Our guest today is Dr. Christoffer Clemmensen, an associate professor and lead researcher at the University of Copenhagen’s Novo Nordisk Foundation Center for Basic Metabolic Research. Christoffer’s lab at the university explores pharmacological and therapeutic treatments for obesity and its related diseases and disorders. He and his colleagues focus on dissecting the neuroendocrine signals involved in coordinating appetite, food-motivated behavior, energy expenditure, glycemic control, and lipid metabolism. We have a fascinating discussion with Christoffer about his lab’s efforts to turn molecular and physiological insights into innovative therapeutic strategies that Christoffer hopes someday can reduce obesity and its associated metabolic disorders. Christoffer is a native of Denmark who earned his Ph.D. in Molecular Pharmacology from the University of Copenhagen in 2013. Joining Ken for today’s interview is IHMC colleague and senior research scientist Dr. Marcas Bamman, who was our guest on episode 116. Marcas is the founder and former director of the University of Alabama at Birmingham Center for Exercise Medicine.  Marcas joined IHMC last year as a Senior Research Scientist. Show notes: [00:03:24] Marcas asks Christoffer about growing up in a small rural town in Denmark in the 1980s and ‘90s. [00:04:05] Christoffer’s talks about his days as an elite tennis player when he was a youth. [00:04:41] Ken asks Christoffer when he first became interested in science. [00:05:48] Marcas asks Christoffer what changed his mind about wanting to study computer science at university. [00:07:04] Christoffer explains how he decided to attend University of Copenhagen. [00:08:19] Marcas mentions that Christoffer’s original focus at university was on exercise biology, but that he became fascinated by the mechanisms of obesity and that interest took him in a new direction. Marcas asks how that shift in interest came about. [00:10:01] Marcas follows up on the previous question and asks if there were a particular instance that persuaded Christoffer to switch from focusing on exercise to focusing more on weight control and obesity. [00:10:40] Ken asks what led Christopher to pursue a Ph.D. in molecular pharmacology after attaining a bachelor’s degree in exercise biology and a master’s degree in human biology. [00:12:11] Marcas asks Christoffer why he went to Munich, Germany, as a postdoctoral fellow at the Helmholtz Diabetes Center after completing his post-doc at the University of Copenhagen. [00:14:00] After mentioning that Christoffer eventually became the group leader at Helmholtz, Ken asks Christoffer why he then transitioned back to the University of Copenhagen. [00:14:52] Marcas asks Christopher to talk about the big questions that get to the heart of his research. [00:16:20] Ken mentions that Christoffer is now an associate professor at the Nova Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, where he is the head of the Clemmensen Group. Ken goes on to mention that the Clemmensen Group’s website says the lab focuses on dissecting the neuroendocrine signals that coordinate appetite regulation, food-motivated behavior, energy expenditure, glycemic control, and lipid metabolism. Ken asks if Christoffer could give an overview of what all these research focuses entail. [00:18:17] Marcas mentions that obesity and its related diseases, such as type-2 diabetes and cardiovascular disease, have become serious problems affecting the world’s public health and global economy. Marcas goes on to say that Christoffer’s 2019 paper titled “Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases” makes the observation that the treatments we have been using to deal with this problem have not been able to effectively reverse the staggering rates of obesity we’re witnessing around the world. Marcas asks Christoffer to talk about this paper and how it underscored the need for better treatments of obesity. [00:19:48] In light of the need to target multiple signaling pathways to effectively treat obesity that Christoffer described in his 2019 paper, Ken asks Christoffer to explain the hormonal-based pharmacotherapies that he has been looking into as potential treatments for obesity. [00:21:58] Marcas asks Christoffer why an overwhelming majority of people who do manage to lose weight end up gaining the weight back, and what are the most effective therapies to help keep the pounds off once a person does lose weight. [00:23:56] Marcas mentions that Christoffer followed his 2019 paper with a review in PLOS Biology that looked at the evolutionary and environmental perspectives on human body weight. The paper asks the question, “Why are we not all obese?” Marcas, considering that poignant question, asks Christoffer why everyone isn’t prone to gaining weight in the same way. [00:26:44] Ken mentions that he has heavy doubts that our species experienced a recent biological change that would have caused a massive increase in obesity within the last 30-80 years, given that only a few decades ago most people were slender. [00:27:52] Marcas asks about the elusive slimming gene, mentioning that biologists have identified the physiological agents that keep our fat mass from becoming too low, but have had trouble understanding the exact mechanisms that regulate excess fat. He asks Christoffer to expound upon the current research as well as evidence dating back to the 1950s for the existence of a blood-borne, weight-gain preventive molecule. [00:30:09] Ken asks Christoffer about other factors that regulate energy balance in the body. [00:32:10] In light of the fact that a chronic state of positive energy balance leads to weight gain, Ken asks Christoffer what he believes is the key pathway to target, whether it be appetite control, energy expenditure, or a combination of both. [00:34:14] Marcas asks Christoffer to explain the remarkable differences between brown fat and white fat, and in this context to summarize his 2018 paper in nature communicationsthat described the potent effects of stimulating brown fat thermogenesis with a drug called icilin. [00:37:14] Marcas mentions that Christoffer’s paper in PLOS Biology addressed how geneticists are starting to uncover potential weight-gain defense genes. The paper, however, argues that for humans to fully benefit from such research, physiologists will have to play a role in the interpretation of such genetic discoveries. Marcas asks Christoffer what kind of collaboration he thinks is necessary between physiologists and geneticists. [00:39:08] Ken asks if the fact that the human genome has stayed stable throughout the rise in obesity over the past several decades suggests that epigenetic modifications play a role, and if Christoffer thinks that differences in obesity susceptibility across individuals might be partially explained by differences in the epigenome. [00:41:28] Marcas asks what the current status of pharmacological obesity treatment is and if Christoffer anticipates that landscape changing in the near future. [00:43:43] In terms of translating promising results in rodents to humans, Ken asks Christoffer to describe the specific challenges we face in using rodents to understand obesity in humans. [00:47:18] Ken mentions the overreliance on weight and BMI as measurements as opposed to body composition, which depreciates the value of muscle as an energy storing organ. [00:49:03] Marcas mentions that the model for pharmacological treatment of obesity seems to be leaning towards suppression of appetite. Marcas asks if such an agent were to be found, how successful does Christoffer think it would be in the long term if the pharmacotherapy was given in the absence of a behavioral change. [00:51:16] Marcas asks Christoffer to elaborate on his belief in the importance of omic-methods as well as how he is using such methods in his own research. [00:53:17] Ken asks about the greatest benefits, as well as the challenges, of using an untargeted approach to metabolomics profiling, which Christoffer wrote about in his 2020 article addressing molecular changes in the body following bouts of endurance and resistance exercise. [00:56:05] Ken asks how Christoffer decided which metabolites to study more closely in the aforementioned study. [00:57:14] Marcas mentions that Christoffer’s aforementioned 2020 study focused on physiological changes that took place within a few hours of exercise. Marcas goes on to mention that efforts are underway to better understand such acute molecular changes in the context of longer-term training, as the acute responses to exercise in a sedentary human are likely to be much different than the acute response of a trained individual. Marcas asks how we can learn from the range of responses in trained vs. untrained states as it pertains to weight management mechanisms or other health benefits. [00:59:08] Marcas brings up Christoffer’s most recent paper published earlier this year in Nature Communication, in which Christoffer asks the question: How does the exercise-and-appetite-related protein GDF15 act in different contexts? Marcas goes on to mention that the paper found that GDF15 acts differently based on whether it is endogenously produced or pharmacologically applied and asks Christoffer to talk about this in more depth. [01:04:00] Marcas explains that exercise-response molecules, of which there are a number, are dose dependent, which is to say that they are produced more, or stay in the body longer, depending on the mode and or intensity of the exercise. He goes on to ask if GDF15 has any dose dependency associated with it in respect to the magnitude of elevation and time it stays elevated. [01:06:30] Marcas congratulates Christoffer on his research gaining more attention and his lab growing to about a dozen people. [01:07:57] Marcas asks Christoffer what he does to stay in shape and if he still plays tennis. [01:08:52] Ken closes the interview asking if this is Christoffer’s first podcast interview in English and if Christoffer enjoys listening to podcasts. Links: Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio

Today we have the second part of our interview with science and health journalist Gary Taubes. In the first part of our interview, episode 124, we talked to Gary about his new book “The Case For Keto: Rethinking Weight Control and the Science and Practice of Low-Carb/High-Fat Eating.” In today’s episode, we talk in detail about a growing body of research and evidence that demonstrates the health benefits and safety of ketogenic diets. We also address why there remains stubborn resistance to low-carb/high fat diets in some nutrition circles. Plus, Gary responds to common arguments used against the ketogenic diet, ranging from health and safety and climate change to claims that ketogenic diets don’t work for women. Gary turned to journalism back in the 1970s after receiving his master’s degree in aeronautical engineering from Stanford University. Today, he continues to practice journalism and is the founder and director of the Nutrition Science Initiative. Be sure to check out part one of our interview, as well as our 2016 interview with Gary which followed the release of his New York Times best-seller “The Case Against Sugar.” Show notes: 00:02:58 Ken starts part two of our interview with Gary by mentioning that there is now substantial evidence supporting the efficacy and safety of low-carb diets. Ken mentions more and more physicians are prescribing this way of eating to their patients and large numbers of people are having success losing weight and managing type-2 diabetes using ketogenic diets. In light of that information, Ken asks Gary for his thoughts on why the U.S. News and World Report annual diet ranking stubbornly continues to describe the ketogenic diet as a detrimental way to eat. 00:09:25 Ken asks Gary to respond to some of the common arguments against the ketogenic diet ranging from human health and safety to climate change. 00:12:50 Ken asks about the claim that people on a ketogenic diet might lose a lot of weight in the short term but gain that weight back in the long term. 00:13:56 Gary tackles the criticism that ketogenic diets do not work for women. 00:16:02 Ken asks Gary to address concerns about the supposed unsustainability of ketogenic diets, noting how it is possible some people might have difficulty maintaining the diet for long periods of time. 00:19:20 Ken supposes that perhaps some of the anxiety surrounding a low-carb/high-fat diet has to do with LDL cholesterol. Ken mentions that some people on the diet, often referred to as hyper-responders, experience elevated levels of LDL and are warned by their physicians that this increases risk for heart disease. Ken asks Gary what he thinks the road forward should be for hyper-responders and others who are anxious about their LDL levels. 00:28:55 Dawn mentions that in 2018, Lancet published a study that aimed to make sense of the increasingly crowded world of low-carb diets. The authors, a team from Harvard, studied more than 15,000 American adults (aged 45-64) from four different communities over a 25-year period using dietary questionnaires. Dawn goes on to explain how these questionnaires revealed that consumers of both extremely low-carb diets and extremely high-carb diets had higher death rates over the course of the study. The lead author of this study was quoted as saying, “Our findings add to the growing evidence that animal-based low-carbohydrate diets are associated with increased mortality and therefore should be discouraged in the long term.” The last line of the paper reads, “Alternatively, when restricting carbohydrate intake, replacement of carbohydrates with predominately plant-based fats and proteins could be considered as a long-term approach to promote healthy aging.” News outlets described this paper as “the most comprehensive study of carbohydrate intake done to date.” She asks Gary to respond to this study and its conclusions. 00:39:31 Dawn asks what Gary’s ideal study design would look like to examine the safety and efficacy of the ketogenic diet. 00:42:30 Considering the recent birth of initiatives like EAT-Lancet, Dawn asks Gary if he sees the diet-science world moving in a more positive direction. 00:45:36 Ken asks Gary to elaborate on his view that the tools and equipment we use in science often shape the way researchers perceive the phenomena they observe. 00:50:21 Dawn asks Gary what it’s like being married to someone who prefers a mostly vegetarian diet. 00:51:52 Dawn mentions that even more than nutrition science or public health in this country, Gary’s interest has always been understanding the difference between good science and bad science. Dawn asks when Gary will write a book on that topic. 00:53:35 Ken mentions how the media often promulgates the notion that “science proceeds by consensus,”and that if the majority of scientists agree on a topic it is societally decided to be true. He goes on to say that this, of course, is not how science works, and the increasing attempts to squash criticism of established thinking parallel Gary’s career since the early 2000s. Ken asks if Gary has any more thoughts on this phenomenon. 00:57:12 Dawn closes the interview by asking if it is true that Gary had a high school guidance counselor who tried to put Gary in his place by saying Gary was “no Einstein.” Links: Gary Taubes bio Gary Taubes on Amazon Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio  

Today we have journalist Gary Taubes making a repeat appearance on STEM-Talk to discuss his new book, “The Case for Keto: Rethinking Weight Control and the Science and Practice of Low-Carb/High-Fat Eating.” Our interview with Gary in 2016, episode 37, followed the release of his book, “The Case Against Sugar,” which went on to become a New York Times best seller. “The Case for Keto” is Gary’s fourth book about diet and chronic disease. Gary made national headlines in 2002 when he wrote an article for the New York Times Magazine challenging the low-fat orthodoxy that had held sway in America since the 1970s. In the article, titled “What if It’s All Been a Big Fat Lie,” Gary wrote that perhaps Dr. Robert Atkins with his Atkins Diet was correct in suggesting that it’s not fat that makes us fat, but carbohydrates. Our conversation with Gary covered a lot of ground, and we have divided his interview into two parts. Today we talk to Gary about his reasons for writing the new book and how opinions on a low-carb and high-fat diet have changed over the past 20 years. In part two of our interview with Gary, we dig deeper into his efforts to set the record straight about the role of diet and weight control in preventing chronic diseases, as well as the role that diet plays in helping people improve their health spans. Gary turned to journalism back in the 1970s after receiving his master’s degree in aeronautical engineering from Stanford University. Today, he continues to practice journalism and is the founder and director of the Nutrition Science Initiative. Show notes: 00:03:43 Dawn welcomes Gary back to STEM-Talk and asks how things went for him as a writer during COVID-19 and the lockdowns. 00:04:24 Dawn gives some background on Gary’s new book The Case for Keto, which is his fourth book to follow and expand upon a 2002 article he wrote for the New Times Magazine titled, “What if It’s All Been a Big Fat Lie?” She asks Gary if he ever anticipated writing four books about the relationship between diet and chronic disease when the article came out 20 years ago. 00:06:09 Ken mentions that Gary’s New York Times Magazine article questioned the effectiveness of low-fat diets, which the government’s dietary guidelines had been recommending since the late 1970s. Ken adds that almost overnight Gary become public health enemy number one, and asks Gary if he expected so much pushback as a result of the article. 00:10:53 Dawn describes how the release of Michael Pollan’s book The Omnivore’s Dilemma, which draws on work by both Gary and Dr. Atkins, seemed to change consumers’ eating habits. Dawn then asks Gary if he remembers seeing or being surprised by the disappearance of pasta and bread from restaurants and grocery shelves. 00:14:41 Ken notes that in the blurb Michael Pollan wrote for the jacket of Gary’s 2007 book, Good Calories, Bad Calories, Michael said the book would change the way people think about eating. While Gary’s work did not end up changing national heart, health and diet guidelines, low-carb and ketogenic diets have become quite popular since then. Ken asks Gary what he thinks is driving this interest in keto. 00:19:41 Dawn describes Gary’s 2011 best seller Why We Get Fat as a condensed summary of the research contained in Good Calories, Bad Calories combined with new research on hormonal-based weight gain. She mentions Gary’s argument that the medical community and the federal government has misinterpreted scientific data on nutrition over the past several decades in developing a U.S. food policy that recommends a low-fat diet. Dawn notes there has recently been a steady accumulation of studies supporting carbohydrate restriction and the safety of saturated fat since Gary’s first two books came out. She asks Gary if this trend has been rewarding to watch. 00:22:47 Ken mentions that Gary’s new book, The Case for Keto, is an attempt to rectify decades-old misunderstandings people have had about the ketogenic diet, weight control, and health span. Gary explains why he chose to tackle the topic. 00:27:15 Dawn notes that although the medical community is beginning to see the benefits of a ketogenic diet, many doctors still promote the low-fat Mediterranean diet because they believe it is safer in the long term. Gary outlines the relative safety of the ketogenic diet compared to a Mediterranean. 00:34:02 Ken asks Gary for his thoughts on the cartoonish portrayals of ketogenic diets that describe them as being comprised of Crisco, butter, and bacon. 00:38:55 Dawn notes that there are many degrees of carbohydrate restriction that can be termed low-carb and asks Gary if there is a threshold that people should aim for in order to derive the metabolic benefits of a low-carb diet. She also asks whether a ketogenic diet provides additional benefits over a low-carb diet that simply limits carbohydrates. 0042:49 Gary ends part one of the interview by discussing the effects of burning fat for fuel rather than carbs.

Episode 123 Steve Chien talks about AI, Mars rovers, and the possibility of intelligent alien life Today’s interview is with Dr. Steve Chien.  Dr. Chien is JPL Fellow, Senior Research Scientist, and Technical Group Supervisor of the Artificial Intelligence Group and in the Mission Planning and Execution Section at the Jet Propulsion Laboratory, California Institute of Technology. In 2018, Steve and Ken were appointed to the National Security Commission on Artificial Intelligence, an independent commission tasked with providing the President and Congress a blueprint for advancing AI and associated technologies to address future national security and defense needs of the United States. The commission recently released a 756-page reportwhich found that the nation is unprepared to compete in a future enabled by AI and that the U.S. could soon be replaced as the world’s AI superpower. The report was two years in the making and offers strategies and recommendations to strengthen and protect the nation’s economy, technology base, and national security. In today’s podcast, we talk to Steve about the report and what he learned over the past two years serving on the commission. Steve heads up the Artificial Intelligence Group at JPL.  JPL is the lead for deep space robotic exploration for NASA. For the past several years, he has worked on the Perseverance Rover mission, which landed on Mars back in February and used an automated ground-based scheduling system called Copilot that Steve and his JPL colleagues developed. Steve joined JPL more than 30 years ago and last year was named a JPL Fellow, an honor that recognizes people who have made extraordinary technical and institutional contributions to the Jet Propulsion Laboratory over an extended period. He is a graduate of the University of Illinois Urbana-Champaign where he earned a doctorate in computer science. Show notes: 00:04:09 Dawn opens the interview welcoming Steve to the show and asking about his background. Dawn mentions that Steve grew up in Urbana-Champaign, Illinois, where he enjoyed basketball, Dungeons and Dragons and attempting to reinvent Decision Theory. 00:05:33 Dawn asks how Steve ended up as a computer science major rather than an economics major. 00:07:01 Dawn asks Steve if it is true that he graduated from the University of Illinois with a bachelor’s degree in computer science at the age of 19. 00:07:41 Dawn asks Steve what he did after attaining his Ph.D. 00:09:18 Ken asks Steve to describe his interest in the search for life beyond earth. 00:11:0 Ken mentions that Pascal Lee, a planetary scientist from NASA Ames Research Center, recently discussed the search for intelligent life in our galaxy on STEM-Talk, episode 121. Ken explains that the discussion centered around the Drake Equation, which was developed to produce a probabilistic estimate of the number of active, communicative extraterrestrial civilizations in the Milky Way galaxy, with Pascal’s conclusion being that the solution to the Drake Equation is likely N = 1. Ken asks Steve about his thoughts on the likelihood of intelligent life in our galaxy. 00:14:23 Dawn mentions that the Perseverance rover is currently maneuvering across the surface of Mars. She asks Steve, as the head of the Artificial Intelligence Group at JPL, NASA’s lead for deep-space robotic exploration, if he could talk about the work he specifically did on the Perseverance rover including the rover’s scheduling system. 00:16:38 Ken mentions that the success of the Perseverance mission so far has rekindled discussions of sending humans to Mars. Ken asks what Steve’s thoughts are on Pascal Lee’s proposal to take a measured approach to sending humans to Mars and that we should first return to the Moon. 00:18:47 Dawn asks Steve about the purpose of the 756-page report by the National Security Commission on Artificial Intelligence that Ken and Steve worked on for more two years. 00:20:16 Dawn asks Steve for his thoughts on the case being made in the media that China is on the verge of replacing the U.S. as the world’s AI superpower. 00:22:13 Ken mentions that in 2016 the National Security Agency was hacked and some of the agency’s cyber tools and code were leaked for any nation, cybercriminal, or terrorist to use, with Russia exploiting some of these leaked cyberweapons to shut down Ukraine in 2017. Ken goes on to mention that he and Steve’s report explains that the limited use of AI-enabled attacks to date represents the tip of the iceberg, and he asks Steve to explain the risks we face in this new and developing AI-enabled world. 00:26:19 Dawn explains that the commission’s report details how AI will enable new levels performance and autonomy for weapon systems, which of course raises several ethical and strategic issues. When it comes to the use of lethal force, Dawn asks Steve how can we ensure that AI-enabled and autonomous weapons are used in safe, reliable, and appropriate ways. 00:28:27 Ken states that for decades, the U.S. led the microelectronics industry. Today, however, we are almost entirely reliant on foreign sources to produce the semiconductors that power the AI algorithms used for our defense systems and other technologies. Ken asks how important it is for the U.S. to recommit to rebuilding a state-of-the-art microelectronics industry domestically. 00:29:56 Dawn explains that the commission and its report spent a lot of time focused on AI and the competitive challenges the U.S. faces from other nations. She goes on to ask if it is also important that we maintain our world-standing as the overall technological leader beyond just AI. She asks Steve how the U.S. can ensure that we are competitive in a world dominated by AI-associated technologies such as biotechnology, quantum computing, 5G, robotics and microelectronics. 00:32:12 Ken asks Steve to address the vital importance of getting a sufficient portion of our most talented kids in the U.S. interested in STEM. 00:34:39 Steve explains why he believes that we need to get more kids and adults interested in practical statistics. 00:39:51 Dawn closes the interview asking Steve what he likes to do in his spare time. Links: Steve Chien bio NSCAI website Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio    

In today’s episode, we talk about zombie cells, a term used to describe senescent cells because of their refusal to die. Our guest on this topic is Dr. James Kirkland, a geriatrics specialist and researcher at the Mayo Clinic in Rochester, Minnesota, who is known for his research into the role that senescence and senescent cells have on age-related dysfunction and chronic disease. As senescent cells build up in the body, they promote cellular aging and a host of chronic conditions related to aging, such as dementia, cancer, atherosclerosis, diabetes and arthritis. In today’s interview, we focus on Jim’s 2015 study where he and his colleagues at Mayo were the first to report on the potential of senolytic drugs to selectively kill zombie senescent cells. Jim’s paper in Aging Cell has been hailed as a major breakthrough in aging research. Jim is the director of the Robert and Arlene Kogod Center of Aging at Mayo and the president of the American Federation for Aging Research. The goal of James’ lab and research is to develop methods to remove senescent cells to delay, prevent, alleviate or partially reverse age-related chronic diseases.  Jim and his colleagues believe that doing this will help extend people’s health span, and, more important, prolong the period of life where people can live free of disabilities caused by chronic disease. Show notes: 00:03:20 Jim starts the interview talking about growing up in Canada. 00:03:31 Dawn asks him when he became interested in science. 00:04:05 Ken mentions that he understands that Jim had an interest in becoming a physician at a very early age, and given Jim’s previous comments, asks if it was Jim’s childhood observations of his grandparents’ aging that drove his interest in geriatrics. 00:04:39 Dawn asks how Jim ended up at the University of Toronto. 00:04:51 Dawn mentions that Jim received his medical degree in 1977 and completed his residency at Toronto General Hospital. Dawn goes on to ask why, after this, did Jim decide to go overseas to study at the University of Manchester. 00:05:37 Dawn mentions that after Jim’s experience in Manchester, he moved back across the Atlantic to work at the National Institutes of Health (NIH), where he mainly studied adipose tissue. 00:06:11 Dawn asks what role Jim’s research at NIH played in his Ph.D., which he earned from the University of Toronto in 1990. 00:07:19 Dawn mentions that in 2007 Jim became the director of the Kogod Center on Aging at the Mayo Clinic and asks how Jim ended up at that position. 00:07:54 Dawn asks Jim to clarify the difference between lifespan and healthspan. 00:09:26 Ken mentions that Jim’s research throughout his career has focused on cellular aging and senescent cells. Ken asks what initially triggered Jim’s interest in senescence. 00:11:42 Dawn mentions Jim’s 2015 paper in Aging Cell, where Jim and his colleagues at the Mayo Clinic were the first to report on the potential of senolytic drugs, which selectively kill senescent cells. Dawn goes on to ask Jim about his research leading up to this breakthrough paper. 00:14:47 Dawn asks Jim to talk about two senolytic compounds that he and his colleagues identified called dasatinid and quercetin, and what the significance of their discovery is. 00:17:20 Ken mentions the senolytic agent called fisetin, which is another agent showing benefit in rodent studies and is now being used in human clinical trials. Ken mentions that some authors have described fisetin as having roughly twice the senolytic potency as quercetin. Ken asks Jim to explain where fisetin fits into the senolytic landscape. 00:19:18 Dawn mentions that Jim began his aforementioned 2015 paper by writing about how the research shows that the healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Jim goes on in that paper describing how a series of experiments by he and his colleagues demonstrated the efficacy of senolytics to alleviate symptoms of frailty and extend health span. Dawn asks Jim to explain the process and results of these experiments. 00:22:13 Dawn mentions that not only did Jim’s findings support the idea that senescent cells could one day be used for treating cardiovascular disease and frailty, but also raised the possibility that these agents have the potential to target a multitude of disorders. Dawn asks Jim to explain this potential and why he believes that the clinical application of senolytic agents could be transformative. 00:24:31 Dawn explains that Jim followed up on his 2015 paper with a clinical trial involving a small group of diabetic kidney patients. This trial led to the publishing of “Senolytics Decrease Senescent Cells in Humans” in The Lancet. Jim explains how this study was designed. 00:27:38 Ken brings up Jim’s 2018 paper in Nature Medicine titled “Senolytics improve physical function and increase lifespan in old age.” Ken asks Jim to describe how he was able to demonstrate that with senolytic drugs he could delay the onset of virtually all age-related diseases that kill mice. 00:31:52 Dawn mentions that despite the promising potential of senolytic drugs, Jim cautions that there could be dangerous side effects, and that people should not be taking these drugs yet. Jim explains his safety concerns, as well as his estimated length of time it will take to test the safety of such anti-aging drugs. 00:33:42 Ken mentions that some STEM-Talk listeners have been experimenting with fisetin on themselves, using the Mayo protocol, which involves taking 20 mg/kg body weight of oral fisetin on two consecutive days and repeating the same dose, one month later. Ken asks if this is the same protocol used in the human clinical trials of fisetin. 00:36:02 Dawn mentions that diabetes and obesity are also associated with the accumulation of senescent cells in fat and other tissues. She mentions that Jim’s paper in Aging Cell in 2019 implicated cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements. Jim explains how he was able to demonstrate that senolytic agents show promise in terms of treating obesity-related metabolic dysfunction and its complications. 00:37:59 Jim talks about a more recent paper he published in Nature Communications that explored the possibility of transplanting organs from older doners to younger recipients. In this study Jim did heart transplants from old mice to young mice as well as young mice to old mice. Jim explains what he found in this study and what its potential significance is. 00:41:39 Ken mentions that Jim’s lab has a number of human clinical trials underway and asks Jim to share the range of conditions which these trials are reviewing. 00:43:36 Ken explains that at IHMC researchers are very interested in skeletal muscle, both in the context of aging and human spaceflight. Ken talks about the declines in physical functioning Jim mentioned in his aforementioned 2018 paper. Ken wonders if after transplantation of senescent cells into mice, if there were a direct or local role for senescence in skeletal muscle cells in the mechanisms of frailty with aging.  If so, Ken asks if there is any evidence so far that specific tissues can be targeted with senolytics. 00:45:27 Ken asks if senescence plays a possible role in muscle atrophy associated with human spaceflight. 00:46:49 Ken asks if bedrest increases senescence. 00:48:28 Dawn mentions that Jim’s 2017 paper in the Journal of American Geriatrics Society titled “The Clinical Potential of Synolytic Drugs” is a good primer for those listeners interested in learning more about these agents. Dawn mentions that since this paper is more than four years old, she wonders if there is anything new Jim would add to it. 00:51:26 Dawn closes the interview asking if Jim feels good about the work his lab is doing and if he feels like he is making progress toward his goal of slowing down and even reversing the symptoms of aging. Links: James Kirkland bio Robert and Arlene Kogod Center of Aging Mayo Clinic Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio    

It has been nearly a month since NASA’s Perseverance rover landed on Mars. So far, the rover hasn’t detected any signs of past life on the planet. But scientists have determined that several of the rocks on Mars are chemically similar to volcanic rocks on Earth. This, of course, has caused quite a bit of buzz. So, the double-secret-selection committee decided it was a perfect time to invite the chairman of the Mars Institute onto the show to get his take on the Perseverance and the Mars Mission so far. Actually, this is Dr. Pascal Lee’s second appearance on STEM-Talk. Pascal is a planetary scientist and director of the NASA Haughton-Mars Project at NASA Ames Research Center who was our guest in 2016 on episode 17.  Back then we talked to Pascal about his annual visits to the High Arctic’s Devon Island, which is the Earth’s largest uninhabited land that has geological characteristics similar to what scientists believe we will find on Mars. Today we catch up with Pascal and his Haughton-Mars Project. We also talk to him about Perseverance and a host of other Mars-related topics. We ask Pascal if he thinks we’ll find signs of life on Mars, or if he believes we will ever find signs of alien life in our galaxy. We also get Pascal’s thoughts about future manned missions to Mars and whether humans will ever colonize the Red Planet. And after listening to today’s interview, be sure to check out Pascal’s artwork and his recent paintings of Mars. Show notes: 00:03:15 Dawn opens the interview welcoming Pascal back to STEM-Talk, mentioning that the last time he was on the podcast he was about to spend his 20th consecutive summer on Devon Island, the Earth’s largest uninhabited land with geological characteristics similar to what Pascal believes we will find on Mars. Dawn goes on to mention that due to COVID-19, last year’s trip to Devon Island was canceled and asks him about his disappointment. 00:05:11 Ken asks if Pascal is confident that he’ll return to Devon Island this coming summer. 00:05:36 Dawn mentions that it takes several stops and trips to reach Devon Island. She asks who makes those travel arrangements and how the journey plays out. 00:08:25 Ken asks about Pascal’s polar bear guard dog, Apollo, inquiring as the protocol when Apollo alerts the team about a nearby polar bear. 00:10:48 Dawn mentions the Webby Award-winning documentary filmed by a team at Google who came to visit Pascal on Devon Island in 2018 called “Mars on Earth: A Visit to Devon Island”. Dawn asks Pascal what he thought of the documentary. 00:12:20 Ken asks Pascal to elaborate on the space suit that he was planning to test on Devon Island last summer but couldn’t because the trip was canceled. 00:16:39 Dawn asks about the glove Pascal wants to test that may enable single-handed drone operation. 00:20:11 Dawn mentions that the atmosphere of Mars is around 60 times less dense than the Earth’s. She asks Pascal about the challenges of flying a drone on Mars. 00:22:15 Dawn asks Pascal to elaborate on his recommendation that scientists study the Inuit culture and history in relation to long-duration space travel. 00:26:01 Ken mentions NASA’s Perseverance rover, which landed on Mars in February and relates that Steve Jurczyk, the NASA acting administrator, described Perseverance’s landing on Mars as a pivotal moment for the United States and space exploration. Given that NASA has landed rovers on Mars before, Ken asks Pascal what makes this particular landing especially significant. 00:28:10 Dawn mentions that NASA recently released recordings of the Perseverance rover driving on the surface of Mars. Dawn goes on to ask what the particular significance is of the audios. 00:29:41 Dawn asks what NASA means when it describes Perseverance as a “robotic astrobiologist.” 00:32:36 Ken asks Pascal to discuss the Mars helicopter, Ingenuity, that made its flight to mars attached to the belly of Perseverance. Pascal describes some of the challenges NASA and its engineers face in attempting to produce powered flight on the surface of Mars. 00:41:06 Dawn mentions that Perseverance is just one of three Mars missions that are currently underway. She explains that The United Arab Emirates and China also have crafts that have reached Mars, with all three of these missions being launched in July of 2020. Dawn asks Pascal to explain what he knows about both of these missions. 00:43:56 Ken asks if Pascal knows what type of entry, decent, and landing method the Chinese mission is employing. 00:45:01 Ken asks Pascal to describe the leading theory regarding what happened to the water that may have once been on the surface of Mars. Pascal also explains his own theory on this topic. 00:51:15 Ken asks Pascal to describe how he would go about testing his theory regarding the water of ancient Mars if he were the NASA Administrator. 00:59:15 Dawn mentions Avi Loeb, who is a Harvard astrophysicist and author of the book, “Extraterrestrial: The First Sign of Intelligent Life Beyond Earth,” argues that aliens have already visited the Earth. Given recent news stories about the uptick of reports from Navy and Air Force pilots observing UFOs, Dawn asks Pascal if he believes we are alone in our galaxy. 01:09:54 Pascal gives his thoughts on what is behind all the UFO sightings often talked about in the media. 01:13:16 Dawn asks Pascal to elaborate on his thought that a manned mission to Mars will require a measured approach consisting of several milestones, including taking a round trip to Mars without landing. 01:18:57 Ken mentions that he agrees with Pascal’s perspective that Phobos and Deimos, the two moons of Mars, are a spectacular choice for human exploration. 01:22:14 Ken mentions that in addition to being a planetary scientist, Pascal is an accomplished artist. Ken asks if Pascal was able to get more painting done this year as a result of COVID-19. 01:23:18 Dawn asks Pascal to name some of his what some of his favorite pieces of artwork. 01:24:44 Dawn mentions that the last time Pascal was on STEM-Talk, Pascal got the chance to talk about his children’s book “Mission to Mars,” written in the hopes of inspiring children to take an interest in science and space travel. Dawn goes on to say that Pascal had also mention that he was working on a book for adults tentatively titled “From Earth to Mars.” Dawn asks how that book is coming. 01:25:17 Dawn closes the interview asking Pascal to elaborate on his thoughts that we are on the verge of a great age of the renewal of human exploration. Links: Pascal Lee bio Pascal Lee artwork Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio

Ever since Cell Metabolism published a study that found the naturally occurring metabolite alpha-ketoglutarate reduces inflammatory signaling as well as chronic inflammation, listeners have been asking Ken and Dawn for their take on the paper. Today, we have the author of the paper, Dr. Gordon Lithgow, as our guest on STEM-Talk. We talk with Gordon in-depth about his study and the potential of alpha-ketoglutarate to have positive effects on lifespan and healthspan. Gordon is a professor and vice president of Academic Affairs at the Buck Institute in Novato, California, where his research focuses on uncovering genes and small molecules that prolong lifespan through enhanced molecular stability. Today we cover Gordon’s research into alpha-ketoglutarate in the second part of a two-part interview. In part one, episode 119, we asked Gordon about his fascination with C elegans, a microscopic worm that Gordon and other geneticists study and often use for their research. He particularly covered two of his studies involving C elgans: one that looked at the role that protein homeostasis plays in aging;  and another study that found vitamin D3 improves protein homeostasis and slows aging. A native of Scotland, Gordon researched the biology of aging at the University of Manchester in England before moving to the Buck Institute in 2000. Gordon is married to Dr. Julie Andersen, who was our guest on episodes 117 and 118 and who also is a researcher at the Buck Institute. Show notes: 00:03:20 Dawn opens part two of our interview with Gordon by mentioning his most recent paper on alpha-ketoglutarate, which has generated a lot of buzz. This study suggests there is a metabolite that one can buy in a health food store that may have a positive effect on lifespan as well as healthspan. Dawn goes on to mention that alpha-ketoglutarate (AKG), is a naturally occurring metabolite. She notes that previous studies on it have shown that blood plasma levels of AKG can drop up to 10-fold as we age. Dawn asks Gordon to explain what AKG is and how it is involved in so many of our fundamental physiological processes. 00:07:41 Ken mentions that in the study, Gordon fed the mice calcium AKG. Ken asks why Gordon chose calcium AKG as opposed to arginine AKG, which is a dietary supplement often used by athletes and bodybuilders to improve their performance and reduce muscle fatigue. 00:09:22 Dawn mentions that when Gordon’s paper came out in Cell Metabolism, Gordon was quoted as saying, “The nightmare scenario has always been life extension with no reduction in disability.” Dawn goes on to state that this study showed that the middle-aged mice who were treated got healthier over time, and that even the mice that died early saw improvements in their health. Dawn asks Gordon to elaborate on this apparent extension in healthspan. 00:12:41 Dawn asks Gordon about the significance of the finding in his study that calcium AKG reduced inflammatory signaling, as well as chronic inflammation, as it relates to degenerative aging. 00:14:57 Ken asks if Gordon’s study has been replicated in any other strains of mice. 00:18:54 Dawn mentions that Ponce De Leon Health, which is based in Florida, is marketing a formulation of calcium AKG under the brand name Rejuvant. She goes on to mention that Gordon and his colleagues at the Buck worked with Ponce De Leon Health to develop the product and that Gordon owns stock in the company. Dawn asks Gordon to give an overview of this partnership and address the concerns that some people may have about a potential conflict of interest. 00:21:17 Ken asks Gordon to explain how the dose of calcium AKG used in the mouse study compares to the dose recommended for humans via the commercial supplement, noting that the dose seems to be substantially and proportionally higher for mice. 00:22:03 Ken asks why Ponce De Leon Health is marketing different formulations of its product for men and women, and what the difference is between the two formulations. 00:24:53 Dawn asks with regard to the consistent positive longevity effects of AKG in C elegans and now mice, if these positive effects are translational to humans. 00:27:39 Ken mentions that there are several biomarkers for determining biological age, and goes on to mention that Ponce De Leon Health distributes a product called “True Age,” a test of biological age based on epigenetic markers. Ken asks if Gordon has any thoughts on this, and what biomarker does he use to evaluate biological age in his research and why. 00:31:09 Dawn mentions that an article published in the Mercury News in San Jose, Calif.,  interviewed a number of scientists who were very impressed by Gordon’s AKG study and its results. A handful of scientists, however, were quoted as saying that while “AKG is likely to be safe, it is possible there are side effects.” Dawn asks Gordon if he knows of any side effects of AKG that people need to be aware of. 00:32:37 Dawn mentions a paper published in Nature communications by Gordon and some international colleagues titled “Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction”which used a genetic model of dietary restriction in C elegans. Dawn goes on to mention that the paper shows that dietary restriction results in increased levels of long chain omega 6 and 3 polyunsaturated fatty acids including linoleic acid and EPA, which are known to signal increased expression of cytoprotective and detox genes that increase lifespan. Dawn asks Gordon to talk about how genetic models of dietary restriction both do and don’t reflect true dietary restriction in animal models and humans. 00:36:01 Ken follows up on the previous question by asking Gordon if he thinks that the metabolic reprogramming seen in the C elegan model gives any insight into how intakes of dietary polyunsaturated fatty acids (PUFAs) might alter health outcomes in humans. Ken goes on to mention that Gordon noted in his paper that supplementing C elegans with monounsaturated fats decreased lipid peroxidation, but exogenous fish oil both increases peroxidation and decreases lifespan. Ken notes that this seems to be in stark comparison to humans, where much time, research and money has been poured into creating various fish oil formulas to improve human health. Gordon provides his thoughts on this matter. 00:39:38 Dawn mentions that when Gordon first joined the Buck institute and started looking at aging and disease, the word geroscience did not exist. She goes on to mention that today there are hundreds of companies around the world devoting themselves to the idea of geroscience. Gordon discusses how he and his colleagues came up with this word and what it refers to. 00:42:07 Dawn says that it is an exciting time to be in the field of aging. She asks Gordon where he thinks the future of aging research is headed, and what are some questions that he and his colleagues at the Buck will be addressing in the years to come. 00:45:31 Dawn closes the interview by mentioning that Gordon’s wife, Julie Andersen (episodes 117 and 118), said Gordon was the cook in the house. Dawn goes on to note that she understands Gordon makes a turmeric curry about every week. Dawn asks if there is any special reason for this fondness of curry, and why the choice of turmeric. Links: Gordon Lithgow lab Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio  

Episode 119: Gordon Lithgow talks about the biology of aging and prolonging lifespan Our guest today is Dr. Gordon Lithgow, a professor and vice president of Academic Affairs at the Buck Institute in Novato, California. Gordon’s research focuses on uncovering genes and small molecules that prolong lifespan through enhanced molecular stability. Because our conversation with Gordon was so extensive and fascinating, we have split his interview into two parts. In today’s part one of the interview, we talk to Gordon about his background and early studies as well as his fascination with C elegans, a microscopic worm that Gordon and other geneticists study and often use for their research. We particularly talk in depth about two of Gordon’s studies involving C elgans: one that looked at the role that protein homeostasis plays in aging;  and another study that found vitamin D3 improves protein homeostasis and slows aging. A native of Scotland, Gordon researched the biology of aging at the University of Manchester in England before moving to the Buck Institute in 2000. Gordon is married to Dr. Julie Andersen, who was our guest on episodes 117 and 118 and who also is a researcher at the Buck Institute. In part two of our interview with Gordon, we talk to him about a recent study of his that found the naturally occurring metabolite alpha-ketoglutarate reduces inflammatory signaling as well as chronic inflammation. The study has generated quite a bit of buzz because it suggests there’s a readily available metabolite that may have positive effects on lifespan and health span. As a result, Ken and Dawn have been getting numerous questions from listeners about alpha-ketoglutarate and Gordon’s recent study that ran in Cell Metabolism, which Gordon talks about in depth in part two. Show notes: 00:03:59 Dawn opens the interview asking Gordon about growing up in a steelwork town outside of Glasgow, Scotland. 00:04:22 Dawn asks Gordon what he was like as a kid. 00:05:07 Dawn asks Gordon how a young boy who had aspirations of becoming a professional rugby or soccer player suddenly becomes passionate about birdwatching. 00:07:07 Gordon talks about how he went to the University of Strathclyde after high school and how he was the first in his family to attend college. 00:07:48 Dawn asks Gordon why he shifted his academic interests from microbiology to genetic engineering. 00:09:05 Ken asks what led Gordon to attend the University of Glasgow for his doctorate after getting a degree in microbiology. 00:10:04 Ken asks why Gordon went to Switzerland after receiving his doctorate. 00:10:57 Ken asks what prompted Gordon to head to Boulder, Colorado, and why he became so interested in the biology of aging. 00:12:57 Dawn mentions that while Gordon was working in Tom Johnson’s lab during his post-doc, Gordon made what Tom referred to as an amazing discovery. Gordon had found that a single heat shock to worms increased their lifespan by 15 percent. Dawn asks Gordon to talk about this discovery as well as his paper that ran in PNAS. 00:15:46 Ken mentions that because of Gordon’s discovery, many people have developed an interest in sauna. 00:16:57 Dawn mentions that a number of years after discovering that heat shocking increased the lifespan of worms, Gordon followed up on that study and demonstrated that giving the worms repeated mild hormetic heat treatments increased their lifespan even more. Dawn goes on to ask if, since this follow-up study, Gordon has a better understanding of hormesis mechanisms at the cellular and molecular level and how that might relate to the prevention and treatment of different diseases. 00:18:02 Dawn mentions that Julie Anderson, Gordon’s wife, was interviewed for STEM-Talk episodes 117 and 118. Dawn goes on to say that when she asked Julie how she and Gordon met,  Julie said, “I was having a transatlantic relationship with Gordon and we met because we’re nerds.” Dawn asks if Gordon would like to respond to this assertion that he’s a nerd, and whether it is true that he ended up at the Buck Institute on Julie’s coattails. 00:20:40 Dawn asks Gordon what are the main questions which have motivated his research. 00:23:07 Dawn mentions that in Gordon’s work he screens natural compounds like vitamins and minerals to determine if they have the potential to affect lifespan. Gordon does this by studying C elegans, tiny nematode worms that are found in rotting fruit and on the backs of snails. Dawn asks why Gordon and other geneticists are so found of using C elegans in their research. 00:25:54 Ken mentions that a lot of Gordon’s recent research with C elegans has looked at the role that protein homeostasis plays in aging. Ken asks Gordon to give an overview of the role that proteins play in determining lifespan. 00:29:07 Ken asks Gordon about his paper in Aging Cell which indicated that the accumulation of insoluble proteins with diverse functions could be a general feature of aging. The paper also showed that many hundreds, if not thousands of proteins, undergo conformational change during aging and come out of solution. Gordon explains what this conformational change is and what it means to come out of solution. 00:29:58 Dawn mentions that, as Gordon has already pointed out, we know that proteins sustain lots of damage in the normal course of metabolism. Dawn asks Gordon to discuss how he and other researchers are trying to better understand the mechanisms of normal aging that are likely to accelerate age-related pathologies and diseases. 00:32:16 Dawn asks why Gordon started looking into how excessive dietary iron affects protein homeostasis in worms. 00:35:11 Dawn asks Gordon for his thoughts on whether or not his findings on the effects of iron in worms may have some physiological relevance for humans. 00:35:42 Ken, in light of the effects iron has on health asks Gordon what effects other metals could potentially have on protein homeostasis and overall physiology. 00:37:02 Dawn shifts to talking about Gordon’s research into vitamin D. Dawn mentions that in Gordon’s interview with Rhonda Patrick, who back in 2016 was one of STEM-Talk’s first guests, appearing in episode 3, Gordon told Rhonda a story about how someone came to the office and suggested studying vitamin D, to which Gordon said “No way. There’s nothing new to learn about vitamin D.” Dawn asks what changed his mind. 00:40:55 Ken mentions that in Gordon’s study, which appeared in Cell Reports, he observed that vitamin D3 improves protein homeostasis and slows aging. Ken states that the obvious takeaway is that it is important to maintain appropriate vitamin D serum levels. He asks if Gordon was able to determine what the appropriate level is for humans. 00:44:43 Dawn asks if Gordon has looked at whether vitamin D deficiency in older adults might explain why seniors and nursing-home residents have an elevated risk when it comes to COVID-19. 00:47:35 Ken shifts to asking Gordon about some work he did a few years ago with two other labs where they dug into the issue of experimental reproducibility. Ken asks Gordon to give a brief background of this research. 00:51:08 Ken closes part one of our interview with Gordon by mentioning that reproducibility is considered a cornerstone of experimental science. Ken asks what Gordon thinks are the primary drivers of irreproducibility in science and what Gordon thinks can be done better. Links: Gordon Lithgow lab Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio  

Today we have part two of our conversation with Dr. Julie Andersen, a professor at the Buck Institute who is conducting fascinating research into the metabolite compound urolithin-A. Laboratory experiments have demonstrated urolithin-A’s ability to induce mitophagy, which is a selective recycling of mitochondria by autophagy, a process that cleans defective mitochondria and becomes less efficient during aging. Julie’s research has focused on the potential of urolithin-A to prevent and treat such diseases such as Alzheimer’s, Parkinson’s, Huntington’s and Lou Gehrig’s disease. In part one of our interview with Julie, she talked about her interest in aging and age-related diseases as well as her early studies into developing new therapeutics for neurodegeneration. Julie has been with the Buck Institute since 2000 and has published more than 170 papers. Show notes: 00:02:15 Dawn starts the second part of our interview asking Julie how the composition of bacteria in the gut affects brain function. 00:07:08 Ken asks Julie to explain what urolithin-A is, where it comes from, and why her lab and others are so interested in it. 00:10:49 Ken mentions that a study was recently published which showed that giving urolithin-A to older mice resulted in a 42 percent improvement in endurance while running compared to a control group of mice of the same age. Ken goes on to ask Julie what it is that makes urolithin-A so impactful. 00:12:43 Dawn mentions that it is known that production of urolithin-A seems to be dependent on the presence of certain gut microbes. She goes on to ask Julie what types of gut microbes are most important in the conversion of ellagic acid. 00:13:33 Ken asks if people vary in terms of how efficiently they convert ellagic acid into urolithin-A, and if so, how much variance is there. 00:14:43 Julie explains what she has learned about how to better analyze the gut microbiome composition from her studies with mice. 00:15:51 Ken asks if there is a test one can take to see if they are a urolithin-A producer. 00:16:19 Ken mentions the June 2019 paper by Chris Rinsch’s team in Nature Metabolismwhich showed a striking up-regulation of mitochondrial gene expression, including some induction of mitophagy genes in the skeletal muscle of older adults after 4 weeks of oral urolithin-A supplementation. He goes on to say that given the well-documented mitochondrial dysfunction in Parkinson’s disease, which seems to be ubiquitous, he asks what Julie’s thoughts are on the use of urolithin-A supplementation in Alzheimer’s or Parkinson’s 00:19:22 Dawn mentions that Julie wrote a paper titled “Senescence as an Amyloid Cascade: The Amyloid Senescence Hypothesis,” about the intersection of amyloid-beta oligomers and cellular senescence in Alzheimer’s disease, cautioning against completely rejecting the amyloid hypothesis. Dawn asks if the intersection of senescence with amyloid burden help to address the lack of correlation between amyloid burden and disease burden in both animal models and humans. 00:26:22 Dawn asks about the compound “C1” that Julie’s lab has demonstrated boosts autophagy and, as a result, shows promise in treating Alzheimer’s. 00:30:27 Dawn mentions Mitopure, which is a commercially available oral formulation of urolithin-A from a Swiss company called Amazentis. This product provides urolithin-A directly regardless of one’s diet or microbiome composition. Dawn goes on to ask if Julie has any thoughts on the benefits of this product. 00:32:23 Dawn asks if there is any evidence that urolithin-A taken orally can cross the blood-brain barrier to reach key target cells in the brain. 00:35:05 Dawn asks if the high concentration of peroxidation-sensitive lipids in the brain, which contribute to its sensitivity, is something that will eventually build regardless, or are there modifiable factors that can alter the susceptibility of lipid species in the brain to peroxidation. 00:36:06 Julie talks about the potential role of senolytics in the treatment of neurodegenerative disorders, and what the current barriers are to implementing them. 00:39:29 Dawn mentions that Julie has recently written about the senolytic effects of lithium. The results of this study suggested that lithium might be beneficial to COVID-19 patients. 00:31:21 Dawn asks Julie about the shift in the conversation about aging from lengthening lifespan, to increasing the quality of life, to achieve a relatively disease-free state for the longest time possible. 00:48:04 Dawn closes the interview asking Julie about using her down time during COVID to learn to play the mandolin and speak Spanish. Links: Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio

Our guest today is Dr. Julie Andersen, who is best known for her research into aging and age-related diseases. A professor at the Buck Institute Buck Institute for Research on Aging, an independent biomedical research institute that researches ways to extend the healthy years of life, Julie and her colleagues at Buck have focused on understanding the underlying age-related processes driving neurodegenerative diseases in order to identify novel therapeutics. Because our conversation with Julie was so fascinating and long, we have divided it into two parts. In today’s part one of her interview, we talk to Julie about her youth and early career. We also talk to her about the potential of of rapamycin to protect brain cells and mitochondria in a mouse model of Parkinson’s disease as well as her thoughts about the Amyloid Cascade Hypothesis. In part two, which will go live in a few weeks, we have an in-depth conversation with Julie about her research into the neuroprotective properties of urolithin A. In terms of Julie’s background, she received her Ph.D. from UCLA and did her post-doc in the department of neurology at Harvard. In 2000 Julie joined the Buck Institute. Show notes: [00:03:33] Dawn opens the interview asking if it is true that Julie was a quiet kid who normally sat in the back of the classroom. [00:03:52] Dawn mentions that Julie was born in Montana but that she grew up in northern Idaho. Dawn asks what it was that brought Julie’s family to Idaho. [00:04:29] Dawn asks Julie what interests she had growing up. [00:05:05] Ken remarks on the fact that one of Julie’s favorite books is a biography of Clementine, Winston Churchill’s wife, and asks where Julie’s interest in Clementine came from. [00:05:46] Dawn mentions that for Julie’s undergraduate degree, she went to Washington State University, where her father was a professor. Dawn asks if Julie knew from the start that she was going to focus her undergraduate studies on plant physiology. [00:07:03] Ken asks Julie took her to UCLA for her Ph.D. [00:08:16] Dawn asks Julie what led to travel across the country to Boston for her post-doc. [00:09:26] Julie explains why she eventually returned to California after her Ph.D. [00:11:32] Dawn asks Julie to tell the story of how meeting someone she described as “a fellow nerd” at an aging conference eventually led her to taking a position at the Buck Institute. [00:14:34] Ken remarks that Julie must like working at the Buck, given she has remained there for the last 20 years. Julie describes what is it about the Buck Institute that makes it such a special place. [00:17:51] Dawn mentions that for the past 20 years, Julie and her lab at Buck have looked at a lot of different aspects of neurodegeneration, with a heavier concentration on autophagy in the past five years. Dawn goes on to mention that Julie has especially been investigating a natural bioactive known as urolithin A. Before diving into all of this work specifically, Dawn asks Julie, what drew her to the study of neurodegeneration to begin with. [00:19:55] Ken asks what prompted Julie’s current focus on autophagy. [00:24:11] Dawn explains that degradation of damaged mitochondria via lysosomal autophagy is a key cellular pathway in the maintenance of mitochondrial homeostasis.  Disruption of this pathway contributes to the progressive cell loss that is associated with Parkinson’s disease. She goes on to mention that Julie published the results of a study in 2015that found rapamycin can protect brain cells and mitochondria in a mouse model of Parkinson’s disease. Julie explains the significance of this study and talks about the importance of rapamycin in the research of therapies for Parkinson’s disease. [00:30:44] Dawn asks Julie to explain the concept, and the significance of, transcription factor EB (TFEB), which is a protein that is encoded in humans by the TFEB gene, and is a master regulator of autophagy and lysosomal function. Julie explains how this has become a potential target for treating Parkinson’s and Alzheimer’s. [00:32:41:] Ken mentions that much of Julie’s work has focused on cellular senescence. Ken asks for Julie to describe the concept of senescence, as well as its impact on neurodegenerative diseases. [00:41:26] Ken mentions that exposure to the herbicide paraquat is associated with increased risk of idiopathic Parkinson’s disease. He goes on to mention that Julie published a study in 2017 that showed exposure to certain environmental toxins promotes accumulation of senescent cells in the aging brain. Julie talks about her finding that therapies targeting senescent cells may constitute a strategy for treatment of sporadic Parkinson’s disease. [00:46:47] Dawn ends part one of the interview by mentioning that Julie followed up her 2017 study with another study that examined whether one could screen known neurotoxicants for their ability to cause astrocytes, which are a mitotic-cell type in the brain important for maintaining neuronal health, to undergo senescence. Julie ends the interview with a discussion about the study, titled “Screening Method for Identifying Toxicants Capable of Inducing Astrocyte Senescence.” Links: Learn more about IHMC STEM-Talk homepage Ken Ford bio Ken Ford Wikipedia page Dawn Kernagis bio