Episode 174: Rudy Tanzi talks about genetics, aging and the hallmarks of Alzheimer’s

Today our guest is Dr. JoAnn Manson, an endocrinologist, epidemiologist, and Principal Investigator of several research studies, including the landmark Women’s Health Initiative. She is a highly cited researcher and was one of the physicians featured in the National Library of Medicine’s exhibition, History of American Women Physicians. Her primary research interests include clinical prevention trials of nutritional and lifestyle factors related to heart disease, diabetes, and cancer and the role of endogenous and exogenous estrogens as determinants of chronic disease. Show notes: [00:02:53] Dawn kicks off the interview by asking JoAnn what it was that drew her to endocrinology. [00:04:33] Ken asks how the things JoAnn witnessed in her early medical practice influenced her interest in disease prevention. [00:05:51] Dawn asks JoAnn to discuss how her mother, who suffered from ovarian cancer, influenced JoAnn’s focus on women’s health. [00:06:40] Dawn asks JoAnn what prompted her interest in clinical research. [00:08:06] Noting the difference between public health and laboratory medical research, Dawn asks JoAnn what the most valuable thing is that she learned from her master’s and Ph.D. work in public health at Harvard. [00:09:10] Ken mentions that while JoAnn and many others are interested in the prevention of disease, our healthcare system does not seem focused on prevention. Ken goes on to asks if this was part of what led JoAnn to work on the Nurses’ Health Study. [00:10:17] Ken asks JoAnn to give an overview of the Nurses’ Health Study for listeners who may not be familiar. [00:11:41] Dawn explains that the Nurses’ Health Study found that women taking hormone therapy had a lower risk of heart disease and a reduction in all-cause mortality. Dawn asks JoAnn to talk about this finding. [00:15:00] Ken asks JoAnn what the impact of the Nurses’ Study has been on public health and women’s health in general. [00:16:29] Dawn asks JoAnn about her experience being a principal investigator in the Women’s Health Initiative starting in 1993. [00:18:17] Ken asks JoAnn to give context regarding how the Women’s Health Initiative (WHI) was designed, how the women were recruited, and what the specific questions were that the study aimed to answer. [00:21:34] Dawn mentions that the three interventions that were evaluated in the WHI were hormone therapy; calcium and vitamin D supplementation; and a low-fat diet. Dawn starts by asking JoAnn about the hormone therapy interventions, and how it was decided which hormone therapies to test. [00:24:25] Dawn asks JoAnn to give some context to the finding from the WHI that women taking the combination of conjugated estrogen and medroxyprogesterone acetate had higher risks of breast cancer and stroke. [00:27:01] Ken asks if the worse outcomes from hormone therapy for older women was due to their advanced age, or the hormone therapy itself. [00:30:25] Ken asks JoAnn to talk about the risk factors for breast cancer that were uncovered by the WHI. [00:35:38] Dawn explains that because of the WHI’s findings, it is more common to use transdermal estradiol, as opposed to the oral form evaluated in the original trial. Dawn asks JoAnn to explain how the different ways these hormone formulations are processed in the body affects the risk benefit ratio. [00:39:04] Dawn asks if these transdermal estradiol treatments might have benefits regarding cognitive decline. [00:43:26] Ken asks JoAnn for her thoughts on the overuse and potential misuse of the term ‘bioidentical hormones.’ Ken goes on to note that the term has seemingly become more related to marketing and further distanced from clinical science. [00:46:48] Dawn asks JoAnn to talk about the role that perimenopausal birth control decisions can play in the management of hot flashes for women in their 40s and 50s. [00:49:14] Ken shifts the conversation to discuss the second pillar of the WHI,

Today we have Dr. Hans Van Dongen, director of the Sleep and Performance Research Center at Washington State University in Spokane. Dr. Kevin Gluck, a senior research scientist at IHMC, joins Dr. Ken Ford to interview Hans about his studies on inter-individual differences in vulnerability to fatigue as well as the cumulative cognitive deficits that follow chronic sleep restriction. Hans is known for his mathematical modeling of fatigue’s effects on performance. At the Sleep and Performance Research Center, Hans and his colleagues investigate how sleep loss and circadian misalignment impact brain function, cognition and behavior. Show notes: [00:02:50] Kevin opens the interview by asking Hans about his childhood growing up in The Netherlands. [00:03:23] Ken asks Hans what he was like as a kid. [00:03:50] Kevin mentions Hans’s father was a math and science teacher and wonders if that influenced Hans’ interest in science. [00:04:48] Hans talks about attending Leiden University and explains why he majored in astrophysics. [00:06:09] Hans shares how working in a psychophysiology lab put him on a path to specialize in sleep research. [00:08:00] Hans talks about how he was part of a study that proved the morning-evening chronotype was a biological trait, rather than a psychological one. [00:09:55] Ken asks Hans what led him to take a post-doc position at the University of Pennsylvania. [00:11:22] Hans explains what led him to move from the University of Pennsylvania to Washington State University. [00:13:36] Ken mentions that The Sleep and Performance Research Center, where Hans serves as the director, is a coalition of basic and applied research laboratories that aim to understand the neurobiology of sleep and sleep loss. Ken goes on to mention that Hans and his colleagues investigate sleep and biological rhythms, and their impact on health and performance. Kevin asks Hans to give an overview of what sleep loss is and the effect it has on our metabolism, immune system, and cognitive performance. [00:15:57] Kevin mentions Hans’ recent paper which investigated how circadian misalignment due to night shift work has been associated with an elevated risk of chronic disease. The paper demonstrated that just a few days of being on a night shift schedule throws off protein rhythms related to blood glucose regulation, energy metabolism, and inflammation. Kevin asks Hans to talk more about the findings. [00:21:18] Ken asks how long it takes for a person’s circadian rhythm to normalize after ceasing to work night shifts. [00:22:13] Kevin brings up Hans’ paper on the continually operating neurobiological mechanisms of homeostatic and circadian processes and their effects on neurobehavioral performance. Before asking about the paper itself, Kevin asks Hans to give an overview of the homeostatic process and its relationship to the circadian process. [00:24:14] Ken notes that the bio-behavioral function and evolutionary advantage of the circadian process is widely recognized, but that the neurobiology of the homeostatic process and its effects on performance are still poorly understood. In a 2011 paper, Hans attempted to shed light on the underlying mechanisms of the homeostatic process to provide an explanation for why the buildup of homeostatic pressure resulting from sleep loss leads to instability in vigilant attention. To explore this, Hans first explored the time-on-task effect. Ken asks Hans to explain the time-on-task effect and its role in cognitive performance. [00:27:06] Kevin brings up the “local sleep hypothesis,” which attempts to explain the time-on-task effect. According to the local sleep hypothesis, groups of neurons involved in performing a task will “fall asleep” as a homeostatic consequence of sustained use, which leads to an interruption in information processing, leading to impaired performance. Kevin asks Hans what empirical and scientific evidence exists for the hypothesis...

Today we have Dr. Rudolph E. Tanzi, who is perhaps best known for co-discovering all three familial early-onset Alzheimer's disease genes. In addition, Rudy’s lab was the first to use human stem cells to create three-dimensional human brain organoids and three-dimensional neural-glial culture models of Alzheimer’s disease, which became known as “Alzheimer’s-in-a-Dish.” These models were the first to recapitulate all three of the key pathological hallmarks of Alzheimer’s disease and have made drug screenings faster and cheaper. Rudy is the director of the Genetics and Aging Research Unit as well as the director of the Henry and Allison McCance Center for Brain Health. Rudy is also co-Director of the Massachusetts General Institute for Neurodegenerative Disease at Massachusetts General Hospital and serves as the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Rudy has published more than 700 research papers and is one of the top 50 most cited neuroscientists in the world. He is author of “Decoding Darkness,” and a co-author of two books with Deepak Chopra, “Super Brain” and “The Healing Self.” Show notes: [00:03:18] Ken opens the interview mentioning that Rudy began playing the accordion when he was just seven years old. Ken goes on to ask Rudy about the time his father gave him a Jimmy Smith album and some advice. [00:05:51] Ken mentions that, in addition to Rudy’s musical talents, he was also interested in science growing up. Ken asks about Rudy’s participation in the Westinghouse Science Talent Search and what that experience was like. [00:07:09] Ken asks Rudy about growing up in Cranston, Road Island. [00:08:39] Rudy talks about how he ended up at the University of Rochester after high school. [00:09:51] Ken mentions that both Rudy’s grandfather and father passed away at the age of 45. Ken asks Rudy if this played a role in his pursuit of a career in genetics research. [00:10:57] Rudy explains how he chose Harvard Medical School for his Ph.D. [00:12:47] Ken pivots to ask Rudy about his time working with Jim Gusella in the early 80’s at Mass General, where they were the first to ever find a disease gene. Family studies at the time had shown that the Huntington's disease gene was linked to a polymorphic DNA marker. Rudy talks about this discovery and how the chromosomal localization of the Huntington's disease gene was the first step in using recombinant DNA technology to identify the primary genetic defect in this disorder. [00:16:07] Ken asks Rudy about his work in 1987, when he discovered the first Alzheimer’s gene, recombinant DNA technology, which causes the production of amyloid. Ken goes on to explain that mutations in the APP gene can cause a rare form of early onset Alzheimer’s. Rudy talks about the paper that came out in “Science” that detailed this discovery. [00:18:38] Rudy discusses his personal philosophy and approach to research. [00:19:43] Ken mentions that in Rudy’s book, Decoding Darkness, he writes that few nightmares on Earth can compare to Alzheimer’s disease. Ken asks Rudy to talk more about this book. [00:21:50] Ken explains that in the same way our physical capabilities will suffer some form of decline with age, it is also expected that we have some decline in memory and cognitive ability as we age as well. However, Ken goes on to say that when people begin to experience age-related memory lapses, it can lead to a lot of anxiety about their genetic predisposition to Alzheimer’s. Ken asks Rudy to talk about the lifestyle factors that play into whether someone predisposed to develop Alzheimer’s can stave off or avoid disease development. [00:26:09] Ken explains that aging appears to intensify when people stop challenging themselves with new things. Given this, Ken asks Rudy what his thoughts are on challenging our brains as they age to protect our cognitive abilities. [00:29:08] Ken asks Rudy about the principal advances in...

Our guest today is Dr. Anurag Singh, the chief medical officer at Timeline Nutrition, a Swiss life-science company that focuses on ways to improve mitochondrial and cellular health. Anurag is particularly known for his research into the gut metabolite, urolithin-A, which has been shown to improve muscle strength, protect immune systems and optimize mitochondrial efficiency. Anurag is an MD in internal medicine with a Ph.D. in immunology. He has led more than 50 randomized clinical trials, many of them focusing on urolithin-A over the past decade. In today’s episode we talk to Anurag about his investigations into urolithin-A and the role it plays as a postbiotic that enhances mitochondrial function. Foods that contain the polyphenols needed to produce urolithin-A include pomegranates, strawberries, raspberries and walnuts. Show notes: [00:02:48] Marcas starts the interview by mentioning that Anurag grew up in India, in Lucknow, and asks what Anurag’s childhood was like. [00:03:56] Marcas follows up, asking Anurag what he was like as a kid, given the competitive environment he grew up in. [00:04:47] Ken asks Anurag if it is true that, at an early age, his parents noticed he was gifted in biology and encouraged him to think about pursuing medical school. [00:05:47] Ken asks if Anurag started medical school at only 18 years of age. [00:06:28] Marcas explains that Anurag went to India’s Armed Forces Medical College for training in internal medicine and asks if it is true that this is one of India’s top medical schools. [00:07:07] Marcas explains that it is typical for graduates from the India Armed Forces Medical College to serve a few years in the Indian army after graduation. Marcas asks Anurag to tell the story of how he was able to go to the U.S. post-graduation rather than serving time in the army. [00:08:00] Ken asks if Anurag’s interest in medical research led him to pursue a Ph.D. in immunology. [00:08:56] Ken asks Anurag what his Ph.D. research was on. [00:09:37] Marcas mentions that in 2009, Anurag accepted a position at Nestlé at a time when the company was entering into the space between food and pharma. Marcas asks Anurag how this move came about. [00:11:20] Ken explains that Anurag quickly became medical director at Nestlé and started initiating clinical trials around food and allergies, as well as research on aging and how the immune system declines with age. Ken asks Anurag to explain what his time at Nestle was like. [00:12:53] Marcas mentions how the shift from practicing physician to research scientist is an interesting course and asks Anurag to talk about a mentor who gave him the advice that led to his career shift. [00:13:55] Ken mentions that in 2014 Anurag joined a Swiss company, Amazentis, as chief medical officer, and later became the lead for their medical and clinical research strategies. Ken asks Anurag to talk about the company and the work he does. [00:15:00] Ken asks Anurag to describe the relationship between Amazentis and Timeline. [00:15:42] Marcas asks Anurag to elaborate on his biotech approach to nutrition science, and how hard biology is used in his nutritional approaches at Amazentis. [00:18:02] Marcas asks Anurag to give listeners an overview of the function and importance of mitochondria. [00:19:15] Ken asks Anurag if there are any other benefits to good mitochondrial health, other than an increased energy supply. [00:20:24] Ken asks Anurag to define the terms “mitochondrial biogenesis” and “mitophagy.” [00:22:13] Marcas pivots to discuss age-related frailty and healthspan, specifically bringing up a study Anurag conducted on a Dutch population comparing active seniors to sedentary seniors. [00:25:09] Ken mentions that Marcas likes to refer to exercise as medicine, given its potent effects on a wide variety of biomarkers. Ken asks Anurag to discuss the importance of exercise. [00:26:59] Following up on the Dutch study,

Few people know as much about inflammation and neuroscience as Dr. Kevin Tracey does. In this episode of STEM-Talk, we learn much from Tracey, who was the first to identify the inflammatory reflex, a physiological mechanism that regulates the body’s immune response to injury and invasion. He is a neurosurgeon, a pioneer in bioelectrical medicine and president and CEO of the Feinstein Institutes for Medical Research in Manhasset, N.Y. The conversation in this episode covers a career spent working on “producing tomorrow’s cures today” in the treatment of inflammatory diseases, including: How the death of his mother from a brain tumor when Tracey was 5 years old ultimately influenced his scientific journey. How the death of a young patient of his from sepsis further fueled his path, leading him to the insight that “good science begins with hard questions,” as Tracey shared in a TedTalk.  The molecular mechanisms of inflammation and the use of vagus nerve stimulation to treat it. His 1987 discovery of tumor necrosis factor (TNF), which contributed to a new class of drugs for inflammatory and autoimmune diseases. Another discovery that allowed him and his colleagues to merge neuroscience and immunology. His work on “The Inflammatory Reflex”, which emphasized the basic neural pathway that reflexively monitors and adjusts the inflammatory response. A sketch he drew while having lunch, which laid out how treating inflammatory diseases using a bioelectronic device might be possible. What advances in bioelectronic medicine he envisions in the next decade, and much more. [00:03:04] Dawn asks Kevin to tell the story of how he developed an interest in science that evolved into him becoming a neurosurgeon. [00:04:56] Dawn mentions that Kevin was a curious youth and asks if it is true that after getting his first car, Kevin removed the entire engine because he wanted to better understand how to do a valve job. [00:06:33] Ken mentions that after Kevin graduated from high school, he enrolled in Boston College where he earned a bachelor’s degree in chemistry. Ken explains that Kevin went to Boston University Medical School for his M.D. and asks Kevin about the transition. [00:08:41] Ken asks if it is true that during Kevin’s first year at medical school his classmates had better luck finding him on the golf course than in the classroom. [00:10:42] Dawn asks Kevin about his transition from medical school to the neurological surgery training program at New York Hospital, home of the Cornell University Medical College. [00:13:11] Dawn pivots to talk about sepsis, which kills more than 350,000 people annually. She asks Kevin to discuss his tragic story of treating a patient with sepsis as a young neurosurgeon and how that changed the trajectory of his career. [00:16:38] Ken explains that since the aforementioned incident, Kevin has focused on determining why septic shock occurs. Ken refers to a Ted Talk of Kevin’s in which he says, “good science begins with hard questions.” Ken asks Kevin to elaborate on this point. [00:20:49] Dawn mentions that Kevin often describes himself as a brain surgeon who is fascinated by inflammation. Dawn asks Kevin how he responds when people ask him what inflammation is. [00:22:29] Ken follows up by explaining that in 1987 Kevin made progress investigating inflammation with his discovery of tumor necrosis factor (TNF), which contributed to a new class of drugs for inflammatory and autoimmune diseases. Ken asks Kevin to discuss this discovery. [00:25:56] Dawn mentions that in the late ‘90s, Kevin made another discovery that allowed him and his colleagues to merge neuroscience and immunology. Before getting into that discovery, Dawn asks Kevin to explain how humans have simple reflex circuits that harmonize the activity of our organs. She also asks him to talk about Charles Sherrington’s Nobel Prize-winning research, which laid the groundwork for contemporary neuroscience by...

In today’s Ask Me Anything episode, Ken and Dawn answer a wide range of questions that cover: A recent FDA approval of a neural implant device for people with degenerative neuromuscular disease or spinal-cord injuries. Global security in the age of AI. A study that looked at ways to optimize glymphatic clearance for people with acute or chronic sleep deprivation. Why more gyms don’t offer blood-flow restriction classes for their clients. Developments in the realm of Generative AI. The tradeoffs between a low-carb diet versus a ketogenic diet. A study on Alzheimer’s titled, “APOE 4 Homozygosity Represents a Distinct Genetic Form of Alzheimer’s Disease.” Plus, Ken reveals his favorite science-fiction author. [00:02:38] Dawn opens the episode with a question for Ken about the FDA’s recent approval of a neural implant device which is touted as a means of allowing people with degenerative neuromuscular disease, or spinal-cord injuries, to interface with external technology via neural signals. The listener asks Ken for his insights into what is being called “brain-computer interface technologies.” [00:05:44] A listener asks Ken if he has a favorite science-fiction writer, or if there is a particular sci-fi series/story that really moves him. [00:08:48] Multiple listeners ask Ken about a paper recently published titled: “APOE 4 Homozygosity Represents a Distinct Genetic Form of Alzheimer’s Disease.” Listeners ask if it is true that people with two copies of APOE4 allele are certain to develop the disease. [00:19:30] A listener asks Ken about his time on the National Security Commission on Artificial Intelligence. The commission issued its report five years ago with specific recommendations on how the government should prepare for and defend against the national security implications of AI. Ken shares his thoughts on the implementation of the commission’s recommendations. [00:21:16] A listener asks Dawn about her collaboration with Dr. Jeff Iliff that looked at a potential approach to optimizing glymphatic clearance for people with acute or chronic sleep deprivation. [00:27:10] A listener asks Ken why more gyms and physical therapy centers don’t have blood flow restriction devices (BFR) available for their clientele, given that studies have shown that BFR improves strength and muscle mass in both young and older adults. (Two STEM-Talk episodes that cover blood-flow restriction include episode 34 and episode 161. [00:28:38] A listener asks Ken for his thoughts on AI given the recent developments in the field, particularly in the realm of Generative AI, with programs like Chat GPT becoming a household name. The listener mentions that one of their friends thinks that AI is about to peak, and another says that AI is just getting warmed up. [00:37:00] A listener writes that they are astounded at how many disorders can be treated with a ketogenic diet and mentions that they themselves have difficulty with a ketogenic diet. Instead, the listener eats low-carb diet and asks if the benefits of a low-carb, non-ketogenic diet are similar to a ketogenic one. [00:38:19] A listener asks if Ken could talk about carotid scans and if this is a test that those with high LDL should consider getting. [00:40:17] A 72-year-old listener explains how they structure their daily exercise routine between resistance and endurance training. The listener asks Ken whether they should focus more on resistance training as they are beginning to lose strength, and if so, how they should implement that given their age and the increasing risk for injury. [00:45:51] To wrap up this episode, a listener asks Ken if he has any new annoyance that he would like to share, as he did in 2022, when he noted his disdain for the phrase “new normal” and the prevalence of cellphone addiction. Links: Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio

Today Dr. David LeMay steps in to co-host with Dr. Ken Ford for our interview with Dr. Charles Serhan. Charles is a Harvard professor best known for his discovery of specialized pro-resolving mediators. SPMs are molecules that can activate the natural resolution of inflammation and help people avoid anti-inflammatory drugs. The discovery of SPMs spurred a paradigm shift in our understanding of inflammation and human disease. Charles is the Simon Gelman Professor of Anesthesia at Harvard Medical School and the director of the Center for Experimental Therapeutics and Reperfusion Injury at Brigham and Women’s Hospital. He also is a co-director of the Brigham Research Institute. David, who was our guest on Episode 69 of STEM-Talk, is a sports medicine and rehabilitation physician with a Pensacola, Florida practice that focuses on lifestyle and performance medicine. He also is a visiting research scientist here at IHMC. Show notes [00:03:33] David opens the interview mentioning that Charles grew up in New York City with a passion for music. David explains that Charles learned to play the vibraphone in junior high and played professionally for a year before going to college. David asks Charles why he decided to pursue science instead of music. [00:04:22] Ken asks Charles what kind of vibraphone he plays. [00:06:02] Ken asks, aside from the desire to help people, if there was something particular about studying science that Charles really enjoyed. [00:06:45] David asks about Charles’ experience at the State University of New York at Stonybrook studying biochemistry and immunohistochemistry. [00:07:16] David asks if there was any carry over of skills for Charles from his career in music to his career in science. [00:08:16] Ken mentions that after Charles earned his bachelor's degree, one of his professors persuaded him to go to New York University for a master's and Ph.D. Ken also mentions that at the time Charles worked in the lab of Gerald Wiseman at Woods Hole Marine Biological Laboratory and asks about that experience. [00:12:37] David asks if this experience led Charles to a focus on neutrophil membrane remodeling for his Ph.D. [00:13:59] David asks Charles if it was at the Karolinska Institute where he met his future wife. [00:14:38] Ken asks Charles about one of his mentors, Michael Heidelberg, who gave Charles advice about how to be a good scientist. [00:17:13] David explains that in the 1990's Charles discovered Specialized Pro-Resolution Mediators and has since pioneered a new field on the utility of SPMs for a variety of inflammatory diseases. [00:25:01] Ken backs up to ask Charles what drew him to study inflammation in the first place and how that led him to do more research on the subject than any other scientist. [00:26:26] David asks Charles to touch on some different types of inflammation that the body experiences. [00:35:12] Ken asks Charles about how a trip to Asia during which he developed a hole in his intestines, resulted in first-hand experience on the importance of controlling inflammation. [00:41:00] David asks if Charles was taking any non-steroidal anti-inflammatory medications when he developed peritonitis. [00:41:53] David asks Charles to explain what non-steroidal anti-inflammatory medications do to the healing process. [00:45:35] David brings up a recent discovery in animal models that as animals age, their ability to produce resolution mediators declines, possibly contributing to the loss of muscle mass with age. [00:48:09] Ken asks Charles to talk about the explosion of research into the potential therapeutic applications of SPMs in the treatment of a variety of chronic diseases known to be driven in part by chronic inflammation. [00:51:06] David asks Charles to explain the differences between resolvins, protectins, and maresins, as well as what role each plays in the healing process. [00:56:04] Ken mentions a review article that Charl...

Dave Feldman is the founder of the Citizen Science Foundation and is known for his research into the ketogenic diet. Dave is a software engineer by training who embraced a ketogenic diet to avoid his progression toward type 2 diabetes. he joins us on this episode of STEM-Talk to share that journey. After undertaking the high-fat/low-carbohydrate diet, Dave’ LDL cholesterol spiked. Dave used his training as an engineer to start learning everything he could about cholesterol and lipids. What he learned led him to create the website Cholesterol Code, a research hub for information and emerging data on cholesterol, particularly in the context of a low-carbohydrate lifestyle. Dave’s Citizen Science Foundation is designed to support projects and research that promote collaborative efforts across multiple disciplines, both in and outside formal scientific institutions. Show notes: [00:02:53] Dawn opens the interview asking Dave what he was like as a kid. [00:03:44] Dawn mentions that Dave divided his time as a child between Denver and Wichita due to his parents’ divorce and asks Dave what the best part of his childhood was. [00:04:28] Ken mentions that Dave has described both his parents as graphic artists and Bohemian, “hippie spirit” types. Ken asks what he learned from them that fueled his interests and goals. [00:05:46] Ken asks about Dave’s first computer, which was a Commodore 64, as well as his early experience with computers. [00:08:50] Dawn mentions that Dave’s interest in computers came in a time before the internet and asks what he learned about computing in those days. [00:10:51] Dawn explains that since Dave grew up in the 1980s, there was not much in the way of computer science curriculum in schools and asks Dave how he supported his interest in programming. [00:12:33] Ken asks Dave about how self-directed learning has been a theme throughout his whole life. [00:14:35] Dawn asks Dave about his childhood hobbies, including running and competitive storytelling. [00:17:01] Ken asks how Dave’s experiences in forensic debate in high school helped his career later in life. [00:18:56] Dawn mentions that Dave initially attended film school and asks if it is true that Dave’s side hustle of doing contract software work overtook his original plan to graduate. [00:20:49] Dawn asks about Dave’s experiences working in the game platform development business in Las Vegas, as well as what these experiences taught him. [00:22:23] Ken asks Dave about a “the piece of paper” that Dave says changed his life in 2015. [00:28:58] Ken follows up, asking Dave if he checked his LDL-P or his ApoB at the same time as his cholesterol levels. [00:30:37] Ken mentions that he knows some people that when consuming a ketogenic diet did not see a substantial increase in LDL-C, but did experience a substantial elevation of LDL-P. [00:35:03] Ken pivots to discuss a paper that Dave and others published in Current Developments in Nutrition in 2022 titled: “Elevated LDL Cholesterol with a Carbohydrate-Restricted Diet: Evidence for Lean Mass Hyper-Responder Phenotype.” Ken asks Dave to describe what it means to be a lean mass hyper-responder. [00:40:19] Ken mentions his caution against the term lean mass hyper-responder, as it is unclear what “lean mass” refers to in this case. Ken goes on to say that while the lean mass hyper-responder phenotype can be objectively measured in terms of LDL, HDL and triglyceride levels, the lean mass aspect is often measured in these studies with BMI, which is unable to measure body composition. Ken asks Dave what his thoughts are on this and if he would like the possibility of moving away from BMI and towards DEXA scans. [00:43:37] Ken mentions that Dave’s original article describing the lean mass hyper-responder phenotype has received a lot of response from individuals claiming to fall into that category. While it is difficult to get a precise estimate of the popul...

Dr. Alessio Fasano, who is considered the world’s leading expert in celiac disease and gluten-related disorders, returns for his second appearance on STEM-Talk. Although just 2 million Americans have celiac disease, an estimated 20 million Americans suffer from gluten sensitivity. Alessio is a professor and director of the Mucosal Immunology and Biology Research Center at Massachusetts General Hospital. In addition to celiac disease and gluten-related disorders, Alessio’s research is also focused on the microbiome, intestinal permeability and autoimmune disorders, which he discussed in his first interview on STEM-Talk, episode 20. Since Alessio’s first appearance on STEM-Talk in 2016, he has published two books, “Gluten Freedom” and “Gut Feelings: The Microbiome and Our Health,” which we discuss in today’s interview. We also talk to Alessio about an exciting new project that’s bringing together an international consortium of researchers and scientists for a long-term study that will follow infants who are genetically at risk of developing celiac. Alessio is a researcher and physician who wears many hats. He is the director of the Center for Celiac Research and Treatment and chief of the Division of Pediatric Gastroenterology and Nutrition at Mass General Hospital. He also is a professor of pediatrics at Harvard Medical School and a professor of nutrition at Harvard’s T.H. Chan School of Public Health. Show notes: [00:03:58] Marcas opens the interview welcoming Alessio back to STEM-Talk, mentioning that since his last appearance he has written two books: Gluten Freedom and Gut Feelings: The Microbiome and Our Health. Marcas asks Alessio how he became interested in pediatrics and gastroenterology. [00:05:42] Ken mentions that Alessio moved to the U.S. in the 1990s and spent 20 years in Maryland at the Center for Vaccine Development in Baltimore. Ken goes on to mention that while Alessio was there, he founded The Center for Celiac Research in 1996, and in 2003, Alessio accepted an offer to join Massachusetts General Hospital. Ken asks how that move came about. [00:08:53] Marcas asks about Alessio’s early career working on cholera, where he discovered the zonula occuldens toxin, the bacteria that causes cholera. Marcas asks Alessio to talk about this finding and the insights he gleaned from it. [00:16:03] Ken asks about Alessio’s discovery of zonulin, which is the molecule that modulates gut permeability in humans. Ken asks Alessio to share how this discovery led him to investigate celiac disease, which is triggered by gluten. [00:20:25] Ken asks Alessio what his thoughts are on why the medical community, historically, has not taken celiac disease seriously. [00:24:08] Marcas mentions that as we age, there is evidence that the gut becomes leakier, which is highly related to chronic inflammation. Marcas asks Alessio whether this happens to the gut over time due to diet and lifestyle rather than the typical aging process. [00:28:45] Ken mentions that there has been an increase in the diagnosis of celiac disease. Ken asks Alessio if that is due to an actual increase in the prevalence of the disease, or is it tied to a growing appreciation that clinicians have now for the disease? [00:29:32] Marcas mentions that Alessio’s book, Gluten Freedom, which he co-authored with his colleague Susie Flaherty, was referred to by the Celiac Disease Foundation as “a must have,” and “an excellent reference for those with gluten related disorders.” Marcas asks Alessio about this reception to his book. [00:31:24] Marcas mentions that the only viable treatment for individuals with celiac disease has been a gluten-free diet, with pharmaceutical companies having had little interest until recently in investigating the disease. Now there are more than 20 drug therapies in development for celiac. Marcas asks Alessio about the progress being made to develop pharmacological interventions for celiac.

Today we have Dr. Nicholas Norwitz, 28, a third-year Harvard Medical School student whose research into the applications of a ketogenic diet as metabolic medicine has attracted a significant following. For a number of years during his youth, Nick suffered from a number of debilitating diseases, including osteoporosis, ulcerative colitis, and inflammatory bowel disease.  In today’s interview, we talk to Nick about research that led him to adopt a ketogenic diet that put him back on the road to metabolic health. After graduating from Dartmouth College in 2018 with a degree in cellular and molecular biology, Nick attended Oxford University where he earned a Ph.D. in metabolism and nutrition. He is the author of peer-reviewed scientific papers and textbook chapters on topics including Alzheimer’s disease, cardiovascular disease, diabetes, gastrointestinal health, genetics osteology and Parkinson’s disease. Show notes:  [00:02:53] Marcas opens the interview mentioning that Neck grew up in Boston, and asks if it’s true that he was a very curious kid growing up. [00:04:09] Marcas asks Nick if as a young child he always knew he wanted to be a physician and a scientist. [00:05:40] Ken mentions that Nick was a runner in high school, and as is the case with many runners, this led to fractures. However, Ken goes on to say that these fractures did not resolve for Nick, and asks what he learned as a result. [00:11:08] Ken asks about Nick’s eating habits in college as he loved to cook and bake. [00:15:40] Marcas follows up, asking Nick at what point during his Ph.D. training was he admitted to palliative care. [00:21:01] Marcas pivots to talk about the need for incorporating metabolic health into our health-care system. He mentions that Nick once said that “we live in a society where our social norms and ecosystem, with respect to health and food, are extremely dysfunctional,” and asks Nick to elaborate on this. [00:26:16] Ken mentions a paper that Nick recently published titled, “Oreo Cookie Treatment Lowers LDL Cholesterol More Than High Intensity Statin Therapy in a Lean Mass Hyper-Responder on the Ketogenic Diet: A Curious Crossover Study.” To provide some background, Ken mentions that some people on a ketogenic or low carb diet experience a dramatic increase in LDL cholesterol. The rationale behind Nick’s paper being that if it is the removal of carbohydrates that causes this increase in LDL, adding carbohydrates back into one’s diet should bring LDL levels back down. Ken asks Nick to talk about this experiment and how he designed it. [00:35:44] Ken mentions that the paper seems to be designed to be provocative, as simply testing carbohydrates against statins would likely have not gotten as much attention as using Oreo cookies. [00:37:00] Marcas mentions that in the Oreo cookie vs statin experiment, Nick’s original fasted-morning LDL was 384, before dropping it with Oreos, then doing a washout before dropping it again with statins. Marcas asks Nick what his fasted-morning LDL was post washout, prior to the statin intervention. [00:39:07] Marcas brings up Nick’s paper titled: “The Lipid Energy Model: Reimagining Lipoprotein Function in the Context of Carbohydrate Restricted Diets.” Marcas goes on to mention that the aim of the paper was to propose a mechanistic explanation for the “lean mass hyper-responder phenotype.” Marcas asks Nick to give listeners an overview of the lipid-energy model. [00:45:18] Ken mentions that according to Nick, BMI is not a requirement for classification as a lean mass hyper-responder. Nick’s paper, however, uses BMI data. Ken mentions that he finds BMI relatively useless and asks why Nick did not use DEXA scans instead. [00:48:52] Ken mentions that adipose tissue contains roughly 25 percent of total body cholesterol, and we know that LDL binding to adipose cell membranes is competitively inhibited by HDL. Ken asks if lean mass hyper-responders were found to hav...