Brain Ponderings podcast with Mark Mattson

Cells have evolved elaborate molecular systems that control cell growth and division in ways that enable optimal function and resilience of all organ systems including the brain.  Cells that have the potential to become cancerous are eliminated by a process called apoptosis. Cells may also acquire a senescent state in which they no longer divide and function normally, but survive and produce potentially damaging proteins such as pro-inflammatory cytokines and proteases. Senescent cells accumulate during normal aging and more so in chronic diseases, but until recently it was not known whether such senescent cells cause or accelerate aging and disease processes . Mayo Clinic Professor Darren Baker who is an expert on the molecular control of cell division and cancers recently used genetic engineering technologies to generate mice in which senescent cells can be selectively eliminated. By studying these mice he and his team have provided convincing evidence that senescent cells contribute to the aging process and are involved in the disease processes that occur in Alzheimer’s disease (AD). There is evidence that several types of glial cells in the brain undergo senescence and removal of these cells can slow disease progression. I talk with Dr. Baker about his research on cell senescence, key issues that remain unresolved, and drugs that target senescent cells – “senotherapeutics” as potential treatments for AD and other neurodegenerative disorders. Dr. Baker’s Mayo Clinic Profile page: https://www.mayo.edu/research/faculty/baker-darren-j-ph-d-m-s/bio-00027985 Review article on senescence and brain aging: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873891/pdf/jci-128-95145.pdf Introduction to special journal issue on senescence: https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/febs.16735 Review article on senotherapeutics: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599677/pdf/nihms-1842277.pdf Targeted removal of senescent cells and senotherapeutics in animal models of AD: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206507/pdf/nihms-1505435.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939718/pdf/nihms-1968907.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605052/pdf/nihms-1031989.pdf

Two interrelated features of the brains of humans and other social animals is that they develop attractions for kin and other members of their local community (tribalism) and perceive strangers as potential threats (xenophobia). Historically, tribalism and xenophobia are of fundamental importance in unnecessary suffering and death from isolated domestic incidents to major wars. It is therefore important to understand both the psychology and neuroscience of tribalism and xenophobia. Pascal Molenberghs is a social neuroscientist who has studied the neural networks that mediate the cognitive processing and decision-making involved in xenophobic beliefs and actions. Here I talk with him about the far-reaching implications of this research for a wide range of issues including religions, politics, and dehumanization.  LINKS: The neuroscience of intergroup threat and violence: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9620594/pdf/main.pdf The neuroscience of in-group bias: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174241/pdf/fpsyg-09-01868.pdf Empathy: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644680/pdf/fnhum-07-00176.pdf

The ability of the human brain to store and recall information, and particularly its ability to create new information, is remarkable. The research of Harvard University professor Daniel Schacter as revealed the fallibilities of memory which he categorizes into ‘the seven sins’: transience, absent-mindedness, blocking, persistence, misattribution, suggestibility, and bias. These are normal, are influenced by emotions, can have adaptive value, and may be exaggerated or absent in pathological conditions. The digital technologies that most of us use every day, often for hours at a time, present new challenges for our memory system. In this episode I talk with professor Schacter about his career in memory research, how memory fallibilities play out in our daily lives, how digital technologies impact our memory, and how some our memory fallibilities – particularly suggestibility and bias – can be hijacked by digital media companies and political operatives.    LINKS: Schacter Memory Lab: https://sites.harvard.edu/schacter-memory/ Book: “The Seven Sins of Memory”: https://www.amazon.com/Seven-Sins-Memory-Revised-Remembers/dp/0358325684/ref=asc_df_0358325684/?tag=hyprod-20&linkCode=df0&hvadid=693388554878&hvpos=&hvnetw=g&hvrand=1921889579114062764&hvpone=&hvptwo=&hvqmt=&hvdev=c&hvdvcmdl=&hvlocint=&hvlocphy=9051570&hvtargid=pla-1184742256946&psc=1&mcid=760a3293f66030f780a64df60d06431f&gad_source=1 Review article on memory fallibilities: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285452/pdf/nihms-1664500.pdf Review article on media, technology and the sins of memory: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373035/

The usual approach for developing treatments for brain disorders is to make a drug that acts on a specific molecular target. But this approach has largely failed. In this episode I talk with Professor Raj Ratan at Weill Cornell Medicine about ways to tap the intrinsic ability of brain cells to respond adaptively to challenges – metabolic, oxidative, and biosynthetic – in ways that protect them against pathological processes such as those occurring in stroke, traumatic brain injury, Alzheimer’s and Parkinson’s diseases.  Raj and his colleagues have developed several different interventions that are highly effective in animal models of stroke and Alzheimer’s disease. Intermittent dosing with such treatments can activate evolutionarily conserved complex and integrated gene expression responses in brain cells that bolster stress resistance and enable recovery and repair. LINKS  Dr. Ratan’s laboratory webpage: https://burke.weill.cornell.edu/ratan-lab/people/rajiv-r-ratan-md-phd  Selenium protects against ferroptosis and stroke: https://www.cell.com/action/showPdf?pii=S0092-8674%2819%2930327-7  HIF prolyl hydroxylase inhibition for stroke ?: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390817/pdf/jcbfm201228a.pdf  2-deoxyglucose for experimental stroke and Alzheimer’s disease: https://pdf.sciencedirectassets.com/272195/1-s2.0-S0896627322X00196/1-s2.0-S0896627323004725/main.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEDMaCXVzLWVhc3QtMSJHMEUCIC02vyvj45WOEJ6cJ%2BO3zLTkbyrmywu3UV2k0tE99ISSAiEAm%2B2Ga7NWSJSMResvqmDJZn87epQuNnoQNFUS%2FM1xh1QquwUIvP%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FARAFGgwwNTkwMDM1NDY4NjUiDKWhJaRjapFKYPcUuSqPBXZt7z6Y%2F%2FFQDTJZNd63uYfGqFnqQ5FraRDyTiOoShRDuHZ%2FFurOQBeXcKh34xKHbYXG3aw4aZ1qknn5rmr5oZKXJEnQKSDQbTIMaZfam7JN223W98JHQjFExQSg1IpIXsJIOpPDRC6SnxewO9HWfK5VsT22Yd1%2FvfyJ6TNHysLd5avZUcCzNwd1Tzg%2F7n5boUZ3bv8ksKJTbXKIa6URMIpJ1Elry%2Bx2cOHHsudyKQHl38MnqJfyBDlsvlSdlvPvqZyiDl41UPQ4wQXG8zxZKtwc4W9Nz3bBDtosARXGGykFw5PGjP8vljwzBmpAIPA2vntVuzKB1GVCjSOPeZIfB%2FT7gbpjO6XFPulqMJfoZSHMIP6U5%2Baluyz25U7gQI0DlHQuqHHQlPp16W1%2FZUDpV6qfCWLDFa86hE3Mk2bUdhVxC7%2F1avNNvRjCVubyOhIY9MrjdQSpJx5FCd9yj2KkOAQSxn0T8ZQ2HZl10eOzNJBv0flA%2BQXys58UySTYb0QHKIOrD1YbjW0M%2B1qrdzwunAYlpugxnqm64BMuZL1aUWPQUzD6Xu59k23wj9IKZ7ysz8OJgHiaxCL%2BmrhMtF1wBO5rkKomJdordmx%2B46wjknrwW9sUy4NFS74JkUYhIGjiZ1lQ6E%2BFcjJe1R%2FeLOfxx2VfcbXyzyjaVgNaS16fRYydqoT0r1xth2rMdDADuFYvT1Mxw909AAZ6ja4ur%2Bcb56eAT7kbwtKDDsTq3l%2FlTVEwX8zAkagg%2Ba2yg2RUF26zTiA9ur%2FR1keAROBxVFyOyhBFg0tX2aHFaPkRmbTLOOeslpmFdWYlYhhLn%2FDgHzXafbqJ6MS29hnDJVpSZNwtkILsv6Fvf7MlT%2FU%2Fdet6sI4w6oKBswY6sQGQdr%2Fyh54qyfoNjp7vTeWRp56lw26rZzdq5JzhPL7AooWioriINJoD5PBTfQ6P9kkjgrbt3KgE0gLwdquV5t8cPemG6Ud6J7FFfiCqdduYGnkdgvqay00lKumUQWivFmbLK1KwV3ZTiHqK6k%2BnwmjmJx6TC2wOb0ri18vlPuaf9tL3twxztVgBXpqCEHtrk2xoln3A%2FxRta1ENiKDj3i%2BeEJsq8LA5%2Ft1DnHnQTTngNeI%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20240605T120054Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYTBFTALVN%2F20240605%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=a28ce7980230f4e238a2b9b01639b4a3771986228a5b71afee77812caae7ec5a&hash=2c8062367af976e82b072e2c70fee70c72e3b4c101e00ffb8e600353969e084d&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0896627323004725&tid=spdf-39789cb0-1edf-4028-964c-0b8b685189bb&sid=957e62f0674d764d5259d1032c07123fda92gxrqa&type=client&tsoh=d3d3LXNjaWVuY2VkaXJlY3QtY29tLnByb3h5MS5saWJyYXJ5LmpodS5lZHU%3D&ua=0f105b59005f5e555053&rr=88f00141e8697283&cc=us

Anxiety, attention-deficit disorder, depression and loneliness have increased dramatically recently as a result, at least in part, of information overload and a relative lack of time for ‘slow thinking’ and self-reflection. In this episode I talk with University of Wisconsin Professor Richard (Richie) Davidson about his research on mindfulness meditation and the neuroscience of happiness. His research has shown that mental well being is a skill that can be learned. He describes the effects of meditation on neuronal networks and well being and talks about ‘the four pillars of a healthy mind: attentiveness, communication, insight, and purpose. He and his colleagues have developed a free App called ‘The Healthy Minds Program’ which has been demonstrated to be effective in bolstering these four pillars.  LINKS Center for Healthy Minds:  https://centerhealthyminds.org Free Healthy Minds Program App: https://hminnovations.org/meditation-app?gad_source=1 Review articles on mindfulness-based intervention research: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609495/pdf/nihms-1521077.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597263/pdf/nihms-1025535.pdf Review article on challenges in research on mindfulness and meditation: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627495/pdf/nihms704718.pdf  

Many of the drugs that are used recreationally or prescribed by physicians were originally isolated from plants. Increasing evidence suggest that in many instances the function of such phytochemicals is to communicate with insects and other organisms in ways that enhance the fitness of the plants.  Pamela Maher at the Salk Institute has been working to identify phytochemicals that can protect neurons from being damaged in experimental models of neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease.. Here she talks about several phytochemicals that are particularly promising including fisetin, sterubin, cannabinol, and a synthetic derivative of fisetin called CMS121.   LINKS: Fisetin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990461/pdf/bpl-6-bpl200104.pdf Sterubin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309122/pdf/main.pdf CMS121: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394765/pdf/main.pdf Cannabinol: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11002867/pdf/main.pdf Perspective article on neuroprotective phytochemicals: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841445/pdf/nihms946635.pdf

In this episode I talk with Professor Sandrine Thuret at Kings College London about her research on how different molecules in the diet affect neuroplasticity in general and hippocampal neurogenesis in particular. She has shown in preclinical studies that certain dietary factor including omega-3 fatty acids can counteract the adverse effects of chronic psychological stress on neurogenesis. She has also shown that intermittent fasting enhances hippocampal neurogenesis and improves cognition. Thuret has also found that factors circulating in the blood can either enhance or inhibit neurogenesis, and may either promote brain health or contribute to brain dysfunction in disorders such as depression and Alzheimer’s disease.  LINKS: Effects of intermittent fasting on neurogenesis and memory: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760057/pdf/41380_2021_Article_1102.pdf Omega-3 fatty acids and neurogenesis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341841/pdf/41398_2020_Article_908.pdf Phytochemicals and brain resilience: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081729/pdf/pr.113.007757.pdf Serum factors: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10151193/pdf/awac472.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8612606/pdf/ad-12-8-2151.pdf

Professor John Cryan discusses gut microbiome-brain communication in health and disease, emphasizing the impacts of diet, lifestyle, and gut bacteria on brain health. The podcast explores the mechanisms of microbial influence on the brain involving the vagus nerve and bacterial chemicals. Topics include optimizing gut bacterial composition for lifelong brain health, treatment of neurological disorders, and the importance of fermented foods and fiber.

David Nutt has made major contributions to understanding mechanisms by which psychoactive drugs affect the brain and has conducted numerous clinical trials of a wide range of drugs in patients with various mental disorders.  He has also been an outspoken critic of the disconnect between drug science and government drug policies. For example, alcohol is legal, widely available, and causes tremendous harm to individuals and society.  On the other hand psychedelics are illegal and yet very safe and can be very beneficial for mental health. In this episode I talk with Professor Nutt about the relative harms and benefits of different drugs to individuals and society.  His efforts and those of many other scientists and psychiatrists are pushing governments to accept the facts and help facilitate rather than obstruct science-based progress in drug research and use of that knowledge for medicine and society.  David Nutt is a distinguished professor in the Division of Brain Sciences at Imperial College in London.  He is the founder and chairman of Drug Science and host of the Drug Science Podcast.  LINKS: Drug Science website: https://www.drugscience.org.uk/drug-information/?gad_source=1&gclid=CjwKCAjwuJ2xBhA3EiwAMVjkVG_peCbmMCI9tKIYTUldYjmfjHNxCLeLX2WYvkLPezA7zaJpciU8HhoCGHcQAvD_BwE Drug Science podcast: https://open.spotify.com/show/2hLSRIS777SKphWxv4HyDK  Recent relevant articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291338/pdf/fpsyt-14-1183740.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669276/pdf/fpsyt-13-1027159.pdf https://www.sciencedirect.com/science/article/pii/S0028390822003161?via%3Dihub https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625009/pdf/nutrients-13-03938.pdf

Some elderly individuals remain cognitively ‘sharp as a tack’ despite the accumulation of large amounts of amyloid in their brains, whereas others exhibit profound cognitive impairment with less amyloid pathology.  In this episode Columbia University Professor Yaakov Stern talks about the concepts of ‘cognitive reserve’ and ‘brain maintenance’ and how he and others have elucidated factors that explain individual differences in cognitive trajectories during aging. The data show that regular exercise and intellectually challenging endeavors promote successful brain aging in the absence or presence of Alzheimer’s disease pathology. We also discuss neural mechanisms that may explain cognitive reserve and brain maintenance during aging.  LINKS: Professor Stern’s webpage at Columbia University: https://www.neurology.columbia.edu/profile/yaakov-stern-phd Review articles on cognitive reserve and brain maintenance: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507991/pdf/nihms416640.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517622/pdf/acab049.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859943/pdf/nihms-1530897.pdf