood STEM-Talk interview, episode 47 Tommy Wood STEM-Talk interview, episode 48 Learn more about IHMC Ken Ford Facebook page Dawn Kernagis Facebook page  

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, mentioning that mTOR inhibition through rapamycin or its analogues is currently one of the hottest topics in longevity research. She asks why mTOR inhibition  appears to be life-extending? [00:30:38] Ken asks what the risks are of excess catabolism, when inhibiting mTOR pharmacologically, in terms of both health and longevity. [00:32:09] Dawn asks if there is data in humans suggesting that suppressing mTOR will extend longevity and healthspan, either pharmacologically, genetically or through diet and fasting. [00:34:23] Dawn asks where mTOR is made, both in terms of the individual cell, as well as specific tissues in the body. [00:35:02] Ken asks if there is a significant difference between the mTOR signaling in organs like the liver, skeletal muscle, and the brain. [00:37:07] Ken asks if tissue specific inhibition of mTOR is possible. [00:38:29] Dawnmentions how it is becoming clear that mTOR plays a role in a number of diseases, most notably is its connection to cancer. She goes on to say that in 2008, David’s team published a highly-cited paper in Science that described the role of Rag GTPases, key mTOR mediators, that sense the amino acid input of a cell. She asks David to discuss this discovery and about the importance of these enzymes in disease processes like cancer? [00:42:27] Ken mentions that protein intake and downstream mTOR activation is often said to be associated with dysregulated cell growth (i.e. cancer). He goes on to ask if there is there sufficient evidence to suggest that high levels of protein or amino acid intake are necessary or sufficient to produce clinically-meaningful cancers? [00:43:59] Dawn comments on the epidemic of type-2 diabetes in the United States, going on to say that the mTOR pathway is a known suppressor of the insulin-signaling pathway. She asks if mTOR modulators have the potential to make an impact in the diabetes world? [00:45:28] Ken asks if the potential negative effects of protein intake on mTOR activation and longevity might be mitigated in the presence of lower-blood glucose or insulin signaling, given the overlap between the insulin and IGF-1 signaling pathways. [00:46:31] Dawn opens the question by mentioning that late last year, the journal Cell Metabolism published two excellent papers related to ketogenic diets and the extension of healthspan and lifespan. She goes on to mention that the paper from Keith Baar’s group at UC Davis titled “A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice” was of particular interest to several people at IHMC. The findings showed that in mouse models, researchers have seen extended longevity, cognitive protection, cancer reduction, improved strength and coordination, and immune rejuvenation.  The paper from the team at UC Davis, showed a 13% increase in median life span for the mice on a high fat vs high carb diet. Ken jumps in and mentions that from his perspective the most important aspect is that those mice retained their quality of health well into later life. He mentions that it was particularly interesting that they found the ketogenic diet increasedprotein acetylation levels and regulated mTORC1signaling in a tissue-dependent manner. Specifically, the ketogenic diet increasedmTOR signaling in skeletal muscle and inhibited mTORC1 signaling in the liver. [00:48:59] Ken mentions that an interesting paper from a year or two ago showed that ketones, particularly BHB, greatly increased IGF-1 sensitivity in the muscle. [00:50:59] Dawn asks what the role of mTOR is in neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease. [00:53:02] Dawn mentions that mTORC1 responds to intracellular and environmental stresses that are incompatible with growth, including hypoxia. She asks about the effect of hypoxia on mTORC1. [00:53:51] Dawn mentions that the amino acid, methionine, is widely appreciated to have interesting effects on animal physiology, and that diets low in methionine increase longevity and overall health. She goes on to mention a paper David and a group of his colleagues published in “Science” that described a potential molecular link between the effects of methionine restriction and mTOR1. She asks David to give a summary of that paper and his findings. [00:55:27] Ken mentions that several human pathologies are linked to mTOR hyperactivation such as TSC and epilepsy due to gene deletions.  He goes on to ask about the consequences of gene deletion-induced mTOR hypoactivation and if it would it confer a longevity benefit. [00:57:02] Dawn comments on how a few years ago, David joined Peter Attia, our very first guests on STEM-Talk, and a few other friends to take a trip to Easter Island to explore the place where rapamycin was discovered. She asks if David could talk briefly about the story of the initial discovery and isolation of rapamycin on Easter Island, and how, at one point, it was only in Suren Sehgal’s hands and almost lost. [00:59:17] Dawn mentions how David has previously written about how caloric restriction might produce the best balance of mTORC1 inhibition and overall organismal health, asking David to expand on that idea since caloric restriction does not consistently produce life extension in animal models. [01:01:14] Dawn asks if rather than restricting nutrients in mass with caloric restriction, might it be possible to manipulate individual nutrients to extend human life. [01:02:11] Ken mentions that in mammalian cells, inhibition of mTOR results in reduced cell size as a result of reduced protein synthesis. He goes on to ask what the downstream effects are of this, and if it results in a specific phenotype when mammals are exposed to mTOR inhibitors. [01:03:40] Following up, Dawn comments that one might speculate that chronic inhibition of mTOR in humans would likely degrade a patient’s health and cause fragility due to immunosuppression and loss of muscle. She asks if intermittent use of low-dose rapamycin would help avoid these effects and some of the widely observed side effects such as mouth sores. [01:05:11] Ken asks if David would hypothesize about intermittent use of low-dose rapamycin and its potential to activate autophagy in a meaningful way. [01:06:04] Dawn mentions a story about David on the Whitehead Institute website that makes the point that rapamycin appears to have all the makings of a magic bullet for treating diseases involving the mTOR pathway. David, however, was quoted as saying “we’re not there yet”. [01:07:08] Ken asks if we know how long mTOR inhibition takes with rapamycin before mTORC2 is inhibited. [01:08:59] Ken mentions that one hears ofphysicians prescribing rapamycin off label for older patients. He goes on to say that there aren’t sufficient studies to justify this behavior, asking David’s for his thoughts on this. [01:10:13] Ken comments on how the captive mouse studies, where the subjects are fed a bad diet, is not too far removed from human life in cities in many ways. [01:11:06] Dawn asks David what evidence would have to be there to get him to consider taking rapamycin as a means for enhancing his own longevity. [01:12:31] Dawn closes the interview by mentioning that Davidwrote a piece for the Proceedings of the National Academy of Sciences Journal titled, “Twenty-Five Years of mTOR.” Toward the end of that article David wrote that his friends in the field laugh at him whenever he says he’s done with mTOR, that there’s nothing left to discover. Dawn then quotes what David had to say about this: “Whenever I feel like calling it quits, the laboratory conveniently makes a great discovery that piques our interest in a new facet of the pathway.” And while, mTOR may not regulate everything, he went on to say, there are enough mysteries in how it senses everything to keep him and his lab occupied for the foreseeable future. [01:13:07] Dawn closes the interview by asking David to describe some of these mysteries he and his colleagues are exploring. Sabatini links: David M. Sabatini MIT profile page Sabatini Lab website David M. Sabatini Wikipedia page Sabatini Lab publications page Peter Attia interview with David M. Sabatini Twenty-Five Years of mTOR RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion Amino Acids and mTORC1 Growing Roles for the mTOR pathway Rapalogs and mTOR inhibitors as anti-aging therapeutics mTOR is a key modulator of ageing and age-related disease Regulation of mTORC1 by amino acids mTOR Signaling in Growth Control and Disease The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span Tim Ferris podcast about trip to Easter Island with David M. Sabatini and friends  

Dr. David LeMay is a sports medicine and rehabilitation physician who is a consultant for the NBA’s Washington Wizards, the NFL’s Oakland Raiders and the National Hockey League’s Washington Capitals, which won the Stanley Cup this year, their first in the franchise history. Dave is also a neighbor of ours in Pensacola who has a practice called Lifestyle and Performance Medicine that is located just a few blocks from IHMC. Dave and his practice partner provide personalized preventative care that helps people reduce the effects of stress on the body and mind to maximize function and health. In his practice, Dave works with a lot of athletes as well as retired and active military members, particularly people in special-ops, who have inflammation as a result of persistent injuries and traumas. Dave often recommends specialized pro-resolving mediators, also known as SPMs, which help promote the natural termination of the inflammation process and allow a person to avoid anti-inflammatory drugs. We will especially be talking with Dave about this rather new way of treatment in today’s interview. Some other topics we cover in Dave’s interview: Neuroendocrine dysfunction, especially among military veterans. The role of inflammation in concussions and traumatic brain injuries. Dave’s work with the NFL Players Association Trust. The role of specialized pro-resolving mediators in an aging population. The proper dosage of SPMs for subacute inflammation. Dave’s efforts to improve the diets of former NFL players. The key components of keeping athletes healthy through an entire season. The correlation between heath-rate variability and athletic performance. Proper sideline protocols for players who sustain head injuries. Optimal treatment for people who suffer TBI and concussions. Establishing baselines for a person’s neuroendocrine function. The role of DHA and EPA consumption for maintaining optimal brain health. And much, much more. Show notes: [00:04:18] Dave begins the interview talking about growing up in Reno, Nevada, and playing sports non-stop as a kid. [00:4:35] Dawn comments on how Dave’s love of sports lead to some injuries, including a few broken fingers and torn ligaments, and says she understands that this is how Dave first became interested in science. [00:05:31] Dawn asks Dave about his decision to head to California after high school to attend Azusa Pacific University. [00:06:37] Dawn asks what lead Dave back home to attend med school at the University of Reno. [00:07:13] Ken asks Dave at what point he decided to specialize in physical medicine and rehabilitation. [00:08:33] Dawn mentions that the University of Texas Health Science Center has one of the best physical medicine and rehab programs in the country. She asks Dave if this was the reason he decided to go there for his residency. [00:09:21] Ken comments on how after Dave’s residency, he stayed in Austin for almost a year. But then Dave moved Pensacola and Ken asks how that came about. [00:11:04] Dawn asks about Dave’s private practice, called Lifestyle and Performance Medicine, which he and his partner opened in 2013 after their time at the Andrews Institute. [00:11:27] Ken points out that veterans, and some active-duty folks, particularly those with special operations backgrounds, comprise about half of Dave’s practice. Ken says he understands Dave has seen a great deal of neuroendocrine dysfunction in this group, and asks Dave for his observations. [00:12:56] Ken mentions that Dave is the medical director for a program that is run through the NFL Players Association Trust. He asks Dave to describe the type of rehab that this program provides the former NFL players. [00:14:54] Dawn comments on the concept of inflammation being a unifying component of many diseases that afflict Western Civilization, and how it is also a major contributor to the magnitude and persistence of different sports injuries and traumas. She asks Dave to talk about inflammation, and specifically its role in concussion and TBI, as well as give a brief overview of what inflammation is. [00:17:51] Dawn mentions how Dave has been looking at how targeting inflammation may serve as a therapeutic way to also treat fear- and anxiety-based disorders. [00:20:34] Ken asks if the process of EPA and DHA conversion into SPM’s through an enzymatic process diminishes in its efficiency as one ages. [00:21:18] Ken asks if Dave thinks there is a role for exogenous SPM’s for the aging population. [00:22:13] Ken asks if there is a particular SPM brand, or collection of brands, that Dave finds to be the most interesting or efficacious. [00:23:01] Ken asks what dosage would Dave suggest for subacute inflammation, and what would be proper for an acute inflammation stage. He goes on to ask about those people who experience a constant, mildly inflamed state. [00:24:52] Ken asks how Dave wound up working as a consultant for the NBA’s Washington Wizards, the NFL’s Oakland Raiders, and the National Hockey League’s Washington Capitals, who won the Stanley cup this year. [00:26:35] Dawn mentions that Dave has been on the Performance Nutrition Advisory Board for EXOS for several years. She points out that one of the things Dave does when working with former NFL players is to walk them through ways to improve their diet. [00:28:19] Dawn asks what are the key components to keep athletes healthy, playing at a peak level throughout an entire season. [00:30:48] Ken asks if Dave ever looks at heart rate variability (HRV) as a way to measure the extent to which people are in a balanced state. [00:31:23] Ken mentions that the Ohio State wrestling team looked at HRV very closely, and that there has been found to be a direct correlation between the performance of the athletes and their HRV. He goes on to mention that in his own life, as well as with the wrestlers at Ohio State, the thing that seems to be the most effective in improving HRV is float tank experience. [00:32:55] Ken asks what the immediate and delayed symptoms of concussion and mild traumatic brain injury are that players experience, and what are the types of treatment that they typically go through? [00:35:15] Ken asks if, after an injury, coaches are still asking players on the sidelines questions like, “Who is the President?” [00:39:12] Ken mentions how he often wonders how much of the benefit of the float tank is from the transdermal magnesium. [00:40:01] Dawn asks if there are any efforts to track TBI in professional hockey, given that concussion is a concern in that sport with its high-speed pace and consequent impacts sustained by players during the game. [00:42:00] Dawn mentions how she appreciates Dave’s approach to TBI and concussion, which is to try to fix the issue from the inside out by getting at the core of the injury. She goes on to mention that Dave has discussed the need for individuals who have been diagnosed with TBI to see someone who practices something along the lines of integrated medicine to have a full system approach to their treatment. She inquires as to what an optimal care plan would look like for someone diagnosed with TBI [00:46:16] Ken mentions that in the Special Ops community, there is a lot of talk about establishing an individual baseline for each person’s neuroendocrine function since these men, prior to service, must have had robust levels of hormones such as testosterone, leading to their exceptional attributes and abilities. Thus the idea of determining their health by comparing their levels to what is considered “normal” for the general population doesn’t seem appropriate for this cohort group. [00:50:42] Dawn asks if Dave thinks that increasing DHA and EPA consumption would be beneficial for TBI patients. [00:52:06] Ken mentions how he once had the opportunity to suggest to a representative of the NFL that they should look at the APOE status for every player, and make the findings known to them. He went on to state that this suggestion was not warmly received. [00:55:13] Dawn comments on how there has been a potential link, suggested by the recent literature, between the uptake of DHA, an SPE precursor, and Alzheimer’s disease or dementia development. She goes on to mention a study done in 2017 that showed grey matter uptake in young adult APOE4 carriers is significantly higher than age-matched APOE4 non-carriers. APOE genotype has been shown to be a significant risk factor for development of Alzheimer’s.  The thought is that increased uptake may be related to increased regional brain activation and higher cognitive abilities observed in young adult APOE4 carriers. As these young adults age, the hypothesis is that this greater uptake of DHA, which yields cognitive benefits at a younger age, also increases susceptibility to greater brain DHA loss due to increased metabolic demands and ultimately brain exhaustion and memory failure with age. Based on these and other recent findings, it has been suggested that APOE4 carriers should increase DHA consumption in order to meet the greater metabolic demand for DHA in the brain, and other clinical trials have reported cognitive benefits from increasing DHA consumption in cognitively healthy APOE4 carriers. Dawns asks Dave for his thoughts on the role of DHA or EPA consumption for maintaining or optimizing brain health?   Or, she adds, would SPMs be more efficacious? [01:01:30] Dawn asks Dave what the role of genotyping will be in optimizing our nutrition, fitness, and overall wellness. [01:07:50] Ken asks what some of the common deficiencies and recommendations are for people who have trouble falling asleep, and also for those who have trouble staying asleep. [01:11:09] Dawn ends the interview asking Dave how he goes about taking care of himself, given his busy schedule, in terms of his diet and fitness routine. Links: Regenesis Performance website Concussion presentation by David LeMay Sports Nutrition presentation by David LeMay DHA brain uptake and APOE4 status Resolution of inflammation is altered in Alzheimer’s disease Infection regulates pro-resolving mediators that lower antibiotic requirements Resolvins, specialized pro-resolving lipid mediators and their potential roles in metabolic diseases Pro-resolving lipid mediators are leads for resolution physiology Specialized pro-resolving mediators from omega-3 fatty acids improve amyloid-b phagocytosis & regulate inflammation in patients with minor cognitive impairment Pro-resolving lipid mediators and mechanisms in the resolution of acute inflammation

What’s the best way to eat and the right way to exercise to ensure a healthy lifespan? Our guest today is Dr. Stephen Anton, a psychologist who has spent his career researching how lifestyle factors can influence not only obesity, but also cardiovascular disease and other metabolic conditions. Steve is an associate professor and the chief of the Clinical Research Division in the Department of Aging and Geriatric Research at the University of Florida. In today’s episode, we talk to Steve about his work in developing lifestyle interventions designed to modify people’s eating and exercise behaviors in an effort to improve their healthspan and lifespan. One of Steve’s best-known papers appeared in the Obesity Journal titled “Flipping the Metabolic Switch.” The study looked at intermittent fasting and suggested that the metabolic switch into ketosis represents an evolutionary conserved trigger point that has the potential to improve body composition in overweight individuals. Topics we cover in today’s interview include: The increasing prevalence of metabolic syndrome associated with aging. Why so many hospital health and wellness programs fail. How fasting and intermittent energy restriction promote autophagy. The relationship between muscle quality, body fat and health. How age-related loss of muscle function and mass leads to sarcopenia. Effects, risks and benefits of testosterone supplementation in older men. Optimal exercise methods for long-term health. Therapeutic approaches that potentially can help avert systemic inflammation associated with aging. Steve’s study that looked at the effects of popular diets on weight loss. Controversies surrounded calorie restriction as a strategy to enhance longevity. Show notes: 2:30: Steve talks about growing up in Tampa and playing sports as a kid. 3:53: Dawn asks Steve about his decision to attend Florida State after high school. 4:17: Dawn comments on how Steve bounced between medicine, business, and psychology before finally deciding to major in psychology. She asks if having two parents who were also psychologists played a role in his decision. 5:24: Ken asks about Steven’s experience pursuing his Ph.D. at the University of Florida. 6:28: Dawn brings up that Steve became a fellow of behavioral medicine at the Pennington Biomedical Research Center in Baton Rouge, La. She mentions that Pennington has one of the nation’s premier programs in obesity metabolism and diabetes. She asks if that was the reason he decided on Pennington. 9:33: Dawn asks what prompted Steve to return to the University of Florida. 10:08: Ken asks what is driving the increased prevalence of metabolic syndrome that’s associated with advanced age. 11:19: Dawn brings up how hospitals have tried to promote health and wellness programs for decades, but notes how hospitals are designed to treat people who are sick and injured rather than delivering lifestyle interventions. She asks if Steve can give a summary of what he has learned in looking at ways to deliver interventions. 13:23: Dawn mentions that the traditional treatment and management approaches for type 2 diabetes are relatively ineffective and only reverse the disease in about one percent of the cases. 15:02: Ken mentions that Jeff Volek, STEM-Talk Guest on episode 43, has been a pioneer in researching type 2 diabetes. 16:49: Dawn points out that she and Ken had an in-depth conversation with Dr. Mark Matson about autophagy on episode seven of STEM-Talk. Matson also discussed fasting, and intermittent energy restriction and how it promotes autophagy, which is often described as the body’s innate recycling system. Dawn asks if Steve can elaborate a little on this process. 18:02: Dawn mentions that Steve has written about muscle quality and body composition and the risk of metabolic diseases and functional decline. She asks about the relationship between muscle quality, body fat and health. 19:17: Dawn asks if Steve can talk about how the age-related loss of muscle function and mass often lead to sarcopenia, and how this condition effects the individual and society. 20:31: Ken asks for Steve’s thoughts on the group of people who could be classified as having “pre-sarcopenia.” Ken mentions his interest in this group given that dietary and exercise intervention can still make a huge difference in their lives. 21:35: Dawn brings up the point of how testosterone tends to decline as men age, which is associated with a number of adverse health problems, including: cardiovascular and metabolic disease, sexual dysfunction, and mood disorders. Dawn asks about Steve’s study on the effects of testosterone supplementation in older men, and about the risks and benefits of supplementation. 24:12: Dawn asks if Steve can describe the difference between muscle quality and quantity, and if there is an easy way we can track and measure muscle quality. 25:28: Ken asks how we should be thinking about pharmaceutical therapies in these conditions as the field goes forward; given that so many new pharmaceuticals are in various stages of development, and that many of the currently available pharmaceutical approaches to age-related muscle loss have, to date, been effective at increasing muscle mass but not necessarily function. 26:30: Dawn asks what exercise methods Steve recommends for optimal, long-term health. 27:57: Dawn mentions that in 2016 a team of Spanish and Italian researchers published an article in the prestigious journal, Nature, showing that autophagy is a critical regulator of stem-cell fate and has implications for fostering muscle regeneration and sarcopenia as well as other disorders. She goes on to mention that autophagy typically declines with age, and this may be because stem cells start to lose their “steminess,” and become senescent (the loss of a cell’s power of division and growth). She goes on to ask about fasting and ketogenic diets, and how both interventions increase autophagy and could account for the common benefits we see in both of those interventions. 29:51: Dawn asks about the emerging concept of normal-weight obesity. 31:07: Ken asks about the consequences and challenges of sarcopenic obesity. 33:20: Dawn mentions that a growing body of evidence strongly indicates that chronic systemic low-grade inflammation plays a significant role in contributing to sarcopenia and associated functional decline. She goes on to say that preserving muscle and mobility is essential to maintaining a high quality of life as we age. She asks Steve what promising therapeutic approaches are out there that can potentially help avert systemic inflammation that’s associated with aging. 34:41: Dawn asks what the connection is between body fat and inflammation. 35:52: Dawn asks about the phenomenon that inflammation seems to be central to many lifestyle-related chronic diseases. 36:40: Dawn mentions that exercise has anti-inflammatory effects and asks if we should be considering anti-inflammatory intervention strategies as a starting point. 37:08: Ken mentions that Steve has a paper published in the obesity journal titled “Flipping the Metabolic Switch,” a study which looked at intermittent fasting and suggested that the metabolic switch into ketosis represents an evolutionary conserved trigger point that shifts metabolism to the mobilization of fat through fatty-acid oxidation and fatty-acid derived ketones. This mobilization shows that intermittent fasting regimes that induce ketosis have the potential to improve body composition in overweight individuals. He asks how the review was designed and what was learned. 39:17: Ken comments on how this whole discussion of intermittent fasting and the resulting elevated level of ketone bodies leads one to wonder whether exogenous ketones such as esters would recapitulate some of the effects of fasting or the ketogenic diet. 41:05: Dawn mentions that from religious to medical practices, fasting has been performed for thousands of years, dating back to the Greeks, Romans, and Chinese. She asks if Steve could give an overview of the history of fasting and also why so many researchers and scientists today are taking a renewed interest in episodic caloric restriction. 42:30: Ken asks if Steve could talk about the role of resistance training in maintaining muscle mass, function and quality as we age. Ken also asks what Steve has learned in examining exercise-based interventions as well as the combination of exercise and dietary interventions. 45:45: Ken mentions that poor muscle quality and functional decline are associated with the loss of type-two muscle fibers, and increased intramuscular fat. Going on to mention that these same changes are regularly seen in endurance athletes. He asks if these adaptations might become maladaptive as these athletes age. 47:15: Dawn asks if there is an upper limit of benefit, in terms of muscle gain, and a lower limit in terms of optimal body fat, when it comes to longevity. Inquiring as to whether there is a point of diminishing returns or increasing harm when it comes to gaining muscle or losing fat. 49:18: Dawn mentions another one of Steve’s major review studies that looked at the effects of popular diets on weight loss. Steve examined the evidence for the diets that were listed in the 2016 U.S. News & World Report’s rankings of the best weight-loss diets, which ranged from the Mediterranean to Atkins to Ornish to the Paleo diets. She goes on to say that the review found the Atkins diet to have the most evidence in producing meaningful short-term and long-term weight loss. 53:00: Dawn asks what Steve’s diet and exercise routine look like. 54:24: Dawn mentions how it is not the lack of knowledge on the biology of disease, and what interventions will be effective for different individuals, but rather the implementation and adherence at a population level. Given his background in psychology, Dawn asks Steve what his thoughts are on ways to help people implement these interventions into their lives. 59:59: Ken mentions how calorie restriction is a controversial strategy to enhance longevity. Some say that it is the only strategy that has worked consistently, across species, to extend lifespan. Ken mentions that there is also evidence from multiple meta-analysis that shows only about 50% of rodent studies result in a longevity benefit. When one accounts for the quality of the food given to primates, the situation becomes even more unclear as to whether or not calorie restriction has a longevity benefit. Ken asks Steve if the same could apply to humans. 1:03:49: Dawn mentions that she understands Steve persuaded his 72-year-old father to try intermittent fasting, and that his father has become a great testimonial for Steve. Links: Dr. Stephen Anton faculty page: http://aging.ufl.edu/profile/anton-steve-phd/ STEM-Talk episode 43, Dr. Jeff Volek: https://www.ihmc.us/stemtalk/episode-43/ STEM-Talk episode 7, Dr. Mark Mattson: https://www.ihmc.us/stemtalk/episode007/ Molecular Inflammation: Underpinnings of Aging and Age-related Diseases: Molecular Inflammation – FINAL Paper Effects of Popular Diets: Popular Diets – Published Article Flipping the Metabolic Switch: Anton_et_al-2017-Obesity  

Today’s guest is Dr. Douglas Wallace, the director of the Center for Mitochondrial and Epigenomic Medicine at Children’s Hospital of Philadelphia. He is internationally known as the founder of mitochondrial genetics. Mitochondria are tiny structures within cells that produce 90 percent of a person’s energy and play an essential role in health and disease. Dr. Wallace’s groundbreaking research in the 1970s defined the genetics of DNA within the mitochondria, as distinct from DNA in a cell’s nucleus. His research has shown that mitochondrial DNA is inherited exclusively from the mother and that genetic alterations in the mitochondrial DNA can result in a wide range of metabolic and degenerative diseases. One of Dr. Wallace’s seminal contributions has been to use a mitochondrial DNA variation to reconstruct human origins and the ancient migrations of women. These studies revealed that humans arose in Africa approximately 200,000 years ago, and that women as well as men left Africa about 65,000 years ago to colonize Eurasia. Dr. Wallace was inducted last year into the Italian Academy of Sciences during the academy’s 234th annual meeting in Rome. Founded in 1782, membership in the academy is limited to 40 Italian scientists and 25 foreign members. Over the years, the academy has seen such notable members as Albert Einstein, Benjamin Franklin, Louis Pasteur and Rita Levi-Montalcini. Links: Dr. Wallace’s Children’s Hospital of Philadelphia bio: https://www.chop.edu/doctors/wallace-douglas-c  Mitochondrial DNA Variation in Human Radiation and Disease Wallace Cell Perspective 9-26-15 Mitochondrial DNA Mutation Associated with Leber’s Hereditary Optic Neuropathy Wallace LHON 11778 Science 1988 A Mitochondrial Bioenergetic Etiology of Disease Wallace JCI Wallace JAMA Psychiatry2017 Association Between Mitochondrial DNA Haplogroup Variation and Autism Disorders Chalkia_jamapsychiatry_2017 Maternal Inheritance of Human Mitochondrial DNA Giles Maternal Inheritance 1980 Show notes:  3:32: Dawn opens the interview by mentioning that Doug grew up exploring the woods outside his neighborhood in the suburbs of Annapolis, Maryland. Dawn asks if his time outdoors sparked his interest in science when he was young. 4:14: Dawn asks Doug what led him to attend Cornell University after graduating from high school. 5:15: Doug talks about his decision to focus on genetics in school. 6:21: Dawn asks Doug how he selected Yale for his graduate studies. 7:49: Ken mentions that mitochondria can be considered bacterial “power-pack” organelles that generate the majority of a cell’s energy, as well as much else. He goes on to say that mitochondria account for about 30 percent of our bodyweight, and that there are roughly 500 trillion of them. He finally points out that despite all this that they are surprisingly under attended to and asks Doug to give listeners a brief mitochondria 101. 13:37: Ken mentions how he’s glad Doug answered the question of how mitochondria ended up losing 99 percent of their original genes, considering that mitochondria used to be free living bacteria with roughly 1,500 genes. 15:25: Dawn points out that Doug and his colleagues are credited with founding the field of human mitochondrial genetics more than 40 years ago.  She then asks if anyone else was doing similar research when Doug started working on human mitochondrial genetics during his post-doc. 17:55: Following his post-doc at Yale, Doug spent seven years at Stanford University School of Medicine. Dawn asks Doug about his work during this time. 22:01: Dawn mentions that in 1983 Doug became the professor of biochemistry, anthropology and pediatrics at Emory University in Atlanta. During this time, he also was chairperson and senior editor of the Mitochondrial DNA Locus-Specific Database for the Human Genome Organization. Dawn asks what that work entailed. 24:11: Ken asks Doug about accepting a professorship of molecular genetics at the University of California, Irvine where he founded the Center for Molecular and Mitochondrial Medicine and Genetics. 26:25: Dawn mentions that in 2010 Doug moved to Philadelphia to become professor of pathology and laboratory medicine at the University of Pennsylvania. Going on to mention that he also became the founding director of the Center for Mitochondrial and Epigenomic Medicine at the Children’s Hospital of Philadelphia (CHOP). She asks what took Doug to CHOP what sort of work goes on at the center. 28:07: Dawn asks Doug to expand on the work he and his colleagues have done that shows that mitochondrial DNA is inherited exclusively from maternal linage, and that genetic alterations to mitochondrial DNA can result in a wide range of metabolic and degenerative diseases. 31:34: Ken brings up that Doug often talks about how Western medicine has generally approached most diseases from a primarily anatomical and Mendelian perspective, and how it seems that our bioenergetics inheritance has been largely ignored. He asks if this is beginning to change, given the recent attention Doug’s work has gained. 33:53: Ken discusses things from a systems perspective, saying that it stands to reason that as energy availability declinesone would expect to see organ specific symptoms of a systemic defect, asking for Doug to elaborateon this rather sensible perspective when viewed through the lens of energetics. 37:10: Dawn asks Doug to discuss his research into the mutation referred to as, “mtDNA ND6 P25L,” which results in elevated reactive oxygen species production and neurological disease. 45:21: Ken asks Doug to further discuss his work in using mitochondrial DNA variation to trace human migrations and origins. 49:03: Ken mentions how some of his friends submitting genetic material to “23 and Me” and seeing the haplogroups they have inherited from their mother has led to some confusion. 52:23: Dawn asks about the aspect of Doug’s research that suggests that there might have been an ancient European migration to the Americas, a conclusion extrapolated from studying a Native American Tribe in Central North America. 55:49: Dawn mentions the molecular clock, which is essentially the concept that mutations accumulate in a piece of DNA at a roughly constant rate because they occur by chance. She asks about the role of the molecular clock in mapping a population’s history? 58:05: Ken asks if Doug has looked at manipulating cells (when there are some cells with mitochondrial DNA mutations, and some without), to enhance autophagy and thereby get rid of the cells with the mutant mitochondria, and if so, would such interventions like intermittent fasting and the ketogenic diet have any benefit in patients. 1:01:23: Ken mentions that interventions such as intermittent fasting inhibit mTOR, asking if this inhibition is sufficient to have a substantial benefit. 1:03:36: Ken asks Doug to dive deeper into the phenomenon of how the high susceptibility of the mitochondrial DNA to mutations, alongside the fact that it is passed only along the maternal lineage, allows for the rapid adaptation to environmental stimuli while also eliminating the majority of detrimental mutations. Ken asks Doug to also talk about how these changes in mitochondrial genes enable animals to adapt swiftly to changing diets and climates. 1:07:18: Shifting gears, Ken asks for Doug’s thoughts on the possibility of life on other planets, and the bacterial basis for mitochondria on earth that allowed for the explosion of complex life on our planet. 1:09:30: Dawn asks Doug to expand on the concept of mitochondrial DNA variations permitting our migrating ancestors to adapt to new environments, and the idea that these adaptations can predispose certain individuals to disease in environments that their mitochondrial DNA isn’t adapted to. 1:12:21: Dawn mentions that Doug and his colleagues at the center are exploring how mitochondrial genes influence adaptation to extremes in our environment, such as artic cold, tropical heat and high altitude. Mentioning thatIHMC does a great deal of work on human performance in extreme conditions, Dawn asks Doug to talk his work in this area. 1:15:00: Ken asks — if it is even possible — if we should attempt to change how coupled we are, given that mitochondrial coupling can affect disease risk. 1:18:05: Dawn asks which haplogroups are at the highest risk for common diseases such as type 2 diabetes, Alzheimer’s, and cancer. 1:20:02: Dawn asks if people should be testing their haplogroups to see their susceptibility to certain diseases. 1:21:00: Dawn asks if Doug could talk a bit about his research into the association between mitochondrial DNA haplogroups and Autism Spectrum Disorder (ASD). 1:23:18: Dawn asks about Doug’s thoughts on the use of pro-nuclease transfer through three-person IVF, which is a very new and somewhat controversial technique designed to allow mothers with mitochondrial disease to have a baby without passing on that mitochondrial defect. 1:28:49: Ken discusses how mitochondria can no longer be viewed only through the lens of bioenergetics but also as platforms for intracellular signaling, regulators of innate immunity, and modulators of stem cell activity. Each of these properties provides clues as to how mitochondria might regulate aging and age-related diseases. Ken asks Doug to discuss how mitochondria participate in aging and whether a new era of mitochondrial-targeted therapies to potentially slow or reverse the aging process might be in prospect? 1:32:44: Dawn asks if there are any common environmental exposures that are negatively affecting mitochondrial function. 1:34:28: Ken asks Doug if, in addition to exercise, there are any other interventions that he thinks are broadly helpful in regards to improving mitochondrial function. 1:35:49: Dawn discusses how mitochondria produce local electromagnetic fields bymoving electrons as part of their normal function. She asks Doug if he has any thoughts on how external electromagnetic fields, such as those generated by electronics or communication devices, might interfere with mitochondrial function? 1:37:33: Ken mentions that Doug has hypothesized that the Qi and energy fields mentioned and targeted in Chinese medicine may actually be a proxy for mitochondrial phenotype and function. Asking how one might measure these in a human, and how could that affect disease treatment? 1:40:54: Dawn mentions how she is looking forward to seeing what comes out of the institute Doug is working on in China, which is bringing together Western, anatomical perspectives with the concepts found in Chinese Medicine. 1:41:09: Dawn comments on how Doug wasinducted into the Italian Academy of Sciences during the Academy’s 234th annual meeting in Rome. The Academy, founded in 1782, has a mission of encouraging scientific research. With a membership limited to 40 Italian scientists and 25 foreign members, the Academy’s long history, has seen such notable members as Albert Einstein, Benjamin Franklin, Louis Pasteur and Rita Levi-Montalcini. She closes the interview by mentioning how rewarding that must have been for Doug.                      

In today’s episode, Ken and Dawn interview their colleague Dr. Peter Neuhaus, a senior research scientist here at IHMC. Peter is an engineer well-known for his work on wearable robotic devices. In particular, Peter has focused on lower extremity exoskeleton devices and their applications for mobility assistance for paraplegics and other people with disabilities or partial paralysis. In 2016, Peter lead an IHMC team that won a silver medal in the international Cybathlon, a competition conducted in Zurich in which people with disabilities used advanced assistive devices, including robotic technologies, to compete against each other. In today’s interview, Peter talks about IHMC’s humanoid robotic efforts as well as his work with NASA designing an exercise machine for a human mission to Mars or other missions beyond low earth orbit. Peter also describes the work he is doing with IHMC High-Performance Director Joe Gomes, the former Oakland Raiders strength and conditioning coach. Peter and Joe as well as others at IHMC are designing exercise technologies to extend the resilience of high-performing humans, such as astronauts and elite warfighters. Many of these technologies will eventually be able to be utilized by the general public. Links:  Peter Neuhaus IHMC page: https://www.ihmc.us/groups/pneuhaus/  DARPA Robotics Challenge videos: http://robots.ihmc.us/drc/  Cybathlon videos: http://robots.ihmc.us/cybathlon/  IEEE Robotics and Automation Magazine article about Cybathlon: https://arxiv.org/pdf/1702.08656.pdf  IHMC newsletter article about Cybathlon: https://www.ihmc.us/wp-content/uploads/2015/08/IHMCNewslettervol10iss3.pdf  IHMC newsletter article about DARPA Robotics Challenge: https://www.ihmc.us/wp-content/uploads/2017/07/IHMCnewslettervol13iss1.pdf  Show notes: 3:03: Dawn asks Peter about growing up in New York City. 3:33: Ken mentions that after high-school, Peter enrolled at MIT. Ken asks Peter what led him there. 4:04: Ken asks why Peter decided to major in mechanical engineering. 4:35: Dawn asks Peter what led him to travel across the country to attend the University of California, Berkeley for graduate school after he graduated from MIT. 5:10: Dawn asks what it was like for Peter to teach science to 5th– and 6th-graders as well as high-schoolers in Brooklyn after he received his master’s degree from Berkeley. 6:23: Peter talks about how after two years of teaching, he decided his window of opportunity to get a doctorate was shrinking and that it was essentially “now or never,” which led him back to Berkeley. 7:02: Dawn mentions that once Peter finished his doctorate, he went to work for a startup as a mechanical engineer. She asks what sort of work he did there. 7:47: Dawn talks about how a year and a half after getting his doctorate Peter met his future wife, who eventually led him to Pensacola, and in a roundabout way, to IHMC. She asks if he could share how that all came about. 9:22: Ken comments on how since joining IHMC in 2003, Peter has focused on wearable robotics systems and legged robots. Ken further mentions that Peter was one of the lead IHMC researchers participating in the DARPA Learning Locomotion project, where he helped develop quadrupedal locomotion algorithms for the Little Dog robot. Ken asks if Peter could talk about his work on this project? 11:08: Dawn, continuing with the discussion about DARPA projects, mentions that Peter played an important role in both the development of technology and in the management of IHMC’s humanoid robotics effort for the DARPA Robotics Challenge that was held between 2013 and 2015. IHMC placed second and brought home $1 million in prize money. Dawn asks what that experience was like. 12:10: Ken mentions there were three competitions that were part of the robotics challenge, and asks Peter to talk about IHMC’s performance in each of the competitions. 12:57: Dawn mentions that for more than a decade, Peter has been working on exoskeletons, wearable robotic devices that assist people with paralysis and other disabilities. She asks Peter how he got interested in this, and if he could give an overview of what is involved in the development of exoskeletons. 14:39: Ken comments on how wearables are a challenging application for robotics. He asks if Peter could elaborate on some of the specific technical challenges that go along with it. 15:27: Dawn changes the topic to the Cybathlon, a competition, held in Zurich, Switzerland for people with disabilities who are supported by modern assistive technology. IHMC won another silver medal in that competition and Dawn asks about the IHMC team’s preparation for the Cybathlon. 18:18: Ken mentions that a key factor that set IHMC’s exoskeleton apart from the rest at the Cybathlon was the incorporation of powered ankles, which improved mobility. Ken asks Peter to talk about the importance of this feature that the team added to the exoskeleton. 20:05: Dawn asks whether the balancing algorithms that are used in humanoid robots could also be used for ekoskeletons. 22:25: Dawn reads something that Peter once said: “Humans are great at perception. We can look around an area and see where we should go, and what we should step on. But communicating that information to a computer is pretty challenging.” Dawn asks Peter what those challenges are, and if he could speculate about the features that might be incorporated into a state-of-the-art exoskeleton 10 years from now. 24:41: Dawn asks about Peter’s involvement in the X1 exoskeleton that was developed in collaboration with NASA Johnson Space Center. 25:32: Continuing the discussion about NASA, Ken mentions that Peter and his team are also working with NASA on an exercise machine for long duration deep-space missions, such as a Mars mission. Ken talks about how astronauts are so susceptible to bone density and muscle loss while in space that exercise is very important. He asks Peter about the challenges of building exercise devices specifically designed for microgravity. 27:22: Dawn quotes the director of exercise physiology of the Johnson Space Center, Dan Hagen, who said, “Exercise is the number one health priority for astronauts when they are in space. No other activity, except eating and sleeping, is given that much priority. Two and a half hours each day are devoted to fitness.” Dawn asks if a computerized exercise machine could reduce the amount of time someone needs to train, which would free them up to be more productive. 28:33: Ken asks about Peter’s thoughts on how his work with NASA on exercise technology could have applications here on earth. 29:21: Dawn mentions that IHMC recently hired Joe Gomes as the institute’s high-performance director. She goes on to mention that Ken is in the process of building a team to search for ways to extend the resilience of high-performing humans operating in extreme environments and conditions. The team multi-disciplinary team is comprised of engineers and software developers, physicians, pathologists, social scientists, and human-performance specialists to improve training and maximize a person’s physical and cognitive performance. In light of that, Dawns asks Peter to give an overview of how he is teaming up Joe to develop an exercise machine. 30:18: Dawn comments on how health and fitness wearables and apps have, up to this point, merely tracked activity and reported it after the fact. She goes on to ask if it’s correct that the device Peter and his team are developing will enable both the trainee and trainer to receive immediate feedback and prompts during a workout. 31:14: Ken asks Peter whether the technology he is developing with Joe and the rest of the team will get away from a one-size-fits-all model and lead to a more personalized-training model. 32:26: Dawn asks Peter about rehabilitation, and if the exercise machine, or some version of it, will help track and quantify someone’s rehab from injury. 33:37: Dawn asks about the potential commercial uses for the exercise device. 34:21: Dawn asks if computer-controlled motorized resistance also makes exercise safer. 34:55: Ken asks Peter to discuss how the exercise device could potentially help the aging population given that muscle mass begins to decrease substantially after age 60 and leads to falls, frailty and insulin resistance, among much else. 36:49: Dawn asks Peter about the Mobility Unlimited Challenge, sponsored by the Toyota Mobility Foundation. She asks about IHMC’s role and why Toyota is interested in exoskeleton technology. 37:34: Dawn mentions that recently IHMC hosted the 13th annual Dynamic Walking Conference, where students, professors and engineers from around the world gathered in Pensacola for five days of presentations and demonstrations. She asked Peter to explain what the conference was about and what were some of the highlights from the meeting. 38:57: Ken mentions that 2020 is shaping up to be a big year for Peter and the entire IHMC Robotics group. In addition to the Toyota Mobility Challenge, the next Cybathlon is also scheduled for 2020. Ken asks if Peter could discuss his plans for that event. 39:45: Dawn brings up how Peter likes to participate in triathlons, and that he’s been quite active in the triathlon club in Pensacola. She says she understands that Peter recently had to give up running and asks about if that’s true. 41:01: Dawn closes by asking Peter if there is any chance that one day some of the technology Peter is developing could help him get back into running.    

Dr. Brendan Egan is an Associate Professor of Sport and  Exercise Physiology at Dublin City University who is well known for research that shows resistance training can improve strength, muscle mass, reduce falls in older people, and perhaps even extend lifespans. In addition to being a first-class researcher, Brendan is also a stand-out player in Ireland’s national sport, Gaelic football. His current research is exploring the synergy between nutrition and exercise interventions to optimize performance in athletes and the elderly. Current projects also involve protein hydrolysates in recovery and glycemic management; leucine and n-3 PUFAs in the elderly; and exogenous ketones and athletic performance. Links:  Brendan Egan’s faculty page:  https://dcu.academic.ie/live/!W_VALOCAL_DCU_PORTAL.PROFILE?WPBPRSN=1631629 Brendan Egan’s Researchgate profile https://www.researchgate.net/profile/Brendan_Egan2/contributions Brendan Egan’s TEDx talk: https://youtu.be/LkXwfTsqQgQ Exercise Metabolism and the Molecular Regulation of Skeletal Muscle Adaptation https://www.sciencedirect.com/science/article/pii/S1550413112005037 Metabolism of ketone bodies during exercise and training: https://physoc.onlinelibrary.wiley.com/doi/epdf/10.1113/JP273185 Fueling performance: Ketones Enter the Mix: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(16)30438-7 Does Strength-Promoting Exercise Confer Unique Health Benefits? https://academic.oup.com/aje/article-abstract/187/5/1102/4582884?redirectedFrom=fulltext Does Strength-Promoting Exercise Confer Unique Health Benefits? https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP275938 Show notes: 2:46: Dawn opens by mentioning that Brendan was born in Detroit, and that his Irish father moved the family to Ireland when Brendan was 3 years old. Dawn asks if Brendan’s mother was American. 4:09: Dawn comments on how Brendan was very athletic as a child and played Gaelic football, which is Ireland’s national sport, and asks if he could explain how this game is played. 6:02: Ken, following up on the last question, asks what Brendan’s training is like for this sport, and how he manages to fit it into his busy schedule as a professor. 7:41: Dawn asks if it is true that even though Brendan’s best grades were in math and physics, he never considered a career in science while he was in high school. 8:37: Dawn mentions that Brendan ended up at the University of Limerick after graduating, asking what made him decide to attend Limerick as well as what prompted him to major in sports and exercise science. 9:46: Dawn asks about two people, Phil Jakeman and John Kirwan, who played a big role in shaping Brendan’s education at Limerick. 11:58: Dawn comments on how after completing his bachelor’s of science degree, Brendan went to work on his master’s, heading to the UK and attending Loughborough University where he graduated with distinction in sports exercise and nutrition. Dawn asks what made him decide to attend Loughborough, and what stood out about his time there. 13:33: Dawn mentions that Brendan returned to Ireland in 2004 to start his doctoral studies under the supervision of Dr. Donal J O’Gorman at Dublin City University. Dawn asks what that experience was like. 15:06: Ken asks what Brendan learned from his research with Dr. O’Gorman, which focused on skeletal muscle adaptation to exercise and, in particular, continuity between acute molecular responses to individual bouts of exercise and the adaptations in skeletal muscle induced by exercise training. 18:30: Dawn asks what took Brendan to Karolinska Institute in Stockholm. 19:51: Brendan talks about his work at Karolinska using animal intravenous cell systems, and his research into transcriptional regulation of skeletal muscle insulin resistance and type 2 diabetes utilizing small non-coding RNA’s. 23:39: Ken mentions that Brendan’s first faculty position was at the University College Dublin in 2011, where he spent five years establishing his own independent research group. He then moved to Dublin City University in 2016. Ken asks how Brendan developed his research group, and what kind of work the group does now. 25:44: Dawn asks Brendan to discuss the prevalence of the age-related loss of muscle function and mass, which often leads to sarcopenia. She also asks about its effects on individuals as well as its impact on society. 27:45: Ken mentions that the heavy use of Prednisone, which a lot of older people are put on for long periods of time, rapidly diminishes their muscle mass. 29:35: Ken mentions that falls are a huge issue, seemingly associated with the loss of fast-twitch muscle as we age, and that falls are more a result of loss of power than loss of strength and mass. He proposes that this is a major, yet overlooked, driver of the prevalence of falling in the older population. 31:11: Ken comments on how there are complex and interacting causes of this loss of mass, strength and power which are not completely understood yet. He lists off certain drivers such as: insulin resistance; decreased availability of anabolic hormones coupled with increased anabolic resistance; the need for more protein as we age; decreased motor neuron function; elevated intercellular oxidative stress; reduction in satellite cell numbers and regenerative capacity; elevated myostatin signaling; reduced physical activity; increased chronic inflammation; changes in autophagy; and mitochondrial abnormalities. Ken asks Brendan to share his thoughts on what he considers the primary drivers of muscle loss. 33:06: Dawn mentions that one of Brendan’s most recent research studies is centered on the optimal way to exercise in terms of time efficiency. She inquires as to what the best combination of exercise would be for someone with a limited amount of time per week. 35:53: Dawn asks Brendan to talk about the importance of leg strength. 37:05: Dawn mentions that it has been well established for many years that resistance training can improve strength and muscle mass, and reduce the incidence of falls and fractures. She asks Brendan to talk about a recent study, done over the course of 15 years with more than 30,000 participants 65 years and older. The study showed that people who did strength training twice a week lowered their risk of dying by almost half. 38:33: Dawn asks what Brendan found in a follow-up study he did where he looked at a nutrition intervention that featured a high protein diet in combination with exercise versus a high protein diet alone. Unlike most similar studies, Brendan’s follow-up study used whole foods rather than protein supplements. 40:47: Dawn mentions that Brendan and other scientists at UCD are currently investigating a dairy-based protein which has been predigested from hydrolysate to see if it will enhance the insulin response and lead to a faster recover compared to other protein and carbohydrate drinks. 42:06: Ken comments on how optimal recovery post-exercise is more and more appreciated, and it’s obviously desired across athletic populations. He asks what happens at the cellular and molecular level during recovery that Brendan finds most relevant and interesting. 43:50: Dawn mentions that Brendan has been looking at exogenous ketone supplementation, particularly in the area of sport science, and how it might relate to athletic performance, and asks what this research is specifically focused on at the moment. 44:41: Ken asks Brendan for his thoughts on increasing the circulating availability of BHB by consumption of exogenous ketones and wonders if it would recapitulate the many positive effects of decreasing carbohydrate intake, which manifests itself in those engaged in a keto-adapted phenotype. 46:20: Dawn mentions that in some circles there is concern that one might overload the mitochondria by providing both high levels of glucose and ketones, asking what Brendan’s thoughts are on this. 47:23: Dawn asks what we know about the impact of exogenous ketones in athletic performance. 51:36: Dawn asks about exogenous ketone esters, particularly the HVMN monoester. She also asks about the AcAc diester developed by Dominic D’Agostino. She supposes that the two different compounds would have distinct pharmacokinetics and somewhat different effects. She asks Brendan to discuss this. 54:39: Dawn mentions that Brendan has given ketone salts and esters to athletes, and that there’s talk in the community about the tolerability of these different compounds. She asks about his experience with them and how he has improved the tolerability in his studies. 56:02: Ken asks about the effects of exogenous ketones on carbohydrate metabolism in high intensity sport, and what he thinks of the glycogen sparing versus glycogen impairing debate around exogenous ketones. 1:00:39: Dawn mentions that exogenous ketones lower blood glucose, asking what the role of the hepatic glucose output is, versus the change in peripheral uptake, and asks Brendan if he thinks BHB could be altering peripheral glucose uptake. 1:02:24: Ken asks about Brendan’s thoughts on studies concluding that exogenous ketone esters helped blood ketone concentrations reach greater than 2 millimolar and is likely a key mediator of any potential ergogenic effect. 1:03:32: Ken mentions the topic of recovery, pointing out that there have been several papers in recent years that look at the BHB monoester and recovery. Ken asks Brendan to discuss these studies and their implications for future research. 1:07:10: Dawn asks if exogenous BHB might have the same effect as exercise, which has long been known to increase brain derived neurotrophic factor (BDNF) which enhances mental abilities, reduces anxiety, and increases neuroplasticity, considering that BDNF has been shown to be inhibited by histone deacetylases (HDACs), and that BHB inhibits HDACs. 1:08:21: Ken mentions that there have been a few ingestibles that have had effects that act as exercise mimetics. He inquires as to Brendan’s thoughts on these compounds. 1:10:14: Dawn asks Brendan about how Ireland is projected to become the fattest nation in Europe in the next 10 to 15 years. 1:11:07: To wrap things up, Dawn asks Brendan to give three to five pieces of advice for living a longer and healthier life, no matter the age.

Today’s episode features Dr. Valter Longo, director of the Longevity Institute at the University of Southern California. Valter is best known for his research on stem cells and aging as well as his fasting-mimicking diet. Often referred to as FMD, the diet is intended to avoid the downsides of fasting while reaping the health benefits of a calorie-restrictive diet. Over a 25-year career, Valter has published numerous papers about the ways specific diets can activate stem cells and promote regeneration and rejuvenation in multiple organs to reduce the risk for diabetes, cancer, Alzheimer’s and heart disease. He writes about this research and diet in a book that was released earlier this year, “The Longevity Diet: Discover the New Science Behind Stem Cell Activation and Regeneration to Slow Aging, Fight Disease and Optimizer Weight.” The book details an easy-to-follow everyday diet that is combined with short periods of the fasting-mimicking diet. Valter says the diet has the potential to help people live healthier and longer lives. Valter is a native of Genoa, Italy and moved Chicago when he was 16. He received his bachelor’s of science degree at the University of North Texas in 1992 and his Ph.D. at UCLA in 1997. Links: Longevity Center website: http://longevityinstitute.usc.edu Longo’s USC faculty page: http://gero.usc.edu/faculty/longo/ “The Longevity Diet”: https://amzn.to/2s1fcky A periodic diet that mimics fasting promotes multi-system regeneration: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509734/ Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration: https://www.cell.com/cell/fulltext/S0092-8674(17)30130-7 Fasting-mimicking diet and markers/risk factors for aging: http://stm.sciencemag.org/content/9/377/eaai8700 Prolon FMD website: https://prolonfmd.com/fasting-mimicking-diet/?doing_wp_cron=1526216346.5062971115112304687500 Show notes: 2:24: Dawn opens the interview by mentioning that Valter was born and raised in Genoa, Italy, the hometown of Christopher Columbus. She asks if reports of him driving his neighbors mad playing Dire Straits, Jimmy Hendricks and Pink Floyd on his electric guitar as a youth are accurate. 2:43: Dawn asks Valter what his parents said when he tried to talk them into letting him go to London to be a rock star when he was 12 years old? 3:10: Valter left home when he was 16 to go visit an aunt in Chicago, but ended up staying in Chicago to go to school and play music. Dawn asks what that was like? 3:49: Dawn comments on how in addition to being exposed to some of the best blues music in the world, Valter also was exposed to some of the unhealthiest food in the world. Valter then talks about what he refers to as “the heart-attack diet.” 4:48: Dawn asks what lead Valter to attend the University of North Texas College of Music. 5:30: Valter joined the Army Reserve to help pay for college and ended up assigned to a battalion of Army tankers. Ken asks Valter what that was like. 6:15: Dawn asks if it’s true that the idea of directing a marching band lead Valter to switch majors as a sophomore. 7:07: Dawn comments on how not many jazz performance majors, who have never taken a biology course, decide to switch their major to biochemistry. She asks Valter what the people in the biochemistry department had to say about that. 8:04: Dawn mentions that when Valter was five years old, he saw his ailing grandfather pass away. She asks him to talk about that experience and the role it played in his decision to study aging. 9:14: Dawn mentions that after switching over to biochemistry and graduating from college in 1992, Valter headed to UCLA, which at the time was one of the world’s leading centers of longevity research. She asks Valter how that opportunity came about. 10:22: Ken brings up Valter’s work at UCLA in the lab of the pathologist, Roy Walford. Valter studied the effects of caloric restriction in the lab and Ken asks Valter to talk about what he learned. 11:25: Dawn comments that while in Walford’s lab, Valter made two important discoveries using a method that he invented. Dawns asks him to describe the discoveries. 13:20: Dawn asks Valter what led him to do his post-doc work at the University of Southern California, and what the focus of his research was at USC. 14:04: Dawn asks what it was like to study in a community of dwarves in Ecuador, a group of people who lack the receptor for the growth hormone, which is known as Laron syndrome. Valter talks what he learned from that experience. 16:08: Ken notes that these dwarves seem to be nearly immune to cancer and diabetes. Accidents, convulsive disorders and alcohol deaths, however, account for 50 percent of their mortality. Among non-dwarf relatives, these same causes of mortality account for just three percent of deaths. Ken asks Valter what causes this big disparity. 17:54: Dawn recounts that Valter went on to become a professor of gerontology and biological sciences at USC, and that in 2011 he became the director of the Longevity Institute. She goes on to say that the institute is not just interested in the idea of people living longer, but also understanding how people can live healthier longer. She asks if Valter could give some background on the institute and the type of research it does. 19:27: Ken notes that Valter believes it is smarter to intervene on aging itself, rather than try to prevent and treat diseases one by one as they come up. Ken asks Valter to talk about that. 21:04: Dawn mentions that Valter has traveled the world studying people in “blue zones,” areas of the world with the longest-lived populations. She goes on to mention that because of his time with centenarians, Valter concluded that in order to understand how people can live healthy lives, one needs to go beyond the scientific, epidemiological, and clinical studies, and investigate actual populations that age successfully. 23:11: Ken mentions that Valter had the opportunity to know Emma Romano, who lived to 117 and was reportedly the oldest person in the world. He goes on to mention that Emma’s sisters also lived into their 90s and some of the sisters made it to 100. These women, it would seem, were rare individuals who could eat and do just about anything they wanted and still age successfully. Ken asks how much of a role genetics played in their lifespan. 24:30: Dawn shifts gears to talk about Valter’s book “The Longevity Diet,” which is the outgrowth of Valter’s 30 years of research on aging. The book describes a daily nutritional regiment that is combined with the “fasting mimicking diet.” Dawn asks if Valter could define the fasting-mimicking diet. 27:02: Ken asks Valter what it is about the fasting-mimicking diet that actually mimics fasting. 28:38: Dawn asks if one should measure markers such as glucose, ketones, insulin, and IGF-1 while undergoing the fasting mimicking diet. 29:42: Dawn asks if the implementation of the diet requires a doctor’s supervision. 30:46: Dawn inquires as to what a typical fasting-mimicking diet meal looks like. 31:13: Dawn asks how Valter arrived at the 5-day period as the necessary time to experience the benefits of the fasting-mimicking diet. 32:22: Dawn asks if there are populations that Valter wouldn’t recommend the diet to. 33:33: Shifting gears, Ken asks if one can have coffee on the fasting-mimicking diet, mentioning that Valter’s grandfather and Emma Romano likely enjoyed espresso. 35:01: Ken mentions that Valter has said that skipping breakfast increases overall morality and asks him to explain this. 36:42: Dawn mentions that Valter has published a number of papers that indicate that cycles of fasting and refeeding can cause multisystem regeneration and rejuvenation that lead to extended health spans and effects ranging from those on the immune system to the nervous system to muscles. She asks Valter to talk about this. 38:27: Ken asks if Valter could share what he calls the “five pillars of longevity.” 41:31: Dawn asks about the mechanism by which fasting causes an unfavorable environment for cancer cells. 44:24: Ken brings up metformin as an example of a compound that can artificially induce some of the benefits of fasting in the body. 45:45: Ken returns to IGF-1, asking what role it plays in both health and disease. 46:31: Ken brings up the epidemiology research done in the 2011 meta-analysis by Burgers Atoll which showed that both low and high IGF-1 concentrations are associated with increased mortality, essentially showing that the hazard ratio appears U shaped in that both ends of the spectrum are hazardous to a person’s health. Ken asks if there is a sweet spot, or if Valter considers it to be a case of the lower the better, or if it somewhat depends on a person’s age? 48:42: Ken mentions that something that tends to be overlooked in discussing IGF-1 is that fasting, the ketogenic diet, and other such things increase the receptor sensitivity for IGF-1. Thus, even at a relatively low level, the effects would not be the same for someone not in a state of ketosis. 49:52: Dawn asks if protein intake is the only dietary factor involved in regulating IGF-1 levels. 50:21: Ken mentions that Valter’s 2014 cell metabolism paper leveled the risk firmly at the door of IGF-1 concentrations. Ken brings up that IGF-1 regulation of metabolism, however, is more about the interactions of IGF-1 with binding proteins. Ken asks how much IGF binding proteins play a role in IGF. 51:42: Dawn brings up that in 2014 Valter published a study with Levine Addal that said, “We provide convincing evidence that a high-protein diet, particularly if the proteins are derived from animals, is nearly as bad as smoking for your health.” She asks Valter to explain the process of coming to that conclusion. 52:33: Following up on that question, Ken mentions that the risks purported in the paper were relative risks, not absolute risks. In other words, the relative risk of dying from cancer in the high-protein group was roughly four times that of the low-protein group, but the absolute change in risk was maybe half of one percent. Ken points out that depending on how one presents the risk, it could lead to different headlines. 53:26: Ken comments on how he believes the presentation of risk to be misleading, because the change in absolute risk was so negligible as to be noise. 53:58: Ken, returning to protein, mentions that protein intake is complex and multifactorial. Ken asks Valter if the epidemiological research that has been discussed in the interview is able to tease out the important nuances and variables. 56:43: Dawn mentions that Valter often receives emails from people diagnosed with cancer, autoimmune disorders and neurodegenerative diseases who are seeking options beyond the standard treatments offered by their doctors. Valter says this was a key reason he established the Create Cures Foundation, and goes on to give an overview of the foundation and how it is funded. 58:01: Interview ends.