STEM-Talk

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.

Dr. Keith Baar joins Ken and Dawn today for the second of his two-part interview for STEM-Talk. Keith is a renowned scientist in the emerging field of molecular exercise physiology who has made fundamental discoveries on how muscles grow bigger, stronger, and more fatigue resistant. He is the head of the Functional Molecular Biology Laboratory in the Department of Neurobiology, Physiology, and Behavior at the University of California, Davis. In his lab, he leads a team of researchers attempting to develop ways to improve muscle, tendon and ligament function. Part one of our interview, episode 62, covered Keith’s childhood in Canada and his undergrad years at the University of Michigan as well as his time at the University of California, Berkeley, where he earned a master’s degree in human biophysics. We talked about Keith’s work at the University of Illinois, where he received a doctorate in physiology and biophysics. We also covered Keith’s time in the lab of John Holloszy, who is known as the father of exercise research in the United States, as well as the five years Keith spent at the University of Dundee in Scotland. Episode 63 picks up with Keith explaining his decision to return to the states and join the faculty at the University of California, Davis.  Ken and Dawn then talk to Keith about his most recent research, some of which is looking at how to determine the best way to train, as well as what types of foods compliment training to decrease tendon and ligament injury and accelerate return to play. This work has the potential to improve muscle function not only in athletes, but also improve people’s quality of life as they age. Another key topic covered in part two of our interview is the research Keith is doing on a ketogenic diet and its potential to reduce cancer rates and improve cognition. Keith also provides his thoughts on what optimal workouts and nutrition should look like. Links: Baar’s UC Davis physiology department bio: https://www.ucdmc.ucdavis.edu/physiology/faculty/baar.html Baar’s UC Davis biology department bio: https://biology.ucdavis.edu/people/keith-baar Functional Molecular Biology Lab website: http://www.fmblab.com/  Molecular brakes regulating mTORC1 activation in skeletal muscle paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137116/ Age-related Differences in Dystrophin article: https://www.ncbi.nlm.nih.gov/pubmed/27382038 Show notes: 2:54: Dawn begins part 2 of our interview by mentioning that for the past eight years, Keith has been working at the University of California Davis. She asks Keith what prompted him to return to the U.S. from Scotland and join the faculty at UC Davis. 3:37: Dawn points out that Keith’s Functional Molecular Biology Lab conducts research across a range of related topics, including musculoskeletal development and adaptation as well as methods for engineering functional musculoskeletal tissues in vitro. She asks Keith to give a high-level overview of some of that research. 4:16: Dawn comments that some of Keith’s recent work has shown that we can use specific nutrition and training strategies to optimize injury recovery and prevention. She goes on to say that musculoskeletal injuries are among the most common problems that active people have. 8:45: Ken talks about how Keith has noted that tendon stiffness is dependent upon collagen content, and the amount of crosslinks within. He goes on to mention that Keith has developed various training modalities, as well as nutritional protocols, that can increase and decrease tendon stiffness. Ken begins this line of inquiry by asking about the training methods for this purpose. 12:04: Following up on the previous question, Ken asks whether anyone has looked at how blood flow restriction training, which is increasing in popularity, affects tendon stiffness. 13:32: Dawn moves on to asking about nutrition. She mentions that Keith’s lab has done a great deal of groundbreaking work on the use of gelatin and a small amount of vitamin C to augment collagen synthesis in tendons, ligaments, cartilage, and bone. She asks if he could talk about this nutrition protocol and its effects, particularly when combined with jumping rope. 17:52: Ken mentions that this work is not only interesting scientifically, but it has an immediate, practical application that people can use in their life. Ken goes on to say that those suffering from stress fractures or a variety of other ailments could benefit from this. 21:09: Ken mentions that there are several different forms of collagen, asking if there is any particularly efficacious form, or if they function equally. 22:40: Ken comments that it is not just lower body weakness and injuries in tendons, but also tendonitis that is found in the shoulders and elbows. He asks if there is a variant of Keith’s protocol that is suited for this sort of tendonitis as well. 24:37: Ken asks a question submitted by friends in the special ops community. He mentions that one of their biggest issues is force absorption, due to the repeated, substantial, damage accrued in both training and in operations. He goes on to ask if a focus on eccentric training would lengthen fascicles to allow for greater absorption, and how does it influence the ability to contract concentrically. 26:13: Dawn mentions that she has heard Keith discuss “sugar cross-linking” in the context of aging and diabetes. She asks if this explains why diabetics suffer an increased incidence of tendon and ligament ruptures and injuries. 28:22: Ken, coming back to tendon stiffness, mentions that in addition to fast exercise, inactivity also leads to increased tendon stiffness, counterintuitive as that is. He asks if Keith could discuss this, somewhat surprising, fact. 30:20: Ken comments that ligament engineering is another fascinating area of Keith’s research; he goes on to say that Keith and his colleagues recently engineered the first in vitro ligaments. He goes on to inquire as to how these ligaments are created, what insights can be gleaned from them, and how Keith sees them being used in the future. 34:23: Ken states that mTOR inhibition by rapamycin is arguably the only strategy that has reliably resulted in lifespan extension across a multitude of different species. He goes on to say that we know that mTORC1 activation increases muscle mass and strength, which is critical for optimizing health span into old age. He goes on to bring up a recent paper Keith co-authored with Megan Roberts that showed the ketogenic diet had tissue-specific effects on mTORC1 signaling; decreasing signaling in the liver, while increasing it in the muscle. Ken postulates that perhaps researchers should focus their attention on tissue-specific mTOR activity, to further elucidate the issue of balancing mTOR for longevity with the maintenance of muscle for strength quality. Ken asks Keith if he had unlimited resources, how would Keith design a study to explore this. 43:32: Ken asks if Keith is familiar with a class of drugs that one could characterize as PPAR-delta agonists, sometimes called exercise mimetics, given the overlap between the effects of the ketogenic diet and this class of drugs. 45:10: In regards to longevity, Dawn mentions that few would argue that many elite athletes train for performance at the expense of health. She asks what would be Keith’s overall training recommendation for someone who wants to maximize healthspan and lifespan, and if that is possible while also striving for top levels of performance. 49:24: Ken comments on a belief in the world of “bro science,” that post-exercise carbohydrate ingestion is absolutely necessary for maximizing the anabolic response of resistance training. Ken asks if this is true, and if not, if Keith would educate us as to why and what optimal nutrition and workouts should look like. 51:18: Ken asks what Keith sees as the role of autophagy in the maintenance of muscle mass in aging adults. 53:48: Ken comments on the phenomenon of older people developing anabolic resistance, much like insulin resistance; mentioning a paper that recently looked at the ketogenic diet in that context and found it increased IGF-1 receptor sensitivity. 54:46: Dawn asks to what extent does Keith think a person’s baseline body composition can impact the response to an exercise stimulus. 55:44: Ken points out that Keith has been a scientific advisor for a number of different athletic teams and organizations, pointing out that Keith works to maximize the effects of training for both endurance and strength as well as ways to minimize injury. Ken asks Keith what that experience has been like. 58:27: Ken mentions his intrigue with the mission statement of Keith’s Functional Molecular Biology Lab: “To perform world class musculoskeletal research in a family environment.” Ken asks Keith to explain the story behind including “a family environment” in his mission statement. 1:01:08: Interview ends.

Today’s episode is the first of a two-part interview with Dr. Keith Baar, the head of the Functional Molecular Biology Laboratory in the Department of Neurobiology, Physiology, and Behavior at the University of California, Davis. In his capacity as a researcher, Keith has made fundamental discoveries on how muscle grows bigger, stronger, and more fatigue resistant. He is a renowned scientist in the emerging field of molecular exercise physiology, and is leading a team of researchers attempting to develop ways to improve muscle, tendon and ligament function. Part one of our interview features our conversation with Keith about his background and his time time in the lab of John Holloszy, who is known as the father of exercise research in the United States. Episode 63 of STEM-Talk has Dawn and Ken talking to Keith about his most recent research, which is looking at how to determine the best way to train, as well as what types of foods compliment training to decrease tendon and ligament injury and accelerate return to play. This work has the potential to improve muscle function and people’s quality of life, especially as they age. Ken and Dawn also have a conversation with Keith about the research he is doing on a ketogenic diet and its potential to reduce cancer rates and improve cognition. Links: UC Davis physiology department bio: https://www.ucdmc.ucdavis.edu/physiology/faculty/baar.html UC Davis biology department bio” https://biology.ucdavis.edu/people/keith-baar Functional Molecular Biology Lab website: http://www.fmblab.com Molecular brakes regulating mTORC1 activation in skeletal muscle paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137116/ Age-related Differences in Dystrophin article: https://www.ncbi.nlm.nih.gov/pubmed/27382038  Show notes: 3:14: Dawn opens the interview by mentioning that Keith grew up in Canada, and asks what he was like as a child. 4:02: Dawn asks if Keith was interested in science as a kid. 4:53: Dawn comments that after high school, Keith came to the U.S. to attend the University of Michigan, where he earned a bachelor’s degree in kinesiology. She Keith if Michigan was where he first became interested in the science of how muscles work. 7:54: Dawn asks Keith if he played any sports at Michigan. 8:34: Dawn asks what lead Keith to attend the University of California, Berkeley to pursue a master’s degree in human biophysics. 9:39: Dawn mentions that after his time at Berkeley, Keith returned to the Midwest to attend the University of Illinois where he received his doctorate in physiology and biophysics. She asks why he decided on Illinois for his doctoral work. 11:12: Ken mentions that Keith’s Ph.D. work focused on the effect of resistance exercise on specific molecular markers that are related to muscle growth. He goes on to say that Keith identified that mTOR complex 1 was activated in response to resistance exercise and that the activation was proportional to the load across the muscle. He asks Keith to talk about this work and its significance. 16:20: Ken comments how surprising that discovery must have been. 17:33: Ken asks Keith to explain the two basic ways of activating mTORC1 in skeletal muscle. Ken also asks whether these two are merely additive, or if together they elicit a greater muscle protein response than either would independently. 29:49: Dawn mentions that after Illinois, Keith went to work in the lab of John Holloszy at Washington University in St. Louis, a professor of medicine who is known as the father of exercise research in the United States. Dawn asks if is Holloszy is the one who discovered that when people do endurance exercise that their muscles accumulate more mitochondria. 32:24: Ken asks about the role of PGC-1a. 38:43: Ken comments that we know most sports require a combination of strength and endurance for optimal performance, bringing up the topic of concurrent training. 48:02: Ken asks if we know which form of AMPK is activated by things such as Metformin or the ketogenic diet. 49:24: Dawn comments that Keith eventually accepted a position at Michigan where he worked with Bob Denis, who figured out how to engineer muscles as well as ligaments. She asks Keith to share some things about the research they did together. 50:41: Dawn mentions that after Michigan, Keith accepted a position at the University of Dundee in Scotland, where he worked for 5 years. Dawn asks what that experience was like. 55:20: Ken mentions that from looking at the literature, it seems as though Keith discovered that the non-contractile portion of the muscle plays a key role in the transfer of force, and that this is nearly as important as the size of the muscle fiber itself. He asks Keith to elaborate on this finding. 58:45: Ken asks if Keith’s work has elucidated a potential countermeasure to the loss of dystrophin, for both the aging population and cancer patients. Keith then talks about research at the University of California, San Diego, that has shown the beneficial effects epicatechin, a flavanol in dark chocolate. 1:00:37: Ken mentions that some athletes are using Transdermal Epicatechin, and asks about the efficacy of such practice. 1:01:54: Interview ends.

More than 90 Americans a day are dying from opioid abuse. Today’s guest, Dr. Christopher McCurdy, is at the forefront of research designed to help the U.S. deal with this drug overdose crisis. Chris is a medicinal chemist and behavioral pharmacologist at the University of Florida who is internationally known as an expert on kratom, a botanical mixture that has been shown to help people struggling with addiction. He recently became president of the American Association of Pharmaceutical Scientists, and has spent his career focusing on the design, synthesis and development of drugs to treat pain and drug abuse. Chris earned his bachelor of science degree in pharmacy from Ohio Northern University, and a Ph.D. in medicinal chemistry from the University of Georgia College of Pharmacy in 1998. He did his postdoctoral work at the University of Minnesota where he focused on opiate chemistry in relation to drug abuse and drug addiction. He joined the faculty at the University of Mississippi in 2001 where much of his research was successful in discovering unique and selective tools for sigma receptors, NPFF receptors and opioid receptors. Dr. McCurdy accepted a post as a professor of medicinal chemistry at Florida in 2017 and became the director of the university’s Translational Drug Development Core.  Links:  Christopher McCurdy UF faculty page: http://pharmacy.ufl.edu/faculty/christopher-mccurdy/ American Association of Pharmaceutical Scientists: https://www.aaps.org/home Translational Drug Development Core: https://www.ctsi.ufl.edu/research/laboratory-services/translational-drug-development-core/  Suspected Adulteration of Commercial Kratom Products with Hydroxymitragyine: https://www.ncbi.nlm.nih.gov/pubmed/27752985 Self-treatment of Opioid Withdrawal Using Kratom: https://www.ncbi.nlm.nih.gov/pubmed/18482427 Herbal Medicines for the Management of Opioid Addiction: https://www.ncbi.nlm.nih.gov/pubmed/22133323 Show notes:  2:58: Ken opens by asking Chris if he ever dreamed of becoming a professional athlete as a result of growing up in Pittsburg during the hay-day of the Stealers and the Pirates. 3:28: Dawn mentions that Chris’s father was a pharmacist, and his mother, a science teacher. She further mentions that in addition to being interested in sports, that Chris also was interested in science, and she asks what role his parents played in that. 4:45: Dawn mentions that Chris moved to a suburb of Youngstown Ohio just as he was starting high school. Chris talks about playing basketball, being part of a competitive swim team, and his reputation as a fairly straight-laced kid. 5:27: Ken mentions that Chris headed to Ohio Northern University after he graduated from high-school and initially pursued a double major in pharmacy and music. Ken asks what prompted that particular combination. 6:39: Ken talks about how at Ohio Northern, Chris’s first real mentor in science noted his talent for research, and suggested that Chris should head to the University of Georgia for the summer to get acquainted with research. Chris talks about how that eventually led to him attend Georgia for his doctorate. 10:39: Ken asks Chris to talk about his doctoral research into Native American Tobacco. 13:28: Dawn comments on how there weren’t too many post-doc opportunities available at the time he finished his studies at Georgia, but that she understands there is an apparent pattern in his life of being at the right place at the right time. She asks if it was this pattern that lead him to the University of Minnesota. 17:05: Dawn inquires as to what got Chris interested in working on the natural product called Salvinorin A (Magic Mint), and what became of that research. 20:40: Dawn mentions that because of his work on salvia divinorum, Chris was invited by the National Institute of Drug Abuse to give a talk in 2004, which is where he first learned about kratom. 23:08: As context, Ken asks if Chris could expound upon kratom’s history, the different types of kratom, and the varying effects they have on users. 32:10: Ken brings up the debate surrounding whether kratom is properly construed as an opioid. Chris goes on to talk about the differences between kratom and classic opioids. 37:33: Following up on the previous question, Ken mentions that the distinction between opioid and opiate is quite important, given that when people talk of opioids they are generally thinking of opiates specifically. Given that respiratory depression is a major issue for those on opiates, Ken asks how many lives could be saved by moving people off opiates. 40:32: Shifting the conversation, Ken asks about the use of kratom among athletes. 43:10: Ken, following up on the last question, mentions that the primary use of kratom among athletes is not for performance enhancement, but rather recovery, and coping with the pain.  One frequently hears of kratom use among athletes, especially those engaged in sports such as wrestling, mix martial arts, bodybuilding, and football to help manage the pain associated with their sport-related injuries. 47:08: Ken comments on the importance of Chris’s endeavor to perform clinical trials with kratom, and asks about the resistance he has faced in doing trials. 50:17: Dawn asks if there are any documented side effects of chronic use of kratom, and if there is the potential to overdose. 53:49: Dawn, shifting gears, mentions that while at the University of Mississippi he met Bonnie Avery, an analytical chemist, and that he began to collaborate with her. Dawn goes on to mention that Bonnie became known as the bearer of bad news, asking how she ended up with that reputation, and also how Chris ended up marrying Bonnie. 57:10: Dawn says that in 2013 the Florida Legislature announced that it was going to create a preeminence program that would provide state universities millions of dollars to attract top level faculty members and scientists. She mentions that because of this program Chris was approached, and that he and Bonnie eventually joined the Florida faculty. Dawn asks how that all came about. 59:39: Dawn asks Chris about a mentor who once advised him, “Always focus on the science, and be true to the science.” Dawn asks Chris if that is advice he, too, shares with people. 1:01:55: Interview ends.