Dr. Dale Bredesen on Preventing and Reversing Alzheimer's Disease
Dale E. Bredesen, M.D., is a professor of neurology at the Easton Laboratories for Neurodegenerative Disease Research at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Dr. Bredesen's laboratory focuses on identifying and understanding basic mechanisms underlying the neurodegenerative process and the translation of this knowledge into effective treatments for Alzheimer's disease and other neurodegenerative conditions. He has collaborated on the publication of more than 220 academic research papers. His work has culminated in the development of a protocol called ReCODE – reversal of cognitive decline – currently used by over 3,000 patients with the goal of not just preventing, but reversing Alzheimer's disease and mild cognitive impairment. .
Dr. Valter Longo on Resetting Autoimmunity and Rejuvenating Systems with Prolonged Fasting & the FMD
This podcast is a spectacular round two podcast with Dr. Valter Longo. Dr. Longo is the current director of the longevity institute at the University of Southern California and also director of the Oncology and Longevity Program at the Institute of Molecular Oncology Foundation in Milan, Italy. Dr. Longo’s research focuses understanding the biological mechanisms that regulate the aging process, the role of fasting and diet in longevity and healthspan in humans as well as metabolic fasting therapies for the treatment of human diseases. In this episode, we discuss... What two seminal studies on chronic caloric restriction in primates from the 80s teach us about caloric restriction as a preventer of age-related disease, and how the effects of caloric restriction may actually be stronger when the diet that is being restricted is an unhealthy one – similar, in some ways, to the typical western diet. How certain macronutrients influence the insulin/IGF-1/growth hormone axis interact to modulate aging in many cell types. How mice and humans who have growth hormone receptor deficiencies have low circulating IGF-1 – as little as 10% of normal levels – and have reduced risk of diseases like cancer, diabetes, and age-related cognitive decline, hinting at what future research might reveal about the beneficial effects of prolonged fasting and fasting-mimicking diets through the downstream effects of periodic deprival of growth-related factors. How the growth hormone / IGF-1 axis got a big boost early on in scientific interest when it was revealed that mice that have either deficiency in growth hormone itself or the growth hormone receptor live up to 40% longer and how this is accomplished through what is essentially a delaying of the decrepitudes of old age. The origins of what Dr. Longo calls the fasting-mimicking diet – a 5-day diet focused on recapitulating some of the benefits of prolonged fasting, like dramatic changes in metabolic biomarkers, but without some of the drawbacks like reduced compliance and other risks that can come with multiple days of grueling strict water fasting in large, heterogeneous populations. How periodic prolonged fasting or the fasting-mimicking diet may be able to render cancer cells more vulnerable while conferring stress resistance to healthy cells, a quality known as differential stress resistance. This can happen because of the way fasting interferes with what is known as oncogenic signaling. The mixed results associated with the use of the ketogenic diet in treatment of cancer and how some cancers seem to be hurt by the metabolic switch of utilizing ketone bodies, which creates oxidative stress from the use of mitochondria, while other cancers seem to be able to use ketones effectively as an energy source, potentially accelerating their growth. Some of the early but promising pre-trial clinical anecdata suggesting potential complementary roles for the ketogenic diet and the fasting-mimicking diet (FMD) used in conjunction with conventional treatments like chemotherapy or radiotherapy for certain cancers like gliomas. In the context of aging, how the fasting mimicking diet has been shown to “reset” metabolism, driving down biomarkers associated with poor metabolic health, inflammation, and cardiovascular health. How fasting, through the shrinking and then re-expansion of whole systems like the liver, kidneys, heart, and immune cells may represent a type of whole-system renewal that originated as a three-billion-year-old self-repair mode that was only activated during periods of famine or inconsistent food availability, but might now be dormant in people living in a modern world of regular food intake. How Dr. Longo’s group has shown that, in animal models of multiple sclerosis and pharmacologically-induced type 1 diabetes, several cycles of the fasting-mimicking diet is able to reverse disease and restore healthful function. This mechanism also may generalize to erasing other diseases of autoimmunity through the destruction of autoimmune immune cells that are essentially reset through fresh differentiation from progenitors untainted by autoimmunity. A very exciting area of continued inquiry! How shorter fasts may fail to approach some of the effects of periodic fasting and the fasting-mimicking diet by failing to achieve adequate glycogen depletion and ketogenesis. Dr. Longo’s “top picks” for assessing biological age – markers a person can ask their doctor to measure to gauge how well they’re aging. A sneak peek at what’s covered in Dr. Longo’s new book, .
Dr. Charles Raison on Depression, the Immune-Brain Interface & Whole-Body Hyperthermia
Charles Raison, M.D. is a professor at the School of Human Ecology at the University of Wisconsin-Madison and Founding Director of the Center for Compassion Studies in the College of Social and Behavioral Sciences at the University of Arizona. Dr. Raison’s research focuses on inflammation and the development of depression in response to illness and stress. He also examines the physical and behavioral effects of compassion training on the brain, inflammatory processes, and behavior as well as the effect of heat stress as a potentially therapeutic intervention major depressive disorder. In this nearly 2-hour episode, we discuss the extremely dynamic interaction that the immune system has with mood, behavior, and the brain, as well as the potential that whole-body hyperthermia, a research technique mostly indistinguishable from sauna use, may have for the treatment of clinical depression. Additionally, we also talk about…. How depression as a disease may be subdivided based on whether or not there is involvement of chronic inflammation and how this could influence how it should be treated. The changes in functional brain connectivity that are associated with the high inflammation subtype of depression. The physiological similarities a sauna, hot bath, steam shower, and hot yoga have with whole-body hyperthermia from the standpoint of potentially therapeutically boosting body temperature. Preliminary evidence that increased expression of a certain heat shock protein in the brain may influence behavior by protecting against stress-induced depression. … and so much more. Go to the timeline on the episode page to see a full breakdown. .
Dr. Eric Verdin on Ketogenic Diet Longevity, Beta-Hydroxybutyrate & HDAC Inhibitors
Eric M. Verdin, M.D. is the fifth president and chief executive officer of the Buck Institute for Research on Aging and is a professor of Medicine at UCSF. Dr. Verdin's laboratory focuses on the role of epigenetic regulators in the aging process, the role of metabolism and diet in aging and on the chronic diseases of aging, including Alzheimer’s, proteins that play a central role in linking caloric restriction to increased healthspan, and more recently a topic near and dear to many of you, ketogenesis. He's held faculty positions at the University of Brussels, the NIH and the Picower Institute for Medical Research. In this episode, we discuss... The effects of a low protein, cyclic ketogenic diet beginning in midlife (12 months of age) in male mice. The result? Increased healthspan and improved memory. Dr. Verdin explains how the cyclic ketogenic diet decreased insulin, IGF-1, and mTOR signaling and decreased fatty acid synthesis, and increased PPAR-alpha (which promotes beta-oxidation and mitochondrial biogenesis in muscle). How this diet is somewhat qualitatively similar to fasting. Some of the possible reasons why the cyclic ketogenic diet created such a striking improvement in memory even when compared to younger mice. How beta-hydroxybutyrate, which is the major circulating ketone body during fasting and nutritional ketosis, may, in addition to being an energy source, regulate inflammation and gene expression by acting as a signaling molecule by inhibiting what are known as class 1 histone deacetylases (HDACs). How this inhibition of class 1 HDACs leads to the increased expression of notorious longevity gene Foxo3, which may help explain why mice given an exogenous beta-hydroxybutyrate ester had lower markers of inflammation and oxidative damage, which are physiological contributors to the aging process. The role of the nicotinamide adenine dinucleotide (NAD+) in the aging process and how replacing declining levels ( or preventing them from declining in the first place ) may prove to be an important anti-aging strategy. Some of the reasons why NAD+ might be declining with age, its role in DNA damage repair via an enzyme known as PARP, and what the literature says about the NAD+ precursor nicotinamide riboside. How a special class of enzymes called sirtuins, also known to be activated by caloric restriction and caloric restriction mimetic resveratrol, is tightly correlated with the level of NAD+ and how this "energetic currency" rises in response to fasting. The role of the sirtuin enzymes in regulating mitochondrial function, neuronal functions, stem cell rejuvenation and why they may be important in delaying the aging process. .
Dr. Satchin Panda on Practical Implementation of Time-Restricted Eating & Shift Work Strategies
This is a nearly 2-hour round 2 episode with none other than Dr. Satchin Panda of the Salk Institute! At nearly two hours of dialog, this episode touches on a lot of material but has a special focus on practical implementation of time-restricted eating. Put another way, I kept a list of a lot of questions that seem to keep coming up and present them directly to Satchin. We talk about dealing with shift work, black coffee when fasting, and some of the distinctions between Satchin's approach to time-restricted eating which is influenced by his deep background in circadian biology and more conventional protocols like 16:8 that many people are familiar with. In addition to these important and very practical how-to tidbits, we dive into lots of interesting new territory as well, including... How human anecdote and animal evidence suggests time-restricted feeding may be especially useful for gut-related issues, including inflammatory bowel disease and acid reflux. The fascinating way Dr. Panda is using human anecdote from his trial to ask new scientific questions he wouldn't think to ask and then going back to animal data to figure it out and how this unique approach forms a sort of closed loop pattern: animal → human feedback → back to animal for mechanism. How labs doing caloric restriction research may have actually been reaping the benefits of time-restricted without realizing it as an incidental to their experimental design. The revelation that 70% of FDA drugs are subject to circadian effects and are either less effective or more effective at certain times of the day. The effect melatonin has on the pancreatic production of insulin and the insight this lends to why we should probably stop eating 3-4 hours before we go to bed. The bizarre way circadian rhythms affects everything from susceptibility to UV damage to recovery from surgery to cancer risk. .