Brain Ponderings podcast with Dr. Mark Mattson

NOTE: This lecture with slides presented can be found on the Brain Ponderings YouTube Channel. This episode begins by highlighting recent evidence showing adverse effects on the brain of excessive activation of the mTOR pathway as a consequence of dietary branched chain amino acid consumption. Then I describe evidence that Beyond the age of 40 years brain aging results in progressive decrements in function which are associated with reductions in gray matter and synapse numbers particularly in brain regions that play critical roles in memory, executive functions, and task switching. Recent progress has been made in identifying molecular markers of brain aging in samples of blood or cerebrospinal fluid heralding a better understanding of factors that accelerate or retard brain aging. This episode reviews some of the salient research in these areas.

NOTE: This lecture with slides presented can be found on the Brain Ponderings YouTube Channel. This video describes 12 major changes that occur in brain cells during aging and their involvement in decline in brain function and the development of neurodegenerative disorders including dementia and Parkinson's disease.

NOTE: This lecture with slides presented can be found on the Brain Ponderings YouTube Channel. This is the first of five lectures on the Neurobiology of Aging. The other four lectures cover cellular hallmarks, structural and functional aspects, biomarkers, how neurodegenerative disorders occur during aging, and how aging can be slowed and brain health span extended by lifestyle and dietary changes.

The lipid membrane bilayer of cells is composed of fats including phospholipids, cholesterol, and sphingomyelin. Enzymes called sphingomyelinases can cleave sphingomyelin resulting in the liberation of ceramides which can diffuse within the cell and act as signaling molecules. In this episode I talk with Tulane University Professor Norm Haughey about research in his laboratory and others which have shown that levels of certain ceramides are increased in the brain, cerebrospinal fluid, and blood of patients with Alzheimer's disease, HIV-associated cognitive disorder, and other neurological disorders. Elevated ceramides may provide a biomarker for individuals at risk for these disorders. Dr. Haughey and his collaborators have shown that drugs that inhibit a particular sphingomyelinase can prevent degeneration of neurons and associated cognitive impairment in animal models of Alzheimer's disease and HIV. Norm Haughey's laboratory webpage: https://haugheylab.org/ Relevant articles https://pmc.ncbi.nlm.nih.gov/articles/PMC2907186/pdf/nihms-209661.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC2933928/pdf/nihms200180.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC3144420/pdf/nihms309072.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC3414665/pdf/znl633.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC7852391/pdf/aba5210.pdf https://www.sciencedirect.com/science/article/pii/S0969996123000013?via%3Dihub https://pmc.ncbi.nlm.nih.gov/articles/PMC10334757/pdf/pnas.202219543.pdf

Brain tumor cells interact with neurons, glial cells, and immune cells in complex ways that often benefit the cancer cells while compromising the function of normal neural cells. In this episode I talk with Washington University Neurology Professor David Gutmann about brain cancer cells and their communication with surrounding normal cells. A major component of Dr. Gutmann's research program focuses on Neurofibromatosis a rare genetic disorder that causes non-malignant brain tumors as well as abnormal growth of cells in other organ systems. The disease results from loss-of-function mutations in the NF1 protein which normally functions to constrain cell growth. Discoveries concerning the 'sociobiology' of brain tumors is providing a foundation for the development of new approaches for treating a range of cancers. LINKS Dr. Gutmann's Wikipedia page: https://en.wikipedia.org/wiki/David_H._Gutmann Related articles: https://pmc.ncbi.nlm.nih.gov/articles/PMC10107403/pdf/nihms-1872327.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC9883043/pdf/nihms-1861630.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC11972679/pdf/djae249.pdf

There is considerable evidence that exposure to certain chemicals in the environment cause Parkinson's disease in many people. In this episode neurologist Ray Dorsey talks about some of the chemicals that may cause Parkinson's disease including the pesticides paraquat and rotenone, and trichloroethylene and perchloroethylene which are chemicals used for degreasing and dry-cleaning. LINKS Relevant journal articles: https://www.thelancet.com/action/showPdf?pii=S1474-4422%2825%2900287-X file:///Users/markmattson/Downloads/Annals%20of%20Neurology%20-%202008%20-%20Gash%20-%20Trichloroethylene%20%20Parkinsonism%20and%20complex%201%20mitochondrial%20neurotoxicity%20(1).pdf Book on how to reduce one's risk for Parkinson's disease: https://www.amazon.com/Parkinsons-Plan-Path-Prevention-Treatment/dp/1541705386/ref=sr_1_1?adgrpid=186412556077&dib=eyJ2IjoiMSJ9.8jetPIdc_D3gQSod-GXEVDXUJcI1IMKFz7jXpUf0jZt-LxGsRBm9oV9TQGQJK_FDpWNY4KOJrayE8WoGPJsMXbouqzGwj3UhO0CZZGHmz8g.M4hWGhlS7Crp9zwfODlDDDNnseiHLTdHHBLooZ1LR-M&dib_tag=se&hvadid=779621628364&hvdev=c&hvexpln=0&hvlocphy=9007816&hvnetw=g&hvocijid=14825241056223650898--&hvqmt=b&hvrand=14825241056223650898&hvtargid=aud-2443140936121%3Akwd-936298351901&hydadcr=15520_13558534_8423&keywords=ray+dorsey+parkinson&mcid=c3eec2c85d703461a8216f138ac2c1e7&qid=1762952366&sr=8-1#averageCustomerReviewsAnchor

A shared feature of neurodegenerative disorders is accumulation of aggregated proteins within neurons: Tau in Alzheimer's disease; alpha-synuclein in Parkinson's disease; huntingtin in Huntington's disease; and TDP43 in amyotrophic lateral sclerosis. In this episode Ai Yamamoto – an Associate Professor Neurology at Columbia University – talks about the trail of discoveries that led to the identification of a protein called ALFY that can prevent and reverse the accumulation of such pathogenic proteins. Remarkably, her team and collaborators found that some people have a variant of the gene encoding ALFY that confers resistance of those individuals to Huntington's disease. This discovery opens many new and exciting directions for future research aimed at better understanding what goes wrong in neurodegenerative disorders and for developing interventions counteract the disease process. LINKS Yamamoto Laboratory web page: https://www.aiyamamoto-lab.org/ Dr. Yamamoto's publications: https://scholar.google.com/citations?hl=en&user=HuJslgMAAAAJ&pagesize=80&view_op=list_works Key research articles: https://www.cell.com/action/showPdf?pii=S0896-6273%2825%2900624-5 file:///Users/markmattson/Downloads/s41583-022-00588-3.pdf https://www.cell.com/action/showPdf?pii=S0896-6273%2819%2931045-1

Remarkable advances are being made in the development and clinical applications of stimulation devices that enable recovery of motor function in patients who have suffered a spinal cord injury, a stroke, and even those with rare disabling genetic disorders. At the forefront of this research is Marco Capogrosso at the University of Pittsburgh. He has shown that certain patterns of stimulation of sensory pathways in the spinal cord can activate motor neurons that were otherwise silenced by the injury or stroke. Initial clinical trials have shown that this approach results in recovery of function which are in some cases very dramatic in patients that have had a stroke, a spinal cord injury, and in people with the genetic disorder spinal muscular atrophy. In this episode Dr. Capogrosso talks about the development of this stimulation-based therapeutic approach, the clinical trials, and the potential applications of this technology to other neurodegenerative disorders. LINKS Dr. Capogrosso's profile at the University of Pittsburgh: https://www.neurosurgery.pitt.edu/people/marco-capogrosso Key studies discussed in this podcast: Stroke https://pmc.ncbi.nlm.nih.gov/articles/PMC10291889/pdf/nihms-1904547.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC12393459/pdf/nihpp-rs7271578v1.pdf Spinal cord injury https://pmc.ncbi.nlm.nih.gov/articles/PMC5108412/pdf/emss-70056.pdf https://www.cell.com/neuron/fulltext/S0896-6273(25)00658-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627325006580%3Fshowall%3Dtrue# Spinal muscular atrophy https://www.nature.com/articles/s41591-024-03484-8

Dietary iron is essential for health as it plays important roles in the ability of hemoglobin to carry oxygen throughout the body and brain. In addition, iron is involved in various functions in cells including the generation of ATP in mitochondria and DNA synthesis. The vast majority of iron is bound to proteins such as ferritin and heme. However, in its ionic form (Fe2+) iron can react with the hydrogen peroxide produced from mitochondrial superoxide radical to generate the highly toxic hydroxyl radical. Hydroxyl radical damages DNA and can also act on the carbon=carbon double bonds in unsaturated member lipids and trigger an autocatalytic process called lipid peroxidation. Lipid peroxidation in neurons occurs in Alzheimer's and Parkinson's disease and may play a major role in the death of neurons in these disorders a process called 'ferroptosis'. In this episode I talk with Scott Ayton a Professor at the Florey Institute at the University of Melbourne about both the normal functions of iron in neurons, its involvement in Alzheimer's and Parkinson's disease, and the potential of interventions that prevent ferroptosis in the treatment of these disorders. LINKS Professor Aytons profile at the Florey Institute: https://florey.edu.au/researcher/scott-ayton/ Relevant articles file:///Users/markmattson/Downloads/s41583-025-00930-5%20(1).pdf https://nyaspubs.onlinelibrary.wiley.com/doi/epdf/10.1196/annals.1306.004?saml_referrer https://www.nejm.org/doi/pdf/10.1056/NEJMoa2209254 https://jamanetwork.com/journals/jamaneurology/article-abstract/2825846

Health depends upon proper regulation of circadian rhythms of cell and organ functions. Disruption of circadian rhythms has detrimental consequences for brain function and resilience and abnormal circadian rhythms are a common feature of Alzheimer's disease. In this episode neurology professor Erik Musiek talks about the roles of specific circadian clock proteins in neurons and glial cells in brain health and Alzheimer's disease. His research is revealing the ways in which these circadian regulatory proteins affect brain cell functions and how disruption of circadian rhythms may contribute to the neuropathological features of Alzheimer's disease (amyloid plaques and neurofibrillary tangles. We also talk about ways in which we can bolster our circadian rhythms by sleep, exercise, diet, light exposure, etc. LINKS Professor Musiek's webpage: https://physicians.wustl.edu/people/erik-musiek-md-phd/ Articles discussed in this podcast: https://pmc.ncbi.nlm.nih.gov/articles/PMC12352436/pdf/nihms-2097957.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC11996435/pdf/nihpp-2025.03.31.645805v1.pdf https://www.nature.com/articles/s43587-025-00950-x https://pmc.ncbi.nlm.nih.gov/articles/PMC9008766/pdf/nihms-1794994.pdf